journal oncology clinical

Volume 31, Issue 15S, Part I of II

May 20, 2013

JOURNAL OF CLINICAL ONCOLOGY Official Journal of the American Society of Clinical Oncology

2013 ASCO Annual Meeting Proceedings

49th Annual Meeting May 31-June 4, 2013 McCormick Place Chicago, IL

www.jco.org

49th Annual Meeting of the American Society of Clinical Oncology May 31-June 4, 2013 Chicago, Illinois 2013 Annual Meeting Proceedings Part I (a supplement to the Journal of Clinical Oncology)

Copyright 2013 American Society of Clinical Oncology

Editor: Michael A. Carducci, MD Managing Editor: Jennifer Giblin Editorial Coordinator: Devon Carter Production Manager: Donna Dottellis Executive Editor: Lisa Greaves

Requests for permission to reprint abstracts should be directed to Intellectual Property Rights Manager, American Society of Clinical Oncology, 2318 Mill Road, Suite 800, Alexandria, VA 22314. Tel: 571-483-1300; Fax: 571-366-9530; Email: [email protected]. Editorial correspondence and production questions should be addressed to Managing Editor, Annual Meeting Proceedings, American Society of Clinical Oncology, 2318 Mill Road, Suite 800, Alexandria, VA 22314. Email: [email protected]. Copyright © 2013 American Society of Clinical Oncology. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without written permission by the Society. The American Society of Clinical Oncology assumes no responsibility for errors or omissions in this publication. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration or administration, or contraindications. It is the responsibility of the treating physician or other health care professional, relying on independent experience and knowledge of the patient, to determine drug, disease, and the best treatment for the patient. Abstract management and indexing provided by The Conference Exchange, Cumberland, RI. Composition services and print production provided by Cenveo Publisher Services, Richmond, VA.

American Society of Clinical Oncology 49th Annual Meeting 2013 Abstracts Descriptions of Scientific Sessions Oral Abstract Sessions Oral Abstract Sessions include didactic presentations of the abstracts of the highest scientific merit, as determined by the Scientific Program Committee. Experts in the field serve as Discussants to place the findings into perspective. The Plenary Session includes the abstracts selected by the Scientific Program Committee as having practice-changing findings. Clinical Science Symposia Clinical Science Symposia provide a forum for science in oncology, combining didactic lectures on a specific topic with the presentation of abstracts. Experts in the field classify studies on the basis of the strength of the evidence and critically discuss the conclusions in terms of their applicability to clinical practice. Poster Discussion Sessions Poster Discussion Sessions highlight selected abstracts of clinical research in poster format. The posters are grouped by topic and are on display for a specified time, followed by a discussion session in which experts provide commentary on the research findings. General Poster Sessions General Poster Sessions include selected abstracts of clinical research in poster format. The posters are grouped by topic and are on display for a specified time. Trials in Progress abstract presentations are presented within a track’s general poster session. Publication-Only Abstracts Publication-only abstracts were selected to be published online in conjunction with the Annual Meeting, but not to be presented at the Meeting. All presented and publication-only abstracts are citable to this Journal of Clinical Oncology supplement. For citation examples, please see the Letter from the Editor. This publication contains abstracts selected by the ASCO Scientific Program Committee for presentation at the 2013 Annual Meeting. Abstracts selected for electronic publication only are available in full-text versions online through ASCO.org and JCO.org. The type of session, the day, and the session start/end times are located to the right of the abstract number for scheduled presentations. To determine the location of the abstract session, refer to the Annual Meeting Program or the iPlanner, the online version of the Annual Meeting Program, available at chicago2013.asco.org.

Dates and times are subject to change. All modifications will be posted on ASCO.org.

Volume 31, Issue 15S

JOURNAL OF CLINICAL O NCOLOGY

Supplement to May 20, 2013 Official Journal of the American Society of Clinical Oncology

CONTENTS 2013 ASCO ANNUAL MEETING PROCEEDINGS Special Award Lecture Abstracts .............................................................................................................

1s

Plenary (Abstracts 1 – 5) ...............................................................................................................................

5s

Breast Cancer—HER2/ER Scheduled presentations (Abstracts 500 – TPS667) .........................................................................................

7s

Breast Cancer—Triple-Negative/Cytotoxics/Local Therapy Scheduled presentations (Abstracts 1000 – TPS1145) .......................................................................................

49s

Cancer Prevention/Epidemiology Scheduled presentations (Abstracts 1500 – TPS1610) .......................................................................................

86s

Central Nervous System Tumors Scheduled presentations (Abstracts LBA2000 – TPS2106) .............................................................................

114s

Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics Scheduled presentations (Abstracts 2500 – TPS2627) ....................................................................................

141s

Developmental Therapeutics—Immunotherapy Scheduled presentations (Abstracts 3000 – TPS3128) .....................................................................................

173s

Gastrointestinal (Colorectal) Cancer Scheduled presentations (Abstracts LBA3500 – TPS3649) ............................................................................

205s

Gastrointestinal (Noncolorectal) Cancer Scheduled presentations (Abstracts LBA4001 – TPS4163) ..............................................................................

243s

Genitourinary (Nonprostate) Cancer Scheduled presentations (Abstracts LBA4500 – TPS4595) ............................................................................

284s

continued on following page

Journal of Clinical Oncology (ISSN 0732-183X) is published 36 times a year, three times monthly, by the American Society of Clinical Oncology, 2318 Mill Road, Suite 800, Alexandria, VA 22314. Periodicals postage is paid at Alexandria, VA, and at additional mailing offices. Publication Mail Agreement Number 863289. Editorial correspondence should be addressed to Stephen A. Cannistra, MD, Journal of Clinical Oncology, 2318 Mill Road, Suite 800, Alexandria, VA 22314. Phone: 703-797-1900; Fax: 703-684-8720. E-mail: [email protected]. Internet: www.jco.org. POSTMASTER: ASCO members should send changes of address to American Society of Clinical Oncology, 2318 Mill Road, Suite 800, Alexandria, VA 22314. Nonmembers should send changes of address to Journal of Clinical Oncology Customer Service, 2318 Mill Road, Suite 800, Alexandria, VA 22314. 2013 annual subscription rates, effective September 1, 2012: United States and possessions: individual, $578 one year, $1,098 two years; single issue, $40. International: individual, $802 one year, $1,524 two years; single issue, $50. Institutions: bundled (print ⫹ online): Tier 1: $899 US, $1,248 Int’l; Tier 2: $1,052 US, $1,395 Int’l; Tier 3: $1,519 US, $1,849 Int’l; Tier 4: contact JCO for quote. Institutions: online only, worldwide: Tier 1, $769; Tier 2: $897; Tier 3, $1,295; Tier 4: contact JCO for quote. See www.jco.org/ratecard for descriptions of each tier. Student and resident: United States and possessions: $289; all other countries, $401. To receive student/resident rate, orders must be accompanied by name of affiliated institution, date of term, and the signature of program/residency coordinator on institution letterhead. Orders will be billed at individual rate until proof of status is received. Current prices are in effect for back volumes and back issues. Back issues sold in conjunction with a subscription rate are on a prorated basis. Subscriptions are accepted on a 12-month basis. Prices are subject to change without notice. Single issues, both current and back, exist in limited quantities and are offered for sale subject to availability. JCO Legacy Archive (electronic back issues from January 1983 through December 1998) is also available; please inquire.

Volume 31, Issue 15S

Supplement to May 20, 2013

....................................................................................................................................................

Genitourinary (Prostate) Cancer Scheduled presentations (Abstracts LBA5000 – TPS5104) .............................................................................

308s

Gynecologic Cancer Scheduled presentations (Abstracts 5500 – TPS5616) .....................................................................................

334s

Head and Neck Cancer Scheduled presentations (Abstracts 6000 – TPS6101) ......................................................................................

363s

Health Services Research Scheduled presentations (Abstracts 6500 – TPS6646) ....................................................................................

389s

Leukemia, Myelodysplasia, and Transplantation Scheduled presentations (Abstracts 7001 – TPS7133) ......................................................................................

425s

Lung Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers Scheduled presentations (Abstracts 7500 – TPS7610) .....................................................................................

458s

Lung Cancer—Non-Small Cell Metastatic Scheduled presentations (Abstracts 8000 – TPS8126) ....................................................................................

486s

Lymphoma and Plasma Cell Disorders Scheduled presentations (Abstracts 8500 – TPS8619) ....................................................................................

518s

Melanoma/Skin Cancers Scheduled presentations (Abstracts LBA9000 – TPS9107^) ...........................................................................

548s

Patient and Survivor Care Scheduled presentations (Abstracts 9500 – TPS9651) .....................................................................................

575s

Pediatric Oncology Scheduled presentations (Abstracts 10000 – TPS10073) .................................................................................

613s

Sarcoma Scheduled presentations (Abstracts 10500 – TPS10595) .................................................................................

632s

Tumor Biology Scheduled presentations (Abstracts 11000 – TPS11124) ....................................................................................

656s

Author Index ......................................................................................................................................................

688s

www.jco.org

Letter from the Editor

T

he 2013 ASCO Annual Meeting Proceedings Part I (a supplement to the Journal of Clinical Oncology) is an enduring record of the more than 2,700 abstracts selected by the ASCO Scientific Program Committee for presentation at the 49th ASCO Annual Meeting. Accepted abstracts not presented at the meeting are included in the online supplement to the May 20 issue of Journal of Clinical Oncology at JCO.org. The majority of abstracts selected for presentation are included here in full and are categorized by scientific track. After the Annual Meeting, abstracts can be accessed online through ASCO University’s Meeting Library (meetinglibrary.asco.org/abstracts). Online abstracts include the full list of abstract authors and their disclosure information. Certain abstracts are represented here by abstract title and presenting author only. These include Plenary Abstracts, which were selected by the Scientific Program Committee for their potential to have practice-changing results; Late-Breaking Abstracts (LBA), which feature results of phase III trials for which data were not available at the time of ASCO’s regular submission deadline; and Clinical Review Abstracts (CRA), many of

which will have important, and in some cases, immediate implications for patient care. The full-text versions of abstracts within these three designations will be publically released through ASCO.org on the morning of their scheduled presentation at the Annual Meeting. These abstracts will also be included in the 2013 ASCO Annual Meeting Proceedings Part II, an online supplement to the June 20 issue of Journal of Clinical Oncology on JCO. org. Print versions of these abstracts will be available onsite at the Annual Meeting in the ASCO Daily News. All of the abstracts carry Journal of Clinical Oncology citations. The following are citation examples for print and electronic abstracts: J Clin Oncol 31:5s, 2013 (suppl; abstr 1) J Clin Oncol 31, 2013 (suppl; abstr e12000) Should you have any questions or comments about this publication, we encourage you to provide feedback by contacting us at [email protected]. Michael A. Carducci, MD Editor, 2013 ASCO Annual Meeting Proceedings

JOURNAL of CLINICAL ONCOLOGY

..................................................................

Official Journal of the American Society of Clinical Oncology

Journal of Clinical Oncology (ISSN 0732–183X) is published 36 times a year, three times monthly, by the American Society of Clinical Oncology, 2318 Mill Road, Suite 800, Alexandria, VA 22314. Periodicals postage is paid at Alexandria, VA, and at additional mailing offices. Postmaster Send all changes of address for Journal of Clinical Oncology subscribers to: JCO Customer Service 2318 Mill Road, Suite 800 Alexandria, VA 22314 Editorial Correspondence (manuscript-related inquiries): Stephen A. Cannistra, MD, Editor-in-Chief Journal of Clinical Oncology 2318 Mill Road, Suite 800 Alexandria, VA 22314 Phone: 703-797-1900; Fax: 703-684-8720 E-mail: [email protected]; Internet: www.jco.org American Society of Clinical Oncology (membership-related inquiries): ASCO Member Services 2318 Mill Road, Suite 800 Alexandria, VA 22314 Phone: 703-299-0158; Toll-free: 888-282-2552 Fax: 703-299-0255 E-mail: [email protected]; Internet: www.asco.org Hours: Monday-Friday, 8:30 a.m.-5:00 p.m. Eastern Time

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Official Journal of the American Society of Clinical Oncology Free Public Access Journal of Clinical Oncology (JCO) provides free online access to original research articles older than one year at www.jco.org. In addition, all ASCO Special Articles, Rapid Communications, Editorials, Comments and Controversies articles, the Art of Oncology series, and Correspondence articles are free immediately upon publication. Disclaimer The ideas and opinions expressed in JCO do not necessarily reflect those of the American Society of Clinical Oncology (ASCO). The mention of any product, service, or therapy in this publication or in any advertisement in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify approved uses, the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the material contained in this publication or to any errors or omissions. Copyright Copyright © 2013 by American Society of Clinical Oncology unless otherwise indicated. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the Publisher. Printed in the United States of America. The appearance of the code at the bottom of the left column of the first page of an article in this journal indicates the copyright owner’s consent that copies of the article may be made for personal or internal use, or for the personal or internal use of specific clients, for those registered with the Copyright Clearance Center, Inc. (222 Rosewood Drive, Danvers, MA 01923; 978-750-8400; www.copyright.com). This consent is given on the condition that the copier pay the stated per-copy fee for that article through the Copyright Clearance Center, Inc., for copying beyond that permitted by Sections 107 or 108 of the US Copyright Law. This consent does not extend to other kinds of copying, such as copying for general distribution, for advertising or promotional purposes, for creating new collective works, or for resale. Absence of the code indicates that the material may not be processed through the Copyright Clearance Center, Inc. CPT © is a trademark of the American Medical Association.

ASCO Abstracts Policy Public Release of Abstracts ASCO has implemented changes to its abstract distribution to ensure simultaneous public release of important scientific information. Please note the new release schedule. The abstracts published in the 2013 ASCO Annual Meeting Proceedings Part I, including those abstracts published but not presented at the Meeting, were publicly released by ASCO at 6:00 PM (EDT) on Wednesday, May 15, 2013. These abstracts are publicly available online through ASCO.org, the official website of the Society. Plenary, Late-Breaking, and Clinical Review Abstracts (Newly Released Abstracts) will be publicly released according to the following schedule: • Newly Released Abstracts presented on Saturday, June 1 will be publicly released Saturday, June 1 through ASCO.org at 7:30 AM (EDT). These abstracts will also be available in the Saturday issue of ASCO Daily News in Section D. • Newly Released Abstracts presented on Sunday, June 2 will be publicly released Sunday, June 2 through ASCO.org at 7:30 AM (EDT). These abstracts will also be available in the Sunday issue of ASCO Daily News in Section D. • Newly Released Abstracts presented on Monday, June 3 and Tuesday, June 4 will be publicly released on Monday, June 3 through ASCO.org at 7:30 AM (EDT). These abstracts will also be available in the Monday issue of ASCO Daily News in Section D. In the unlikely event that ASCO publicly releases an abstract in advance of the scheduled time, the release will be publicly announced on ASCO.org.

Abstract Notice All abstracts presented at and published in conjunction with the Annual Meeting are included in online supplements to the Journal of Clinical Oncology. The abstracts released on May 15, 2013, are included in the May 20 (Vol. 31, No. 15S) issue (2013 Annual Meeting Proceedings Part I), and the Plenary, Late-Breaking, and Clinical Review Abstracts, released on a daily basis during the Meeting, are included in the June 20 (Vol. 31, No. 18S) issue (2013 Annual Meeting Proceedings Part II).

Copyright 2013 American Society of Clinical Oncology

ASCO Conflict of Interest Policy and Exceptions In compliance with standards established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006; 24[3]:519 –521) and the Accreditation Council for Continuing Medical Information (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the Society’s Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006;24[3]:520). The ASCO Conflict of Interest Policy requirements apply to all abstract authors. Per the ASCO Conflict of Interest Policy Implementation Plan for CME Activities, all Oral Abstract Presenters will be subject to the same disclosure review and management strategies as faculty who participate in ASCO CME activities. For clinical trials that began accrual on or after April 29, 2004, the Conflict of Interest Policy places some restrictions on the financial relationships between a trial’s Principal Investigator(s) (PI) and the trial’s company sponsor (J Clin Oncol. 2006;24[3]:521). If a PI holds any restricted relationships, his or her abstract may be ineligible for placement in the 2013 Annual Meeting unless the Ethics Committee grants an exception. Exceptions are generally not granted for PIs who have employment relationships with their trial’s company sponsor or stock in the company sponsor. Abstracts that receive exceptions will be subject to additional management strategies, including but not limited to additional peer review, advance slide review, and session audits. ASCO will collect information on accrual initiation date, financial relationships of the principal investigator, and National Institutes of Health (NIH) funding upon abstract submission. NIH-funded trials are exempt from the PI restrictions in the Conflict of Interest Policy. Abstracts for which authors requested and have been granted an exception in accordance with ASCO’s Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information on the ASCO Conflict of Interest Policy, the Conflict of Interest Policy Implementation Plan for CME Activities, and the restrictions on PIs, please visit asco.org/rwi.


Special Awards

ABSTRACTS American Society of Clinical Oncology 49th Annual Meeting May 31–June 4, 2013 McCormick Place Chicago, IL SPECIAL AWARD LECTURE ABSTRACTS David A. Karnofsky Memorial Award and Lecture Saturday, June 1, 9:30 AM Academic research worldwide: Quo vadis? Martine J. Piccart-Gebhart, MD, PhD; Jules Bordet Institute, Brussels, Belgium The Breast International Group (BIG) is the largest academic network in the world dedicated to conducting research designed to accelerate and refine the use of anticancer treatments and diagnostic tools for the benefit of women with breast cancer. BIG is the umbrella organization harnessing the efforts and supporting the activities of its 50 national and international cooperative group members worldwide. BIG’s collaborative research model provides academic leadership in industry-sponsored randomized clinical trials. Some of these trials have successfully led to the rapid registration of new anticancer drugs with a significant impact on breast cancer mortality such as the HERA trial, which contributed to the registration of adjuvant trastuzumab in many countries around the world in less than 4 years. BIG also supports clinical trials sponsored by its academic member groups and facilitates collaboration between international researchers and the U.S. cooperative groups; for example, first results are anticipated at the end of this year for the SOFT and TEXT trials evaluating endocrine therapies for 5,738 premenopausal women. The “co-lead” model ensures rapid patient accrual as well as compliance with today’s quality requirements, such as auditable data systems and quality-controlled molecular testing. BIG also champions innovative ideas, for example, in the conduct of difficult clinical trials targeting small subgroups of patients with defined molecular profiles. This lecture will first provide a critical look at the recent past and highlight how the pathway to “personalized” therapies in oncology is costly, labor-intensive, and too slow for our patients, even in the context of a very large, dedicated academic network such as BIG. Despite its success, BIG and its affiliated cooperative groups must battle constantly to remain vigorously involved in clinical trial design and conduct. Any failure of academic researchers to secure and further increase their involvement in clinical trial activities will have negative consequences for public health. Without academic leadership in the research process, critical issues important for patient care will remain unaddressed. Moreover, health care costs will continue to rise substantially as a consequence of the worrisome “add on” approach in registration trials, which serves primarily to minimize risks vis-a`-vis regulatory agencies. The second part of this lecture will look into the future and stress the need for a dramatic change in the vision, culture, and methodology of cancer research in general and breast cancer research in particular.

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Special Awards

Science of Oncology Award and Lecture Sunday, June 2, 1:00 PM Overcoming resistance to cancer drug therapy. Charles L. Sawyers, MD; Memorial Sloan-Kettering Cancer Center, New York, NY My laboratory studies molecular drivers of cancer progression and strategies to overcome drug resistance. I first developed this interest during our studies of ABL kinase inhibitors in chronic myeloid leukemia, where we discovered that resistance to imatinib is caused by point mutations in BCR-ABL and that the second-generation drug dasatinib can overcome much of this resistance. A collaboration with John Kuriyan’s group (University of California, Berkeley) was instrumental in this success by providing a structural understanding of distinct conformations of the ABL kinase domain bound by imatinib and dasatinib and the impact of missense mutations on these conformations. More recently my group has explored the molecular basis of resistance to hormone therapy in prostate cancer, which led to the discovery of a novel antiandrogen called enzalutamide (formerly MDV3100) that prolongs survival in men with castration-resistant prostate cancer (CRPC). Despite its impressive clinical benefit, enzalutamide is not effective in all patients. Roughly half of men with metastatic CRPC do not have meaningful responses, and half of the men who do respond develop resistance within 1 to 2 years. Current efforts are focused on understanding this heterogeneity in clinical response and developing next-generation treatment strategies.

ASCO–American Cancer Society Award and Lecture Monday, June 3, 4:45 PM Personalized cancer genomics and prevention. Kenneth Offit, MD,MPH, Memorial Sloan-Kettering Cancer Center, New York, NY Heritable factors remain among the most significant determinants of cancer risk. The past two decades have witnessed the discovery of genetic mutations associated with syndromes of cancer predisposition, and the successful translation of this research to the practice of preventive oncology. Despite these accomplishments, a significant portion of the heritability of cancer remains unexplained. Rapid advances in the technology of massively parallel sequencing have identified new targets for cancer therapies, as well as new mechanisms of cancer susceptibility. This presentation will outline current challenges impacting the scientific research, clinical translation, and social implications stemming from advances in clinical cancer genomics. The functional characterization of rare variants in noncoding genomic regions, interactions of gene variants with each other and with nongenetic factors, and the mechanism of origin of germline predisposing events are currently the focus of laboratory research in hereditary cancer. The tailoring of surgical preventive, screening, or pharmacologic interventions to decrease the burden of hereditary cancers has become part of clinical practice and continues to evolve. Oncologists are also increasingly incorporating next-generation sequencing (NGS) approaches into the analysis of tumor-normal pairs. In this process, it is becoming clear that the technical speed of this analysis will soon surpass our ability to interpret and appropriately apply the vast amounts of data generated. Among these genomic data are incidental findings relating to hereditary risk that may or may not be medically actionable. NGS technologies are driving the paradigm shift toward “personalized” or “precision” medicine. While exciting progress has been made, significant challenges remain to be addressed to responsibly incorporate genomic risk assessment into individualized cancer prevention.

Special Awards

B. J. Kennedy Award and Lecture for Scientific Excellence in Geriatric Oncology Monday, June 3, 3:00 PM Cancer in older adults: The top five things oncologists need to know. Arti Hurria, MD; City of Hope, Los Angeles, CA The U.S. and worldwide populations are aging rapidly, and because cancer is a disease directly associated with aging, 20-year projections point to an enormous increase in cancer incidence and mortality. At the same time as cancer occurrence in older adults will be increasing, the number of geriatricians is projected to decrease. Also projected is a workforce shortage of oncologists and very few dually trained geriatric oncologists to care for these individuals. Oncology health care teams will eventually have to provide most of the care for this growing population of older adults with cancer, so practitioners should be versed in the basic principles of geriatric medicine. However, training in geriatric medicine is not a routine part of the oncology curriculum and there are less data available to guide oncology health care practitioners in choosing the best treatment regime for older adults with cancer because older adults have been under-represented in clinical trials and studies of U.S. Food and Drug Administration-approved cancer therapeutics. To complicate matters further, older adults are at higher risk for toxicity to cancer therapy and a more thorough assessment is needed to identify the factors that place certain older adults at increased risk. Multidisciplinary oncology teams are striving to cope with this growing demand and increased complexity of treatment decisions, while health care reform poses new and unforeseen changes, with novel metrics for quality of care. Understanding the key principles of geriatric oncology can help practitioners cope with these enormous challenges, facilitating comprehensive, personalized, and evidencebased care to the growing population of older adults. This lecture will outline the essentials of geriatric oncology that will guide health care oncology teams in optimizing their care of older adults with cancer.

Pediatric Oncology Award and Lecture Friday, May 31, 2:45 PM Genetics, biology, and treatment of human neuroblastomas. Garrett M. Brodeur, MD; Children’s Hospital of Philadelphia, Philadelphia, PA Neuroblastoma is the most common and deadly solid tumor in children, and it is characterized by heterogeneous clinical behavior, from spontaneous regression to relentless progression. However, studies of the genetics, genomics, and biology of these tumors have provided considerable insights that facilitate clinical management. Genetic predisposition: About 1% to 2% of neuroblastomas are hereditary. We and others determined that alterations of two genes (ALK, PHOX2B) are responsible for over 90% of these cases. Molecular profiling: Amplification and overexpression of the MYCN gene is the most common (20%) and potent oncogenic driver in neuroblastomas. MYCN amplification is almost always accompanied by deletion of 1p36, with loss/inactivation of one or more tumor suppressor genes, including CHD5. Other recurrent structural alterations include deletions of 3p, 4p, and 11q, with unbalanced gain of 17q. Patterns of genetic change are being used to classify neuroblastomas into subsets that are predictive of clinical behavior. Whole genome sequencing showed that gene sequence alterations are relatively uncommon in neuroblastomas: ALK (9%), ARID1A/B (3%), PTPN11 (3%), ATRX (2.5%), and MYCN (1.7%). Thus, genomic modulation in neuroblastoma pathogenesis occurs mainly by copy number changes and epigenetic mechanisms. Targeted therapy: Favorable neuroblastomas have high TrkA expression, and these tumors are prone to spontaneous regression or differentiation. In contrast, unfavorable neuroblastomas have high expression of TrkB and its ligand, brain-derived neurotrophic factor. This autocrine survival pathway promotes invasion, metastasis, angiogenesis, and drug resistance. Targeted therapy of TrkB causes apoptosis and inhibits tumor growth in preclinical studies, and in a phase I clinical trial. We are evaluating second-generation Trk inhibitors to treat neuroblastomas and other tumors with Trk activation. Our group has also piloted therapy targeting neuroblastomas with activated ALK, and we are developing MYCN-targeted agents. We are also developing nanoparticle technology to deliver conventional and biologic agents with greater efficacy and less toxicity.

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Plenary Session

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ABSTRACTS American Society of Clinical Oncology 49th Annual Meeting May 31–June 4, 2013 McCormick Place Chicago, Illinois

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Plenary Session, Sun, 1:00 PM-4:20 PM

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RTOG 0825: Phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM). Presenting Author: Mark R. Gilbert, University of Texas M. D. Anderson Cancer Center Department of Neuro-Oncology, Houston, TX

Effect of visual inspection with acetic acid (VIA) screening by primary health workers on cervical cancer mortality: A cluster randomized controlled trial in Mumbai, India. Presenting Author: Surendra Srinivas Shastri, Tata Memorial Centre, Mumbai, India

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.


Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.

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Plenary Session Plenary Session, Sun, 1:00 PM-4:20 PM

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Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: A phase III randomized trial of the Gynecologic Oncology Group. Presenting Author: Krishnansu Sujata Tewari, University of California, Irvine, Medical Center, Orange, CA

Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The phase III DECISION trial. Presenting Author: Marcia S. Brose, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA



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aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. Presenting Author: Richard G. Gray, University of Oxford, Oxford, United Kingdom



Breast Cancer—HER2/ER 500

Oral Abstract Session, Sun, 8:00 AM-11:00 AM

7s

501


Clinical and translational results of CALGB 40601: A neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer. Presenting Author: Lisa A. Carey, The University of North Carolina at Chapel Hill, Chapel Hill, NC

Impact of neoadjuvant chemotherapy plus HER2-targeting on breast conservation rates: Surgical results from CALGB 40601 (Alliance). Presenting Author: David W. Ollila, The University of North Carolina at Chapel Hill, Chapel Hill, NC

Background: Recent trials in HER2-positive (HER2⫹) breast cancer (BrCa) demonstrate increased pathological complete response (pCR) using dual HER2-targeting in the neoadjuvant setting and increased progression-free survival in metastatic disease. CALGB 40601 aimed to further quantify the pCR rates of weekly paclitaxel (T) and trastuzumab (H) alone or combined HER2-blockade of H with the small molecule lapatinib (L), and to identify biomarkers of sensitivity to these HER2-targeted agents. Methods: Eligible patients had newly diagnosed, noninflammatory stage II-III HER2⫹ BrCa and were randomized to receive T (80mg/m2/week IV) ⫹ H (4mg/kg then 2mg/kg/week IV) alone (TH) or with the addition of L (750 mg/d PO) (THL) for 16 weeks preoperatively. A third arm, T ⫹ L (1500 mg/d) (TL), was closed early when negative efficacy and toxicity data emerged from preliminary analysis of ALTTO. After surgery, 4 cycles of adjuvant dosedense AC and 1 year H was recommended. Tumors were biopsied for research before therapy; post-Rx samples of residual disease were requested. The primary endpoint was in-breast pCR rate; the study had 85% power to detect an increase from 30% (TH) to 50% (THL). Results: 305 patients were randomized (118 THL, 120 TH, 67 TL); 68% were clinical stage II and 59% hormone receptor-positive. Grade 3⫹ toxicity was higher among L-containing arms, including neutropenia (12% TL, 7% THL, 2% TH), rash (15% TL, 14% THL, 2% TH), and diarrhea (20% TL, 20% THL, 2% TH). Breast pCR rates with 95% confidence limits were: 51% (42-60%) THL, 40% (32-49%) TH, 32% (22-44%) TL. pCR rate in the TH arm was higher than previous studies, and was not significantly different from THL (p⫽0.11). We will present molecular subtype, sequence and gene copy number abnormalities in primary tumors and residual disease. Conclusions: pCR rate was higher with combined THL compared with standard TH but did not reach statistical significance. These results are qualitatively similar to other neoadjuvant studies in HER2⫹ BrCa, and contribute to estimates of pCR rates after these agents. Tissue-based studies may illuminate which patients benefit from HER2-targeting using these agents. Clinical trial information: NCT00770809.

Background: Neoadjuvant systemic therapy improves breast conserving therapy (BCT) rates, but the magnitude of this benefit is unknown in operable breast cancer. We sought to quantify this benefit in CALGB 40601, a phase III trial of paclitaxel (T) ⫹ HER2 blockade with either trastuzumab (TH), lapatinib (TL), or both (THL), by requiring the treating breast surgeon to determine BCT eligibility before and after neoadjuvant therapy and examining surgical results. Methods: Eligible patients (pts) had operable, newly diagnosed, noninflammatory stage II-III HER2⫹ breast cancer randomized to receive TH, TL or THL. Prior to, and again after neoadjuvant therapy, the treating breast surgeon determined whether the patient was a BCT candidate based on clinical and radiographic criteria, but the subsequent breast cancer operation was at the discretion of the surgeon and patient. Two endpoints examined were: (1) the conversion rate from BCT-ineligible to BCT-eligible and (2) the rate of successful BCT as determined by tumor-free surgical margins. Results: Of 305 pts randomized (118 THL, 120 TH, 67 TL), 294 were evaluable. Prior to neoadjuvant therapy, 136 (46%) patients were candidates and 158 (54%) were non-candidates for BCT. 107/136 (79%) remained BCT candidates following neoadjuvant therapy and 78 chose BCT, of whom 69 (88%) were successful. 29 pts (21%) initially thought to be BCT candidates became non-candidates after neoadjuvant therapy. Conversely, 76/158 (48%) pts considered non-BCT candidates prior to neoadjuvant therapy down-sized sufficiently to be considered BCT candidates; 40 of these opted for BCT with a 75% (30/40) BCT success rate. In total, 183 pts were deemed BCT candidates after neoadjuvant therapy, yet 65 (36%) proceeded directly to mastectomy. Conclusions: This is the first neoadjuvant trial to prospectively quantify a nearly 50% conversion rate from BCT-ineligible to BCT-eligible in HER2⫹ breast cancer pts treated with modern systemic therapy. Neoadjuvant chemotherapy combined with targeted anti-HER2 treatment permits potential BCT in approximately 80% of properly selected patients. Clinical trial information: NCT00770809.

502

503


ACOSOG Z1041 (Alliance): Definitive analysis of randomized neoadjuvant trial comparing FEC followed by paclitaxel plus trastuzumab (FEC ¡ PⴙT) with paclitaxel plus trastuzumab followed by FEC plus trastuzumab (PⴙT ¡ FECⴙT) in HER2ⴙ operable breast cancer. Presenting Author: Aman Buzdar, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Neoadjuvant chemotherapy (NAC) and concomitant trastuzumab (T) have produced high pathologic complete response (pCR) rates in HER2⫹ breast cancers. Z1041 addresses the timing of initiation of T with NAC. Methods: Women with operable HER2⫹ invasive breast cancer were randomized 1:1 to: FEC ¡ P⫹T (Arm 1) or P⫹T ¡ FEC⫹T (Arm 2) where treatment was administered as 5-FU 500 mg/m2, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 day 1 of a 21-day cycle x 4 (FEC); paclitaxel 80 mg/m2 weekly x 12 and trastuzumab 4 mg/kg once then 2 mg/kg weekly x 11. Eligibility also included: tumor ⬎ 2 cm or a positive lymph node and left ventricular ejection fraction ⬎ 55%. The primary aim was to compare the pCR rates in the breast (pBCR) between the regimens. Secondary endpoints were pCR rate in the breast and lymph nodes (pBNCR) and safety profile. All pts who began study treatment were included in the analyses. With 128 pts per regimen, a two-sided alpha⫽0.05 test of proportions would have a 90% chance of detecting a difference of 20% or more in the pBCR rates, when the pBCR rate with the poorer regimen is ⱕ 25%. Results: From September 15, 2007 to December 15, 2011, 282 women (Arm 1: 140 pts) were enrolled. Two pts (Arm 1) withdrew without receiving treatment. The two arms were similar in age, stage, and hormone receptor (HR) status (HR neg: 40%). The severe (grade 3⫹) treatment-related toxicities included: neutropenia (Arm 1: 24.6%; Arm 2: 32.4%), fatigue (Arm 1: 4.3%; Arm 2: 8.5%), and neurosensory problems (Arm 1: 3.6%; Arm 2: 4.9%). The pBCR rate and pBNCR rates (Table) were not found to differ between the two regimens (Fisher’s exact p values: 0.905 and 0.811, respectively). Conclusions: High pCR rates can be achieved with trastuzumab in combination with anthracyclines and taxanes. The pBCR or pBNCR was not different between regimens based on the timing of initiation of trastuzumab. Clinical trial information: NCT00513292. n % pCR in breast (95% CI) % pCR in breast and nodes (95% CI)

FEC ¡ PⴙT

PⴙT ¡ FECⴙT

138 55.1 46.4- 63.5 50.7 42.1 – 59.3

142 54.2 45.7-62.6 48.6 40.1-57.1


Follow-up results of NOAH, a randomized phase III trial evaluating neoadjuvant chemotherapy with trastuzumab (CTⴙH) followed by adjuvant H versus CT alone, in patients with HER2-positive locally advanced breast cancer. Presenting Author: Luca Gianni, San Raffaele Hospital, Milan, Italy Background: The monoclonal antibody trastuzumab (H) has been shown to improve event-free survival (EFS) and pathologic complete response (pCR) in patients with HER2-positive locally advanced or inflammatory breast cancer receiving neoadjuvant chemotherapy with or without one year of trastuzumab in the primary analysis of the NOAH study (Gianni L, Lancet 2010). Updated EFS and overall survival (OS) results are now presented. Methods: In this international, multicenter, open-label, randomized phase III trial patients with locally advanced or inflammatory breast cancer were randomized 1:1 to receive CT⫹H followed by adjuvant H versus CT alone. A parallel cohort of 99 comparable patients with HER2-negative disease was included and treated with the same chemotherapy regimen. The neoadjuvant chemotherapy regimen included doxorubicin, paclitaxel, cyclophosphamide, methotrexate and 5-fluorouracil. The primary objective was to compare EFS defined as time from randomization to disease recurrence or progression [local, regional, distant or contralateral] or death due to any cause). Results: After a median follow up of 5.4 years, the EFS benefit with trastuzumab was confirmed. Cardiac tolerability was good despite concurrent administration of trastuzumab with doxorubicin. Two patients (2%) developed reversible symptomatic congestive heart failure and are presently alive. Conclusions: Present analysis confirms the significant EFS benefit observed in the primary analysis of the NOAH study, and shows a strong trend towards improved OS with the addition of trastuzumab to chemotherapy. pCR rate may be considered as a possible primary endpoint and early indicator of benefit in future neoadjuvant studies of HER2targeted agents. Clinical trial information: 86043495.

Parameter 5-yr EFS (%) 5-yr EFS in pCR (%) 5-yr OS (%) 5-yr BCSS (%)

CTⴙH (Nⴝ117) 57.5 86.5 73.5 77.4

HER2-positive CT alone (Nⴝ118) 43.3 54.8 62.9 63.9

HR, p value

HER2-negative (Nⴝ99)

0.64, 0.016 0.29, 0.008 0.66, 0.055 0.59, 0.023

60.5 85.9 76.4 78.6

Abbreviations: EFS, event free survival; OS, overall survival; BCSS, breast cancer specific survival; HR, hazard ratio.


8s

Breast Cancer—HER2/ER

505


Phase III, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and vinorelbine in trastuzumabresistant, advanced breast cancer (BOLERO-3). Presenting Author: Ruth O’Regan, Georgia Cancer Center for Excellence at Grady Memorial Hospital, Atlanta, GA Background: Everolimus (EVE) is an inhibitor of mammalian target of rapamycin (mTOR), a protein kinase central to a number of signaling pathways regulating cell growth and proliferation. Data from preclinical and phase 1/2 clinical studies indicated that adding EVE to trastuzumab (TRAS) plus chemotherapy may restore sensitivity to and enhance efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapy. The international BOLERO-3 phase 3 study is being conducted to evaluate the addition of EVE to TRAS plus vinorelbine. Methods: Adult women with HER2⫹ advanced breast cancer and who received prior taxane therapy and experienced recurrence or progression on TRAS were randomized 1:1 to receive either EVE or placebo (5 mg/day) in combination with weekly TRAS and vinorelbine (25 mg/m2). The primary endpoint is progression-free survival (PFS). Secondary endpoints included overall survival, response rate, clinical benefit rate, safety, quality of life, and pharmacokinetics. Final analysis will be conducted after approximately 417 PFS events. Results: The trial accrued 569 patients between October 2009 and May 2012. Previous therapy included TRAS (100%), a taxane (100%), and lapatinib (28%). The median age was 54 years, and 76% of patients had visceral metastases, 5% had stable brain metastases, 56% had hormonereceptor–positive disease, 33% had Eastern Cooperative Oncology Group performance status of 1 or 2, and 41% had 3 or more metastatic sites. The median number of prior chemotherapy lines in the metastatic setting was 1. As of February 4, 2013, a total of 396 PFS events were reported. Conclusions: Final PFS analysis will be performed in early May 2013; primary and secondary efficacy endpoints will be presented. Clinical trial information: NCT01007942.

506


Identifying clinically relevant prognostic subgroups in node-positive postmenopausal HRⴙ early breast cancer patients treated with endocrine therapy: A combined analysis of 2,485 patients from ABCSG-8 and ATAC using the PAM50 risk of recurrence (ROR) score and intrinsic subtype. Presenting Author: Michael Gnant, Comprehensive Cancer Center, Department of Surgery, Medical University of Vienna, Vienna, Austria Background: Most postmenopausal women with node positive HR⫹ EBC receive adjuvant chemotherapy. We hypothesized that a molecular-based characterization of residual risk after endocrine therapy using the ROR score and IS may identify node-positive patient subgroups with limited long-term recurrence risk after endocrine therapy better than clinicalpathological risk assessment by clinical treatment score (CTS) alone. Methods: Long-term follow-up and tissue samples were obtained from 2,485 postmenopausal HR⫹ patients from the ABCSG-8 (N⫽1,478) and transATAC (N⫽1,007) trials. The PAM50 test was conducted on RNA extracted from paraffin blocks using the NanoString nCounter Analysis system. The ability of ROR, IS and ROR-defined risk groups (ROR-RG) to add prognostic information to CTS was assessed by the likelihood ratio test in a prospectively defined analysis plan. Results: Patients in the combined data set were grouped by the number of positive nodes into 1 (N1), 2 (N2), or 2 or 3 (N2-3),Baseline hazards for these subgroups were similar in the two trials. ROR score, IS and ROR-RG added statistically significant prognostic information (10-year distant recurrence risk) beyond CTS in all groups. In patients with one positive node, the absolute 10-year risk of distant recurrence was 6.6% [95% CI: 3.3%-12.8%] in the PAM-50-low risk group (40% of patients) and 8.4 % [5.3%-13.3%] in the Luminal A subgroup (69% of patients). Conclusions: The results of this combined analysis demonstrate that a significant proportion of N1 EBC patients have very limited long term recurrence risk and suggest the same for some N2 patients. The PAM50 ROR score, IS and ROR-RG reliably provide additional prognostic information beyond CTS and may be useful in deciding which women with node-positive HR⫹ EBC can be spared adjuvant chemotherapy. N1 (Nⴝ331) P value ⌬LR ␹2 ROR IS ROR-RG

507


Prognostic impact of the 21-gene recurrence score in patients presenting with stage IV breast cancer. Presenting Author: Tari A. King, Department of Surgery, Breast Service, Memorial Sloan-Kettering Cancer Center, New York, NY Background: The 21-gene Recurrence Score (OncotypeDX Breast Cancer Assay) predicts outcome and benefit from chemotherapy (CT) in early stage ER⫹ BC treated with adjuvant endocrine therapy. We evaluated the association between Recurrence Score (RS), time to progression (TTP), and overall survival (OS) in patients with stage IV BC enrolled in TBCRC 013. Methods: TBCRC 013 is a registry study evaluating surgery of the primary tumor in pts presenting with Stage IV BC. From 7/09 - 4/12, 128 evaluable pts were enrolled in two cohorts (A: metastases (mets) with intact primary tumor (n⫽112); B: mets within 3 months of primary surgery (n⫽16)). This study includes 110 pts with pretreatment primary tumor samples available for analysis. Clinical variables, TTP and OS were correlated with RS using long-rank, Kaplan-Meier and Cox regression. Results: Median pt age was 52yrs (21-79) and median tumor size 3.1cm (0.7-15). 82 (80%) were ER⫹, 83 (81%) Her2(-) and 51 (46%) had bone-only mets. Cohorts A and B did not differ. At a median follow-up of 26 mos (1-47), median TTP is 19 mos (95%CI16-25) and surgery is not associated with OS. 102 samples qualified for RS. 23 (23%) had low RS⬍18, 29 (28%) intermediate RS, 18-30; and 50 (49%) high RSⱖ31. Age, tumor size or site of 1stmets was not associated with RS. Risk groups were prognostic for TTP in ER⫹ pts and for 2 yr OS in ER⫹Her2- pts (Table). In Cox models continuous RS was also prognostic for TTP in ER⫹ pts (HR 3.5; for 50 point difference (PD) 95%CI 1.5-8.1, p⫽0.003) and for OS in ER⫹Her2- pts (HR 21.4, for 50 PD 95%CI 2.2-204.4, p⫽0.008). In MVA, adjusting for clinical variables, RS remained prognostic for TTP in ER⫹ pts (p⫽0.01). Further analysis of surgery in this trial is ongoing. Conclusions: The 21-gene RS is independently prognostic for TTP in ER⫹ Stage IV BC. RS is also prognostic for OS in ER⫹Her2- BC, suggesting that a high RS may be a surrogate for endocrine resistance and could be used to select pts with ER⫹ Stage IV BC for CT. A randomized trial to address this hypothesis is warranted. Clinical trial information: NCT00941759. RS30 nⴝ23 nⴝ29 nⴝ50 Log rank, p Median TTP, mos ERⴙ ERⴙHER22 yr OS, % ERⴙ ERⴙHER2NR, not reached.

32 (16-NR) 32 (16-NR)

22 (20-NR) 22 (20-NR)

12 (8-21) 13 (9-26)

0.002 0.015

100 100

100 100

80 (68-98) 73 (56-96)

0.049 0.005

508

17.53 12.16 11.32

⬍0.0001 0.0005 ⬍0.004

N2 (Nⴝ145) ⌬LR ␹2 P value

N2-3 (Nⴝ212) ⌬LR ␹2 P value

12.18 7.80 7.95

14.16 8.58 13.15

0.0005 0.0052 ⬍0.02

0.0002 0.0034 ⬍0.001


A randomized double-blind phase II study of the combination of oral WX-671 plus capecitabine versus capecitabine monotherapy in first-line HER2-negative metastatic breast cancer (MBC). Presenting Author: Lori J. Goldstein, Fox Chase Cancer Center, Philadelphia, PA Background: uPA and its inhibitor PAI-1 play a key role in tumor invasion, metastasis and tumor growth. uPA and PAI-1 are biomarkers validated at highest level of evidence in breast tumors and are recommended for clinical decision making by ASCO. WX-UK1 is a competitive inhibitor of uPA with an inhibition constant in the submicromolar range. WX-671 (upamostat) is an oral prodrug of WX-UK1. Methods: Female patients aged ⬎18, with HER2 negative MBC were randomized in a double-blind fashion to receive upamostat (200 mg orally daily for 21 days) plus C (1000 mg/m2 orally twice daily for 14 days) vs. C (same regimen) in 3 week treatment cycles until progressive disease or unacceptable toxicity. 132 from five countries were enrolled. The primary objective was to evaluate the efficacy of the combination of upamostat and C compared to C alone by assessment of progression free survival (PFS). The study also evaluated the objective response rate and safety as well as pharmacokinetics (PK). Efficacy was evaluated by RECIST by independent central read. Results: Median treatment duration was 8 cycles in both arms. In the total study population (intent to treat; ITT) upamostat led to an increase of median PFS from 7.5 months (95% CI: 4.2; 12.8) in the control group to 8.3 months (95% CI: 5.6; 9.6) in the combination therapy. An unexpectedly high rate (50%) of study patients presented within their first two years after initial diagnosis. In patients who had received prior adjuvant chemotherapy, PFS improved from 4.3 months (95% CI: 2.6; 9.7) in the C alone group to 8.3 months (95% CI: 5.6; 10.9) in the upamostat plus C group. The overall response rate was higher in the combination group compared to C alone (20% vs. 12% at Week 24). PK analysis demonstrated no drug-drug interactions between upamostat and C. The combination therapy was safe and well tolerated. Conclusions: This is the first proof of efficacy of an anti-uPA therapy in breast cancer. The heterogeneity of the patients in this study may underestimate the potential treatment effects of upamostat. Additional subset analyses will be presented. Future biomarker-stratified strategies may reveal better efficacy. Clinical trial information: NCT00615940.


Breast Cancer—HER2/ER LBA509

Clinical Science Symposium, Mon, 1:15 PM-2:45 PM

Correlation of molecular alterations with efficacy of everolimus in hormonereceptor–positive (HRⴙ), HER2-negative advanced breast cancer: Preliminary results from BOLERO-2. Presenting Author: Gabriel N. Hortobagyi, Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

511


510

9s Clinical Science Symposium, Mon, 1:15 PM-2:45 PM

Predictive markers of everolimus efficacy in hormone receptor positive (HRⴙ) metastatic breast cancer (MBC): Final results of the TAMRAD trial translational study. Presenting Author: Isabelle Treilleux, Centre Léon Bérard, Lyon, France Background: Hormone resistance is linked in part to cross-talk between ER signalling and PI3K/Akt/mTOR pathway. Following results of the BOLERO-2 trial, everolimus (E), a potent mTOR inhibitor, has recently been approved in combination with exemestane in women with HR⫹ MBC refractory to aromatase inhibitor (AI). However, E is frequently associated with specific toxicities, and predictive markers of efficacy are needed. We report here the final results of translational studies within the TAMRAD randomized Phase II trial, comparing tamoxifen (TAM) to TAM⫹E in AI pre-treated MBC. Methods: Tumor samples from 51 patients among the 111 treated in the TAMRAD trial were retrieved. Hot spot mutations of PI3K (exon 9-20), and KRAS (exon 2) were described. TMA analysis evaluated IHC expression of PTEN, pAkt, PI3K, LKB1, S6K, pS6K, 4EBP1, p4EBP1, and eIF4E. Exploratory analysis of E efficacy in each biomarker subgroup (high vs low expression defined by median percentage of marked cells) was done. Results: Patients characteristics and treatment efficacy among this sub-population were similar to the results from the whole population: Time to progression was 10 months for the TAM⫹E treated patients vs. 5.5 months for the TAM treated patients, HR: 0.59 (95% CI 0.33-1.07). PI3K-Akt pathway: All patients derived benefit from E regardless of PI3K mutational status, PTEN or pAkt expression. Surprisingly, E efficacy was greater in patients with low PI3K expression (n⫽12, HR⫽0.11, 95%CI 0.01-0.96) than in patients with high PI3K expression (n⫽ 28, HR⫽0.9; 95%CI 0.49-2.41) PI3K independent pathway: Patients with low expression of the anti-oncogene LKB1 derived greater benefit from E (n⫽22, HR⫽0.33; 95%CI 0.13-0.89) than patients with high LKB1 expression (n⫽25, HR⫽0.75; 95%CI 0.32-1.74) mTOR downstream effectors: Patients with high p4EBP1 (n⫽27, HR⫽0.37; 95%CI 0.150.90) or low 4EBP1 (n⫽21, HR⫽0.39; 95%CI 0.14-1.08) were the subgroups most likely to benefit from E. Conclusions: Those results are in favor of a better efficacy of E for patients with PI3K independent activation of mTOR. If confirmed, they could have important implications for future patient selection. Clinical trial information: NCT01298713.

512


Array CGH and DNA sequencing to personalize targeted treatment of metastatic breast cancer (MBC) patients (pts): A prospective multicentric trial (SAFIR01). Presenting Author: Fabrice Andre, Institut Gustave Roussy, Villejuif, France

Kinome reprogramming response to MEK inhibition: A window-ofopportunity trial in triple-negative breast cancer (TNBC). Presenting Author: Gary L. Johnson, University of North Carolina - Lineberger Comprehensive Cancer Center, Chapel Hill, NC

Background: The aim of the present study was to profile the metastatic lesion of pts using high throughput technologies, and to treat them accordingly. Methods: SAFIR01 trial aimed to include 400 pts with MBC, selected for not presenting a progressive disease at the time of biopsy. A biopsy was done in a metastatic site. DNA was extracted if the tumor contained ⬎50% cancer cells, and sent to one of the 5 genomic centers who performed array CGH (copy number changes) and sanger sequencing on PIK3CA (exon 10/21) and AKT1 (exon 3). A targeted therapy matched to the genomic alteration was expected to be proposed at the time of progressive disease. The primary endpoint was the % of pts who received a targeted therapy according to the genomic alteration. Results: A biopsy of metastatic site was done successfully in 408 out of the 423 included pts. Biopsy was complicated by a serious adverse event in 9 pts. A discrepancy between primary and metastatic lesion was observed in 8% and 19% of pts for Her2 and HR. Array CGH and sequencing were successfully obtained in 277 (68%) and 295 (72%) pts. The main reason for failure of genomic test was the low cellularity (n⫽93). A targetable genomic alteration was identified in 204 pts. The most frequent genomic alterations were PIK3CA mutations, CCND1, FGF4 and FGFR1 amplifications. 76 pts presented a rare targetable genomic alteration (⬍5%), including AKT1 mutations, EGFR, FGFR2, PIK3CA, MDM2 amplifications. Early Feb 2013, 46 out of 277 pts with genomic analyses (17%) had received a targeted therapy matched to the genomic alteration, covering twelve different targets. Updated results on number of pts treated, together with efficacy data will be presented. Next generation sequencing on metastatic lesions is ongoing and results will be presented. Conclusions: This trial evaluated the concept of personalized medicine for MBC and provided a large scale genomic analysis of metastatic tissue. This study suggests that assessing the biology of metastatic tissue could allow driving pts to targeted therapy. A randomized trial (SAFIR02) testing this approach is expected to start during summer 2013. Clinical trial information: NCT01414933.

Background: Targeted therapy (Rx) in TNBC is challenging due to heterogeneity and cancer cell kinome “reprogramming” in response to targeted kinase inhibitors (Cell 149:307, 2012). In preclinical TNBC models specific kinases (e.g., DDR1/2, PDGFRbeta, VEGFR2, AXL) are activated in response to MEK inhibition. Our studies define unique kinome reprogramming in basal-like (BBC) versus claudin-low (CL). This study compared kinome profiles of TNBC pre- and post- MEK1/2 inhibition with GSK1120212 (trametinib, T) using multiplexed inhibitor beads coupled with mass spectrometry (MIB/MS). Methods: Eligible patients (pts) with untreated TNBC received T (initial dose 1.5mg/d raised after interim analysis of kinome effects to 2mg/d) for 7 days preceding breast surgery. Fresh tumor tissue was obtained before and after T. Kinase activation state was analyzed as post:pre(-)treatment ratio; molecular subtype was by gene expression analysis. Results: Kinome response profiling was completed in 7 of 9 pts by abstract submission. Toxicities included grade 2 (2pts) or grade 1 (1pt) rash, grade 1 diarrhea (1pt), and grade 1 nausea (1pt). Two of the 9 pts profiled did not have sufficient pre-treatment tumor for kinome analysis. Molecular subtypes included 6 BBC patients (one of which was CL after T), 2 CL patients (one of which was BBC after T), and 1 normal-like patient (which was BBC after T). MEK1/2 inhibition and kinase reprogramming was seen in 6 of the 7 tumors where both pre- and post T samples could be analyzed. The results show kinome reprogramming in response to MEK1/2 inhibition occurs in human tumors similar to preclinical modeling in TNBC cell lines and credentialed engineered mouse models; the kinase reprogramming pattern differed between BBC and CL. Conclusions: MEK1/2 inhibition upregulates and activates specific receptor tyrosine kinases in BBC that are different from CL.A subset of BBC and CL may have plasticity, changing their molecular subtype and kinome profile, and responding heterogeneously to MEK1/2 inhibition. Analysis of kinome reprogramming identifies upregulation of druggable targets for individual patients that suggest rational combinations with MEK inhibition in TNBC. Clinical trial information: NCT01467310.


10s 513

Breast Cancer—HER2/ER Poster Discussion Session (Board #1), Sat, 8:00 AM-12:00 PM and 12:00 PM-1:00 PM

Phase II trial of carboplatin (C) and bevacizumab (BEV) in patients (pts) with breast cancer brain metastases (BCBM). Presenting Author: Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA Background: The anti-tumor and anti-edema effects of BEV provide a rationale for testing in BCBM. Carboplatin (C) is associated with CNS responses across multiple tumor types. We evaluated BEV ⫹ C in pts with BCBM. Methods: Pts with progressive, measurable BCBM (⬎/⫽ 1 cm in longest dimension) were eligible. Cycle 1: BEV 15 mg/kg on Day 1, followed on Day 8 by carboplatin AUC⫽5 (plus trastuzumab if HER2⫹). In subsequent cycles, pts received BEV ⫹ C on Day 1 (plus trastuzumab if HER2⫹) of a 3 week (wk) cycle. Standard brain MRI was obtained at baseline (BL) and every 2 cycles. Non-CNS scans (CT or MRI) were performed after 2 cycles, 4 cycles, then every 4 cycles. Correlative brain imaging was obtained at BL, 12-96 hours after the first dose of BEV, and after 2 cycles. Circulating tumor cells and blood for VEGF polymorphisms were also collected. The primary endpoint was composite CNS objective response rate (CNS ORR). CNS partial response required all of the following: ⬎/⫽ 50% reduction in volumetric sum of target CNS lesions compared to BL, no progression of non-target lesions, no new lesions, stable/decreasing steroid dose, no progressive neurologic signs or symptoms, and no progression of non-CNS disease by RECIST 1.0. The study used a 2-stage design to distinguish between ORR 5% vs 20% (responses in ⬎/⫽ 1/12 pts to enter 2ndstage; responses in ⬎/⫽ 4/37 pts needed to be promising). Results: 38 pts were enrolled between 11/3/09-8/24/12 (30 HER2⫹; 8 HER2-negative). Most (76%) pts had received ⬎/⫽2 lines of metastatic chemotherapy. 97% of pts with HER2⫹ disease received prior trastuzumab; 73% had prior lapatinib. All but 5 pts progressed after WBRT and/or SRS. As of 1/15/13, 3 pts remain on protocol therapy; 22 patients have died. The composite CNS ORR was 63% (95% CI 46%-78%). CNS ORR by RECIST was 45%. CNS responses were observed in both HER2⫹ and HER2-negative pts. Of 34 pts with ⬎/⫽ 24 wks potential follow-up time, median number of cycles was 8 (range 1-19). One grade 2 CNS hemorrhage event was reported; there were no cases of grade 3/4 CNS hemorrhage. Conclusions: BEV ⫹ carboplatin is associated with a high rate of durable CNS response in pts with BCBM. Updated results, including progression-free and overall survival will be presented. Clinical trial information: NCT01004172.

515

Poster Discussion Session (Board #3), Sat, 8:00 AM-12:00 PM and 12:00 PM-1:00 PM

TBCRC 018: Phase II study of iniparib plus chemotherapy to treat triple-negative breast cancer (TNBC) central nervous system (CNS) metastases (mets). Presenting Author: Carey K. Anders, The University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel Hill, NC Background: Nearly half of women with advanced TNBC develop CNS mets. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that penetrates the blood brain barrier (BBB), and the topoisomerase I inhibitor, irinotecan, in patients (pts) with TNBC CNS mets. Methods: Eligible pts had TNBC with new or progressive CNS mets with at least 1 measurable (⬎ 5mm) lesion. Pts received irinotecan 125mg/m2 IV days (d) 1, 8 and iniparib (initial dose 5.6mg/kg, later changed to 8mg/kg) IV d 1, 4, 8, 11 every 21d. Tumor response rate (RR) was assessed by brain MRI and body CT every 9 weeks. The Kaplan Meier method estimated the primary endpoint of time to progression (TTP, intracranial [modified RECIST] or extracranial [RECIST 1.1]). Secondary endpoints were RR, PFS, OS, quality of life (QOL) and correlative endpoints. Results: Of 37 pts who began treatment, 34 were evaluable for efficacy. Mean age was 48 yrs (34 – 80 yrs). BRCA status was known for 16 patients of whom 5 had a mutation (4 BRCA1, 1 BRCA2). 88% received prior (neo)adjuvant and 68% prior metastatic chemotherapy (median 2 [1–14] lines). While 15% were CNS radiation (RT) naïve, 32% had received whole brain RT, 21% stereotactic RT, and 32% both. The most common grade (gr) 3/4 adverse events were neutropenia (14%), fatigue (5%), leukopenia (5%), hypokalemia (5%). Diarrhea was common (54%), but gr 3/4 was rare (3%). Median TTP (CNS and non-CNS) was 2.1 months (mos) (95% CI 1.7– 4.3) and OS was 7.6 mos (95% CI 5.1-10.2). First progression site was CNS in 39%, non-CNS in 29% or both in 32%. CNS best RR was (12%; 0 CRs, 4 PRs); CNS clinical benefit rate (CBR, CR ⫹ PR ⫹ SD ⱖ 6 mos) was 30%. Non-CNS RR was 5% (0 CRs, 1 PR) and CBR was 11%. Conclusions: Iniparib and irinotecan was well-tolerated among pts with TNBC CNS mets. While TTP was shorter than expected and contribution of iniparib to irinotecan remains uncertain, 30% of pts demonstrated CNS clinical benefit raising the question of whether predictive biomarkers could be identified. QOL, volumetric analysis of CNS lesions and translational studies evaluating molecular subtype, germline BRCA1/2, and DNA repair gene expression/methylation are ongoing. Clinical trial information: NCT01173497.

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Clinical evidence for drug penetration of capecitabine and lapatinib uptake in resected brain metastases from women with metastatic breast cancer. Presenting Author: Aki Morikawa, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Brain metastasis (BM) is a challenging complication of metastatic breast cancer (MBC). Although systemic therapy is not commonly considered as a primary therapeutic approach, its potential in BM management has recently become apparent (Bachelot T et al Lancet Oncol 2013). Capecitabine and lapatinib in particular have been evaluated in HER2⫹ breast cancer BM (BCBM), but evidence for drug/metabolite CNS penetration is solely derived from preclinical animal models. In this study, we examined capecitabine, its metabolites, and lapatinib uptake in BCBMs resected due to medically indicated craniotomy. Methods: Study patients had BCBM requiring surgical resection. Patients with HER2-negative MBC received a single preoperative oral dose of capecitabine (1250mg/m2) 2-3 hrs before surgery. Those with HER2⫹ MBC received 2-3 oral doses of lapatinib (1250mg) daily, the last dose 2-3 hrs before surgery. On the day of surgery, serum was collected serially starting just before drug administration, intraoperatively, and through one hour after the conclusion of surgery. The concentration of capecitabine, its metabolites, and lapatinib from serum and BM were measured using liquid chromatography with tandem mass spectroscopy (LC-MS/MS). Results: 10 patients enrolled; PK data is available for 9: 6 for capecitabine and 3 for lapatinib. Capecitabine, its intermediate metabolites, 5FU, and lapatinib were detected in all BMs. Tumor capecitabine and 5-FU concentrations ranged from 3% to 129% and from 168% to 1422%, respectively, of serum concentrations. For lapatinib, the range was 21% to 700%. In a number of the BMs, drug concentrations were in the therapeutic range, whereas in others the concentrations were up to 10 fold lower. Conclusions: This is the first study to show capecitabine and lapatinib were detected in clinically relevant concentrations in a number of non-irradiated human BCBMs. This provides evidence for their ability to cross the blood-brain barrier, is consistent with prior published clinical activity, and supports further evaluation in a clinical setting prior to whole brain radiotherapy. Clinical trial information: NCT00795678.

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A phase II randomized trial of lapatinib with either vinorelbine or capecitabine as first- and second-line therapy for HER2 overexpressing metastatic breast cancer (MBC). Presenting Author: Christos A. Papadimitriou, Hellenic Cooperative Oncology Group (HeCOG), Athens, Greece Background: Lapatinib (L) is approved for the treatment of human epidermal growth factor receptor 2 (HER2) positive MBC in combination with capecitabine (C) following progression after trastuzumab, anthracyclines and taxanes. Vinorelbine (V) is an important chemotherapy option in MBC. This randomized, open-label, multicenter phase II study (NCT01013740) evaluated the efficacy and safety of L with either V or C in women with HER2⫹ MBC. The analysis of progression-free survival (PFS) and safety showed comparable rates of efficacy and tolerability between the 2 arms (Janni et al, SABCS 2012). Here we report the results of the overall survival (OS) and crossover analyses. Methods: Patients with MBC who had received ⱕ1 chemotherapy regimen in the metastatic setting were randomized 2:1 to either L 1250 mg orally once daily (QD) continuously ⫹ V 20 mg/m2 intravenously on days 1 and 8, every 3 weeks, or L 1250 mg orally QD continuously ⫹ C 2000 mg/m2/day orally in 2 doses, 12 hours apart on days 1-14 every 3 weeks. Patients were stratified by prior receipt of therapy for MBC and site of metastatic disease. The primary endpoint was PFS. Other endpoints included OS, overall response rate and safety. Patients progressing on one treatment arm were given the option of crossover to the other arm. All analyses were conducted with a descriptive intent only. The control arm of L⫹C was included in the study design to validate the patient population and lend support to the activity of L⫹V. Results: 112 patients were randomized in the study; 37 to the L⫹C arm and 75 to the L⫹V arm. The median OS in the L⫹C arm was 19.4 months [95% CI: 16.4-27.2] and 24.3 months [95% CI: 16.4-NE] in the L⫹V arm. At the time of analysis 42 patients had crossed over; 29 patients to L⫹C and 13 to L⫹V. Median PFS after crossover was 4 months [95% CI: 2.1-5.8] in the L⫹C arm and 3.2 months [95% CI: 1.7-5.1] in the L⫹V arm. Conclusions: L⫹V has shown consistent median OS with that reported in the pivotal study of L⫹C. The exploratory analysis of patients retreated with L after progression on L supports the biological rationale for maintaining HER2 suppression in HER2⫹ patients with progression on prior lines of anti-HER2 agents. Clinical trial information: NCT01013740.




Phase III trial of non-pegylated liposomal doxorubicin (M) in combination with trastuzumab (T) and paclitaxel (P) in HER2ⴙ metastatic breast cancer (MBC). Presenting Author: Lorena De La Pena, SOLTI, Barcelona, Spain

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A phase Ib study of an anti-HER2 inhibitor, lapatinib, in combination with a c-MET and VEGFR inhibitor, foretinib, in HER2-positive metastatic breast cancer (MBC): Results from NCIC CTG IND.198. Presenting Author: Stephen K. L. Chia, British Columbia Cancer Agency, Vancouver, BC, Canada

Background: M in combination with T has shown promising activity and cardiac safety in MBC patients (pts). We conducted a randomized Phase III trial of first-line M plus T and P (MTP) versus T plus P (TP) in HER2⫹ MBC pts. Methods: Pts with HER2⫹ (by FISH) MBC ⱖ 18 years and ECOG 0-1, who had received no prior chemotherapy for metastatic disease, were eligible. Left ventricular ejection fraction should be within normal institutional limits. Prior (neo-) adjuvant anthracyclines, T or P were permitted, if completed ⬎1 year before the start of the study. Pts received M 50 mg/m2 q3w for 6 cycles, T 4 mg/kg loading dose followed by 2 mg/kg qw, and P 80 mg/m2qw, or T⫹P at the same doses until progression or toxicity. Primary outcome was progression-free survival (PFS). Enrollment of 332 pts would provide 80% power with a 5% significance to detect an improvement in PFS with MTP, assuming a median PFS of 8 months in TP and a hazard ratio (HR) of 0.70. Results: 363 pts enrolled (MTP 181, TP 183), 360 received treatment. The two groups were well balanced for demographics, pretreatment characteristics and extent of disease. One third of the pts had prior exposure to anthracyclines, but almost none to trastuzumab (1% and 2% in MTP and TP arms, respectively). Six cycles of M could be given to 72% of the pts. With a median follow-up of 31 months, median PFS was 16.1 and 14.5 months with MTP and TP, respectively (HR 0.84, P⫽0.174). In pts with ER and PR-negative tumors, PFS was 20.7 and 14.0 months, respectively (HR, 0.68; 95% CI 0.47– 0.99). Median overall survival (OS) was 33.6 and 28.9 months, respectively (HR, 0.79, P⫽0.083). In ER and PR-negative tumors, OS was 38.2 and 27.9 months, respectively (HR, 0.63; 95% CI 0.42– 0.93). The incidence of NYHA Class III/IV congestive heart failure was 3% with MTP and there were 2 cardiac deaths with TP. The frequency of adverse events was higher with MTP, especially myelosuppression, stomatitis and gastrointestinal intolerance. Conclusions: The trial failed to demonstrate a significant clinical improvement with the addition of M to TP. The clinical benefit observed in an exploratory analysis in the ER and PR-negative population deserves consideration for further clinical trials. Clinical trial information: NCT00294996.

Background: The mechanisms of resistance to targeted anti-HER 2 therapy are unclear. Proposed pathways include MET, VEGF and AXL. Multitargeted pathway inhibition may delay or prevent acquired resistance to HER2 inhibition. Foretinib, an oral multi-kinase inhibitor of MET and VEGFR2, as well as PDGFRB, AXL, FLT3, TIE-2, RET and RON kinases, has pre-clinical anti-tumor activity in breast tumor models. This phase 1b study sought to establish the associated toxicities, pharmacokinetics (PK) and recommended phase II doses (RP2D) of this combination of oral tyrosine kinases inhibitors in a cohort of HER-2 positive MBC patients. Methods: Women with HER2 positive (determined locally) MBC, PS 0-2, and no limit on number of prior chemotherapies or lines of anti-HER2 therapies were enrolled. A 3⫹3 dose escalation design was utilized. 4 dose levels were planned with starting doses of foretinib 30 mg and lapatinib 750 mg PO OD (dose level 1) on a q 4 weekly cycle. Correlative studies from primary archival tissue are planned. Results: 19 patients were enrolled, all of whom were evaluable for toxicity assessment and 16 were evaluable for response. Median age was 60 years (34-86), 95% were PS 0-1, 53% were ER- and 95% had at least one prior anti-HER2 based regimen. A median of 2 cycles (range: 1-20) was delivered across 4 dose levels. At the 4th dose level (foretinib 45 mg/lapatinib 1250 mg) dose limiting toxicities were documented in 4/7 patients. These included grade 3 fatigue (2 cases); grade 3 ALT elevation; grade 3 diarrhea and grade 2 joint effusion. There was only one grade 4 non-hematological toxicity (grade 4 vomiting: dose level 1) across all dose levels. One patient discontinued treatment due to toxicity with grade 3 limb edema and grade 3 proteinuria. PK of both drugs from DL1-3 did not appear to demonstrate a significant interaction. The RP2D was declared to be foretinib 45 mg and lapatinib 1000 mg PO OD. The full efficacy data and correlative studies will be presented at the meeting. Conclusions: The combination of foretinib and lapatinib can safely be delivered together, though at lower doses than either agent alone.

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A phase II trial of an oral CDK 4/6 inhibitor, PD0332991, in advanced breast cancer. Presenting Author: Angela DeMichele, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA Background: The G1/S checkpoint of the cell cycle is frequently dysregulated in breast cancer (BC). Initial efficacy of PD0332991, a potent oral inhibitor of cyclin-dependent kinases (CDKs) 4/6 was shown in a variety of solid tumors and in combination with letrozole in a randomized phase II trial. Methods: We performed a phase II, single arm trial of PD0332991 in women with advanced BC. The primary objectives were safety and efficacy. Eligible patients had histologically-confirmed, stage IV BC with primary or metastatic tumor positive for retinoblastoma (Rb) protein expression, measureable disease by RECIST and adequate organ function/performance status. PD0332991 was given at 125 mg orally, days 1 – 21 of a 28-day cycle. Tumor was assessed every 2 cycles. A two-stage statistical design was employed. Secondary objectives included predictive biomarker assessment. Results: 36 patients were enrolled; 28 who completed cycle 1 are reported: 18 (64%) HR⫹/Her2-, 2 (7%) HR⫹/Her2⫹ and 8 (29%) HR-/Her2-. 90% had prior chemotherapy for metastatic disease (median 3 lines); 78% had prior hormonal therapy (median 2 lines). Grade 3/4 toxicities were limited to transient neutropenia (50%) and thrombocytopenia (21%). One episode of neutropenic sepsis occurred in cycle 1 in patient with 6 prior chemo regimens. All other toxicities were grade 1/2. Treatment was interrupted in 7 (25%) and dose reduced in 13 (46%) pts for cytopenias. For response data see table. Responses occurred at dose levels as low as 50 mg. Median PFS (months, 95% CI) was 4.1 (2.3,7.7) for ER⫹/Her2-, 18.8 (5.1,⬁) for ER⫹/Her⫹ and 1.8 (0.9,⬁) for ER-/Her2-. 27/28 patients discontinued study for progressive disease (PD); 1 due to patient preference. Conclusions: Therapy with PD0332991 alone is welltolerated and demonstrates response or prolonged stable disease (SD) in patients with BC despite prior hormonal and chemotherapy. Expansion within subtypes and molecular predictors of response are being investigated. Clinical trial information: NCT01037790. Response Partial response (PR) SD > 6 months SD < 6 months PD Clinical benefit (PR ⴙ SD>6 months)

HRⴙ/Her2(nⴝ18)

HRⴙ/Her2ⴙ (nⴝ2)

HR-/Her2(nⴝ8)

Total (nⴝ28)

1 (6%) 3 (17%) 9 (50%) 5 (27%) 4 (23%)

1 (50%) 0 1 (50%) 0 1 (50%)

0 1 (13%) 0 7 (87%) 1 (13%)

2 (7%) 4 (14%) 10 (36%) 12 (43%) 6 (21%)


The relationship between quantitative HER2 gene expression by the 21-gene RT-PCR assay and adjuvant trastuzumab (H) benefit in NCCTG (Alliance) N9831. Presenting Author: Edith A. Perez, Mayo Clinic, Jacksonville, FL Background: There is considerable interest in developing HER2 testing criteria for adjuvant H. We used the 21-gene assay to examine the relationship of HER2 mRNA to benefit from H. Methods: N9831 compared adjuvant chemotherapy AC-T to concurrent chemotherapy-trastuzumab AC-TH in stage I-III HER2⫹ breast cancer. Recurrence Score (RS) and HER2 mRNA expression were determined by Oncotype DX (neg⬍10.7, equiv 10.7 to ⬍11.5, and pos ⱖ11.5 log2 expression units). Cox regression was used to assess the association of HER2 expression with H benefit for distant recurrence. Results: Median follow-up: 7.4 yrs. Of 1,940 total pts, 901 had consent and sufficient tissue. HER2 by RT-PCR was neg in 130 (14%), equiv in 85 (9%), and pos in 686 (76%) pts. Concordance between HER2 assessments was 95% for RT-PCR vs central IHC (⬎10% ⫹ cells ⫽ ⫹), 91% for RT-PCR vs central FISH (ⱖ2.0 ⫽ pos) and 94% for central IHC vs central FISH. In the primary analysis, the association of HER2 expression with H benefit was marginally non-significant (P⫽0.057). In hormone receptor pos pts (local IHC) the association was significant (P⫽0.002). The association was nonlinear with the greatest estimated benefit at lower and higher HER2 mRNA expression levels. The observed treatment benefit in low HER2 pts was not due to imbalance between arms in RS and individual gene expression values. Conclusions: Concordance among HER2 assessments by central IHC, FISH, and RT-PCR was high. Association of HER2 mRNA expression with H benefit was marginally non-significant. A consistent benefit of trastuzumab irrespective of mHER2 levels was observed in the pts with either IHC⫹ or FISH⫹ tumors. Benefit was observed in pts with high HER2 by RT-PCR but also observed for the small groups of pts with negative results by quantitative RT-PCR or FISH (Table). Plausible mechanisms for this observation will be discussed. H benefit Cox hazard ratios (95% CI) by central HER2 status (adjusted for nodes). IHC FISH RT-PCR

Neg

Equivocal

Pos

0.31 (0.05, 1.37) P⫽0.127 0.33 (0.09,0.93) P⫽0.034 0.31 (0.09,0.83) P⫽0.017

0.85 (0.27, 2.31) P⫽0.763

0.49 (0.33, 0.71) P⬍0.001 0.54 (0.37,0.78) P⬍0.001 0.55 (0.37,0.81) P⫽0.002

0.44 (0.09,1.59) P⫽0.217


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Combination trastuzumab and chemotherapy to induce immunity to multiple tumor antigens in patients with HER2-positive metastatic breast cancer: NCCTG (Alliance) studies N0337 and N98-32-52. Presenting Author: Raphael Clynes, Columbia University, New York, NY

Generation of adaptive HER2-specific immunity in HER2 breast cancer patients by addition of trastuzumab to chemotherapy in the adjuvant setting: NCCTG (Alliance) study N9831. Presenting Author: Keith L. Knutson, Mayo Clinic, Rochester, MN

Background: The addition of trastuzumab to chemotherapy improves responses to therapy and extends survival among patients with metastatic HER2 breast cancer. Several mechanisms have been proposed for the activity of this combination therapy. Trastuzumab, specifically, is thought to activate NK cells and blunt HER2 signaling. Prior work from us has shown that combination trastuzumab and chemotherapy induces HER2specific antibodies which correlate with response to therapy. Despite that, it remains unclear whether the immunity that was induced was due to complexing of non-tumor derived HER2 or antigen derived from the tumor site. In the present work, we addressed this question by assessing if combination therapy induced epitope spreading to tumor antigens other than HER2. Methods: Pre-and post-treatment sera were obtained from 56 women enrolled in 2 NCCTG clinical trials, N0337 and 98-32-52. IgG antibodies to HER2 intracellular domain (HER2), p53, IGFBP2, CEA and tetanus toxoid (TT) were examined using ELISAs. Sera from an agematched group (N⫽56) of controls and 12 patients treated in the adjuvant setting were also examined. Results: Prior to therapy, metastatic patients had higher IgG levels (ⱖ 2-fold) to p53 and HER2 but not CEA, IGFBP2 and TT, relative to the controls. Similarly, adjuvant patients had elevated IgGs to multiple tumor antigens prior to therapy, relative to controls. Following therapy, levels of IgG to IGFBP2, HER2, and p53 increased in 81% of metastatic patients, with mean increases of 3.2 (⫾0.6 sem), 6.2 (⫾2.7) and 2.7 (⫾0.7) fold, respectively (p⬍0.05). Levels of antibodies to TT and CEA were not elevated by treatment. In contrast, IgGs were not increased in adjuvant patients; consistent with the idea that immunity depends on the presence of threshold levels of antigens. Conclusions: These results show that combination treatment induces adaptive immunity to antigens released by tumor and that metastatic patients remain capable of responding immunologically to their cancer. Thus, in metastatic breast cancer patients, combination trastuzumab and chemotherapy may behave as a vaccine.

Background: In the adjuvant setting, patients with HER2 breast cancer treated with trastuzumab and chemotherapy have superior survival compared to patients treated with chemotherapy alone. We previously showed that trastuzumab and chemotherapy induces HER2-specific antibodies which correlate with response to therapy in patients with HER2⫹ metastatic breast cancer. It remained unclear from those studies, however, whether the HER2-specific immunity played a role and if antibody immunity was associated with improved disease free survival in the adjuvant setting. In the present study, we addressed these questions by analyzing sera samples from a subset of patients enrolled in the NCCTG adjuvant trial, N9831, which includes an arm (Arm A) in which trastuzumab was not used. Arms B and C received trastuzumab sequentially or concurrently to chemotherapy, respectively. Methods: Pre-and posttreatment initiation sera were obtained from 50 women enrolled in N9831 (22 Arm A; 14 Arm B, and 14 Arm C). Lambda IgG antibodies (to avoid detection of trastuzumab) to HER2 were measured and presented as an index (⬎0.2 was considered a positive response). Results: Prior to therapy, across all three arms, N9831 patients had similar mean HER2 IgG levels (0.19 units in Arm A, 0.14 in Arm B, and 0.23 in Arm C, P⫽0.85). Following treatment, the mean levels of antibodies increased in Arm B to 0.35 units and in Arm C to 0.56 units and were higher (p⬍0.001) than in Arm A where levels did not increase. The proportion of patients who demonstrated antibody immunity increased by 9% in Arm A, 50% in Arm B and 28% in Arm C (P⫽0.026). Although the event rate was low in this cohort, Cox modeling suggested that larger increases in antibodies were associated with improved disease free survival (HR⫽0.23; p⫽0.04). Conclusions: These results show that the increased antibody immunity observed in adjuvant patients treated with combination trastuzumab and chemotherapy is clinically significant and results from the inclusion of trastuzumab. The findings may have important implications for improving treatment outcomes in patients treated with trastuzumab.

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Treatment (tx) patterns and clinical outcomes for patients (pts) with de novo versus recurrent HER2ⴙ metastatic breast cancer (MBC). Presenting Author: Adam Brufsky, University of Pittsburgh Cancer Institute, Pittsburgh, PA Background: Use of adjuvant trastuzumab (T) in pts with HER2⫹ early breast cancer is associated with decreased recurrence. As fewer patients relapse, the proportion of pts with de novo metastatic disease in the first-line (1L) setting will increase, which could have implications for the design/interpretation of results from HER2⫹ MBC trials. To date, little data exist on potential differences in prognosis and outcomes between pts with recurrent vs de novo HER2⫹ MBC. Methods: registHER is an observational cohort of pts with HER2⫹ MBC diagnosed ⱕ6 mo from enrollment and followed until death, disenrollment, or June 2009 (median follow-up: 27 mo). Demographics and 1L tx patterns (using descriptive analyses), as well as clinical outcomes (median PFS and OS estimated by Kaplan-Meier method) were examined for pts with de novo vs recurrent HER2⫹ MBC. De novo was defined as disease-free interval (DFI) between initial and metastatic diagnosis ⱕ90 days; recurrent was defined as DFI ⬎90 days. Cox regression analyses were used to generate hazard ratios (HRs). Results: Pts with de novo HER2⫹ MBC (327 of 1001 enrolled) were more likely to be younger and non-white; have lymph, bone, and/or liver metastases and ⬎4 sites of metastatic disease; less likely to have lung or CNS metastases; and have received 1L regimens of TCH or AC more frequently vs pts with recurrent disease (who received T ⫹ vinorelbine more frequently). PFS and OS were longer in the de novo vs recurrent group (Table). Conclusions: Despite presenting with more advanced-stage disease accompanied by higher tumor burdens, pts with de novo HER2⫹ MBC had more favorable clinical outcomes vs those with recurrent disease. Differences in disease characteristics and tx patterns resulting in more refractory disease (including acquired resistance from adjuvant tx) may account for these observations. Clinical trial information: NCT00105456. Clinical outcomes. De novo (nⴝ327) a

Median PFS, mo (95% CI) Cox HR Unadjusted Adjusted Median OS, mo (95% CI) Cox HR Unadjusted Adjusted a

Recurrent (nⴝ674)

12.5 (11.6–13.8) 9.4 (8.2–10.2) 0.740 (0.640–0.855) 0.711 (0.613–0.824) 41.7 (36.1–47.2) 32.8 (29.3–36.7) 0.775 (0.643–0.935) 0.750 (0.619–0.908)

PFS as reported by physicians’ standard practice.


Is the proportion of patients with synchronous stage IV breast cancer surviving > 2 years increasing over time? Presenting Author: Shaheenah S. Dawood, Dubai Hospital, Dubai, United Arab Emirates Background: Studies have shown a moderate increase in survival over time among pts with stageIV breast cancer. Median survival is approximately 2 yrs. The aim of this study was to evaluate trends over time of pts with synchronous stage IV disease who survive ⬎2 yrs. Methods: Using the SEER registry we identified female pts with synchronous stage IV breast cancer diagnosed between 1990-2007. Pts were divided into 3 groups according to year of diagnosis(1990-1995, 1996-2000, 2001-2007). Probability of surviving more than ⬎2 yrs was computed within each group. A multivariable logistic regression model was then fitted to determine the association between year of diagnosis and the probability of surviving ⬎2 yrs after adjusting for other prognostic factors. Results: 22,492 pts were identified of whom 9,388 (41.7%) had a survival of ⬎2 yrs. The probability of surviving ⬎2 yrs was 36.2%, 40.1%, and 44.2% among pts diagnosed in periods 1990-1995, 1996-2000, and 2001-2007 respectively (p-value ⬍ 0.0001). The probability of surviving ⬎2 yrs was 55.3% and 29.3% among pts with ER⫹ and ER- disease respectively (p-value ⬍0.0001) and was 32.9% and 43.5% among pts of black and white race respectively (p-value ⬍0.0001). In the multivariable model the probability of surviving ⬎2 yrs increased with increasing year of diagnosis (OR 1.04, 95% CI 1.03-1.05, p ⬍0.0001). Other factors significantly associated with an increased probability of surviving ⬎2 yrs included radiation therapy, lower grade, younger age, hormone receptor (HR) positive disease and non-inflammatory disease. Interaction term between race and year of diagnosis was marginally significant, such that black pts had a more slowly increasing probability of surviving ⬎2 yrs compared to whites (OR 0.97, 95% CI 0.96-1.00, p ⫽ 0.037). Interaction term between HR status and year of diagnosis was not significant. Conclusions: Our results indicate that among pts with synchronous stage IV breast cancer the probability of surviving ⬎2 yrs has increased over time reflecting the introduction and FDA approval of multiple efficacious chemotherapeutic and endocrine therapeutic options. Of concern, the probability of surviving ⬎2 yrs has increased more slowly among pts of black race.




Long-term (8 years) assessment of trastuzumab-related cardiac events in the HERA trial. Presenting Author: Evandro De Azambuja, Institut Jules Bordet, Brussels, Université Libre de Bruxelles, Ixelles, Belgium, Brussels, Belgium Background: Trastuzumab-related cardiac dysfunction may occur in patients (pts) treated with adjuvant therapy and it is mostly reversible. We report the long-term outcome of pts with cardiac dysfunction treated with adjuvant trastuzumab (T) in the Herceptin Adjuvant (HERA) trial. Methods: HERA is a three-arm, randomized trial that compared 1 year or 2 years of T with observation (Obs) in women with HER2-positive early breast cancer (EBC). Eligible pts had a left ventricular ejection fraction (LVEF) ⱖ 55% at study entry (i.e. after completion of (neo)adjuvant chemotherapy with or without radiotherapy). Cardiac function was closely monitored throughout the trial. This analysis at 8-year median follow-up considers pts randomly assigned to 1 year or 2 years of T therapy or observation. Results: 5102 pts were randomized to HERA. The “as treated” safety population is considered: 2 years T (N⫽1,673), 1 year T (N⫽1,682) and Obs (N⫽1,744). Cardiac events leading to T discontinuation in the 1-year and 2-year arms were observed in 5.2% and 9.4% of pts, respectively. Cardiac death, severe congestive heart failure (CHF) and confirmed significant LVEF drop remained low in all three arms (Table). In the 1 year T arm, 71.4% of pts with severe CHF, and 81.2% of pts with confirmed LVEF drop recovered cardiac function (at least 2 sequential LVEF assessments ⬎ 50%). The median time to recovery was 9.7 months and 6.3 months, respectively. In the 2 years T arm, 87.5% of pts with confirmed LVEF drop recovered cardiac function and median time to recovery was 8.3 months. Conclusions: At 8-year median follow-up the incidence of cardiac events during adjuvant T remains low and these events are mostly reversible. These results confirm low cardiac events when T is given as part of the adjuvant therapy for pts with HER2-positive EBC. Clinical trial information: NCT00045032. Summary of cardiac events in HERA.

Cardiac death Severe CHF1 Confirmed significant LVEF drop2

Obs* (Nⴝ 1,744)

1 year T (Nⴝ 1,682)

2 years T (Nⴝ 1,673)

2 (0.1%) 0 (0%) 15 (0.9%)

0 (0%) 14 (0.8%) 69 (4.1%)

3 (0.2%) 13 (0.8%) 120 (7.2%)

NYHA class III or IV. LVEF ⬍ 50% and at least 10 EF points below baseline confirmed by repeat assessment. *Cardiac events in the Obs group are only those reported prior to start of any T as part of the selective crossover. 1

2

526


ACOSOG Z1041 (Alliance): Cardiac events (CE) among those receiving neoadjuvant anthracyclines (A) and taxanes with trastuzumab (T) for HER2ⴙ breast cancer. Presenting Author: Michael Ewer, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Z1041 randomized women with HER2⫹ operable breast cancer to: FEC ¡ P⫹T (Arm 1) or P⫹T ¡ FEC⫹T (Arm 2). Treatment administered as 5-FU 500 mg/m2, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 day 1 of a 21-day cycle x 4; paclitaxel 80 mg/m2weekly x 12 and T 4 mg/kg once then 2 mg/kg weekly x 11. T was to continue q3 weeks post-op for 40 weeks. A secondary aim was to examine the cardiotoxicity (CE). Methods: Ejection fraction (EF) was measured at baseline (BL), between regimens (wk 12), prior to surgery (wk 24) and PRN. Eligibility: BL EF ⱖ 55%. CEs included decline in EF of ⬎ 15%, or ⬎10% points to a value ⬍ LLN. Reversibility was adjudicated by blinded investigators as reversible (R: recovery of EF to ⱕ 5% below BL), partially reversible (PR: recovery of ⬎ 10% points from nadir, but ⱕ 5% points below BL), indeterminate (IN: no additional EF data), or irreversible (IRR: follow-up EF studies showed no improvement). Results: Of the 280 patients (Arm 1: 138) who began treatment, 15 pts (Arm 1: 10; Arm 2: 5) did not receive T. The number of weeks of T was 13 (range: 1-18) in Arm 1 and 24 (range: 1-31) in Arm 2. Changes in EF and severe treatment related cardiac toxicities prior to surgery (sx) are tabled below. There were 271 pts (Arm 1: 131) who had post-BL EFs. Prior to sx, there were 11 CE (8.3%) in Arm 1 and 13 CE (9.2%) in Arm 2. CEs were R in 12 pts (Arm 1: 5; Arm 2: 7); PR in 6 pts (Arm 1: 4; Arm 2: 2); IN in 4 pts (Arm 1: 2; Arm 2: 3) and IRR in 1 Arm 2 pt. Conclusions: The number of CE events in arms 1 and 2 showed no significant difference; greater scatter was observed in arm 2 patients. While concern for late cardiac events makes ongoing cardiac surveillance prudent due to A, concomitant use of A and T appear to not be associated with increased cardiac risk. Clinical trial information: NCT00513292. EF changes and percent of Pts with cardiac toxicity. Toxicities Arm 1 (nⴝ138) Grade Cardiac ischemia Hypertension Left ventricular systolic dysfunction Sinus tachycardia Atrial fibrillation Median (n; range) Baseline Change at 12 weeks Change at 24 weeks

527


TBCRC 002: A phase II, randomized, open label trial of preoperative letrozole versus letrozole (LET) in combination with bevacizumab (BEV) in post-menopausal women with newly diagnosed stage II/III breast cancer. Presenting Author: Andres Forero-Torres, University of Alabama at Birmingham, Birmingham, AL Background: A study from UAB Breast SPORE showed that expression of vascular endothelial growth factor (VEGF) in MCF7 breast tumor xenografts imparts tamoxifen resistance, increases tumor growth and metastatic potential. We postulated that anti-VEGF therapy would enhance antiestrogen therapy. Methods: Randomized 2:1 phase II selection trial of LET (2.5 mg/day) with/without BEV (anti-VEGF monoclonal antibody; 15 mg/kg q3 weeks) for 24 weeks prior to surgery in post-menopausal patients with stage II/III, ER⫹/HER2- breast cancer. Primary objective was pathologic complete remission (pCR). Secondary objectives included response rates, down-staging, and toxicity. The trial was not powered to compare arms, but sized to estimate pCR rates to a certain precision (SE⬍5% for combination, SE⬍2% for single agent). Biopsies of the tumor and circulating tumor cells were collected. Results: 75 patients were randomized; 50 in the combination and 25 in the LET alone arm; 45 and 24 patients underwent surgery, respectively. Median age was 61 and 65 years, respectively. 5 patients in the combination arm had a pCR (11%; CI 1.9-20.1%) (no evidence of invasive cancer) , and 3 a near pCR (7%; 0%-14.5%) (microscopic disease only); thus pCR/near pCR rate 18% (6.8-29.2%). No patient treated with LET alone achieved a pCR/near pCR. The objective response rate was 64.5% in the combination arm and 37.5% in the single agent arm. 45% of the patients in the combination arm attained stage 0/I; 25% in the letrozole alone arm attained stage I, none attained stage 0. Therapy was well tolerated in both arms with no grade 4/5 toxicity. The most common AEs in the letrozole arm were hot flashes, fatigue, arthralgias/stiffness, myalgias, nausea/vomiting, and night sweats; in the combination arm they were hypertension, arthralgias/stiffness, hot flashes, headache, fatigue, proteinuria, dyspnea, rash, and myalgias. Conclusions: Neoadjuvant therapy with LET and BEV was well-tolerated and resulted in increased objective responses and down-staging. “Next-Gen” genomic analysis of the biopsies will allow for a trial with a targeted patient enrolment. Clinical trial information: F061229006.

13s

528

Arm 2 (nⴝ142)

2 0 2.1 2.9

3 0 0.7 0

4 0 0 0

2 0 1.4 3.5

3 0 0.7 0.7

4 0.7 0 0

0.7 0

0 0

0 0

0.7 0

0 0.7

0 0

EF 65% (53 to 79%) -2% (130; 12 to -16%) -3% (128; 20 to -20%)

65% (53 to 83%) -3% (137; 14.0 to -25%) -5% (139; 17.0 to -22%)


The prognostic role of androgen receptor in early-stage breast cancer patients: A meta-analysis. Presenting Author: Ivana Bozovic-Spasojevic, Institut Jules Bordet, Brussels, Belgium Background: Androgen receptor (AR) expression has been observed in ~70% of breast cancer (BC) patients, but its prognostic role is not established yet. To assess this we performed a meta-analysis of studies that evaluated the impact of AR on disease free survival (DFS) and/or on overall survival (OS) in early stage BC. Methods: Published studies were identified by an electronic search on PubMed using the MeSH terms ⬙breast neoplasm⬙ and ⬙androgen receptor⬙ (up to June 2012). Identified studies were assessed against the following criteria for inclusion in the analysis: early stage BC and reported results of AR status in correlation with clinical outcome. We report combined HRs with 95% confidence intervals (CI) using AR negative patients as reference. Results: Twenty studies were eligible for the meta-analysis out of 493 initially identified and 12 among them, including 6,525 patients, were considered as evaluable (i.e., reporting enough information to allow aggregation of results). AR positivity was associated with lower risk of relapse in all breast cancer patients, and better overall survival in both univariate (U) and multivariate (M) analysis. AR prognostic impact in different subtypes was also assessed (see Table). Conclusions: Our analysis demonstrated that AR delivers prognostic information overall, serving as a positive prognostic factor in early stage BC. Further studies are needed to delineate its prognostic impact within the different subtypes of the disease. HR

95% CI

P

0.65

0.50-0.76

⬍0.001

0.37

0.29-0.47

Overall U DFS (12 studies, Nⴝ5,658) M DFS (5 studies, Nⴝ3,207) U OS (12 studies, Nⴝ6,525)

0.60

0.47-0.78

M OS (6 studies, Nⴝ4,671)

0.44

0.27-0.72

ERⴙ DFS (5 studies, Nⴝ2,048)

0.52

0.42-0.65

⬍0.001

ERⴙ OS (5 studies, Nⴝ3,047)

0.58

0.47-0.71

⬍0.001

ER- DFS (2 studies, Nⴝ316)

0.33

0.04-2.49

0.45

ER- OS (3 studies, Nⴝ620)

1.38

1.01-1.88

0.04

HER2ⴙ/ER- DFS (3 studies, Nⴝ358)

1.21

0.86-1.7

0.28

HER2ⴙ/ER- OS (3 studies, Nⴝ358)

1.50

1.01-2.22

0.04

TN DFS (5 studies, Nⴝ536)

0.52

0.34-0.79

0.002

TN OS (4 studies, Nⴝ495)

0.49

0.28-0.86

0.01

Subtypes (univariate analysis)

TN, triple-negative.


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Relative effectiveness of letrozole alone or in sequence with tamoxifen for patients diagnosed with invasive lobular carcinoma. Presenting Author: Otto Metzger Filho, Dana-Farber Cancer Institute, Boston, MA Background: BIG 1-98 is a randomized, phase III study that compares five years of tamoxifen (tam) or letrozole (let), (monotherapy arms), or their sequences (tam-let or let-tam) in post-menopausal women with ER⫹ early BC. In the monotherapy arms, the magnitude of benefit of adjuvant let compared with tam varies by histology (greater in invasive lobular carcinoma (ILC) than invasive ductal carcinoma (IDC)). In this analysis we investigate the magnitude of benefit of let compared to tam-let and let-tam according to histology (IDC and ILC) at 96 months of median follow-up. Methods: There were 4,634 patients enrolled in the let, tam-let and let-tam arms of BIG-98. This analysis includes patients with centrally-reviewed histological subtype (n⫽4,223); classified as classic ILC or IDC (n⫽3,790); and with centrally reviewed ER, PgR and Ki67 (n⫽3,212). Results: The 8-year DFS and OS univariate estimates (⫾SE) for IDC and ILC are presented in the Table. When correcting for classic clinicopathological variables, treatment assignment was not a significant predictor of DFS and OS. Conclusions: We observed a trend toward greater magnitude of benefit in favor of let monotherapy for ILC than IDC. In the ILC subset, improvements for both DFS and OS were seen for let when compared to tam-let or let-tam, though not statistically significant. This may be due to the reduced number of ILC patients across subgroups. The present analysis is consistent with previous data from the monotherapy arms where let was associated with better DFS and OS than tam for ILC, and suggests that let might be the preferred upfront regimen for patients diagnosed with ILC. Clinical trial information: NCT00004205. IDC (Nⴝ 2,849)

Number of patients 8-Year DFS No. of events Let vs tam-let HR(95%CI) Let vs let-tam HR(95%CI) 8-Year OS No. of events Let vs tam-let HR(95%CI) Let vs let-tam HR(95%CI)

531

ILC (Nⴝ363)

Let

Tam-Let

Let-Tam

Let

Tam-Let

Let-Tam

941 79 ⫾ 1.4 202

972 79 ⫾ 1.3 209 0.99 (0.82-1.20) 0.97 (0.80-1.18) 86 ⫾ 1.2 135 0.89 (0.70-1.14) 1.02 (0.79-1.32)

936 79 ⫾ 1.4 206

123 85 ⫾ 3.6 22

127 75 ⫾ 4.1 33

88 ⫾ 1.1 114

90 ⫾ 3.0 12

113 76 ⫾ 4.5 27 0.71 (0.41-1.25) 0.66 (0.38-1.13) 85 ⫾ 3.6 17 0.61 (0.29-1.28) 0.82 (0.39-1.76)

88 ⫾ 1.1 117

89 ⫾ 3.0 15


Phase II randomized study of the EGFR, HER2, HER3 signaling inhibitor AZD8931 in combination with anastrozole (A) in women with endocrine therapy (ET) naive advanced breast cancer (MINT). Presenting Author: Stephen R. D. Johnston, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom Background: Preclinical data suggest a key role for EGFR inhibition in delaying acquired resistance to ET in ER⫹ breast cancer (BC). Retrospective analyses of 2 Phase II studies suggested adding gefitinib to ET delayed PFS in ET naive (ETN) BC. This randomized, double-blind, placebocontrolled multi-center study (NCT01151215) was conducted to prospectively test the hypothesis that adding AZD8931, an inhibitor of EGFR, HER2 and HER3 signaling, to A would be beneficial in delaying endocrine resistance in an advanced ETN BC population. Methods: Post-menopausal women with ER⫹ and/or PR⫹, ETN, HER2-negative, advanced BC were randomized (1:1:1) to receive A (1 mg od) plus AZD8931 20 or 40 mg bd or placebo (P). The primary endpoint was PFS (ITT population). Data presented are from an interim analysis (data cutoff 31 Aug 2012; 39% pts had a progression event). Results: Between Jun 2010 and Jun 2012, 359 pts (median age 61 years) were randomized to A combined with AZD8931 20 mg (n⫽118), 40 mg (n⫽120) or P (n⫽121). At the interim analysis, median PFS in the AZD8931 20 mg, 40 mg and P arms was 10.9, 13.8 and 14.0 months, respectively; PFS HR (95% CI) for AZD8931 20 mg:P was 1.37 (0.91–2.06, P⫽0.135) and for AZD8931 40 mg:P was 1.16 (0.77–1.75, P⫽0.485). Deaths were reported for 20 (17%), 16 (13%) and 12 pts (10%) in the AZD8931 20 mg, 40 mg and P arms, respectively. Grade ⱖ3 AEs were reported for 22 (19%), 44 (37%) and 18 (15%) pts in the AZD8931 20 mg, 40 mg, and P arms, respectively, the most frequent being rash (0% vs 8% vs 2%), acneiform dermatitis (0% vs 7% vs 0%) and hypertension (3% vs 3% vs 2%). Serious AEs were reported for 12%, 14% and 9% pts in the AZD8931 20 mg, 40 mg and P arms, respectively, and discontinuation (of AZD8931 or P) due to an AE in 5%, 8% and 2% pts, respectively. Conclusions: Co-blockade of EGFR, HER2, HER3 in combination with aromatase inhibition does not appear to delay endocrine resistance to ETN BC. Based on the low probability of demonstrating superior efficacy with addition of AZD8931 to A and the overall risk/benefit, the study was closed at the recommendation of the IDMC and pts discontinued AZD8931. Clinical trial information: NCT01151215.

530


Preoperative letrozole plus lapatinib/placebo for HRⴙ/HER2 negative operable breast cancer: Biomarker analyses of the randomized phase II LET-LOB study. Presenting Author: Valentina Guarneri, Department of Oncology, Hematology, and Respiratory Diseases, Modena University Hospital, Modena, Italy Background: This is a randomized, double-blind, placebo controlled study aimed to evaluate the clinical and biological effects of letrozole ⫹ lapatinib or placebo as neoadjuvant therapy in previously untreated hormone receptor positive/HER2 negative operable breast cancer. Methods: 92 postmenopausal patients with stage II-IIIA breast cancer were randomly assigned to 6 months letrozole-lapatinib (Arm A, n⫽43) or letrozoleplacebo (Arm B, n⫽ 49). Clinical response was evaluated according to RECIST. The following biomarkers were centrally evaluated by IHC on diagnostic core biopsy and on surgical specimens: HER2, Ki-67, EGFR, pAKT, PTEN. PIK3CA mutations were evaluated by pyrosequencing. Results: 81 patients were evaluable by USG, 8 were assessed with mammography and/or palpation. Three patients who discontinued therapy and withdrew consent were counted as non-responders according to the ITT analysis. No differences in terms of objective response rate (partial⫹complete response) were observed between the two arms (70% vs 63%). The percentage of patients achieving disease progression, disease stabilization, partial response and complete response were 2%, 23%, 58%, 12% respectively in the letrozole-lapatinib arm, and 6%, 29%, 61%, 2% respectively in the letrozole-placebo arm. No patients achieved pCR. All the patients were centrally confirmed as having HER2 negative disease. A significant decrease in Ki67 and pAKT expression from baseline to surgery was observed in both arms. A trend for a greater Ki67 suppression was observed in responding patients (mean Ki67 suppression -8.8 in responders vs -3.6 in non responders, p⫽ 0.06). A mutation in PIK3CA exon 9 or 20 was observed in 37% of the patients. Overall, no differences in response were observed according to PIK3CA mutations, however, in the letrozole-lapatinib arm, the probability of achieving a clinical response was significantly higher in the PIK3CA mutation subgroup (ORR 93% vs 63% in PIK3CA WT, Pearson’s chi2 p⫽0.040). Conclusions: This is the first trial showing a significant correlation between PIK3CA mutation and response to letrozole-lapatinib in Hormone Receptor ⫹/HER2- disease. Clinical trial information: NCT00422903.

532


Breast cancer evaluation and targeted investigational therapy (BEAT-IT): A pilot prospective tissue testing to guide clinical trial selection. Presenting Author: Lajos Pusztai, Yale Cancer Center, New Haven, CT Background: An increasing number of molecularly targeted drugs are now available in Phase I and II clinical trials. Many of these drugs target specific molecular abnormalities such as mutated, amplified or rearranged genes. Our hypothesis is that cancers that carry a molecular abnormality that corresponds to the mechanism of action of a given investigational drug are more sensitive to that particular drug than other cancers. The objective of this study is to perform molecular analysis of metastatic breast cancer biopsies (bx) using methods already established within CLIA approved laboratories, and to use the results to triage pts to various therapeutic clinical trials or standard of care therapy. Methods: Four core needle biopsies (CNB) and 4 fine needle aspirations (FNA), or 8 FNA are obtained from the most safely accessible metastatic site in a single bx session. Pathological confirmation of successful aspiration is performed. Two core bx (or 4 FNA passes) are formaldehyde fixed and paraffin embedded for Immunohistochemistry (IHC), FISH and mutation analysis (CMS11 or CMS46) and 4 FNA are placed in RNA-later and snap-frozen for transcriptional profiles and storage. Samples are transferred to the Molecular Diagnostic, IHC, and Cytogenetics Laboratories. All reports are included in the electronic medical record. Results: FromFeb 2012 to Jan 2013, 142 pts referred, 128 pts registered, 101 bx completed and 78 (77%) bx with available results. Bx sites included: liver (37), lymph node (26), soft tissue (16), bone (13), lung (5), other (4). Successful results were obtained for IHC: PTEN (73%), AR (78%), MET (73%), FISH: EML4-ALK (78%) and MET (74%), and mutation analysis (76%). To date, there have been no reported hospitalizations, ER visits, bleeding, pain, infection or organ dysfunction at the bx sites. 16 pts have been treated on trials with investigational agents hypothesized to result in response based upon the molecular profile of the tumor. Conclusions: Prospective tissue collection to determine the molecular targets and to evaluate pts for clinical trial selection is feasible and safe.




Impact of routine tumor genotyping on enrollment in targeted therapy trials for metastatic breast cancer (MBC): 4-year review. Presenting Author: Aditya Bardia, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA Background: Major barriers to enrollment in therapeutic clinical trials (⬍5% in United States) include low response rate in phase 1/2 trials and low enthusiasm among oncologists. Stratified clinical trial enrollment based on molecular profiling of tumors represents a potential paradigm shift in drug development. Here we assess the clinical utility of tumor genotyping for identification of oncogenic driver mutations and enrollment in therapeutic clinical trials for patients with MBC. Methods: A robust, high-throughput tumor genotyping assay (Snapshot), was developed at our institution to assess for presence of potentially actionable oncogenic driver mutations (15 genes, 130 mutations) using DNA derived from formalin-fixed, paraffinembedded (FFPE) tissue. The tumor genotyping assay was ordered by oncologists in clinic for patients with MBC. Relevant clinical information was gathered from chart reviews. Descriptive statistics were used for analysis. Results: From 2009-2012, 347 breast tumors were prospectively genotyped in the study population (median age ⫽ 50, range 27-90). PIK3CA mutation (23.3%) was the most common mutation detected overall, albeit at varying frequency in tumor subtypes: HR⫹ (29.1%, N⫽ 210), HER-2⫹ (21.5%, N ⫽ 65), TN (8.3%, N ⫽ 72). Unanticipated mutations in KRAS, BRAF, IDH, and HER-2 were also discovered. Clinical genotyping helped identify breast origin for carcinomas of unknown primary and revealed changes in mutation profile in metastatic tumors from primary tumors. Enrollment in clinical trials for MBC almost quadrupled from 2005-2008 to 2009-2012, with 35.5% of patients undergoing tumor genotype testing enrolling in trials, particularly phase-1 genotype-directed targeted therapy, such as PI3K inhibitors, Akt inhibitors, and combined PI3K/MEK inhibitors. Conclusions: Routine tumor genotyping can be successfully incorporated into clinical practice to significantly enhance therapeutic clinical trial enrollment and potentially accelerate development of genotype-directed targeted therapies for MBC.

535


534

15s


Frequent LOH of CYP2D6 in ERⴙ breast cancer determined by nextgeneration sequencing (NGS). Presenting Author: Mark J. Ratain, The University of Chicago, Chicago, IL Background: The role of CYP2D6 genetic variation in predicting response to tamoxifen in ER⫹ breast cancer is a subject of ongoing debate. There has been great variability in approaches to both genotyping and phenotyping, and in particular many investigators have extracted DNA from breast cancer samples rather than peripheral blood. We hypothesized that CYP2D6 gene copy number alterations are common in ER⫹ breast cancer, affecting genotype results, and used NGS to characterize CYP2D6 in patients with ER⫹ disease. Methods: CYP2D6 sequencing was performed as part of a comprehensive NGS profile of cancer-related genes for 261 predominantly relapsed and metastatic ER⫹ breast cancer FFPE specimens. Sequence data were resolved into genotypes according to the * allele nomenclature. Tumor LOH was determined at CYP2D6, and its error impact on genotyping methods was estimated. To assess biological significance, the prevalence of CYP2D6 alleles and LOH in ER⫹ disease was compared against a control set of 99 ER- tumors. Results: CYP2D6 allele frequencies in our full cohort (ER⫹, 261; ER-, 99) were consistent with prior studies; 64.4%, 16.8%, 9.0% vs. 63.1%, 17.2%, 7.0% for *1/*2, *4, and *41 respectively, and 1%-2% for the rarer alleles *9, *10, and *5. The rate of CYP2D6 LOH was higher in ER⫹ disease (41% vs. 26%, p⬍0.01), with all excess arising from copy-loss (as opposed to copy-neutral) changes (22% vs. 7%, p⬍0.002). The estimated impact of LOH on germline genotype assessment from tumor was considerable; an assay sensitive at ⬎20% minor allele frequency (e.g., Sanger sequencing) can misclassify ⬎10% of heterozygotes, leading to significant Hardy-Weinberg disequilibrium (e.g., p⫽8.3x10-8 for *4). Interestingly, an enrichment of reduced or nonfunctional CYP2D6 alleles in ER⫹ samples was observed (61% vs. 47%, p⬍0.03). Conclusions: Our results demonstrate the distorting effect of extensive LOH on genotype assessment of CYP2D6 in breast cancer. Therefore, tumor DNA should not be routinely used for determination of germline 2D6 genotype, although it appears possible to use NGS. The apparent association between reduced function CYP2D6 alleles and ER⫹ breast cancer in our dataset requires further investigation.

536


Integration of Ki67 with residual cancer burden (RCB) compared to Ki67 or RCB alone to predict long-term term outcome following neoadjuvant chemotherapy. Presenting Author: Amna Sheri, The Royal Marsden NHS Foundation Trust, London, United Kingdom

Association of ERCC1 (rs11615) and DNASE2B (rs3738573) polymorphisms with pathologic complete response to neoadjuvant chemotherapy for HER2-overexpressing breast cancer. Presenting Author: Agnes Ducoulombier, Centre Oscar Lambret, Lille, France

Background: RCB and Ki67 after neoadjuvant chemotherapy have each been shown to predict long-term outcome. Their combined use might provide greater prognostic information. RCB requires collection of data beyond that in routine pathological work-up of residual disease, which may not be required when Ki67 is added. Aims: (i) To test the hypothesis that combining Ki67 and RCB as the residual proliferative cancer burden (R-P-CB) provides significantly more prognostic information than either alone. (ii) To determine if a simplified algorithm integrating Ki67 and standard characteristics of residual disease can provide as much information. Methods: Cases at the Royal Marsden Hospital between 2002-2010 were identified and residual disease assessed. The primary endpoint of the study was time to recurrence. The primary analysis compared the prognostic information from Ki67, RCB and R-P-CB. Analyses employed a Cox proportional hazards model. Prognostic indices (PIs) were also created adding Ki67, grade and ER to the RCB and AJCC staging. Leave-one-out cross validation was used to reduce bias. The overall change in chi-square (⌬X2) of the best model for each index was used to compare the prognostic ability of the different indices a ⌬X2 of more than 3.84 indicates statistical significance. Results: A total of 222 evaluable patients were included in the study, median age was 50 with a median follow up of 60 months. The addition of Ki67 improved the prognostic power of all indices. The R-P-CB (⌬X2⫽69.5) was significantly more prognostic than the RCB alone (⌬X2⫽35) and Ki67 alone (⌬X2⫽41.4). A novel proliferative residual cancer index (PRECI) using post-treatment values of T size, number of involved lymph nodes, grade, ER status (⫾) and Ki67 gave ⌬X2⫽81.1 and performed similarly to a model including the RCB, Ki67, ER and grade (⌬X2⫽80.2). Conclusions: Addition of Ki67 to RCB improved prediction of long-term outcome. In this study, a novel index the PRECI provided as much prognostic information as a more complex assessment involving RCB and warrants further investigation for estimating post-neoadjuvant risk of recurrence.

Background: Pathological complete response (pCR) is the main prognostic factor after preoperative chemotherapy. Predictive factors of pCR are mainly histological type, hormonal status, HER2 overexpression. Single nucleotide polymorphisms (SNP) in genes encoding drug transporters, drug metabolizing enzymes and target genes can affect drug efficacy and may explain therapeutic failures. The aim of the study was to identify SNPs associated with pCR in breast cancer (BC) patients (PTS) with HER-2 overexpression and treated with sequential neoadjuvant chemotherapy. Methods: Among PTS treated with NCT and included between 2007 and 2012, 46 PTS had HER-2 overexpressing BC, mostly ductal carcinoma (91.3%), greater than or equal to T2 (97.7%) and N1 (65.2%).91.3% of PTS received 3 FEC 100 - 3 Taxotere and 18 cycles of trastuzumab (3-18). Genotyping of 46 SNPs was performed on germline DNA using real time PCR. pCR was correlated with clinicopathologic features and genotypes using logistic regression. Results: pCR was evaluable for 45 PTS according to Sataloff criteria: pCR rate was 40% (95% CI 25.7-55.7%) and was significantly associated with hormonal status: 60.9% in negative hormone receptor tumors and 18.2% in positive hormone receptor tumors (p ⫽ 0.004). Four SNPs were significantly associated with pCR. All patients homozygotes CC for ERCC1-rs11615 respond to NCT (p⫽0.024). The response rate was higher for patients homozygotes TT for NQO2rs1143684 (59.1%; p⫽0.018), PTS carrying one or two C allele for DNASE2B-rs3738573 (50%; p⫽0.025) and PTS carrying one or two C allele for MDR1-rs1045642(51.5%; p⫽0.012). Conclusions: In this pilot study 4 SNPs were significantly associated with pCR and may be useful to predict response to NCT (Anthracyclines/Taxanes/Trastuzumab regimen) for HER-2 overexpressing breast tumors. Moreover, DNASE2B-rs3738573 and ERCC1-rs11615, two polymorphisms located in genes involved in DNA reparation, have never been described as predictive markers for BC neoadjuvant chemotherapy. (The first 3 authors contributed equally to this work.)


16s 537


Freedom from progression (FFP) by adding paclitaxel (T) to doxorubicin (A) followed by CMF as adjuvant or primary systemic therapy: 10-yr results of a randomized phase III European Cooperative Trial in Operable Breast Cancer (ECTO). Presenting Author: Milvia Zambetti, San Raffaele Hospital, Milan, Italy Background: At the time the ECTO was designed in 1996, taxanes were only indicated for patients with metastatic breast cancer. However, paclitaxel and docetaxel were still to be tested in the adjuvant setting. In addition there was relatively scarce information on the comparative efficacy of neoadjuvant and adjuvant regimens. The ECTO trial was designed to evaluate the addition of paclitaxel to an anthracycline-based adjuvant regimen and to compare this combination with the same regimen given as primary systemic (neoadjuvant) therapy. Methods: A total of 1,355 women with operable breast cancer were randomized to one of three treatments: 1) surgery followed by adjuvant single agent doxorubicin (A) followed by CMF (arm A); 2) surgery followed by adjuvant paclitaxel plus doxorubicin (AT) followed by CMF (arm B); 3) AT followed by CMF followed by surgery (arm C). The two co-primary objectives were to assess the effects on freedom from progression (FFP) of: 1) the addition of paclitaxel to post-operative chemotherapy (arm B versus arm A); and 2) primary versus adjuvant chemotherapy (arm B versus arm C). Results: At 10 years, in the adjuvant setting FFP remained statistically significant in favor of AT followed by CMF (arm B, HR 0.77, P⫽0.045). Distant FFP was similarly improved but overall survival was not (HR 0.82, P⫽0.24). There was no significant difference in FFP when chemotherapy was given after surgery compared with the same regimen given before surgery (arm B vs arm C, HR 0.79, P⫽0.07). In the primary chemotherapy arm, patients who achieved a pathological complete remission (pCR) had improved distant FFP (P ⬍ 0.001) compared to patients who did not achieve pCR. When given as primary systemic therapy, the paclitaxel-containing regimen allowed breastsparing surgery in a significant percentage of patients, which did not translate in an increased risk of ipsilateral breast recurrence compared to the risk observed in patients in the adjuvant arms. Conclusions: Incorporating paclitaxel into anthracycline-based adjuvant therapy resulted in a significantly improved FFP and DFFP.

539

General Poster Session (Board #1B), Sat, 1:15 PM-5:00 PM

538

General Poster Session (Board #1A), Sat, 1:15 PM-5:00 PM

Expression of enhancer of zeste homologue 2, correlated with HIF-1␣, to refine relapse risk and predict poor outcome for breast cancer. Presenting Author: Min Dong, Department of Medical Oncology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China Background: Overexpression of enhancer of zeste homologue 2 (EZH2), a key component of polycomb proteins, has been linked to aggressive tumor behavior for breast cancer. In vitro, hypoxia-inducible factor 1 alpha (HIF-1␣) transcriptionally activates EZH2 and promotes breast tumor initiating cells progression. Here, we characterized the clinicopathological effect of HIF-1␣ and EZH2 in breast cancer patients. Methods: Tumor specimens from 410 luminal subtype breast cancer patients were used to construct tissue microarray. EZH2 and HIF-1␣ level were examined by immunohistochemistry staining and Western blot analysis. With the 5-year follow up, the prognostic effect of EZH2 was subjected to multivariate analysis. Results: EZH2 and HIF-1␣ were highly expressed in 99 (24.1%) and 272 (70.6%) patients, respectively. EZH2 overexpression was associated with high histological grade (P⫽0.030), lymphatic invasion (P⫽0.025), HER2 overexpression (P⫽0.005) and hypoxic condition (P⬍0.001). Forced expression of EZH2 predicted a poor 5-year overall survival (OS, 74.8% vs. 93.4%, P⫽0.001), disease-free survival (DFS, 72.2% vs. 88.6%, P⫽0.031), local failure-free survival (LFFS, 95.7% vs. 97.9%, P⫽0.045) and distant metastasis-free survival (DMFS, 75.4% vs. 90.5%, P⫽0.039). However, the prognostic effect of HIF-1␣ was not detected for breast cancer. Cox multivariate analysis confirmed that EZH2 was an independent prognostic factor for OS, DFS and LFFS. Moreover, a positive correlation was detected between EZH2 and HIF-1␣ (r⫽0.299, P⬍0.001). Importantly, tumors with HIF-1␣ and EZH2 co-overexpression were correlated with a worsened OS (P⫽0.007). Conclusions: EZH2 was an independent negative prognostic biomarker for luminal subtype breast cancer. Targeting HIF-1␣ transcriptionally regulated EZH2 pathway might be of benefit in the treatment of luminal subtype of breast cancer.

540

General Poster Session (Board #1C), Sat, 1:15 PM-5:00 PM

Extended adjuvant tamoxifen for early breast cancer: A meta-analysis. Presenting Author: Eitan Amir, Division of Medical Oncology & Hematology, Princess Margaret Cancer Center, Toronto, ON, Canada

Pro-COL11A1: A biomarker to predict malignant relapse of breast intraductal papillomas. Presenting Author: Javier Freire, Hospital Universitario Marqués de Valdecilla-IFIMAV, Santander, Spain

Background: Hormone receptor positive breast cancer is characterized by the potential for disease recurrence many years after initial diagnosis. Endocrine therapy has been shown to reduce the risk of such recurrence, but the optimal duration of endocrine therapy remains unclear. Methods: We conducted a systematic review and meta-analysis to quantify the relative and absolute benefits and harms of extended adjuvant tamoxifen (⬎5 years of therapy) compared with adjuvant tamoxifen (ⱕ5 years of therapy). Odds ratios (ORs), 95% confidence intervals (CIs), absolute risks, and the number needed to treat (NNT) were computed for pre-specified events including disease recurrence, distant recurrence, all-cause death, endometrial carcinoma, cardiovascular death and treatment discontinuation. Subgroup analyses by timing of recurrence and baseline lymph node and menopause status were carried out. Results: Six trials comprising 25,326 patients were included. Extended adjuvant tamoxifen was associated with a non-significant reduction in the risk of recurrence (OR 0.89, 95% CI 0.77-1.04, p⫽0.14, NNT 74). Similar results were seen for distant recurrence (OR 0.88, 95% CI 0.75-1.04, p⫽0.14, NNT 70). There was no association between extended adjuvant tamoxifen and all-cause death (OR 1.06, 95% CI 0.86-1.31, p⫽0.58). There was no reduction in risk during extended adjuvant therapy (i.e. between years 5 and 9), but a potential reduction in the risk of recurrence after completion of extended adjuvant tamoxifen (i.e. beyond 10 years after diagnosis). Subgroup analysis suggested benefit in lymph node positive patients. Endometrial carcinoma was substantially more frequent with extended adjuvant tamoxifen (OR 1.81, 95% CI 1.45-2.25, p⬍0.001, NNT 102), but among those with endometrial carcinoma, the odds of death were lower among the extended tamoxifen group (OR 0.50, 95% CI 0.28-0.90, p⫽0.02). Conclusions: Extended adjuvant tamoxifen is not associated with a significant reduction in recurrence or death in unselected patients. Patients with lymph node positive breast cancer may derive more benefit. Reduction in the risk of recurrence only appears after completion of extended adjuvant therapy.

Background: Breast cancer is currently the most frequent tumor among women. Despite the huge progress achieved in its early diagnosis, there are still many unsolved clinical issues, being the diagnosis, prognosis and treatment of papillary diseases (and specifically intraductal papilloma), one of the highest challenges. Because of its unpredictable clinical behavior, treatment of intraductal papilloma has generated a great controversy. Even though considered as a benign lesion, it presents high rate of malignant recurrence. This is the reason why there are clinicians supporting a complete excision of the papillary lesion, while others support an only expectant follow up. Previous results of our group have suggested that pro-Collagen 11 alpha 1 (pro-COL11A1) expression in cancer associated fibroblasts (CAFs) correlates with an infiltrating phenotype in breast lesions. We have analyzed the correlation between the differential expression of pro-COL11A1 in intraductal papilloma and their risk of malignant recurrence. Methods: Immunohistochemistry of pro-COL11A1 (clone 1E8.33, ONCOMATRIX, Bilbao, SPAIN) was performed in formalin fixed, paraffin embedded Core Needle Biopsy samples of 51 patients with intraductal papilloma. All patients had a minimum follow-up of 5 years. Results: Twenty-three out of 51 cases showed positive staining for COL11A1. Nine patients out of the positive cases relapsed as infiltrating carcinoma, two as intraductal papilloma and the rest had not recurred after five years of follow up. Only one case out of the 28 negative cases relapsed as invasive carcinoma. There were significant differences (p⫽0.0013) when comparing staining of individuals with malignant recurrence versus non recurrence and benign relapse patients, with a sensitivity of 90% and specificity of 66%. Conclusions: These data suggest that COL11A1 expression in CAFs is a highly sensitive biomarker to predict malignant relapse of intraductal papilloma. The low specificity might be biased by the complete excision of this lesion as the routine treatment or by a short follow-up of the patients.



General Poster Session (Board #1D), Sat, 1:15 PM-5:00 PM

A phase II study of combined fulvestrant and everolimus in metastatic estrogen receptor (ER)ⴙ breast cancer after aromatase inhibitor (AI) failure. Presenting Author: Suleiman Alfred Massarweh, University of Kentucky and Markey Cancer Center, Lexington, KY Background: Fulvestrant, an ER downregulator, can be effective in metastatic ER⫹ breast cancer but resistance is a problem. Everolimus inhibits mTOR; a key pathway in endocrine resistance. We hypothesized that everolimus may delay resistance to fulvestrant and thus improve its efficacy. Methods: We enrolled postmenopausal women with ER⫹ breast cancer who experienced disease relapse or progression within 6 months of AI use and had measurable/evaluable disease. Fulvestrant was given at 500 mg IM on day1, 250 mg d14, d28, and monthly thereafter. Everolimus was given at 10 mg po daily. Primary endpoint was time to progression (TTP) and secondary endpoints included safety, response, and biomarker analysis. A sample size of 40 patients was calculated to meet a median TTP of 7 vs. 3.7 months for fulvestrant alone as reported in the EFECT trial. Tumor blocks were collected and biopsies done for accessible disease. Results: 33 patients were enrolled. 2 were ineligible and are excluded from analysis. Median age was 54 years (range 40-85). Most common disease sites were bone 84%, liver 62%, and lung 55%. 81% of patients received prior tamoxifen, 71% had prior chemotherapy and 23% had multiple AIs. Median TTP is currently 7.4 months with 4 patients remaining on therapy. Responses include complete response 3%, partial response 10%, and stable disease 42%. 32% of patients had primary refractory disease and 13% discontinued therapy before disease assessment. Most common adverse events were elevated AST 81% or ALT 68%, hyperglycemia 61%, anemia 61%, elevated cholesterol 60%, hypokalemia 52%, mucositis 48%, and weight loss 48%. The majority of adverse events were grade I/II. Fasting lipid profile data is summarized. Conclusions: These results suggest that adding everolimus to fulvestrant improves its efficacy in heavily pretreated ER⫹ metastatic breast cancer. Toxicity was manageable but needs close monitoring. Biomarker analysis is ongoing in order to identify patients not likely to benefit from this treatment strategy. Clinical trial information: NCT00570921.

Total cholesterol LDL HDL Triglycerides

543

Baseline median

2 months median

Wilcoxon signed rank test

178.5 112 39 127

241.5 149 43 226.5

P⬍0.0001 P⬍0.0001 P⫽ 0.007 P⫽ 0.0007

General Poster Session (Board #1F), Sat, 1:15 PM-5:00 PM

Factors predicting endoxifen levels in breast cancer patients taking standard-dose tamoxifen and following dose escalation. Presenting Author: Peter Fox, Westmead Hospital, Sydney, Australia Background: Tamoxifen (TAM) is transformed via CYP2D6 to its major active metabolite endoxifen (Endox). Recent data suggest that 15nM Endox may be a therapeutic threshold for breast cancer. This study identified predictors of achieving specified Endox target levels (15nM and 30nM) on standard dose TAM, and following dose escalation. Methods: Baseline Endox was measured in 122 breast cancer pts on TAM 20mg pd. Pts with baseline Endox ⬍30nM underwent incremental dose escalation to a maximum of 60mg pd until Endox reached 30nM or dose limiting toxicity. Clinical data were collected and CYP2D6 genotype was used to specify extensive, intermediate or poor metabolizer categories (EM, IM, PM). Multiple regression analyses examined associations between Endox and potential predictive factors. Results: Baseline Endox ranged from 3.172.2nM (mean 27.6nM). In 19% (n⫽23), baseline Endox was below 15nM and 62% (n⫽76) were below 30nM. Low baseline Endox was associated with CYP2D6 genotype (IM or PM, p⬍0.001) and younger age (p⫽0.02). Following dose escalation, 96% (n⫽117) attained an Endox level of 15nM and 76% (n⫽93) reached 30nM. Baseline Endox level was the only variable independently associated with achieving both targets (p⫽0.02, p⬍0.001 respectively). CYP2D6 genotype did not independently predict attainment of Endox targets following dose escalation (p⬎0.4). The ratio of Endox to its precursor N-desmethylTAM, an indicator of CYP2D6 activity, was stable with dose escalation, suggesting that CYP2D6 was not saturated. Conclusions: Although IM/PM predict for low Endox on 20mg TAM, only low baseline Endox predicted failure to achieve both 15nM and 30nM targets following dose escalation. These results suggest a role for Endox level monitoring to determine optimal TAM dose. Clinical trial information: NCT01075802. 15 or 30nM Endox targets according to baseline Endox and CYP2D6 phenotype. Dose escalation Baseline Endox (nM) All patients 0-10 10-15 15-20 20-30 >30 CYP2D6 PM IM EM

n

Mean baseline Endox (nM)

Mean maximum Endox (nM)

% reached 15nM target

% reached 30nM target

122 12 11 21 32 46

27.6 6.6 12.6 18.0 24.3 43.3

37.4 16.8 31.9 39.0 37.2 -

95.9 66.7 100 -

76.2 0 54.5 94 81.3 -

17 37 68

12.3 23.2 33.8

22.9 36.7 41.5

76.5 100 98.5

23.5 78.4 88.2

542

17s General Poster Session (Board #1E), Sat, 1:15 PM-5:00 PM

Predictors of patient-reported toxicities from endocrine therapy: Importance of illness perceptions, treatment beliefs, and fear of recurrence. Presenting Author: Xinni Song, The Ottawa Hospital Cancer Center, University of Ottawa, Ottawa, ON, Canada Background: Numerous studies have documented the toxicities of endocrine therapy (ET) for early breast cancer (EBC) and their deleterious impact on quality of life and adherence. However, little is known about the factors that underlie patient’s susceptibility to report toxicities. The identification of risk factors for toxicities from ET is important as it would allow early targeting of symptom management interventions for women more vulnerable to adverse effects of ET. This prospective study aims to examine the impact of pre-treatment perceptions of EBC, ET beliefs and fear of breast cancer (BC) recurrence (FBCR) on toxicities reported after 6 months of ET. Methods: Women diagnosed with EBC completed a survey prior to initiating endocrine therapy, then at 3, 6 and 12 months. Standardized self-report instruments were used to assess EBC perceptions, ET beliefs, FBCR and toxicities. Clinical and treatment variables were also evaluated. Univariate analyses and mulitivariate regression were conducted to identify factors associated (p⬍0.1) with side effects at 6 months. Results: Since 9/2010, 173 patients have consented and 84 (mean age ⫽ 60 y) have completed the questionnaires at baseline and after 6 months of ET. Controlling for age, none of the clinical or treatment variables (stage of disease, type of surgery, receipt of chemotherapy and radiation therapy) were significant univariate predictors of toxicities. In multiple regression, stronger perceptions that BC has serious consequences on their lives (␤⫽0.218, p⬍0.05), greater concerns about the adverse effects of ET (␤⫽0.215, p⬍0.05) and higher levels of FBCR (␤⫽0.316, p⬍0.01) at baseline were associated with higher levels of reported toxicities. Conclusions: Baseline psychological factors predicted level of patientreported toxicities to a larger extent than clinical/treatment factors. How patients perceived their illness, their beliefs about ET side effects and their fear of cancer recurrence are strongly associated with side effects experienced after 6 months of ET. These results could facilitate the identification of a subgroup of patients for early interventions to improve symptom management.

544

General Poster Session (Board #1G), Sat, 1:15 PM-5:00 PM

Single nucleotide polymorphisms to predict for neoadjuvant chemotherapy in breast cancer according to estrogen receptor (ER) status. Presenting Author: Diane Pannier, Centre Oscar Lambret, Lille, France Background: Neoadjuvant chemotherapy (NCT) using anthracyclines and taxanes is a standard treatment for locally advanced breast cancer and pathologic complete response (pCR) is a major prognostic factor for survival. Gene polymorphisms have been identified as modulators of chemotherapy response. Our study investigated constitutional variants of genes associated with a change in the response to neoadjuvant chemotherapy using taxanes and/or anthracyclines in patients with breast adenocarcinoma. Methods: From November 2007 to January 2012, 118 women with breast adenocarcinoma histologically proven, with no Her2 surexpression, receiving or having received a neoadjuvant chemotherapy with taxanes and/or anthracyclines were included in the study. NCT associated 3 FEC100 then 3 Docetaxel every 21 days. Genotyping of 46 SNPs was performed on germline DNA using real time PCR. pCR was correlated to clinical characteristics and genotypes using univariate logistic regression. Results: 21.2% had a pCR according to Sataloff classification. pCR is increased in SBRIII (p⫽0.009), estrogen receptor negative (p⫽0.005) and triple negative (p⫽0.006) tumors. 7 SNP are significantly associated with pCR in ER⫹ breast tumors (pCR⫽13.5%). Among these SNP, pCR is increased for patients carrying almost one G allele for SLCO1B3rs11045585 (pCR⫽28.6%; p⫽0.032), for homozygotes GG for SHTM1rs1979277 (pCR⫽24.3%, p⫽0.006) and for homozygotes CC for CYP1B1rs1056836 (pCR⫽25.7%; p⫽0.003). Moreover, 4 SNPs are significantly associated with pCR in ER- breast tumors: ERCC1-rs11615 (carriers of almost one C allele: pCR⫽50%; p⫽0.030), CD24-rs52812045 (Homozygotes CC pCR⫽56.3%, p⫽0.033), CYP2B6-rs2279343(carriers of one or two G allele: pCR⫽52.6%; p⫽0.046) and GSTP1-rs1695 (carriers of one or two G allele: pCR⫽48%; p⫽0.050). Conclusions: Besides ER status, polymorphisms could be useful markers to predict response to anthracyclines/taxanes NCT in breast cancer. Furthermore, this work is the first describing ERCC1-rs11615, SLCO1B3-rs11045585 and SHTM1rs1979277 as new potential genetic markers for NCT in breast cancer. (The first 3 authors contributed equally to this work.)


18s 545

Breast Cancer—HER2/ER General Poster Session (Board #1H), Sat, 1:15 PM-5:00 PM

546


Clinical significance of ER␤ mRNA expression in ER␣-negative and triple-negative breast cancers. Presenting Author: Young Choi Kim, Yale School of Medicine, Bridgeport, CT

A new 5-gene signature predictive of risk of relapse in early breast cancer. Presenting Author: Giorgio Mustacchi, Medical Oncology, University, Trieste, Italy

Background: Previously at the 2012 ASCO meeting, we reported significant ER␤ mRNA expression in ER␣-negative (ER␣-) and triple negative breast cancers (TNBC). In this study, we analyzed its clinical outcome and correlation with other clinical parameters. Methods: A total of 141 cases consisted of 69 ER␣- BC including 41 TNBC and 72 ER␣⫹ BC were obtained from patients aged 29 to 97 years old between 2003 and 2010. Treatments included surgery, hormone, chemo- or radiotherapy, or any combinations. The follow-up period ranged from 1 to 132 months. ER␤ mRNA was analyzed from formalin-fixed tumor tissues by RT-PCR. ER␣, PR, Her-2, Ki-67, AIB-1, NFk/p65, p-c-jun, Ki-67, TIF-2, SRC-1, CK5/6 and p53 were tested by immunohistochemistry. The correlation was deemed significant if p value less than 0.05 from Chi-square. Overall survival (SVR) was defined from the date of diagnosis to last follow-up or death attributed to BC and was analyzed by the Kaplan-Meier curves and Wilcoxon rank sum. Results: Single or combination of ER␤ isoform(s) was highly expressed in both ER␣- and TNBC and ER␤2 was the most frequent (48.8%) and ER␤5, the least (30.2%). In contrast, ER␤5 was the most frequent in ER␣⫹BC. Presence of all or any ER␤ isoform was associated with significantly higher SVR in all cases, and in TNBC (ER␤ total, Wilcoxon p ⫽ 0.0177, ER␤2, p⫽ 0.0329), and also with negative LN (p⬍ 0.0001). ER␤2 and ER␤5 were expressed in 63.2% and 30 %, respectively, in 20 patients died in 1 to 60 months. Over expression of AIB-1, NF-kB/p65 and TIF-2 was associated with ER␤1 and ER␤2 (p⬍0.05). Ki-67 ⫹ cells were mostly ER␤ ⫹ BC than ER␣⫹. ER␣ mRNA expression was up-regulated, and ER␤,downregulated, with the ER␣: ER␤⫹ ratio of 3-1000:1. There was no association between ER␤ expression and the stage, age, tumor size, and postmenopausal status. Conclusions: Specific ER␤ isoform appears to be a significant discriminating factor for SVR and negative node. ER␤2 is the predominant isoform in ER␣- but ER␤5 in ER␣⫹BC, suggesting a distinct role of ER␤ isoform in ER␣- and ER␣⫹BC. ER␤ isoform may be a selective therapeutic target in this cohort. ER␤⫹/ Ki-67⫹cells appear to be a sub-population of BC arising from basal-myoepithelial cells in this cohort.

Background: The aim of this study was look for the ⬙core-genes⬙ of published Signatures in order to find a simpler one Methods: To select candidate genes we used data of NCBI Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) including 408 breast cancer cases. Raw intensity data of Affymetrix HU133A and HU133B arrays of the two datasets (GSE1456 and GSE3494) were preprocessed using R/Bioconductor and the supercomputer Michelangelo (www.litbio.org). The candidate genes were selected from the “70-gene signature” (van ’t Veer, Nature 2002), the “21-gene recurrence score” (Paik, NEJM 2004), the “two-gene–ratio model” (Ma, Cancer Cell 2004) and the “15-gene Insuline Resistence” signature (Gennari , JCO, Vol 25, No 18S, 2007: 10597), for a total of 98 genes.The 20 mRNA more significantly related to DFS were evaluated by quantitative reverse transcriptase PCR on 261 consecutive breast cancer cases, from paraffin embedded sections, split into a training (n 137) and a validation set (n 124). Results: The signature was developed on the training set and a multivariate stepwise Cox analysis selected 5 genes independently associated with DFS: FGF18 (HR⫽1.13, p⫽0.05) , BCL2 (HR⫽0.57, p⫽0.001), PRC1 (HR⫽1.51, p⫽0.001), MMP9 (HR⫽1.11, p⫽0.08), SERF1a (HR⫽0.83, p⫽0.007). These 5 genes were combined into a linear score weighted according to the coefficients of the Cox model, (0.125 FGF18 0.560 BCL2 ⫹ 0.409 PRC1 ⫹ 0.104 MMP9 - 0.188 SERF1A). The linear score was highly associated with DFS (HR⫽2.7, 95%CI⫽1.9-4.0, p⬍0.001). The signature was then evaluated on the validation set assessing the discrimination ability by a Kaplan Meier analysis, using the same cut offs classifying patients at low, medium or high risk of relapse as defined on the training set. The score resulted highly associated with DFS also in the validation set (p⬍0.001). Conclusions: Overexpression of BCL2 and SERF1A are related to a higher probability of relapse; overexpression of FGF18, PRC1 and MMP9 to a higher probability of survival without recurrence. The signature has a good discriminating ability and a further clinical validation is planned.

547

548


Final results of a phase II trial of trabectedin (T) in patients with hormone receptor-positive, HER2-negative advanced breast cancer, according to xeroderma pigmentosum gene (XPG) expression. Presenting Author: Ahmad Awada, Medical Oncology Clinic, Jules Bordet Institute, Brussels, Belgium Background: Hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (BC) is currently associated with 3-4 years survival and, after ⱖ2 relapses, therapeutic approaches are reduced. XPG expression is frequently modified in BC. T forms cytotoxic complexes with XPG inducing apoptosis, thus, the inhibitory effects of T may depend on XPG presence. In fact, a better response to T in BC pts with XPG RNA overexpression has been observed. Methods: Pts withHR positive, HER2 negative advanced BC, pretreated with anthracyclines and/or taxanes, who had progressed after 2-5 chemotherapy lines, were stratified according to their XPG expression from paraffin embedded tumor samples, to stratum A (XPG high [⬎3]) or to stratum B (XPG low [ⱕ3]) (threshold was selected from median XPG expression values observed in a previous trial) and treated with T (1.3 mg/m2 in 3-hour iv infusion every 3 weeks). Primary endpoint: to evaluate the efficacy of T as progression free survival rate at 4 months (PFS4) according to XPG expression. Secondary endpoints: Comparison of PFS, overall response rate, duration of response, overall survival and safety in XPG high and XPG low pts. Statistical methods: A 2-stage design was chosen: at a 1st stage, 20 pts were enrolled in each stratum. A futility analysis (O’Brien Fleming boundary) based on the primary endpoint was done once 40 evaluable pts were recruited. If ⱖ 7 out of 20 pts achieved PFS4, recruitment would continue to a maximum of 50 pts per stratum. Results: 44 pts (21 XPG high and 23 XPG low) were enrolled from three countries and five centers. Efficacy is shown in the Table. Most frequent AEs were nausea (54%) and fatigue (70%). ALT increase G4 occurred in 7% of pts and neutropenia G4 in 28%. Conclusions: Trabectedin showed modest activity in advanced HR-positive, HER2-negative BC previously treated with anthracyclines and taxanes, with an acceptable safety profile. XPG does not seem to be a predictor of outcome to T treatment in this patient population. Clinical trial information: 2010-022968-13. XPG high Nⴝ21 N % PFS4 PR SD >3 mos. Median PFS/95% CI

4 1 7 1.9

19 5 33 (1.6-3.5)

XPG low Nⴝ23 N % 6 2 6 1.9

26 9 26 (1.7-3.8)

Total Nⴝ 44 N % 10 3 13 1.9


Phase II randomized, open-label study of YM155 (sepantronium bromide) plus docetaxel versus docetaxel alone as first-line treatment for HER2 negative metastatic breast cancer. Presenting Author: Michael R. Clemens, Klinikum Mutterhaus, Trier, Germany Background: YM155 (YM) is a small molecule survivin suppressant. In a phase I/II study of YM plus docetaxel (D) in solid tumors evidence of anti-tumor activity was observed in women with human epidermal growth factor 2 non-overexpressing (HER2 negative) metastatic breast cancer (mBC). Methods: This was a randomized study of YM plus D versus D as 1st line treatment in subjects with HER2 negative mBC. Eligibility criteria were: ECOG ⬍ 1, no prior chemotherapy for mBC, and at least one measurable lesion. Primary endpoint was progression free survival (PFS); secondary endpoints were: objective response rate (ORR), overall survival (OS), duration of response (DOR), clinical benefit rate (CBR), time to response (TTR) and safety. YM was administered at 5 mg/m2/day as a 168 hr continuous infusion followed by 14 Day (d) observation and D was administered at 75 mg/m2over 1 hr on d1 every 21d. In the control arm, D was dosed per investigator choice q 21d. Results: 101 subjects were randomized (50 YM ⫹ D; 51 D). Median (m) age 55 (range: 25 – 79), 25% had triple negative disease, ⬎ 60% had bone and lymph mets, 86% had prior therapy for BC. mPFS (days) was 251 (95%CI: 176 – 333) YM ⫹ D vs 252 (95%CI: 202-433) D (p⫽0.34). ORR, CBR and TTR (YM⫹D; D): 26% vs. 25.5%; 82% vs. 84.3% and 45 vs 59 d. OS data are immature but showed no difference (p⫽0.911). Adverse events [AEs (⬎ 25%)] [YM ⫹ D% vs D %]: neutropenia 83 vs 84, alopecia 62.5 vs 53, fatigue 50 vs 41.2, nausea 35.4 vs 41.2, leucopenia 27 vs 33 and dyspnoea 33 vs 14. Common (⬎10%) serious AEs [YM ⫹ D% vs D%]: febrile neutropenia 21 vs 8 and neutropenia 10 vs 8. Conclusions: Preclinical and clinical evidence suggested the combination of YM ⫹ D may offer additional benefit to D alone in subjects with mBC. This study showed no difference in efficacy, but the combination appeared to be well tolerated. Clinical trial information: NCT01038804.

23 7 30 (1.8-3.5)




550


Luminal A and Luminal B subtypes in patients with breast cancer 65 years of age and older. Presenting Author: Robert Konigsberg, ACR-ITR VIEnna & LBI-ACR VIEnna, Centre for Oncology and Haematology, Kaiser Franz Josef-Spital, Vienna, Austria

Post-surgical highly sensitive C-reactive protein (hsCRP) and prognosis in early stage in breast cancer (BC). Presenting Author: Ariadna Tibau Martorell, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada

Background: In 2011, the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer (bc) suggested the distinction between Luminal A and Luminal B subtypes. In Luminal A patients (pts) endocrine therapy seems to be sufficiently effective, whereas in Luminal B pts the additional application of chemotherapy should be considered. It is currently unknown, whether the risk stratification into Luminal A and B is comparably or more discriminatory than the established pathologic tumor size (pT) and lymph node (pN) status in pts ⱖ 65 years. This analysis evaluates the discriminatory capacity of the new distinction between Luminal A and B and the established prognostic factors in bc pts ⱖ 65 years treated with endocrine therapy only. Methods: Clinico-pathological data of 190 bc pts ⱖ 65 years diagnosed between 1998 and 2004 were retrospectively analyzed. Pts were classified as Luminal A [ER (⫹) and/ or PR (⫹) and Her/2neu (-) and Ki-67 ⬍ 14%] or Luminal B [ER (⫹) and/ or PR (⫹) and Her2 (-) and Ki-67 ⱖ 14%]. The Kaplan-Meier method was used to assess the progression-free survival (PFS) and overall survival (OS) estimates. Differences in survival between groups were tested for significance by the log-rank test. Results: Median age was 74 years (65–92 years) and median time of follow-up was 69 months (0 –134 months). 68.9% and 31.1% pts had Luminal A and B subtypes, respectively. 73.3% and 26.7% of pts had pT1 and pT2 tumors, respectively. 79.7% and 20.3% of pts had pN0 and pN1 status, respectively. Overall, median PFS was 33 months. No significant difference regarding PFS could be detected between Luminal A and B pts, between pT1 and pT2 tumors and between pN0 and pN1 status (p⫽0.458; 0.172; 0.156), respectively. Overall, median OS was not reached. No significant difference regarding OS could be detected between Luminal A and B pts, between pT1 and pT2 tumors and between pN0 and pN1 status (p⫽0.328; 0.951; 0.976), respectively. Conclusions: In bc pts ⱖ 65 years treated with endocrine therapy only, neither the recently consented dichotomization into Luminal A and B subtypes nor pathologic tumor size and lymph node status could be confirmed to be discriminative as propagated in the 2011 St. Gallen Consensus for the overall bc population.

Background: Obesity, commonly associated with inflammation, is associated with poor prognosis in BC. Previous research suggests CRP, an obesity-associated marker of systemic inflammation, may mediate the adverse prognostic effects of obesity and be associated with fatigue. We examined the association of hsCRP with obesity-related factors, fatigue and distant disease-free and overall survival (DDFS, OS) in an early BC cohort. Methods: 501 non-diabetic women with T1-3, N0-1, M0 BC diagnosed 1989-96 provided fasting blood (mean 7.7 ⫾ 4.3 weeks after surgery, prior to systemic therapy, stored at -80°C) which was analyzed for hsCRP (Roche Elecsys immunochemistry). 359 women also completed the EORTC QLQC30 (mean 8 ⫾ 3.9 weeks post-surgery). Women were followed prospectively to 2007. Data were analyzed using Spearman’s rank correlation coefficients (r) and Cox models. Results: Mean age was 50.5 ⫾ 9.7 years; 282/159/24/36 subjects had T1/T2/T3/TX cancers; 350 were N0; 306 had ER⫹ and 278 PgR⫹ cancers (HER2 was not performed); 76/208/142 cancers were grade 1/2/3; adjuvant treatment involved radiation (369 subjects), chemotherapy (196), tamoxifen (107). Median hsCRP was 0.9 mg/L (25th/75th percentiles: 0.4/2.4 mg/L). hsCRP was correlated (all p ⬍ 0.0001) with age (r ⫽ 0.25), Body Mass Index (BMI, r ⫽ 0.6), insulin (r ⫽ 0.44), Homeostasis Model Assessment (r ⫽ 0.45) and leptin (r ⫽ 0.54), but not with EORTC fatigue (r ⫽ 0.02), T or N stage, grade or ER/PgR status (any ⫹ vs. both -). Median follow-up was 12 years. hsCRP was not associated with DDFS or OS in univariate analyses (Q4 vs. Q1 HR 1.03, 95% CI 0.69-1.52, p ⫽ 0.9 and HR 1.27, 95% CI 0.86-1.86, p ⫽ 0.24 respectively) or multivariate analyses adjusting for age, T, N, grade, ER/PgR status, treatment (HR 1.02, 95% CI 0.66-1.59, p ⫽ 0.93 and HR 1.17, 95% CI 0.76-1.81, p ⫽ 0.48 respectively). Conclusions: hsCRP (measured post-op, prior to systemic therapy) was associated with age, BMI and obesity associated physiologic factors; it was not associated with fatigue, DDFS or OS. Funded by The Breast Cancer Research Foundation (New York), The Canadian Cancer Society Research Institute (formerly The Canadian Breast Cancer Research Initiative).

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Ki-67 level in hormone reptor positive breast cancer patients: A retrospective review of 9,061 Korean women. Presenting Author: Jisun Kim, Department of Surgery, Seoul National University Hospital, Seoul Korea, Seoul, South Korea Background: Although young age breast cancer represents poor prognosis, no definitive explanation could have been made for the phenomenon. A tumor proliferation marker Ki67 is known to be a marker for both prognosis and prediction for chemotherapy responsiveness, and its level varies widely depending on the breast cancer subtype. This study was aimed to analyze Ki67 in relationship with age in hormone receptor positive breast cancer patients. Methods: We retrospectively reviewed 9061 consecutive cases of hormone receptor positive invasive breast cancer from data base at Seoul National University Hospital (SNUH) (between 2000 and 2012), Samsung Medical Center (SMC) (between 2004 and 2010), and National Cancer Center (NCC) (between 2001 and 2010) in Korea. Patients with estrogen receptor (ER) or progesterone receptor (PR) positive tumors were included irrespective of HER2 amplification. A multicenter data of Ki67 level identified by immunohistochemistry (IHC) and age at diagnosis were analyzed. Patients who underwent neoadjuvant systemic therapy were excluded. Results: Total 6222 cases from SNUH, 976 from SMC and 1863 from NCC were included. The three datasets were analyzed separately due to variable IHC methods in each institute. Mean ages were 49.30 years (range 20-86), 47.75 years (range 22-81) and 45.31 years (range 25-59), and mean Ki67 levels were 4.66% (range 1-100), 22.98% (range 1-97) and 14.58% (range 1-90), at SNUH, SMC, NCC respectively. Ki67 level was inversely proportional with age at diagnosis in all three datasets, and the level was significantly higher for patients ⬍40 years compared to ⱖ40 years (mean Ki67: 5.97 vs 4.41, p⬍0.001; 28.60 vs 21.88, p⬍0.001; 17.01 vs 14.03, p⬍0.001, respectively). There was an inverse relation with age as well when Ki67 level was categorized into ‘⬍10% vs ⱖ10% (p⬍0.001)’, ‘⬍20% vs ⱖ20% (p⫽0.03)’ and ‘⬍14% vs ⱖ14% (p⬍0.001)’ respectively. Conclusions: Despite the variability of assessing Ki67 expression, Ki67 level was significantly higher in young age hormone receptor positive breast cancer from all three analyses. This could partly explain the poor prognosis and substantial responsiveness to chemotherapy in this age group of patients.


Impact of body mass index (BMI) on the prognosis of women with high-risk early breast cancer (BC) receiving adjuvant chemotherapy (CT). Presenting Author: Alessandra Gennari, E.O. Ospedali Galliera, Genoa, Italy Background: Obesity has been shown to impact the prognosis of early BC; this effect was not consistently observed across the different biological subtypes, and is less clear when aggressive tumor phenotypes are considered. The aim of this study was to evaluate the influence of BMI (kg/m2) on the prognosis of women with high risk early BC enrolled into a phase III clinical trial of adjuvant CT. Methods: The relationship between BMI and Disease Free (DFS) or Overall Survival (OS) was assessed in 1066 early BC patients with rapidly proliferating tumors (Thymidine Labeling Index ⬎ 3% or G3 or Ki67 ⬎ 20%), randomized to receive adjuvant CT with or without anthracyclines (Epirubicin ¡ CMF vs CMF ¡ Epirubicin vs CMF). BMI was defined as follows: normal ⬍ 25 kg/m2, overweight 25-30 kg/m2, obese ⬎30 kg/m2. DFS and OS were calculated by Kaplan-Meier estimation; multivariate Cox analysis was performed according to menopausal status, type of CT, hormonal, HER-2 and nodal status. Results: Information on BMI at baseline, was available on 959 women. Of these, 430/959 (44.8%) were normal, 331 (34.5%) were overweight and 198 (20.7%) were obese. Median age was 52 years (range 26 to 70); 48% was node positive, 62% was ER positive and 33% was HER-2 positive. At a median follow-up of 69 mos (range 1-119), 5-year DFS was 80% (95% CI 78-83) and 5-year OS was 94% (95% CI 90 –94). 5-year DFS was 81% (95% CI 77-85), 82% (95% CI 77-86) and 76% (95% CI 70-83), in normal, overweight and obese women, respectively (p 0.6). 5-year OS was 92% (95% CI 89-95), 94% (95% CI 91-96) and 89% (95% CI 84-93), respectively (p 0.4). By multivariate analysis only ER, HER-2 and nodal status were significantly associated with differences in DFS and/or OS. Conclusions: BMI at baseline was not associated with the prognosis of early BC patients with rapidly proliferating tumors, receiving adjuvant CT. These results confirm those achieved in triple negative BC and suggest that neither dietary restriction or medical interventions aimed at reducing BMI and/or underlying insulin resistance nor specific anticancer strategies seem to be appropriate in this subgroup.


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Patient-reported physical, emotional, and social functioning in advanced breast cancer: Insights from BOLERO-2. Presenting Author: Denise Aysel Yardley, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN Background: The phase 3 BOLERO-2 study at 18 months’ median follow-up showed that everolimus (EVE) ⫹ exemestane (EXE) significantly improved progression-free survival (PFS) vs EXE alone in 724 hormone-receptor– positive (HR⫹) advanced breast cancer (ABC) patients with recurrence/ progression during/after nonsteroidal aromatase inhibitor (NSAI) therapy. A higher rate of grade 3/4 adverse events was noted with EVE ⫹ EXE, but was not associated with deterioration in quality of life (QOL) based on the EORTC QLQ-C30 Global Health Status scale. Additional patient-reported post hoc analyses of QOL are reported herein. Methods: During BOLERO-2, QOL (EORTC QLQ-C30 and QLQ-BR23) was assessed at baseline and q 6 wk thereafter until progression or discontinuation. Physical, emotional, and social functioning subscales of QLQ-C30 were analyzed. Time to definitive deterioration (TTD) was defined based on either a 5% (protocol specified) or 10-point (more stringent) decrease from baseline for each subscale and analyzed by Kaplan-Meier methods. The difference between treatments was assessed by a log-rank test stratified by randomization factors. Results: QLQ-C30 compliance was ⬎ 80% at week 48. Among the 3 protocolspecified QLQ-C30 subscales, analyses based on a 5% decrease in QOL showed a longer TTD for both physical and emotional functioning in the EVE ⫹ EXE group vs EXE alone (log-rank P ⫽ .0120 and P ⫽ .0277, respectively). The TTD for social functioning was similar in both treatment arms (log-rank P ⫽ .3374). Analyses based on a 10-point decrease indicated a longer TTD for physical functioning in the EVE ⫹ EXE group (15.2 mo) vs EXE alone (9.7 mo; log-rank P ⫽ .0211). The TTDs for emotional and social functioning were similar between EVE ⫹ EXE and EXE alone: 13.9 vs 13.8, respectively (log-rank P ⫽ .4023), and 11.5 vs 9.5, respectively (log-rank P ⫽ .2507). Conclusions: The treatment goal for ABC is to maximize clinical benefit with minimal negative effects on QOL. These additional BOLERO-2 QOL analyses confirmed that the more than doubling of PFS with EVE ⫹ EXE was accompanied by maintained physical, emotional, and social functioning compared with EXE alone in patients with HR⫹ ABC progressing after NSAI. Clinical trial information: NCT00863655.

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A prognostic factor (PF) index for overall survival in a HER2-negative endocrine-resistant metastatic breast cancer (MBC) population: Analysis from the ATHENA trial. Presenting Author: Antonio Llombart-Cussac, MEDSIR ARO - Hospital Arnau de Vilanova de Valencia, Valencia, Spain Background: Chemotherapy is the standard of care for patients (pts) with HER2-negative endocrine-resistant MBC. The considerable variability in overall survival (OS) within this population relates essentially to prognostic factors (PF). Increasingly, large studies based on progression-free survival (PFS) as a primary endpoint are now being questioned. An accurate PF index may help in designing innovative trials with appropriate pts selection according to overall survival (OS) prognosis. Methods: The ATHENA trial assessed the safety of first-line bevacizumab combined with nonanthracycline-containing therapy in 2264 pts treated in 37 countries from 2006 to 2009. Pt characteristics, safety, and efficacy have been reported [Breast Cancer Res Treat 2011;130:133-43]. Sixty-one HER2-positive pts were excluded. A multivariate Cox regression model selected PF generating a simple PF index. Of note, skin, lymph node, ipsi-/contra- breast, or other soft tissue involvement was scored as a single organ. Results: After a median follow-up of 20.1 months and 1171 OS events (53% of pts), median OS for the entire sample and triple-negative (TNBC) and non-TNBC subgroups was 25.2 (95% CI 23.9 –26.3), 18.3 (16.3–19.7) and 27.3 (26.3–29.3) months, respectively. PF most closely associated with poorer OS were: liver mets or ⬎2 involved organs (HR 1.6; 95% CI 1.5–1.8); DFI ⱕ24 months (HR 1.7; 1.5–2.0); adjuvant anthracyline and/or taxane (HR 1.1; 1.2–1.4); and TNBC (HR 1.6; 1.4 –1.8). A predictive model was designed stratifying by number of PF present (0/1 vs 2 vs 3/4). The model was consistent in both TNBC and non-TNBC populations (Table). Conclusions: A PF index may estimate figures and balance arms in future trials considering OS as primary objective. A well-defined group of non-TNBC accounting for 37% of patients has an OS estimate similar to the most aggressive TNBC. PF

N (%)

Non-TNBC (Nⴝ1,618) 0/1 1016 (62.8) 2 480 (29.8) 3 122 (7.5) TNBC (Nⴝ585) 1 102 (17.4) 2 179 (30.6) 3/4 304 (52.0)

Deaths, % Median OS, mo

95% CI

42.9 60.4 68.0

32.8 22.3 15.9

29.9–35.2 20.5–24.8 13.5–19.0

37.3 51.4 76.3

34.1 24.8 13.7

21.1–39.2 19.6–30.0 11.7–15.8

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MDS/AML risk post-breast cancer and association with age: SEER data 2001-2009. Presenting Author: Henry G. Kaplan, Swedish Cancer Institute, Seattle, WA Background: Increased acute myeloid leukemia (AML) incidence has been identified post chemotherapy and radiation treatment for primary breast cancer (BC). Risk has not been evaluated in large populations or included myelodysplastic syndrome (MDS). Methods: We used 2001-2009 Surveillance, Epidemiology and End Results (SEER) database records to identify a cohort of first primary stage I-III BC patients. We identified subsequent MDS/AML diagnoses in the BC cohort, using SEER to query appropriate ICD-O-3 codes. We compared observed MDS/AML rates in the BC cohort to expected rates, estimated for first primary MDS/AML in the entire population, and calculated observed/expected rate ratios with 95% confidence intervals (CI) with age adjustment. Due to SEER data limitations, disease stage was used as a proxy for likelihood of radiation and chemotherapy treatment. Results: BC case distribution by stage was 51% stage I, 39% stage II and 11% stage III. Age distribution was 26% 20-49, 38% 50-64 and 36% 65⫹ years. Out of 306,691 BC cases, 470 had a subsequent diagnosis of MDS or AML (.15%) with 19% among women age 20-49 years, 36% women age 50-64 and 45% among women age 65⫹ years. Age adjusted number of expected myeloid leukemia cases is 171. Follow up time to myeloid leukemia diagnosis was on average 2.92 years post BC diagnosis (range .25-8.75 years). Myeloid leukemia cases were 56% AML and 44% MDS. We found an overall increased risk of MDS/AML among all age (20-65⫹)/all stage (I-III) breast cancer cases compared to the general population (RR⫽2.75, 95% CI 2.51, 3.00). Risk increased with increasing BC stage: stage I (RR⫽1.87, 95% CI 1.61, 2.16), stage II (RR⫽3.57, 95% CI 3.12, 4.06), and stage III (RR⫽5.66, 95% CI 4.45, 7.07) and decreased with increasing age with the highest risk among women age 20-49 (RR⫽10.60, 95% CI 8.57, 12.92) (age 50-64 (RR⫽5.60, 95% CI 4.79, 6.49), age 65⫹ (RR⫽1.81, 95% CI 1.57, 2.06)). Conclusions: Patients with stage I-III breast cancer have a significant high risk of MDS/AML post BC diagnosis increasing with higher stage cancer, most likely the result of radiation and/or chemotherapy treatment. Younger age women, 20-49 years, appear to be the most susceptible to this outcome.

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Prognostic impact of estrogen receptor (ER) level changes during progression for patients with both ER-positive (ERⴙ) primary breast cancer and paired recurrence. Presenting Author: Maria Vittoria Dieci, Department of Oncology, Hematology and Respiratory Diseases, Modena University Hospital, Modena, Italy Background: We have previously reported that ER⫹ breast cancer (BC) patients (pts) who become ER-negative at relapse have a poorer overall survival (OS) as compared to those still ER⫹ at relapse [Dieci et al., Ann Oncol 2013]. Our aim is to evaluate whether, among the group of patients with an ER⫹ status on both primary and recurrence, changes in the level of ER expression may be of prognostic value. Methods: A total of 81 pts with ER⫹ primary BC and ER⫹ paired recurrence who underwent relapse biopsy at Modena University Hospital were studied. ER status was assessed by IHC and the cutoff for ER-positivity was ⬎⫽10%. Samples were defined as ER-high (⬎50%) and ER-low (⬎⫽10% and ⬍⫽50%). HER2-status was defined according to IHC and/or FISH results. OS was calculated as the time interval between primary BC diagnosis and death or last follow up. Results: Biopsied recurrences were: distant (86%) and local relapses (14%). Fifteen percent of primary and 21% of recurrent tumors were HER2-positive. Sixty-two pts maintained the same ER level (i.e. high or low) on both primary and relapse (ER-level concordant), whereas 19 changed from ER-high to ER-low or viceversa (ER-level discordant). No difference in OS was observed between the ER-level concordant and the ER-level discordant groups (p⫽0.3). However, we identified those pts whose ER-high primary BC turned into ER-low as having a particularly poor outcome. Indeed, 10yrs-OS rates were 51% for the ER-level concordant group, 50% for pts changing from ER-low to ER-high and 14% for pts changing from ER-high to ER-low (p⫽0.0019). Finally, we focused on the subset of pts starting from an ER-high primary BC and showing an ER⫹/HER2-negative phenotype on both primary and relapse (n⫽51). The drop of ER-level expression below the 50% cut-off at relapse was confirmed as a poor prognostic factor, as compared to pts maintaining an ER-high level (10yrs-OS 53% vs 17%, p⫽0.0063). Conclusions: We demonstrated that, even in the case of maintenance of the same single-receptor status (ER⫹) and/or tumor phenotype (ER⫹/HER2-negative) between primary BC and recurrence, relapse biopsy may provide relevant prognostic information.




Characterization of patients who received prior chemotherapy for advanced breast cancer (ABC) in BOLERO-2. Presenting Author: Mario Campone, CLCC René Gauducheau, Centre de Recherche en Cancerologie, Nantes Saint Herblain, France Background: In patients with hormone-receptor–positive (HR⫹) breast cancer, endocrine therapy is the standard of care both in the adjuvant setting and as first-line treatment for ABC. For selected HR⫹ patients with ABC, chemotherapy (CT) may be utilized if disease burden is high and rapid symptom control is required (Barrios CH. GAMO.2010). In the phase 3 BOLERO-2 study (NCT00863655), 1 line of prior CT in the ABC setting was allowed. This subset analysis examined disease characteristics and the efficacy of everolimus (EVE) plus exemestane (EXE) in patients who received CT for ABC prior to BOLERO-2 study entry. Methods: In BOLERO-2, 724 patients with HR⫹, human epidermal growth factor receptor2–negative (HER2–) ABC whose disease recurred or progressed during/after a nonsteroidal aromatase inhibitor were randomized 2:1 to EVE (10 mg/d) ⫹ EXE (25 mg/d) or placebo (PBO) ⫹ EXE. The primary endpoint was progression-free survival (PFS) by local investigator review and confirmed by blinded independent central review. Results: A subset of 186 patients (26%) received prior CT for ABC: 125 in the EVE ⫹ EXE group and 61 in PBO ⫹ EXE. In this subset, 54% (67 of 186) of patients received prior CT only in the advanced setting and 46% (58 of 186) of patients received prior CT in both the neoadjuvant/adjuvant and advanced settings. Incidences of visceral metastases (67% vs 56%), multiple metastases (79% vs 66%), and ⱖ 4 metastatic sites (18.3% vs 15%) were higher in ABC patients with prior CT for ABC at study entry versus those with no prior CT for ABC. Disease recurrence ⬍ 6 months from initial diagnosis was recorded in 32.2% (n ⫽ 60) of prior CT patients versus 17.3% (n ⫽ 93) of patients with no prior CT. Median PFS (by local assessment) in patients who received prior CT for ABC was substantially longer with EVE ⫹ EXE versus PBO ⫹ EXE (6.1 vs 2.7 mo; HR ⫽ 0.38; 95% CI, 0.27-0.53). PFS by central review showed similar results (7.1 vs 2.8 mo, respectively; HR ⫽ 0.42; 95% CI, 0.27-0.65). Conclusions: These results demonstrate that patients with HR⫹, HER2– ABC who received previous CT in the advanced setting had a higher tumor burden and derived clinically significant benefit from combination treatment with EVE ⫹ EXE. Clinical trial information: NCT00863655.

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Tissue sampling frequency and breast pathology diagnoses following mammography: Time trends and age group analysis from the Breast Cancer Surveillance Consortium (BCSC). Presenting Author: Kimberly H. Allison, Stanford University, School of Medicine, Stanford, CA Background: Pathology diagnoses in a well-characterized population of women can be used to identify tissue sampling and diagnosis trends following mammography. Methods: Screening and diagnostic mammography, patient characteristics, and pathology reports from the BCSC performed from 1996-2008 were identified. Diagnosis was based on the most severe pathology interpretation in the same breast within 60 days of a post-mammogram tissue sample. Age, mammogram year and type, breast density, and family history of breast cancer were evaluated for associations with tissue sampling and most severe pathology diagnosis. Results: 4,022,506 mammograms (88.5% screening; 11.5% diagnostic) were performed in 1,288,886 women; 76,567 (1.9%) were followed by tissue sampling (1.2% screening; 7.1% diagnostic). Tissue sampling frequency following diagnostic mammography increased over time in women over 50 but remained stable following screening mammography. The frequency of invasive cancer increased with age and was more common following a diagnostic (29.3%) vs screening (19.8%) mammogram; the frequency of high risk lesions (ADH; lobular neoplasia) was highest in women aged 50-59. For tissue sampling following screening mammograms, the frequency of DCIS increased over time while benign diagnoses decreased. No significant time trends were noted for diagnoses associated with diagnostic mammograms. Women aged 40-59 with dense breasts and a tissue sampling following screening mammogram had a significantly higher frequency of DCIS (40-49: 4.8% vs 3.2%, P⬍ 0.001; 50-59: 7.0% vs 5.7%, P⫽0.007). Women aged 40-59 with ⬎ 1first degree relative with breast cancer vs none that had a tissue sampling following screening mammogram had a significantly higher frequency of invasive cancer (40-49: 11.4% vs 9.4%, p⫽0.008; 50-59: 19.8% vs 18.2%, p ⫽0.086) and DCIS (40-49: 6.2% vs 4.0%, p⬍ 0.001; 50-59: 8.2% vs 6.2%, p⬍ 0.001). Conclusions: There was an increase in DCIS and a decrease in benign diagnoses in tissues samples after screening mammography over time. No trends were seen following diagnostic mammography. DCIS was also more frequent in women with dense breasts.

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Clinical management and resolution of stomatitis in BOLERO-2. Presenting Author: Alejandra T. Perez, Memorial Cancer Institute, Hollywood, FL Background: In BOLERO-2, adding everolimus (EVE) to exemestane (EXE) more than doubled progression-free survival without affecting quality of life vs EXE alone in postmenopausal women with hormone-receptor–positive advanced breast cancer who had recurrence or progression on/after nonsteroidal aromatase inhibitor therapy. Although mTOR inhibitors are generally well tolerated, stomatitis is one of their most clinically relevant and potentially dose-limiting toxicities (Sonis Cancer2010). The incidence, grade, and clinical course of stomatitis among patients (pts) participating in the BOLERO-2 study are described. Methods: Pts were randomized 2:1 to receive EVE⫹EXE or placebo (PBO)⫹EXE. Stomatitis incidence, severity, consequent dose interruptions/adjustments, study drug discontinuations, and time to resolution were recorded. Results: The median duration of EVE⫹EXE treatment exposure was 30 wk (range, 1-123 wk). Stomatitis (any grade) occurred more frequently with EVE⫹EXE than with PBO⫹EXE (59% vs 12%, respectively). Grade 3 stomatitis occurred in 8% vs 1% of pts receiving EVE⫹EXE vs PBO⫹EXE, respectively; no grade 4 was reported. Onset of grade ⱖ2 stomatitis after treatment initiation was earlier in the EVE⫹EXE arm vs the PBO⫹EXE arm: median time was 15d vs 24d, respectively. In the EVE⫹EXE arm, 97% of pts with grade 3 stomatitis (n⫽38) improved to ⱕ1 after a median of 13 d. Complete resolution was observed in 82% of these pts after a median of 38 d. In the PBO⫹EXE arm, all pts with grade 3 stomatitis (n⫽2) improved to ⱕ1 after a median of 18 d. Complete resolution was observed after a median of 29 d. Overall, 24% of pts in the EVE⫹EXE arm required dose interruptions/adjustments vs 1% of pts in the PBO⫹EXE arm, and 3% of pts (n⫽13) discontinued EVE⫹EXE vs ⬍1% of pts (n⫽1) discontinuing PBO⫹EXE, all related to stomatitis. Conclusions: The BOLERO-2 data foster a new era of combining targeted and endocrine therapies. In the study, treatment-emergent stomatitis was of mild to moderate intensity, occurred shortly after treatment initiation, and was generally reversible. Most incidents were successfully managed with palliative interventions and temporary dose modifications. Oral hygiene and other preventive measures are recommended. Clinical trial information: NCT00863655.

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Ethnic differences in tumor proliferation in women with early-stage breast cancer. Presenting Author: Kevin Kalinsky, Columbia University Medical Center, New York, NY Background: Hispanic women have a higher mortality rate and lower incidence of breast cancer (BC) compared to Caucasian women. Studies report higher tumor proliferation in African American (AA) women compared to Caucasian women. The 21-gene assay (OncotypeDX) Recurrence Score (Score) is based on the expression of 16 cancer related genes, including 5 proliferation genes that are grouped to provide the proliferation axis score (PAS). We evaluated the differences in the Score and PAS between Hispanic and Caucasian women with early-stage BC in a matched cohort analysis. Methods: Women with early-stage BC who had a Score obtained from 2005- 2011 were identified. Hispanic women were matched to Caucasians in a 1:2 ratio, based on age (⫹/- 10 years), stage, and nodal status. Lymphovascular invasion (LVI) and grade were collected. The Score result, 10-year distant recurrence, ER/PR/HER2 expression, and PAS were obtained from the OncotypeDX assay. Assuming equal variances, we expected ⬎ 90% power to detect a difference in the mean PAS between Hispanic and Caucasian women Results: We identified 219 women who had OncotypeDX testing (74 Hispanic: 145 Caucasian). Of the 74 Hispanic women, 84% were from the Dominican Republic or Puerto Rico. Mean age was similar between groups (56.3 and 56.8). All but 8 patients were node(-). Mean PAS was higher in Hispanic (5.53, range: 3.9-7.8) vs Caucasian women (5.26, 3.7-7.3) (p⫽0.03, 95% CI: 0.03-0.51). The mean Score was 18.3 (0-54) and 16.3 (1-50) for Hispanic vs Caucasian women. There was no statistical difference in Score (p⫽ 0.17) or 10-year distant recurrence (p⫽0.13) between groups. No differences were observed in median ER (9.8% vs 9.9%: Hispanic vs Caucasian), PR (7.3% vs 7.6%), or HER2 (9.1% vs 9.0%) by RT-PCR. Rates of LVI and grade 3 tumors were also not statistically different. Conclusions: Similar to higher PAS in AA women, Hispanic women with ER/PR(⫹), HER2(-) early-stage BC have higher tumor proliferation markers, measured by RT-PCR in the Oncotype DX assay, than Caucasian women. This may contribute to ethnic differences in BC mortality. We plan to evaluate ethnic differences in the 5 single PAS genes (CCNB1, MKI17, MYBL2, BIRC5, AURKA) to determine which are driving proliferation differences.


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Incidence, management, and resolution of noninfectious pneumonitis in BOLERO-2. Presenting Author: Yoshinori Ito, Cancer Institute Hospital, Japanese Foundation for Cancer Research Breast Medical Oncology, Breast Oncology Center, Tokyo, Japan

Phase II trial evaluating the use of 21-gene recurrence score (RS) to select preoperative therapy in hormone receptor (HR)-positive breast cancer. Presenting Author: Amelia Bruce Zelnak, The Winship Cancer Institute of Emory University, Atlanta, GA

Background: The BOLERO-2 trial showed that adding everolimus (EVE) to exemestane (EXE) more than doubled progression-free survival (PFS) without reducing quality of life versus placebo (PBO) ⫹ EXE alone in postmenopausal women with hormone-receptor–positive (HR⫹), HER2negative (HER2–) advanced breast cancer (ABC) progressing on/after nonsteroidal aromatase inhibitor (NSAI) therapy. Although generally well tolerated, mTOR inhibitors such as EVE have been associated with noninfectious pneumonitis (NIP). Methods: Patients (pts) were randomized 2:1 to receive EVE⫹EXE or PBO⫹EXE. Incidence and severity of NIP, consequent dose interruptions/adjustments, study drug discontinuations, and time to resolution were recorded. Results: Median duration of exposure to EVE was 24 weeks with median dose intensity of 8.6 mg/d. Pulmonary adverse events (AEs) of any grade (NIP, interstitial lung disease, lung infiltration, pneumonia, or pulmonary fibrosis) were recorded in 97 of 482 pts (20%) in the EVE⫹EXE arm versus 1 of 238 pts (⬍1%) in the PBO⫹EXE arm. Of these, 16% of pts (77 of 482) in the EVE⫹EXE arm versus 0 in the PBO⫹EXE arm had a diagnosis consistent with NIP. In the EVE⫹EXE arm, grade 1 (no symptoms), grade 2 and 3 NIP occurred in 7%, 6% and 3% of pts, respectively, and no grade 4 events were reported. Complete resolution of NIP to grade ⱕ1 was recorded for all but 4 pts for whom NIP was still observed at last follow-up before study discontinuation. Overall, in the EVE⫹EXE arm, NIP was recorded as the reason for dose interruption and treatment discontinuation in 7.5% and 5.6% of pts, respectively. Conclusions: Data from BOLERO-2 support the combination of EVE and EXE to significantly prolong PFS in postmenopausal women with HR⫹, HER2– ABC progressing on/after NSAI. The incidence of NIP in this study was generally consistent with reports from other oncology settings, was of mild to moderate severity, and was generally reversible with appropriate interventions and temporary dose modifications. Patient and healthcare provider education for early diagnosis and management of NIP are highly recommended. Clinical trial information: NCT00863655.

Background: Hormone receptor (HR)- positive breast cancer patients (pts) typically have lower pathological responses to pre-operative chemotherapy than HR-negative breast cancers. Objective: We evaluated the pathologic and radiologic response rates to pre-operative endocrine therapy or chemotherapy, as directed by RS, in pts with HR-positive resectable breast cancers. Methods: Pts with HR-positive breast cancers had RS performed on the initial diagnostic biopsy. Pts were treated pre-operatively as follows based on RS: ⱕ10, exemestane ⫹/- goserelin for 6 to 12 months (ET); 11 to 25 randomized to ET or docetaxel-cyclophosphamide (TC) for 6 cycles (CT); ⱖ 26, CT. Results: From 4/2009 to 12/2012, 66 pts signed consent for RS testing and 46 are evaluable for efficacy analysis. Median age is 57 (40 to 78); one-third of pts are African-American; 41% have clinically node positive disease. RS ranged from 2 to 57. 28 pts received CT: Pathologic complete response (PCR) rate was 10% and 60% of cancers were down-staged based on initial T-stage. Radiologic response is available for 20 pts: complete radiologic response (CRR) 15%, partial RR (PRR) 40%, progressive disease (PD) 5%. In 11 pts with RS 11 to 25: PCR 0%, down-staged 45%, up-staged 18%, radiologic responses: CRR 17%, PRR 50%, PD 17%. In 17 pts with RS ⱖ 26: PCR 18%, down-staged 71%, up-staged 0%, radiologic responses: CRR 14%, PRR 36%, PD 0%. 18 pts received ET for between 6 to 22 months, 5 remain on study and have not had surgery: PCR 0%; down-staged 38%; up-staged 15%; radiologic responses: CRR 13%, PRR 40%, PD 0%. There was no correlation between RS and efficacy of ET. To date, 3 pts have relapsed, all of whom received CT. Conclusions: This is the first prospective use of the 21-gene RS to select pre-operative therapy for pts with HR-positive breast cancer. Pre-operative CT results in tumor down-staging in the majority of cancers with RS ⱖ 11, though it appears to be more effective with RS ⱖ 26. ET was moderately effective in down-staging cancers with RS ⱕ 25. Updated results will be presented. Clinical trial information: NCT00941330, NCT00832338.

563

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Eribulin mesylate (Erib) plus capecitabine (X) for adjuvant treatment in post-menopausal estrogen receptor–positive (ERⴙ) early-stage breast cancer: Phase II, multicenter, single-arm study. Presenting Author: John W. Smith, US Oncology Research, Compass Oncology, Portland, OR Background: Erib and X have both shown single agent activity in MBC; and X also has activity in ER⫹ adjuvant tx. This study was designed to evaluate the feasibility of the combination in the adjuvant setting. Methods: Female pts stage I-II, HER2 negative, ER⫹ BC received Erib at 1.4 mg/m2 iv D1 and D8 and X at 900 mg/m2 po bid on days 1-14 of 21 day cycle, for 4 cycles. The study was considered feasible if 80% of pts are able to achieve the target relative dose intensity (RDI) of at least 85% of the regimen and lower 95% confidence boundary (LCI) is above 70%. Results: Final results of 67pts enrolled are reported here. 88% pts completed 4 cycles of tx. Pt characteristics: Median age 62 yrs (range 28-80), ECOG 0(90%), stage 2(52%). 64/67 pts were evaluable for feasibility. The study met its primary endpoint demonstrating feasibility rate of 81%(95% LCI:71%) with average RDI of 91%. Results were mainly affected by X dose adjustments (Erib RDI-93%, X RDI-88%). X related dose reductions(24, (36%)), missed doses (57,(85%)) and discontinuations due to AE (11(16%)) were higher compared to that with Erib(14(21%), 5(8%) and 7(10%)), respectively. Most common AEs with dose reductions were gr 3/4 hand foot syndrome (HFS) (12%), neutropenia(8%), neuropathy(8%), and GI disorders(6%); and drug discontinuation were HFS(8%), neutropenia(3%), neuropathy(2%), and GI disorders(3%). Tx related AEs and SAE are reported in the Table. 14(21%) pts had an SAE with 12(18%) requiring hospitalization. Conclusions: Adjuvant tx with the Erib-X combination can be given safely with the majority of the patients able to achieve full dosing regimen. We plan to explore an alternative schedule of X(7wk on/off) with this regimen to see if it will further improve tolerability and the RDI. Clinical trial information: NCT01439282. Tx-related AEs (>30%)

Most common SAEs (>2%)

Alopecia 78%; 46% gr1 Fatigue 57% Nausea 51% HFS 40% Diarrhea 37% Neutropenia 36% Constipation 30% Neuropathy 33%; 8% gr3/4 Pulmonary embolism 5% Diarrhea 3% Febrile/neutropenia 3%


Competing risks of death in NCIC CTG MA.27 adjuvant exemestane versus anastrozole. Presenting Author: Judy-Anne W. Chapman, NCIC Clinical Trials Group, Queen’s University, Kingston, ON, Canada Background: Our group previously examined if baseline patient/tumor characteristics, or prior treatment affected cause of death in MA.17, a placebo controlled extended adjuvant trial of the aromatase inhibitor (AI) letrozole. We now examine factor effects on all cause mortality in MA.27. Methods: MA.27 was an adjuvant phase III superiority trial of 5 yrs of exemestane vs anastrozole, in ER⫹ postmenopausal breast cancer accrued between 2003 and 2008; event free survival was similar. We examined by intention-to-treat, the multivariate time-to-breast cancer-specific (BrCa), cardiovascular (Cardio), and other causes (OT) of death with log-normal survival analysis adjusted by treatment and stratification factors (lymph node status, adjuvant chemotherapy, celecoxib, aspirin, and trastuzumab). We tested whether factors were associated with 1) all cause mortality, and if so, 2) cause-specific mortality. We also fit step-wise forward causespecific adjusted models. Results: 7,576 women (median age 64.1 years; 5417 (71.5%) ⬍70 yrs and 2159 (28.5%) ⬎70 yrs) were enrolled and followed for a median of 4.1 yrs. The 432 deaths comprised: 187 (43.3%) BrCa, 66 (15.3%) Cardiovascular, and 179 (41.4%) OT MA.27 therapy was not associated with mortality (p⫽0.84). Five baseline factors were differentially associated with cause of death. Older age was associated with greater BrCa (p⫽0.03), Cardio (p⬍0.001), and OT (p⬍0.001) mortality. Pre-existing cardiovascular history led to worse Cardio mortality (p⬍0.001). Worse ECOG performance status led to worse OT death (p⬍0.001). T1 tumors were associated with less BrCa mortality (p⬍0.001). PgR⫹ tumors were also associated with less BrCa mortality (p⬍0.001). There were fewer BrCa deaths with Node –ve disease (p⬍0.001), ER⫹ tumors (p⫽0.001) and without adjuvant chemotherapy (p⫽0.005); there was worse Cardio mortality (p⫽0.01) with receipt of trastuzumab; worse OT (p⫽0.03) for non-whites, and without adjuvant radiotherapy (p⫽0.003). Conclusions: 56.7% of deaths in MA.27 patients were non-breast cancer related. We showed baseline patient and tumor characteristics, and prior treatment differentially affected cause of death. Clinical trial information: NCT00066573.




Initial results from the 21-gene breast cancer assay registry: A prospective observational study in patients (pts) with ERⴙ, early-stage invasive breast cancer (EBC). Presenting Author: Jeffrey L. Vacirca, North Shore Hematology Oncology Associates, PC, East Setauket, NY Background: Genomic assays such as the 21-gene breast cancer assay (Oncotype DX), have improved the ability to individualize pt treatment based on their individual tumor’s biology. Since 2004, when the 21-gene assay became commercially available, more than 300K assays have been ordered. While several studies have been conducted assessing the impact of having the Recurrence Score (Score) result on treatment decisions, most have been retrospective or evaluating the treatment recommendation. The Oncotype DX Breast Cancer Registry is a large prospective study conducted in clinical practices evaluating the types of pts having the assay ordered and the actual treatments delivered. We report here the first set of analyses. Methods: Pts with ER⫹ EBC were eligible to enroll. Data collected at baseline (BL) included age, size, grade, ER, PR and HER2 status. Data collected at the 6-month visit included Score and treatment given. Pt demographics, Score distribution, and associations with clinicopathologic (CP) factors are described. Results: A total of 890 pts were enrolled at 15 U.S. sites between 11/09-3/12. 803 eligible pts were included in the analyses. The Table shows BL characteristics, Score distribution and %CT given. Distribution of Score values across the CP factors was similar to the cohort overall. 30% of pts received CT. Among low Score patients, CT was given in 17% of pts ⬍50y, 9% of Grade 3 tumors and 11% of tumors ⬎2cm. Conclusions: A large, prospective registry for pts with EBC receiving the 21-gene breast cancer assay examined the application of the Score to treatment. The Score distribution is consistent with other retrospective cohorts. The association between the Score and the CP factors was modest. The CP factors did not predict the Score. In general, CT decisions followed the Score with the exception of younger pts; 17% received CT despite a low Score. These findings from a real-world cohort underscore the importance of understanding breast cancer biology in order to make more informed and individualized treatment decisions. All pts Age 70 Grade 1 3 Size 2cm RS Low Intermed High

567

N

%CT

803

30

171 135

43 15

201 134

13 53

209 201

27 35

55 35 10

7.5 47 86


566


Characteristics and clinical outcome of T1 breast cancer: A national multicenter retrospective cohort study. Presenting Author: Anthony Gonçalves, Medical Oncology, Institut Paoli-Calmettes, Marseille, France Background: T1N0M0 breast cancer (BC) are generally considered as carrying good prognosis and cancer-specific survival rates after 5 to 10 years are as high as 90 or 95% in many studies. However, they constitute a heterogeneous group and many studies identified biologically-defined at-risk patients within T1 BC. The objectives of our study were to describe the main characteristics of T1a, b, and c (11-15mm) BC and to identify prognostic factors for survival. Methods: We retrospectively collected the medical files of all patients diagnosed with BC who underwent sentinel lymph node biopsy (SLNB) between January 1999 and December 2008 in 13 French sites and examined overall survival (OS) and Relapse-free survival (RFS) in T1a, T1b and T1c 11-15 mm. Results: Among 8,100 women operated, 5,423 had T1 tumors (708 T1a, 2,208 T1b and 2,508 T1c 11-15mm). T1a differed significantly from T1b tumors with respect to several parameters : younger age, more frequent negative hormonal status and positive HER2 status, less frequent lymphovascular invasion (LVI), exhibiting a mix of favorable and poor prognosis factors. After a median follow-up of 60.5 months, OS rate was 97.6% (95CI: 97.1-98) at 60 months, 95.4%(94.5-96.4) at 84 months and 90.7% (85.2-96.4) at 120 months. No significant difference was observed between T1a, T1b and T1c tumors (p⫽0.335). RFS rates were 94% (95CI: 93.8-95.2), 92.1% [91.1-93.2] and 83.8% (77.6-90.5) at 60, 84 and 120 months respectively. RFS was significantly higher in T1b tumors (95.9%, 95CI: 95-96.9) as compared to T1a (93.2%, 91-95.4) or T1c tumors (93.8%, 92.8-94.9), p⫽0.0099. In multivariate analysis, SBR tumor grade, hormone therapy and LVI were independent prognostic factors for RFS, while hormone therapy and SBR grade were independently associated with OS. Conclusions: Relatively poor outcome of patients with T1a tumors might be explained by a high frequency of risk factors in this subgroup (frequent negative hormone receptors and HER2 overexpression) and by a less frequent administration of adjuvant systemic therapy (endocrine treatment and chemotherapy). Tumor size might not be the main determinant of prognosis in T1 breast cancer.

568


Phase I clinical trial of bavituximab (Bavi) and paclitaxel (P) in patients (pts) with HER2-negative metastatic breast cancer (MBC). Presenting Author: Pavani Chalasani, University of Arizona Cancer Center, Tucson, AZ

Periodontal health in early-stage postmenopausal breast cancer survivors on aromatase inhibitors. Presenting Author: L. Susan Taichman, University of Michigan, Ann Arbor, MI

Background: Bavituximab is a novel tumor vascular targeting agent. It is an unconjugated, chimeric immunoglobulin G1 monoclonal antibody directed against phosphatidylserine (PS). PS is externally expressed on endothelial cells when exposed to hypoxia and/or other physiological stressors frequently observed in tumor-associated vasculature. On attaching to PS, Bavi triggers antitumor effects by inducing antibody-dependent cellular cytotoxicity and promoting antitumor immunity. Methods: We conducted a phase I clinical trial of Bavi in combination with P in pts with HER-2 negative MBC. Pts were treated with weekly P (80mg/m2 for 3/ 4 weeks) and weekly Bavi (3mg/kg for 4/ 4 wks). Microparticle generation, activation and circulating endothelial cell apoptotic markers were measured by flow cytometry. Results: 14 pts with MBC were enrolled. Median age at MBC diagnosis was 50yrs. Seven pts had triple negative MBC; 4 pts presented with de-novo metastatic disease. Prior treatments included chemotherapy in the adjuvant/ neoadjuvant setting (8); metastatic setting (2); adjuvant hormonal therapy (3). Best responses to date include complete response (1), partial response (6), stable disease (1), progressive disease (2) and too early to evaluate (4). Bavi related toxicities include grade2/3 infusion related reactions in 2 pts (1 discontinued Bavi). Bone pain, fatigue, headache and neutropenia were the most common adverse effects. 1 pt had a catheter associated upper extremity thrombosis requiring anticoagulation. Laboratory correlative studies revealed no evidence of platelet activation of PAC-1 or P-Selectin. Median platelet and endothelial microparticles decreased from baseline in response to therapy. Conclusions: Bavi is a novel vascular targeting agent that is well tolerated in combination with P. Early results show promise in terms of clinical responses with 8 of 10 evaluable patients having clinical benefit. Early biomarker results suggest no effect of therapy on platelet activation but decreases in circulating microparticles is observed. Clinical trial information: NCT01288261.

Background: Aromatase inhibitors (AIs) are associated with profound estrogen deprivation resulting in reduced bone mineral density (BMD). Periodontal diseases and tooth loss are associated with estrogen withdrawal and decreased systemic BMD. Little is known as to the impact of AIs on oral health. To investigate oral health as a breast cancer (BCA) survivorship concern, a prospective study was initiated to determine the prevalence of periodontal diseases in postmenopausal early stage (I-IIIA) BCA survivors on adjuvant AI therapy. Baseline assessments are presented here. Methods: Women within 6 months of initiating adjuvant AI for hormone receptor positive BCA were eligible to participate in this study of serial assessments of oral health. A control group of women without BCA and not on AI underwent parallel assessments. Periodontal status was evaluated by the following established dental techniques; (1) periodontal pocket depth (PD), (2) number of teeth with bleeding on probing (BOP), (3) the number of teeth with clinical attachment loss (CAL). Questionnaires regarding socio-demographic and dental utilization were administered to all participants. Linear regression modeling was used to analyze the outcomes. Results: The study met its target accrual of 58 postmenopausal women; 29 with BCA on AI and 29 controls. Demographics were similar regarding age, education, income level, frequency of dental visits, and dental insurance status across both groups. Baseline assessments demonstrated no differences in PD (2.0 mm vs. 2.0 mm; p ⬍ 0.95) or the number of teeth (26.6 vs 26.1; p⬍ 0.39). Interestingly, the AI group had significantly more sites of BOP (27.9 vs 16.7; p ⬍ 0.02), and higher CAL (5.2 mm vs 4.0 mm; p ⬍ 0.01) than did controls. In linear regression analysis adjusted for income, AI use increased CAL by 1 mm (95% CI: 0.15 -1.88). There was also a trend for decreased CAL in subjects with incomes over $75,000 per year (p⬍ 0.06). Conclusions: This first investigation of the periodontal status of women initiating adjuvant AI therpay identifies this population to have signs of increased risk for periodontal disease. Serial oral health assessments are being conducted to assess AI therapy and periodontal changes over time. Clinical trial information: NCT01693731.


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Aromatase inhibitor pain syndromes: Classification and determination of specific risk factors—A prospective multicenter cohort study. Presenting Author: Paul H. Cottu, Institut Curie, Paris, France Background: Pain is frequent during Aromatase Inhibitors (AIs) treatment for breast cancer and several pain syndromes have been reported but not precisely defined. We developed a prospective multicentre study aiming at classifying AIs-related pain syndromes, comparing their impact on daily life, and identifying their specific determinants for a more targeted prevention approach. Methods: A one-year multicenter cohort prospective study, with 5 pre-scheduled visits, was carried out in early stage breast cancer women, free of pain, starting an AI treatment, recruited from 4 oncology centres. At baseline, clinical data (demography and psychosocial, cancer characteristics and treatments, pain, sleep, rheumatologic examination, cancer-related quality of life), biological data (sex hormones, vitamin D, bone biomarkers, oxidative stress, immunological and inflammatory markers), and genetic polymorphism for pain mechanisms (opioid and serotonin pathways) were recorded. Results: A cohort of 135 women was evaluated. Among them, 77 (57%) developed a pain syndrome along the study period, leading to AIs discontinuation in 12 cases. Five main different types of pain syndromes were identified: joint pain, in 48 women overall over the follow-up (36%), diffuse pain, in 30 women (22%), tendinitis, in 29 women (22%), and neuropathic pain, in 12 women (9%) and mixed types, which were frequent and often transient. Analyses demonstrated that risk factors for developing pain syndromes were baseline anxiety and impaired quality of life, while cancer features, genetic background, inflammation, immunological and sex hormone levels were not involved. Conclusions: In pain-free women with breast cancer starting an AI, risks for developing pain during the first year of treatment are slightly greater than 50%. We identified 5 main pain syndromes, joint and widespread pain being the most frequent. In all instances, initial psychological dimensions (personality, impaired quality of life and anxiety) are identified as major risk factors for pain development.

571


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Comparative analysis of bone marrow micrometastases with sentinel lymph node status in early-stage breast cancer. Presenting Author: Madan L. Arora, Michigan State University, Flint, MI Background: A definitive relationship between bone marrow (BM) micrometastases (M) and sentinel lymph node (SLN) status has not been established in Breast Cancer (BRCa). Hence, a retrospective study was done to examine the relationship between BMM and SLN status in BRCa patients (pts). Methods: T1/T2 BRCa pts underwent SLN biopsy and definitive surgery for primary tumors. At the operation, BM aspiration from bilateral post-superior iliac spines was performed. BM samples were examined using a Cytokeratin Detection Kit using CAM 5.2 monoclonal antibody and visualization achieved with a Ventana iView V-Red detection system. An Automated Cellular Imaging System was applied to identify metastatic BRCa cells. Pts with ⫹ve BM underwent repeat BM analysis 6 months after completing initial treatments. Data was collected for T-stages, SLN, BM, ER/PR receptor and Her-2/neu statuses and analyzed using Chi-Square Analysis or Fischer’s Exact Test. Results: We analyzed 458 consecutive pts, of which SLN metastasesv(mets) were detected in 22.9% and BMM were detected in 8.1%. BMM were found 23% bilaterally and 77% unilaterally. BMM were detected in 11.4% of SLN ⫹ve pts versus 7.1% of SLN -ve ptsv(p⫽0.15) and 6.8% of T1 pts versus 12.3% of T2 ptsvv(p⫽0.07). BMM were found in 8.7% of ER/PR ⫹ve pts versus 4.5% of ER/PR –ve ptsvv(p⫽0.1) and 9.5% of HER2/neu ⫹ve pts versus 7.7% of HER2/neu –ve ptsv (p⫽0.5) (Table). Repeat BM analysis detected BMM only in 6.6% pts. Conclusions: Bilateral BM aspirate resulted in a significant increase in detection of micrometastases. BM metastases may occur independently of lymphatic metastasis. Therefore, evaluation for the presence of BMM may help identify high risk pts with node negative disease in early stage BRCa. Comparison of bone marrow status versus four variables. Variable (No. of pts)

BM ⴙVE (37)

BM –VE( 421)

P value

SLN ⴙVE( 105) SLN-VE (353) T1 (352) T2 (106) ER/PR ⴙVE (391) ER/PR –VE (67) HER2/NEU ⴙVE(95) HER2/NEU –VE(363)

12 (11.4%) 25 (7.1%) 24 (6.8%) 13 (12.3%) 34 (8.7%) 3 (4.5%) 9 (9.5%) 28 (7.7%)

93 (88.6%) 328 (92.9%) 328 (93.2%) 93 (87.7%) 357 (91.3%) 64 (95.5%) 86 (90.5%) 335 (92.3%)

0.15 OR-1.6 (0.8-3.3) 0.07 OR-1.9 (0.93-3.8) 0.1 OR-2 (0.6-6.8) 0.5 OR-1.2 (0.5-2.7)

572


Relationship of tumor and stromal autophagy and endocrine responsiveness in breast cancer tissues. Presenting Author: Takayuki Ueno, Department of Breast Surgery, Kyoto University, Kyoto, Japan

Effect of fertility concerns on tamoxifen use in young survivors of breast cancer. Presenting Author: Natalia Llarena, Northwestern University, Feinberg School of Medicine, Chicago, IL

Background: Neoadjuvant endocrine therapy has been employed to improve surgical outcomes for endocrine responsive breast cancers in postmenopausal women. Endocrine responsiveness is estimated by the expression levels of hormone receptors although heterogeneity in the response is well recognized. To improve the clinical outcome, it is critical to understand how cancer tissues react to the endocrine treatment. Methods: Pre-treatment biopsy samples and post-treatment surgical samples were obtained from 116 patients enrolled onto the multicenter prospective study of neoadjuvant exemestane therapy, JFMC34-0601. Fifty-four paired samples were available for the study. Estrogen receptor, progesterone receptor, HER2, Ki-67 by immunohistochemistry and pathological response were centrally evaluated. Apoptosis was assessed by TUNEL (Roche Diagnostics, Mannheim) and M30 (Roche Diagnostics, Mannheim). Autophagy was assessed by anti-beclin 1 (Novus Biologicals, CO) and anti-LC3 (MBL, Nagoya). Clinical response was assessed based on the RECIST criteria. The Wilcoxon rank-sum test and chi-square test were used for the statistical analysis. Results: The expression of autophagy markers, beclin and LC3, in cancer cells showed significant increases by exemestane (beclin p⫽0.016; LC3 p⫽0.0004) whereas TUNEL did not show any change and M30 expression decreased (p⫽0.01). The increase of beclin expression was associated with the clinical response: responders showed an increase (p⫽0.039) while non-responders did not. Importantly, the treatment increased autophagy markers not only in cancer cells but in stromal cells (beclin p⬍0.0001; LC3 p⫽0.024) while it did not change TUNEL in stromal cells. Patients with stromal beclin-positive showed poor clinical response (3/12) and poor pathological response (0/12) while those with stromal beclin-negative showed good clinical response (26/39) and good pathological response (16/38) (clinical response p⫽0.011; pathological response p⫽0.0064). Conclusions: This study suggested that exemestane induced autophagy in both cancer and stromal cells. In addition, stromal autophagy correlated with clinical and pathological response to the endocrine treatment.

Background: For premenopausal patients with ER⫹ breast cancer, a 5-year course of tamoxifen results in a 47% reduction in annual recurrence risk and a 26% reduction in annual mortality. Despite these benefits, adherence rates for tamoxifen are low, particularly among younger women. We hypothesize that fertility concerns are causally related to the poor tamoxifen adherence rates observed among young breast cancer survivors. Methods: With IRB approval, a retrospective analysis of 535 women with breast cancer between 2000-2012 was undertaken. Patients were younger than age 46, premenopausal and had ER⫹ breast cancer. 138 patients did not complete a 5-year course. Patient and provider factors that influenced tamoxifen initiation and adherence were reviewed: (1) evidence of referral to a fertility specialist; (2) documentation of discussion about tamoxifenrelated fertility concerns; (3) agreement to take tamoxifen; (4) duration of tamoxifen use. Phone interviews conducted with 27 patients focused on lack of initiation or early discontinuation. The Log-rank (Mantel-Cox) test was used to compare Kaplan-Meier curves and generate hazard ratios. Results: Of the 138 patients who did not complete 5 years of therapy, 38 (27.5%) failed to initiate or discontinued tamoxifen secondary to fertility concerns. Only 114 (21.3%) charts documented referral to a fertility specialist. Patients who expressed a desire to maintain fertility or to have children in the future (115 patients, 21.5%) were more likely to discontinue tamoxifen treatment (HR⫽2.7, p⫽0.001). Other critical factors included being unmarried (HR⫽1.9, p⫽0.011) and lack of college education (HR⫽2.5, p⫽0.0008). Major themes from phone interviews: (1) patients felt they were not adequately informed about fertility preservation and had to pursue information independently; (2) patients did not initiate/resume tamoxifen postpartum because of inadequate physician guidance. Conclusions: Concerns about fertility have a significant negative impact on the initiation and adherence to tamoxifen for young breast cancer patients. Efforts to improve tamoxifen adherence among young cancer patients should include prioritization of fertility preservation as part of the treatment plan.




Low HER2-expression to predict impaired activity of endocrine therapy in patients with estrogen-receptor (ER) positive metastatic breast cancer (MBC). Presenting Author: Cornelia Sparber, Department of Medicine 1, Medical University of Vienna, Vienna, Austria Background: ER cross-activation by growth-factor signalling causes resistance to endocrine therapy (ET) in patients (pts) with Her2-positive MBC. Moreover, low levels of Her2-expression (Her2 1⫹; Her2 2⫹ without gene amplification), may result in reduced efficacy of ET in early breast cancer pts. In a recently published study, these tumours had a less favourable outcome as compared to tumours with a Her2-score of 0. Here, we investigated if low levels of Her2-expression could predict for shorter progression-free survival (PFS) in MBC pts on ET. Methods: PFS on first-line ET was chosen as primary endpoint and estimated with the Kaplan-Meier method. To test for differences between PFS curves, the log-rank test was used. Association of the following variables with PFS was investigated: low Her2-expression, grading, level of ER-expression, progesterone-receptor status, Ki67 (cut-off ⱕ20%), prior adjuvant ET, and presence of visceral metastases. For an estimated superiority of 40% in terms of PFS in favour of the Her2-negative group, a sample of 130 pts in two groups was needed in order to rule out the null-hypothesis with a 80% power and a two-sided ␣ of 0.025. Results: A total number of 320 ER-positive MBC pts were identified from a breast cancer database; 170 pts were available for this analysis. Median PFS on first-line ET was 11 months (m) (8.56-13.44), corresponding numbers for second-line were 6 m (4.65-7.36), and third-line 4 m (1.52-6.48), respectively; median OS from diagnosis of MBC was 58 m (48.15-67.86). None of the variables investigated were significantly associated with first-line PFS. Second-line PFS, however, was significantly shorter in pts with grade 3 tumours and prior adjuvant ET; a trend towards shorter PFS was observed in high proliferating tumours. Conclusions: In this chart review, low levels of Her2 expression did not predict for shorter PFS in pts receiving ET; PFS in different treatment lines was well in line with data from clinical trials. High tumour grading and prior adjuvant ET were associated with accelerated onset of resistance, rendering those patients candidates for early combination of ET with targeted treatment approaches.

575


A meta-analysis of endocrine therapy trials in early breast cancer (BC) evaluating the impact of obesity: Are aromatase inhibitors (AIs) optimal therapy in obese ERⴙ BC? Presenting Author: Lina Pugliano, Jules Bordet Institute, Breast International Group, Brussels, Belgium Background: Obesity is an adverse prognostic factor in BC. Mixed results are reported for the relative efficacy of AIs compared to tamoxifen (T) in obese ER⫹ BC patients. Our purpose was to conduct a meta-analysis of adjuvant randomised trials of AIs vs T assessing the impact of body mass index (BMI). Methods: We identified four studies evaluating BMI and endocrine therapy. Of these, 3 were randomised (non-steroidal AIs vs T) and were evaluable for the aggregation of results for DFS and OS in our metaanalysis. We extracted published data from ATAC, ABCSG-12 and BIG0198, analyzed according to standard meta-analytic techniques. Results: A total of 11,383 patients were included in our study. BMI⬎25 is associated with reduced disease free survival (DFS) and a trend towards worse overall survival (OS) (Table 1). A significantly shorter DFS was seen for patients with BMI⬎25 treated with an AI while a trend was seen for OS. Reduced relative efficacy was seen for DFS for AIs compared to T for BMI⬍25 (HR⫽0.78; 95%CI 0.66- 0.91; p⫽0.002) and a trend for BMI⬎25 (HR⫽0.85; 95%CI 0.70- 1.02; p⫽0.08). The test for interaction was not significant (p⫽0.48), with similar results for OS for BMI⬍25 (HR⫽0.79; 95%CI 0.63-0.9; p⫽0.009) and BMI⬎25 (HR⫽0.98; 95%CI 0.61-1.60; p⫽0.95). The test for interaction was not significant (p⫽0.37). Notably, significant heterogeneity in patients treated with anastrozole and a BMI⬎25 did not allow a comparison between anastrozole and letrozole. Conclusions: BMI⬎25 has a negative prognostic effect in BC. AIs demonstrate improved outcomes in normal weight BC patients (BMI⬍25). Obesity was associated with observed relative reduced efficacy of AIs; however, we were not able to detect a significant interaction between BMI and treatment effect. Further analyses into the differing impact of type of AIs on BC outcomes in obese patients are warranted. HR DFS DMI>25 vs 25 vs 25 vs 25 vs 25 vs 25 vs 40 99016 Age < 40 >40 99016 (AC/P) Age < 40 >40 99016 (AP/wP) Age < 40 >40 Pooled 01062 and 99016 Age < 40 >40 P value

592

171 815 92 593 43 301 49 292

88 (82 - 93) 83 (80 - 85) 75 (64 - 84) 75 (71 - 79) 75 (58 - 85) 74 (68 - 79) 76 (56 - 88) 77 (71 - 81)

168 1457 102 1,043 45 526 57 517

86 (78 - 91) 91 (89 - 92) 79 (68 - 86) 85 (83 - 88) 74 (55 - 85) 86 (82 - 89) 82 (68 - 91) 85 (81 - 88)

263 1048

84 (79 - 88) 80 (77 - 82) 0.08

270 2500

83 (78 – 88) 89 (87 - 90) 0.07


Clinical and pathologic correlation of the activated form of the estrogen receptor (ER) in breast cancer (BC). Presenting Author: Jacques Bonneterre, Centre Oscar Lambret, Lille, France Background: About 50% of ER positive (ERpos) BC are resistant to hormone treatment. In absence of ligand, ERs are evenly distributed in nuclei in normal tissue. Upon ligand binding, ERs dimerizes and form a discrete focal subnuclear distribution pattern (FDP), which are associated with transcriptional activation of ER. This ER FDP is observed in BC. We hypothesized that in BC that the presence/absence of ER in the FDP could predict antiestrogen activity. This study describes an immunohistochemistry (IHC) method, by which a biomarker could be developed to investigate this hypothesis. Methods: 303 archived BC biopsies were obtained along with clinical and pathology data. Biopsies were analyzed for standard HES, ER, progesterone receptor (PR) and Ki67. PR positivity was determined with distinct antibodies to the A and B isoforms. The A-ER and D-ER nuclear patterns were analyzed at x1000 magnification. Results: Mean age; 58 (17 -89). Histology: ductal 85% lobular 13%, other 2%; 84% ERpos and 84% either PRApos or PRBpos, 7% ERpos and 7% PRApos or PRBpos only. All but 3 ERpos cases had received AntiEs; Adj. chemotherapy 51%, Stage: I 51%, II 43%, III 6 %. Grade: I 24%, II 51%, III 25%. Median follow up 31 months (mo). Local or distant progression (PD) was 19%. ER status was D-ER in 78% and A-ER in 22% of the biopsies and PD was associated with the D-ER pattern (p ⫽ 0.06), e.g. the hypothetically non-functional pattern D-ER was associated with a higher rate of PD (4 vs 35). With DFS defined as time to PD or death (5 year cut off), ERpos was better that ERneg (HR⫽ 0.38, p ⫽ 0.016). For ERpos BC, A-ER was numerically better than D-ER (HR ⫽0.3, p⫽0.24 two-sided). In univariate analyses, A-ER pattern was associated with higher grade (p⫽0.035), anisonucleosis (p⫽0.06), mitotic index (p⫽0.02), and Ki67 (⫽0.08). No association was found between ER pattern and age, stage or HER2 status. Conclusions: This study supports the hypothesis that AntiEs are mainly active in BC with A-ER pattern, which is targetable by AntiEs. A larger number of events are needed to reach significance in time-dependent analyses and confirmatory studies are warranted.


30s 593


594


Identification of the activated form of the progesterone receptor (PR) in breast cancer (BC). Presenting Author: Jacques Bosq, Institut Gustave Roussy, Villejuif, France

Prediction of early and late distant recurrence in early-stage breast cancer with Breast Cancer Index. Presenting Author: Yi Zhang, bioTheranostics, Inc., San Diego, CA

Background: Upon ligand binding, PRs dimerize and form a discrete focal subnuclear distribution pattern (FDP), which are associated with transcriptional activation of PR (APR). FDP and are observed in BC independently of menopausal status. The feasibility of using an IHC technique to characterize the PR functional status has previously been reported in BC and presence/absence of APR is hypothesized to predict anti-progestin activity. This study describes an immunohistochemistry (IHC) method, by which a biomarker could be developed to investigate this hypothesis. Methods: 303 paraffin embedded/formalin fixed archival BC samples were processed with PR-A or PR- B isotype specific antibodies. Nuclear morphology was analyzed with standard microscopy at x1000, interpretation of the IHC slides was done by an experienced pathologist. Standard PR, estrogen receptor (ER), and Ki67 testing were done. Tumor grading/stage was obtained from the patients’ records. Results: Histology was ductal 85%, lobular 13%, other 2%. Consistent with prior research observations, tumors had two PR nuclear morphologies: 1. Diffuse pattern (D) where the PR was distributed evenly in a fine granular pattern or, 2. Aggregate pattern (A) where the PR is distributed in discrete clumps or aggregates. This defined 3 tumor phenotypes: A cells only (A), D cells only (D), and a heterogenous mix of A⫹D cells (AD). The APRpos group is defined as the A and A⫹ D phenotypes. Tumors were PR positive in 76% for PRA and 80% for PRB. Tumors were APRpos for PRA in 23% and independent of PR intensity score, ER, Ki67, and HER2, but associated with higher PR % positivity and higher tumor grade. Tumors were APRpos for PRB in 22% and associated with lower PR intensity and higher tumor grade, independent of ERpos %, PRpos %, Ki67 and HER2. Conclusions: PR positive BC tumors can be grouped in two categories based on PR nuclear morphology: 1. a group with diffuse and homogenous nuclear staining, 2. a group with heterogeneous area of cells having a nuclear pattern consistent with a functional or activated PR (APR). The described IHC technique to identify APR has the potential to be developed as companion diagnostic as a potential predictor of anti-progestin efficacy in patients with BC.

Background: Breast Cancer Index (BCI) is a continuous risk index based on the combination of HOXB13:IL17BR (H:I) and the Molecular Grade Index (MGI) that estimates the individual risk of recurrence in ER⫹, LN- breast cancer patients. In the current study, a modified BCI model was developed using untreated breast cancer patients in order to evaluate its pure prognostic value, and to better optimize BCI for both early and late risk assessment. Methods: A model was built by linearly combining H:I and MGI weighted by their corresponding Cox regression coefficients using ER⫹ LNpatients from the untreated arm of the prospective Stockholm trial (N⫽283). Validation was performed in 2 independent ER⫹, LN- cohorts: the TAM arm of the Stockholm trial (N⫽317), and a multisite cohort of TAM-treated patients (N⫽358). Correlation of BCI with distant metastasis was evaluated by Kaplan-Meier analysis using the log rank test, and multivariate analysis adjusting for standard prognostic factors was performed using Cox proportional hazards. Results: The BCI linear model was significantly associated with risk of cumulative (0-10y), early (⬍5y) and late (ⱖ5y) distant metastasis. Based on pre-specified cutpoints, BCI classified 64% and 55% patients as low-, 21% and 22% as intermediate-, and 16% and 23% as high-risk, with 10-y rates of distant recurrence (95% CI) of 4.8% (1.7-7.8%) and 6.6% (2.9 –10.0%), 11.7% (3.1–19.5%) and 23.3% (12.3-33.0%), 21.1% (18.5–32.0%) and 35.8% (24.5– 45.5%), in the Stockholm TAM and multisite cohort, respectively. Conclusions: BCI demonstrated significant prognostic performance beyond clinicopathological factors to predict cumulative, early and late risk of recurrence in early stage breast cancer patients. Use of BCI at diagnosis should enable clinicians to identify patients who are at high risk of late recurrence and may benefit from an additional 5y of hormonal therapy.

595

596


Effect of PK-guided tamoxifen dose escalation on endoxifen serum concentrations in CYP2D6 intermediate and poor metabolizers. Presenting Author: Frans Opdam, Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, Netherlands Background: Breast cancer patients with absent or reduced CYP2D6 activity may benefit less from tamoxifen treatment because of impaired biotransformation to the active metabolite endoxifen. We investigated whether a temporary one-step dose escalation of tamoxifen in CYP2D6 poor (PM) and intermediate metabolizers (IM) could increase endoxifen serum concentration to a similar level observed in CYP2D6 extensive metabolizers (EM) without increasing toxicity. Methods: From a prospective study population of early breast cancer patients using tamoxifen, 12 CYP2D6 poor and 12 intermediate metabolizers were selected and included in a one-step tamoxifen dose escalation study during two months. The escalation dose (120 mg maximum) was calculated by multiplying the individual’s endoxifen level divided by the median endoxifen concentration (33.7 nM) observed in CYP2D6 extensive metabolizers by 20 mg. Toxicity was assessed and all patients returned to the standard dose of 20 mg after two months. Results: Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased endoxifen concentrations (PMs: from 8.0 nM to 27.3 nM, p⬍0.001; IMs: from 17.8 nM to 30.3 nM, p⫽0.002) without increasing side effects. In intermediate but not in poor metabolizers dose escalation increased endoxifen to levels comparable with those observed in extensive metabolizers using tamoxifen 20 mg once daily (33.7 nM). Conclusions: CYP2D6 genotype and endoxifen guided tamoxifen dose escalation increased endoxifen concentrations without increasing short term side effects. Whether such tamoxifen dose escalation is effective and safe in view of long term toxic effects is uncertain and needs to be explored. Clinical trial information: NTR1509.

Stockholm TAM (Nⴝ317) HR (95% CI)

P

Multisite cohort TAM-treated (Nⴝ358) HR (95% CI) P

Cumulative (0-10y) 4.2 (1.5, 11.8) 0.006 9.3 (4.2, 20.5) ⬍0.0001 Early (5y) 3.59 (1.07, 12.0) 0.039 11.7 (3.1, 43.6) 0.0003


Independent characterization by duel staining of progesterone receptor (PR) and estrogen receptor (ER) in breast cancer (BC). Presenting Author: Alexander A. Zukiwski, ARNO Therapeutics, Flemington, NJ Background: The oncology literature indicates that ER and PR are linked and in BC the presence of PR usually indicates functional ER. BCs express both ER and PR to varying degree, but little has been published on expression of ER ⫹ PR in individual cancer cells. The goal of this study is to 1. Determine the expression ER and PR at the cellular level, 2. Determine if ER and PR are expressed in the same BC cells. If ER and PR are separate, this may indicate that antiestrogens and antiprogestins may target different cells. Methods: Archived 1° BC specimens were processed using standard IHC techniques for ER/PR testing. The procedure consisted of sequential double staining on the same microtone section, where the PR was visualized through brown staining using HRP/DAB, and the ER was visualized through red staining using AP/Permanent Red. The initial testing on 13 tumor samples utilized a duel anti-PR-A/B antibody (Ab) and an ER Ab. The next 63 tumor samples utilized; 1. anti-ER and anti-PR-A Abs, 2. anti-ER and anti-PR-B Abs. A pathologist experienced with IHC, interpreted and enumerated the cells staining positive for ER only, for PR only and cells staining positive for both ER & PR. The number of cells expected to be stained for both ER & PR by chance can be calculated as the rate of total ER by the rate of total PR and compared with the observed rate (paired rank test). ER/PR positivity is defined as ⱖ 5% cells positive. Results: In the first series, 11/13 tumors were ERpos, 13/13 were PRpos, 7/13 tumors had both ER & PR expressed in 5-20% (median 5%) of the same tumor cells. In the 2nd series of 63 tumors; 1. 50/53 were ERpos, 52/53 were PRApos and 44/53 had both ER & PRA expressed in ⬍5-20% (median 5%) of the same tumor cells, 2. 44/52 were ERpos, 52/52 were PRBpos and 42/52 tumors had both ER & PRB expressed in ⬍5-20% (median 10%) of the same tumor cells. Areas of ER or PR only predominance were frequent. A paired rank test indicates that the observed rate (median 9%) of ER/PR duel staining is less than predicted (median 18%, p ⬍0.000). Conclusions: ER & PR were expressed in the majority of tumors examined with a minority the tumor cells expressing both ER & PR. These data support evaluating antiprogestins as a different therapeutic target from ER.




CYP2D6 genotype related to tamoxifen efficacy: An analysis with exclusion of potential false CYP2D6 genotype assignment caused by loss of heterozygosity in tumor tissue. Presenting Author: Vincent O. Dezentje, Department of Clinical Oncology, Leiden University Medical Center, Leiden, Netherlands Background: The clinical importance of CYP2D6 genotype as predictor of tamoxifen efficacy is still unclear. Recent genotyping studies on CYP2D6 using DNA derived from tumor blocks have been criticized because loss of heterozygosity (LOH) in tumors may lead to false genotype assignment. Methods: Postmenopausal early breast cancer patients who were randomized to receive tamoxifen, followed by exemestane in the Tamoxifen Exemestane Adjuvant Multinational trial (TEAM) were genotyped for 5 CYP2D6 variant alleles. CYP2D6 genotypes and phenotypes were related to disease free survival during tamoxifen use (DFS-t) in 731 patients. By analyzing three microsatellites flanking the CYP2D6 gene, patients whose genotyping results were potentially affected by LOH were excluded. Results: Analysis of the CYP2D6 alleles and the microsatellite markers demonstrated heterozygosity for at least one of the CYP2D6 alleles or microsatellite markers in 97.7% of patients with a specified CYP2D6 phenotype. The 14 patients (2.3%) with a homozygous CYP2D6 genotype in which no heterozygosity could be demonstrated for the microsatellite markers were excluded from the analysis. No association was found between the CYP2D6 genotype or predicted phenotype and DFS-t. Conclusions: In postmenopausal early breast cancer patients treated with adjuvant tamoxifen followed by exemestane neither CYP2D6 genotype nor phenotype was associated with DFS-t. This is in accordance with two recent studies in the BIG1-98 and ATAC trials. Our study is the first CYP2D6 association study using DNA from paraffin embedded tumor tissue in which potentially false interpretation of genotyping results because of LOH was excluded.

599


Differential impacts of Oncotype DX and Mammostrat prognostic indices upon the management of ERⴙ N0 breast cancer. Presenting Author: Jeffrey Gary Schneider, Winthrop-University Hospital, Mineola, NY Background: Oncotype DX (Genomic Health, Redwood City CA) and Mammostrat (Clarient, Aliso Viejo CA) are two distinct prognostic measures currently marketed to facilitate adjuvant chemotherapy decision making for ER⫹ breast cancer patients and their physicians. Both assays define three prognostic strata—favorable, intermediate, and unfavorable. Both assays were also validated in the same retrospective cohorts, but there is significant discordance between these assays, suggesting that assay selection may affect clinical decisions. Methods: We have previously reported that Oncotype DX significantly reduces adjuvant chemotherapy use in 89 consecutive ER⫹, N0 patients for whom this assay was ordered at our institution. Mammostrat assays were performed on 46 of these cases for which tumor blocks were available. Decision analysis was applied to determine changes in management that would have been most likely if Mammostrat had been substituted for Oncotype DX. Results: Oncotype DX and Mammostrat were concordant for prognostic strata in just 11 (24%) cases. Oncotype DX predicted a more favorable prognosis than Mammostrat in 27 (59%) cases, while Mammostrat predicted a more favorable prognosis in the remaining 8 (17%) cases. As shown in the Table, Oncotype DX reduced chemotherapy utilization whereas Mammostrat would have increased it. Conclusions: Despite being validated in identical patient cohorts, Oncotype DX and Mammostrat are frequently discordant and may often affect adjuvant treatment decisions in opposite directions. Adjuvant Rx Hormones alone Chemotherapy plus hormones

Conventional criteria alone

Oncotype DX

Mammostrat

59%

74%

35%

41%

26%

65%

598


A comparative analysis of distant recurrence risk assessments by Oncotype DX recurrence score alone and integrated with clinicopathologic factors in early-stage breast cancer. Presenting Author: Ciara Marie Kelly, Department of Medical Oncology, Cork University Hospital, Cork, Ireland Background: Treatment planning for patients with node negative, ERpositive, HER-2 negative breast cancer often incorporates the use of prognostic and predictive tools like Oncotype DX. Prior to the availabilty of Oncotype DX, clinicopathologic factors such as age, nodal status, tumour size and grade were used to determine risk of recurrence (ROR). RSPC represents a validated formal integration of oncotype DX recurrence score (RS) and clinicopathologic factors that further refines prognostic accuracy. RSPC does not improve the prediction of likelihood of chemotherapy benefit. The objective of this study was to compare distant recurrence risk assessment by RS and RSPC. Methods: We included patients with node negative, ER-positive, HER2-negative breast cancer who had Oncotype DX testing routinely or on clinical trial. We retrospectively reviewed patient charts and extracted clinicopathological and RS data. We calculated the RSPC using the RSPC educational tool. A comparative analysis was performed looking at the statification of patients into low (LR), intermediate (IR) and high (HR) ROR groups by RS and RSPC. The cut offs for low, intermediate and high risk by the RSPC were set to less than 12%, 12-20% and more than 20% risk of distant recurrence at 10yrs, corresponding to the risks of recurrence associated with the RS categories. Results: We identified 658 patients from 5 academic hospitals in Ireland and the US. Oncotype DX RS classified the following proportions of patients into three risk groups for distant recurrence: LR, n⫽334 (50.5%), IR, n⫽259 (39.4%), HR, n⫽67 (10.1%). RSPC classified the following proportion of patients into the three risk groups for recurrence: LR, n⫽ 455 (69.1%), IR, n⫽110 (16.7%), HR, n⫽93 (14.1%). RSPC reclassified 72.6% (n⫽188) of the IR group (59.1% (n⫽153) from IR to LR and 13.5% (n⫽35) from IR to HR). RPSC reclassified 10.5% (n⫽35) of the LR group (8.1% (n⫽27) from LR to IR, and 2.4% (n⫽8) from LR to HR). RSPC reclassified 25.3% (n⫽17) of the HR group (17.9% (n⫽12) from HR to IR, and 7.4% (n⫽5) from HR to LR). Conclusions: RSPC reclassified 240 patients (36.5%) and was most helpful reassigning the IR group.

600


Efficacy and safety of first-line (1L) pertuzumab (P), trastuzumab (T), and docetaxel (D) in HER2-positive MBC (CLEOPATRA) in patients previously exposed to trastuzumab. Presenting Author: Eva Maria Ciruelos Gil, University Hospital 12 de Octubre, Medical Oncology Department, Madrid, Spain Background: CLEOPATRA is a global phase III trial of P ⫹ T ⫹ D vs placebo ⫹ T ⫹ D in HER2-positive 1L MBC. Results showed a significant improvement in PFS (Baselga NEJM 2012) and OS (Swain SABCS 2012) favoring P ⫹ T ⫹ D. CLEOPATRA started recruitment in 2008 soon after the approval of T in the adjuvant setting in 2006 and mandated a disease-free interval (DFI) of ⱖ12 mos from the end of adjuvant therapy to MBC diagnosis. Due to this, a low proportion of pts with prior T exposure was included. Here we present the efficacy and safety of 1L P ⫹ T ⫹ D in the subset of pts in CLEOPATRA with prior T exposure. Methods: Pts received P ⫹ T ⫹ D or placebo ⫹ T ⫹ D, had a DFI ⱖ12 mos, baseline left ventricular ejection fraction (LVEF) ⱖ50% and no LVEF decline to ⬍50% during/after prior T therapy. Exploratory analyses of PFS and OS in pts with (neo)adjuvant therapy with or without T were conducted. Results: Of the study population, 47% had received (neo)adjuvant therapy and 11% had received (neo)adjuvant T; 82% of the prior T group came from Europe or North America. A univariate Cox regression analysis did not identify prior T therapy as a statistically significant risk factor for developing left ventricular systolic dysfunction (LVSD). However, due to the low number of LVSD events overall, this analysis has limited sensitivity. Conclusions: Data from CLEOPATRA show that pts with HER2-positive 1L MBC who have received prior T (DFI ⱖ12 mos) derive the same magnitude of benefit from the combination of P ⫹ T ⫹ D when compared with the whole study population or those who are T-naïve. This is in agreement with prior evidence of the activity of P ⫹ T in pts pretreated with T (Baselga JCO 2010). Efficacy and safety of P-T-based therapy is being explored in the PERUSE and PHEREXA trials, in a pt population with wider exposure to prior T and a shorter DFI, which may better represent current clinical practice. Clinical trial information: NCT00567190. Placebo ⴙ T ⴙ D

PⴙTⴙD Median PFS, mos

All pts n ⴝ 808

12.4

18.5 HR 0.62 (0.51, 0.75) p < 0.0001

(Neo)adjuvant therapy with T n ⴝ 88

10.4

(Neo)adjuvant therapy without T n ⴝ 288

12.6

16.9 HR 0.62 (0.35, 1.07) 21.6 HR 0.60 (0.43, 0.83)

Median OS All pts n ⴝ 808 (Neo)adjuvant therapy with T n ⴝ 88

HR 0.66 (0.52, 0.84) p ⴝ 0.0008 HR 0.68 (0.30, 1.55)


32s 601


Leptomeningeal disease and breast cancer: Relationship of outcome and subtype. Presenting Author: Sausan Abouharb, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Breast cancer (BC) is one of the most common tumors to involve the leptomeninges. Outcome of leptomeningeal disease (LMD) across BC subtypes is not well documented. We aimed to characterize clinical features and outcomes of LMD based on BC subtypes. Methods: We retrospectively reviewed medical records of patients diagnosed with LMD from BC (1997 to 2012). All patients had BC. Cases of LMD were based on the presence of neoplastic cells on cerebrospinal fluid examination and/or evidence of LMD by imaging studies. Survival was estimated by the Kaplan-Meier method and significant differences in survival were determined by Cox proportional hazards or log-rank tests. Results: 232 patients were included, 189 of them had available tumor subtype classified as: hormone receptor positive (HR⫹) BC N⫽67 (35.5%), human epidermal growth factor receptor 2 positive (HER2⫹) N⫽55 (29%), and 67 (35.5%) triple-negative BC (TNBC). Median age at diagnosis of LMD was 49.7 years. (Range 24-89). Median overall survival (OS) from LMD diagnosis across all subtypes was 3.1 months (95% CI, 2.5 to 3.7). Median OS correlated with BC subtype: 3.7 months (95% CI: 2.4, 6.0) in HR⫹, 4.0 months (95% CI: 2.6, 6.9) in HER2⫹, and 2.2 months (95% CI: 1.5, 3.0) in TNBC, (p⫽0.0002). There was an 11.4% chance a patient diagnosed with LMD would survive 1 year and the chance of surviving at least 3 years was 1.3%. When age was used as a continuous variable, older age was associated with worse outcome (p⬍0.0001). Patients with HER2⫹ BC and LMD were more likely to have received systemic therapy (ST) (70%), compared to HR⫹ (41%) and TNBC (41%) (p⫽0.002). 38% of patients with HER2⫹ BC received HER2 directed therapy. There was no difference in the use of intrathecal therapy (IT) (52%) across subtypes (p⫽0.3). Use of IT therapy (p⬍0.0001) and ST (p⬍0.0001) were both associated with improved age-adjusted OS. After adjusting for age, ST, there was no difference in OS between patients with HR⫹ and HER2⫹ BC (p ⫽0.14), but a significant difference remained between TNBC and HER2⫹ BC (p ⬍ 0.0001). Conclusions: LMD carries a dismal prognosis. Our data shows that OS correlates with tumor subtype. Patients with TNBC had a significantly shorter OS compared to patients with HER2⫹ BC. New treatment strategies are needed.

603


Trastuzumab-based adjuvant chemotherapy for breast cancer: Early myocardial dysfunction detected by “speckle tracking” echocardiography (STE). Presenting Author: Giovanni Mantovani, Department of Internal Medical Sciences, Medical Oncology, University of Cagliari, Cagliari, Italy Background: While anthracycline-induced type 1 cardiotoxicity is well established, type 2 trastuzumab (TZM)-induced cardiotoxicity, although less relevant and reversible, is nonetheless significant in combination with other drugs, such as taxanes (TAX). A paradigmatic clinical example of this regimen is the adjuvant setting of breast cancer patients overexpressing HER-2. In the present study we chose STE with longitudinal and circumferential Strain (S) and Strain Rate (SR), as a very sensitive tool to timely identifying left ventricular dysfunction. The biological markers of chronic inflammation/oxidative stress were also studied. Methods: A phase IV prospective non-randomized study was carried out to assess cardio-toxicity induced by the combination of epirubicin (EPI) ⫹ TAX followed by TZM administered with the conventional schedule in adjuvant setting of breast cancer patients (pts) overexpressing HER-2. Inclusion criteria: 18 –70 y, histologically confirmed HER-2⫹ve breast cancer candidates for TZMbased 3 weekly regimen; LVEF ⱖ55%; ECOG PS score 0-1, no history of cardiac disease. STE parameters (longitudinal and circumferential S and SR) and chronic inflammation (IL-6 and TNF-a)/oxidative stress (reactive oxygen species) markers were assessed at baseline before TZM and after each of the subsequent 18 TZM administrations. Results: Forty pts (mean⫾SD age 53⫾10 y) were assessed up to the 8th TZM administration. A progressive reduction of longitudinal SR was observed, becoming significant from the 4th TZM dose (0.65⫾0.18 s-1 vs 0.81⫾0.16 s-1, p⬍0.005); a significant reduction of circumferential SR (0.60⫾0.15 s-1 vs 0.51 ⫾0.14 s-1, p⬍ 0.01) and rotation index was also observed from the 2ndTZM dose. These changes are all indicative of myocardial systolic dysfunction. No changes of biological parameters were observed. Conclusions: The sequential administration of TZM after EPI/TAX induced an early left ventricular dysfunction detected by STE which persisted at least up to the 8th TZM administration. This study is in progress with close monitoring of pts and its ultimate goal is to select pts candidates for an effective cardio protective treatment.

602


Efficacy of trastuzumab re-therapy in routine treatment of HER2-positive breast cancer patients who relapsed after completed (neo-)adjuvant antiHER2 therapy. Presenting Author: Lars Christian Hanker, Universitaetsklinikum Schleswig-Holstein, Campus Luebeck, Klinik für Frauenheilkunde und Geburtshilfe, Luebeck, Germany Background: Addition of trastuzumab (Roche; T) to chemotherapy (CT) has improved outcomes in patients (pts) with HER2⫹ breast cancer at all stages, including locally advanced and metastatic disease. Anti-HER2 re-treatment with T is an increasingly used therapy option for the treatment of recurrent/metastatic breast cancer (MBC). However, limited data on T re-treatment is currently available. Methods: Patients with locally recurrent and/or MBC who received T re-therapy were included in this noninterventional study. Among 232 pts enrolled at 121 sites in Germany, 174 pts (33 locally recurrent disease, 141 MBC) were already sufficiently documented to be analyzed for efficacy of T re-therapy in this ongoing study. Progression-free survival (PFS) was assessed by the investigator. Results: The median disease-free interval (calculated from the time of resection of the primary tumor to diagnosis of local recurrence/MBC) was 3.1 years. Median duration of re-therapy with T was 9.3 months. The median PFS of all patients was 10.1 months (95% confidence interval (CI), 8.5 to 13.1). PFS for pts with only locally recurrent disease (n⫽ 33) was 23.6 months. PFS for MBC pts (n⫽141) was 8.9 months (95% CI, 7.4 to 10.6). For pts with visceral metastases (n⫽96) a PFS of 8.0 months compared to 10.1 months in patients with only non-visceral (n⫽45) was recorded. 104 pts were re-treated with T ⫹ CT (⬎70% paclitaxel, vinorelbine, capecitabine or docetaxel alone; PFS⫽ 9.3 months), 26 pts with T ⫹ hormonal therapy (HT) (mostly anastrozole, fulvestrant, exemestane, letrozole or tamoxifen; PFS⫽10.1 months), 24 pts with T⫹CT⫹HT (PFS⫽ 19.9 months) and 20 pts with T monotherapy (PFS⫽ 9.4 months). Conclusions: This study provides clinical evidence that re-application of T in combination with either CT, HT or alone is effective in the routine treatment of patients with MBC and/or locally recurrent disease. The benefit observed for pts receiving first-line treatment with T in combination with taxane in pivotal trials as well as recently published data seems comparable to the presented results of pts receiving T re-therapy.

604


Quantitative measurements of p95HER2 (p95) protein expression in tumors from patients with metastatic breast cancer (MBC) treated with trastuzumab: Independent confirmation of the p95 clinical cutoff. Presenting Author: Renata Duchnowska, Military Institute of Medicine, Warsaw, Poland Background: Expression of p95 in HER2-positive breast cancer is potentially a major determinant of trastuzumab resistance because p95 lacks the trastuzumab binding site while retaining kinase activity. Previously, an optimal clinical cutoff for a continuous measurement of p95 expression was defined in a training set of trastuzumab-treated MBC patients (Clin Cancer Res, 16:4226, 2010). Methods: Quantitative H2T (HERmark HER2-total) and p95 assays (VeraTag, Monogram Biosciences) were retrospectively performed on formalin-fixed, paraffin-embedded tumors from an independent series of 240 trastuzumab-treated MBC patients. The pre-specified cutoff for p95 was tested to determine whether p95 above the cutoff in the HER2-positive subset correlated with worse progression-free survival (PFS) and overall survival (OS), as was observed in the training set. P95 expression was also assessed by immunohistochemistry (IHC) using the same antibody as the p95 VeraTag assay. Results: In the subset of tumors assessed as H2T-positive (N⫽190), p95 VeraTag values above the pre-defined cutoff correlated with shorter PFS (HR⫽1.41; p⫽0.043) and shorter OS (HR⫽1.72; p⫽0.021) where both outcomes were stratified by hormone receptor status and tumor grade. The hormone receptor positive patients (N⫽78) primarily drove the shorter PFS (HR⫽2.08, p⫽0.0026) and OS (HR⫽2.28, p⫽0.0099) observed in the p95-high subset. In contrast to the quantitative p95 VeraTag measurements, p95 IHC was not significantly correlated with outcomes. Conclusions: A clinical p95 cutoff (VeraTag assay) predictive of clinical outcomes derived from a previous training dataset was confirmed in a second independent clinical series. In contrast, p95 IHC did not correlate with outcomes. The observed consistency in the p95 VeraTag cutoff across different cohorts of MBC patients treated with trastuzumab justifies additional studies employing blinded analyses in larger series of patients. Clinical relevance of p95 protein expression remains to be established in a controlled clinical trial.




Phase (Ph) I/II study of investigational Aurora A kinase (AAK) inhibitor MLN8237 (alisertib): Updated ph II results in patients (pts) with small cell lung cancer (SCLC), non-SCLC (NSCLC), breast cancer (BrC), head and neck squamous cell carcinoma (HNSCC), and gastroesophageal cancer (GE). Presenting Author: Bohuslav Melichar, Fakultní Nemocnice OlomoucOnkologická Klinika, Olomouc, Czech Republic Background: MLN8237 is an investigational oral AAK inhibitor being evaluated in pts with hematologic (Ph III) and non-hematologic malignancies. We report here Ph II results from a, 5-arm study of single agent MLN8237 in pts with advanced, predominantly refractory, solid tumors (NCT01045421; closed for enrolment). Methods: Pts ⱖ18 years with relapsed/refractory disease measurable by RECIST, ECOG PS 0 –1, and ⱕ2 prior (ⱕ4 for BrC pts) cytotoxic chemotherapy regimens were enrolled. Pts with stable brain metastases were eligible. Pts were treated at the recommended Ph II dose; 50 mg BID for 7 d in 21-d cycles. For each cohort, a Simon’s 2-stage design was employed for Ph II, with ⱖ2 responses required in the first 20 response-evaluable pts to proceed to stage 2. The primary endpoint was overall response rate (ORR) by RECIST v1.1; safety and progression-free survival (PFS) were key secondary endpoints. Results: As of Dec 2012, 47 SCLC, 23 NSCLC, 49 BrC, 45 HNSCC and 47 GE pts in Ph II were response-evaluable (median age, 61 yrs [range 30 – 88]). NSCLC did not proceed to stage 2. ORR was 9%, 6%, and 4% in HNSCC, GE, and NSCLC pts, respectively; median PFS was 2.7, 1.5 and 3.1 months. BrC and SCLC data are shown in the Table. 92% of pts had a drug-related adverse event (DRAE). 57% of pts had Gr ⱖ3 DRAEs; including neutropenia (38%), anemia (10%), stomatitis (8%), and thrombocytopenia (6%). 22 pts died during the study; none were study-drug related. Conclusions: Single-agent activity of MLN8237 was evaluated across a range of solid tumors with a manageable toxicity profile. Encouraging Ph2 data in BrC and SCLC pts suggest that MLN8237 warrants further evaluation in these tumor types. Clinical trial information: NCT01045421. SCLC

Treatment cycles, median (range) Responseevaluable, n ORR (PR*), n (%) Stable disease, n (%) Median PFS, months

BrC

All

Chemorefractory

Chemosensitive

All

Triplenegative

HER2ⴙ

HRⴙ

3 (1–10)

2 (2–6)

3.5 (1–10)

5 (1–20)

2 (1–14)

6 (1–19)

8 (1–20)

47

11

36

49

14

9

26

10 (21)

3 (27)

7 (19)

9 (18)

1 (7)

2 (22)

6 (23)

15 (32)

2 (18)

13 (36)

24 (49)

5 (36)

3 (33)

16 (62)

2.8

1.4

2.6

5.4

1.5

4.1

7.9

606


Phase II study of pertuzumab, trastuzumab, and weekly paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC). Presenting Author: Farrah Mikhail Datko, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Pertuzumab is a monoclonal antibody which binds to extracellular domain II of HER2 distally from trastuzumab, disrupting HER2 dimerization and signaling. Pertuzumab improves progression-free survival (PFS) and overall survival when combined with docetaxel/trastuzumab. We report results of a phase II study to evaluate the efficacy and safety of pertuzumab, trastuzumab and weekly paclitaxel. Methods: Patients (pts) with HER2⫹ MBC with 0-1 prior treatment (Rx) were eligible. Rx is weekly (w) paclitaxel (80mg/m2), q3w trastuzumab (loading dose 8mg/kg ¡ 6mg/kg), and q3w pertuzumab (flat loading dose 840mg ¡ 420mg). The primary endpoint is PFS at 6 months (mo). Evaluable pts are those who started study Rx and are assessed at 6 mo for PFS, including pts who progressed prior to 6mo. Secondary endpoints include response, safety (including cardiac events), and tolerability. Left ventricular ejection fraction (LVEF) is monitored by echocardiogram every 3 mo. Cardiac events are defined as symptomatic LV systolic dysfunction (LVSD), non-LVSD cardiac death, or probable cardiac death. Results: As of 1-18-13, 53 pts are enrolled; 36 are evaluable at 6 mo. At 6 mo, 29/36 pts (81%) are progression-free (4 CR, 14 PR and 11 SD); 7 pts progressed. The 6 mo PFS results for all patients will be updated. Median LVEF is 64% at baseline (range 50-72%), 63% at 3 mo (range 50-73%), and 62% at 6 mo (range 49-69%). There are no cardiac events to date. Of the 36 pts, grade 3/4 toxicities include fatigue (3 pts, 8%), peripheral neuropathy (2 pts, 6%), sepsis (1pt, 3%), cellulitis (1pt, 3%), neutropenia (1pt, 3%), and skin ulceration (1pt, 3%). There are no grade 3 diarrhea or febrile neutropenic events in the evaluable pts to date. Conclusions: The preliminary 6-month PFS is 81% (95% CI 67-91%) in evaluable patients. The study is closing to accrual. Treatment is ongoing, with few grade 3/4 toxicities and no signal of increased cardiac toxicity to date. This phase II study demonstrates efficacy and safety for pertuzumab with trastuzumab and weekly paclitaxel in HER2⫹ MBC. Clinical trial information: NCT01276041.

* Partial response.

607


608


Choice of primary endpoints in first-line phase III trials of HER2-negative or HER2-unknown metastatic breast cancer (MBC). Presenting Author: Sherko Kümmel, Breast Cancer Centre, Kliniken Essen-Mitte, Evangelische Huyssens-Stiftung, Essen, Germany

The Long-HER study: Clinical and molecular analysis of advanced HER2ⴙ breast cancer treated with trastuzumab and associated to long-term survival. Presenting Author: Enrique Espinosa, Hospital Universitario La Paz, Madrid, Spain

Background: OS is considered the most clinically relevant endpoint in cancer therapy trials, but OS can be confounded by post-trial therapy, particularly in settings with long post-progression survival (PPS). Based on statistical modelling with 50,000 simulated trials, Broglio & Berry [JCNI 2009] suggested the association between improved progression-based endpoints (eg, PFS) and OS is weak in settings with PPS ⬎12 months and can only be shown in very large trials. To test this hypothesis, we analysed efficacy outcomes and choice of primary endpoints in first-line MBC trials. Methods: Data wereanalysed from:randomised, controlled phase III trials comparing systemic chemotherapies and/or targeted agents; enrolling ⱖ150 pts; published in peer-reviewed journals from 2000 –2011. Trials that enrolled only HER2-positive MBC pts or evaluated non-EU approved agents were excluded. Results: Of27 trials, 1 (3.7%) had OS as the primary endpoint, while 18 (66.7%) had progression-based parameters, commonly PFS (9 trials, 33.3%). A significant increase in progression-based parameters was seen in 14 trials (51.9%). All 5 trials (18.5%) showing a significant OS benefit had a PPS ⬍12 months. Mean PPS was considerably longer in trials published in 2006 –2011 vs 2000 –2005 (14.1 ⫾ 4.0 vs 9.7 ⫾ 2.3 months, respectively), as was mean PFS (8.3 ⫾ 2.2 vs 6.6 ⫾ 1.6 months) and mean OS (25.4 ⫾ 5.6 vs 18.6 ⫾ 3.0 months). A weak correlation was seen between OS and PFS (Pearson’s coefficient r⫽0.32), but a higher correlation was seen in treatment arms with an OS benefit (r⫽0.59), as well as in treatment arms with a PPS ⬍12 months (r⫽0.43) or older studies (r⫽0.51). Data were insufficient to allow a valid analysis of the effect of further-line therapies or cross-over on OS (16 trials reported further-line therapies; 9 cross-over therapy). Conclusions: In support of the hypothesis by Broglio & Berry, a significant OS advantage was shown exclusively in trials with a PPS ⬍12 months. Due to the weak correlation between PFS and OS, it is difficult to determine the possible surrogacy of PFS for OS. Thus, as an OS benefit might be increasingly difficult to attain, progression-based parameters appear to be valid endpoints in MBC clinical trials.

Background: Some patients with advanced HER2⫹ breast cancer survive in the long-term after receiving trastuzumab-based therapy. Long-HER study was an observational, multicenter study that compared long-term survivors and a control group from the clinical and molecular point of view. Methods: Patients with metastatic HER2⫹ breast cancer that had been treated with trastuzumab-based therapy and had an objective response or stable disease for at least 3 years were included. A control group having a progression in the first year of therapy was selected for comparison (similar first-line therapy). A microarray platform was used to assess whole genome expression analysis in paraffin-embedded samples. Differential expression, ontology and analysis of metabolic pathways were performed. Results: 103 patients were registered, 71 of who had a long-term complete remission. Only 5 of these patients had received trastuzumab in the adjuvant setting: this was the only clinical factor associated to long-term survival. The molecular study included 35 Long-HER and 18 control samples. Gene expression ontology revealed alterations in HIF, apoptosis, and EGF, PI3K and p53 pathways. The PI3K pathway was mostly related with a poor response to therapy. Conclusions: trastuzumab-based therapy achieves long-term survival in a selected group of women with advanced HER2positive breast cancer. Whole genome analysis comparing such a group with a control group found some alterations that may predict early progression to trastuzumab.


34s 609


Phosphorylated ribosomal S6 (p-S6) as an indicator of HER2 signaling targeted drug resistance. Presenting Author: Gloria Wangrong YangKolodji, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, CA

610


Progression-free survival (PFS) as surrogate endpoint for overall survival (OS) in clinical trials of HER2-targeted agents in HER2-positive metastatic breast cancer (MBC): An individual patient data (IPD) analysis. Presenting Author: Stefan Michiels, Department of Biostatistics and Epidemiology, Institut Gustave Roussy, Villejuif, France

Background: Thetargeting of HER2/neu oncoprotein with trastuzumab (Herceptin) has altered the natural history of HER2⫹ breast cancer, however, its clinical benefit is limited by de novo and/or acquired resistance which almost always develops in the advanced setting. While several mechanisms of resistance have been postulated, none are validated for clinical use to best select patients for treatment. Our study aims were to identify predictive biomarkers based on reproducible differences in HER2 initiated signaling pathway observed in trastuzumab-resistant, HER2overexpressing human breast cell line models. Methods: Exposing HER2⫹ breast cancer cells BT474 and SKBR3 to 200 ␮g/ml of trastuzumab for 12 months, we established two trastuzumab-resistant, HER2 overexpressing breast cancer models BtRT and SkRT. MTT assay was used to characterize drug sensitivities of the cells. Immunocytochemistry and immunoblotting were used to assess the expression levels of HER2 signaling pathway proteins. The impact of trastuzumab on cell cycle process was analyzed by FACS. EdU incorporation was adapted to measure cell proliferation. Results: Trastuzumab-resistant cells had a higher proliferation rate and altered expression levels of HER2 signaling pathway proteins such as p-mTOR, p-S6k1, p-Akt, p-S6, and p-4EBP1, in comparison with parental cell lines. A downstream effector of HER2/Akt/mTOR pathway, phosphorylated ribosomal protein S6 (p-S6), was highly expressed and could not be suppressed by trastuzumab in the resistant cells. When the resistant cells were treated with selected HER2/Akt/mTOR pathway targeted drugs including lapatinib, erlotinib, linsitinib, AZD2014, MK-2206, everolimus and BEZ235, the level of p-S6 in these cells was found to be inversely correlated to the drug induced growth inhibition of these cells. Conclusions: p-S6 is a feasible and easy to measure molecular readout of HER2-targeted therapy resistance. This marker is a good candidate for further clinical validation to predict or efficiently measure a patient’s response to HER2/Akt/ mTOR targeted drugs and to test novel agents that would reverse resistance and improve the outcome of trastuzumab refractory, HER2 overexpressing breast cancer.

Background: The gold standard endpoint in randomized clinical trials (RCTs) in MBC is OS, which has the disadvantage of requiring extended follow-up and being confounded by subsequent anti-cancer therapies. Although therapeutics have been approved based on PFS, its use as a primary endpoint is controversial. This study, the first IPD meta-analysis of targeted agents in MBC, aimed to collect data from RCTs of HER2-targeted agents in HER2⫹ MBC, assessing to what extent PFS correlates with, and may be used as, a surrogate for OS. Methods: A search was conducted in April 2011. Eligible RCTs accrued HER2⫹ MBC patients (pts) in 19922008. Collaboration was obtained from industrial partners (Roche, GSK) for industry-led studies. Investigator-assessed PFS was defined as the time from randomization to clinical or radiological progression, or death. A correlation approach was used: at the individual level, to estimate the association between PFS and OS using a bivariate survival model and at the trial level, to estimate the association between treatment effects on PFS and OS. Squared correlation values close to 1.0 would indicate strong surrogacy. Results: The search strategy resulted in 2137 eligible pts in 13 RCTs testing trastuzumab or lapatinib. We collected IPD data from 1963 pts in 9 RCTs. One phase II RCT did not have sufficient follow-up data so that 1839 pts in 8 RCTs were retained (5 evaluating trastuzumab, 3 lapatinib); 6 out of 8 RCTs were first-line. At the individual level, the Spearman rank correlation using Hougaard copula was equal to r⫽0.66 (95% CI 0.65 to 0.66) corresponding to an r2 of 0.42. At the trial level, the squared correlation between treatment effects on PFS and OS was provided by R2⫽0.33 (95% CI -0.22 to 0.86) using Hougaard copula and R2⫽0.53 (95% CI 0.22 to 0.83) using log hazard ratios from Cox models. Conclusions: In RCTs of HER2-targeted agents in HER2⫹ MBC, PFS is moderately correlated with OS and treatment effects on PFS are modestly correlated with treatment effects on OS, similarly to first-line chemotherapy in MBC (Burzykowski et al JCO 2008). PFS does not completely substitute for OS.

611

612


Coexpression of HER3 as a predictor of survival in HER2-positve breast cancer patients. Presenting Author: Rupert Bartsch, Department of Medicine 1, Clinical Division of Oncology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria Background: Improved understanding of the pathobiology of the metastatic cascade as well as the identification of new prognostic markers may lead the path to the development of novel targeted agents in breast cancer patients (BC pts). Recently, HER3-expression was postulated as independent risk factor for metastatic spread. Methods: Pts of different BC subtypes (luminal, HER2-amplified, triple-negative) with metastatic disease were identified from a breast cancer data base. Tissue of the primary tumor was retrieved from the local pathology institute. Immunohistochemical staining of estrogen-receptor, progesterone-receptor, and HER2 and HER3 was performed. In HER2 equivocal cases, subsequent FISH analysis was performed. Results: Specimens of 110 pts (36/110 luminal, 35/110 HER2-amplified, 40/110 triple-negative) were available for this analysis. 23/110 (21%) specimens showed strong, complete, membranous staining for HER3 of at least 10% of all tumor cells. HER2/HER3 co-expression was observed in 12/110 (11%) specimens. HER3 showed a statistically significant association with HER2-expression (p⫽0.02; Chi square test). No correlation was observed for HER3-expression and overall survival (OS), incidence of brain metastases, or time to diagnosis of brain metastases in the entire patient cohort (p⬎0.05; log rank). In the HER2-amplified subgroup, however, HER3-expression was significantly associated with shorter OS (median 30 vs. 63 months; p⫽0.02; log rank test) and remained significant when entered into a multivariate model (p⫽0.02; Cox regression). Conclusions: HER2/HER3 co-expression is significantly associated with impaired OS in pts with HER2-positive metastatic breast cancer. Co-inhibition of HER2 and HER3 or inhibition of HER2/HER3 heterodimerization could improve prognosis of this patient population.


A phase I pharmacokinetics trial comparing PF-05280014 (a potential biosimilar) and trastuzumab in healthy volunteers (REFLECTIONS B32701). Presenting Author: Donghua Yin, Pfizer Inc., San Diego, CA Background: PF-05280014, a proposed biosimilar to trastuzumab, has an identical amino acid sequence and similar physicochemical and in vitro functional properties to trastuzumab. This study was designed to demonstrate PK similarity of PF-05280014 to trastuzumab from the US (trastuzumab-US) and EU (trastuzumab-EU), and between the licensed drugs. Safety and immunogenicity were also evaluated. Methods: In this doubleblind trial (NCT01603264), 105 healthy male volunteers, 18-55 years old were randomized 1:1:1 to receive a single 6 mg/kg IV dose of PF05280014, trastuzumab-US or trastuzumab-EU. All subjects provided informed consent. PK, safety, and immunogenicity assessments were conducted for 70 days. PK similarity for a given test-to-reference comparison was considered to be demonstrated if the 90% CI of the test-toreference ratio of the AUC from time 0 to the last time point (AUCT) and maximum concentration (Cmax) were within 80% – 125%. Results: The baseline demographics for the 101 subjects evaluable for PK were similar among 3 treatment arms. The 3 study drugs exhibited similar characteristics of target-mediated disposition and similar PK parameters (Table). The 90% CI for the ratios of Cmax, AUCT, and AUC0-⬁were within 80% – 125% for the comparisons of PF-05280014 to trastuzumab-EU or trastuzumabUS, and trastuzumab-EU to trastuzumab-US. Adverse events (AE) were similar for the 3 arms with treatment-related AEs reported by 71.4%, 68.6%, and 65.7% subjects in the PF-05280014, trastuzumab-EU and trastuzumab-US, respectively. No serious AEs were reported. Only 4 subjects had treatment interruptions; 2 discontinued. Only 1 subject (trastuzumab-EU) developed anti-drug antibodies after dosing. Conclusions: This study demonstrates PK similarity of PF-05280014 to both trastuzumab-US and trastuzumab-EU and of trastuzumab-EU to trastuzumabUS. The three study drugs also showed similar safety profiles. Clinical trial information: NCT01603264. Mean (ⴞSD) PK exposure estimates. Parameters (units) N Cmax (␮g/mL) AUCT (␮g·hr/mL) AUC0-ⴥ (␮g·hr/mL)

PF-05280014

Trastuzumab-EU

Trastuzumab-US

34 159 ⫾ 26 35700 ⫾ 6287 37130 ⫾ 6305

35 174 ⫾ 31 38510 ⫾ 6569 40330 ⫾ 6994

32 164 ⫾ 31 35870 ⫾ 6878 37310 ⫾ 6728




Safety of trastuzumab in HER2-positive primary breast cancer in Japan: Initial safety report for the large-scale cohort study (JBCRG C-01). Presenting Author: Naohito Yamamoto, Chiba Cancer Center, Chiba, Japan Background: The global randomized trials with trastuzumab (H) shows increased cardiotoxicity in patients (pts) with HER2 positive early breast cancer (BC). Safety in Japanese has not been fully evaluated. We evaluated the safety, especially focused on cardiotoxicity, of H adjuvant (adj) therapy in an observational study in Japan (UMIN000002737). Methods: Pts with histopathologically confirmed HER2 positive invasive BC were registered. Women with stage I-IIIC disease who received H as neo-adj and/or adj therapy were eligible. Mean LVEF at 3, 6, 9 and 18 months (M) was evaluated. The time points represent examination on day 60-120, 150210, 240-330 and 455-635, respectively. Results: A total of 2024 pts were registered from 56 institutes between July 2009 and June 2011. Data of 1875 pts were collected and finalized by September 2012, and 1800 of them were analyzed for safety. The median follow-up was 35 M. The mean age was 54.5 years. Elderly pts ⱖ60 years were 32.7%. Treatments after surgery were: concurrent chemotherapy (CT) and H in 20.1%, sequential CT and H in 43.5% and H monotherapy in 35.9%. Adverse events (AEs) associated with H were reported in 350 pts (19.4%) and grade (G) 3/4 AEs in 12 pts (0.7%). G 3/4 cardiotoxicity was reported in 7 pts (dysfunction, 4pts; angina, 1 pt; myocardial infarction, 1 pt and heart failure, 1 pt). The mean LVEF at the baseline was 69.4%. Mean LVEF at 3, 6, 9 and 18M were 66.9%, 66.3%, 65.3% and 66.3%, respectively. Compared to the baseline, LVEF decreased with significant difference at all time points (p⬍0.0001). LVEF decrease ⱖ10% occurred in 177 pts (during H treatment,130 and after H treatment, 47). Follow-up data were available in 66 pts: 34 pts recovered to the baseline. Mean time to recover was 262 days. The univariate analysis showed using anthracycline (odds ratio 2.312, p⫽0.003) was the only risk factor for cardiotoxicity. However, elderly, radiation concurrent/sequential treatment with CT and H had no impact. Conclusions: From our study, we found the AE profiles of H were consistent with previously known AEs. We found using anthracycline was the risk factor for cardiotoxicity at the moment. We should carefully follow pts and watch long-term safety. Clinical trial information: 000002737.

615


Prognostic significance of the chemokine CXCL13 in node-negative breast cancer. Presenting Author: Marcus Schmidt, Department of Obstetrics and Gynecology, Johannes Gutenberg University, Mainz, Germany Background: The chemokine CXCL13 is chemotactic for B cells. We examined the prognostic significance of CXCL13 mRNA expression in node-negative breast cancer. Methods: Microarray based gene-expression data for CXCL13 (205242_at) were analysed in four previously published cohorts (Mainz, Rotterdam, Transbig, Yu) of node-negative breast cancer patients not treated with adjuvant therapy (n⫽824). A meta-analysis of previously published cohorts was performed using a random effects model. Prognostic significance of CXCL13 on metastasis-free survival (MFS) was examined in the whole cohort and in different molecular subtypes (ER⫹/ HER2-, ER-/HER2-, HER2⫹). Independent prognostic relevance was analysed using multivariate Cox regression. Results: Higher RNA expression of CXCL13 was related to better MFS in a meta-analysis of the whole cohort (HR 0.88, 95% CI 0.83-0.94, P⬍0.0001). Prognostic significance was most pronounced in the HER2⫹ positive molecular subtype (HR 0.72, 95% CI 0.59-0.87, P⫽0.0009) as compared to ER⫹/HER2- (HR 0.86, 95% CI 0.76-0.98, P⫽0.0024) and ER-/HER2- (HR 0.85, 95% CI 0.75-0.98), P⫽0.02) carcinomas of the breast. CXCL13 showed independent prognostic significance (HR 0.81, 95% CI 0.7336 0.8982, P⫽0.0001) in multivariate analysis. In addition to CXCL13, only histological grade of differentiation (HR 2.20, 95% CI 1.41-3.42, P⫽0.0005) and tumor size (HR 1.72, 95% CI 1.13-2.61, P⫽0.012), but neither age nor HER2 status nor hormone receptor status retained an independent prognostic association with MFS. Conclusions: The chemokine CXCL13 has independent prognostic significance in node-negative breast cancer. Higher expression of CXCL13 is associated with improved outcome.

614


Association of MiR-1290 and its potential targets with characteristics of estrogen receptor ␣-positive breast cancer. Presenting Author: Yumi Endo, Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan Background: Recent analyses have identified heterogeneity in estrogen receptor (ER) ␣-positive breast cancer. Subtypes called luminal A and luminal B have been identified, and the tumor characteristics, such as response to endocrine therapy and prognosis are different in these subtypes. However, little is known about how the biological characteristics of ER-positive breast cancer are determined. Methods: In this study, expression profiles of microRNAs (miRNAs) and mRNAs in ER-positive breast cancer tissue were compared between ERhigh Ki67low tumors and ERlow Ki67hightumors by miRNA and mRNA microarrays. Results: Unsupervised hierarchical clustering analyses revealed distinct expression patterns of miRNAs and mRNAs. We identified a down-regulation of miR-1290 and up-regulations of 6 miRNAs in ERhigh Ki67lowtumors. We picked up 11 genes that were potential target genes of the selected miRNAs. Protein expression patterns of the selected target genes were analyzed in ERpositive breast cancer samples by immunohistochemistry: miR-1290 and its 4 putative targets, BCL2, forkhead box A1 (FOXA1), microtubule associated protein tau (MAPT) and N-acetyltransferase-1 (NAT1) were identified. Transfection experiments revealed that introduction of miR1290 into ER-positive breast cancer cells decreased mRNA and protein expression of NAT1 and FOXA1. Conclusions: Our results suggest that miR-1290 and its potential targets, NAT1 and FOXA1, might be associated with characteristics of ER-positive breast cancer.

616


Completion of adjuvant trastuzumab for older patients with early-stage breast cancer (BC). Presenting Author: Rachel A. Freedman, Dana-Farber Cancer Institute, Boston, MA Background: Few data are available about factors associated with completion of adjuvant trastuzumab in older women with BC. We examined rates and predictors of adjuvant trastuzumab completion for older women with early-stage BC. Methods: We used Surveillance, Epidemiology, and End Results (SEER)Medicare data to identify 1,319 patients ⱖ66 years with early-stage BC diagnosed between 1999-2007 who received trastuzumab. Completion of trastuzumab was defined as ⬎270 days of therapy. We examined patient, clinical and geographic characteristics associated with trastuzumab completion using multivariable logistic regression. We also assessed rates of hospital admissions for cardiac events during treatment. Results: Most of the 1,319 women were aged ⱕ76 (70%) and had a comorbidity score⫽0 (88%); 37% and 23% received anthracyline-taxane-based and taxane-based therapy, respectively, and 16% received trastuzumab without chemotherapy. Overall, 982 women (74.5%) completed trastuzumab. Factors associated with completion are shown below. During treatment, 56 patients (4.2%) had 65 hospital admissions for cardiac events (3.0% in those who completed trastuzumab versus 8.0% in those who did not, p⬍.001). Conclusions: One-quarter of older patients who initiated adjuvant trastuzumab did not complete therapy. Older women, Hispanic women, those with more comorbidity, and those receiving anthracyclinetaxane-based chemotherapy all had lower odds of completion. Rates of hosptializations for cardiac events were higher in those who did not complete therapy. Adjusted odds ratio for completion (95% confidence interval) Age 66-70 71-75 76-80 >80 Race/ethnicity White Hispanic/other/unknown Non-Hispanic black Comorbidity 0 1 2ⴙ Year of diagnosis 2005 Hormone receptor status Positive Negative Surgery Mastectomy Breast-conserving surgery No surgery/unknown Chemotherapy Anthracycline/taxane Anthracycline based Taxane based Single taxane Other chemotherapy Other/no chemotherapy

-1.0 .8 (.6-1.1) .6 (.4-.8) .5(.4-.7) -1.0 .7 (.5-.99) .8 (.5-1.3) -1.0 .1 (.3-.8) .3 (.2-1.5) -1.0 4.2 (2.5-6.9) -1.0 .8 (.7-1) -1.0 1.3 (1-1.6) 1.1 (.5-2.4) -1.0 1.2 (.8-1.8) 2.0 (1.6-2.6) 1.0 (.8-1.4) .6 (.3-1.2) 1.1 (.8-1.5)


36s 617


Adverse prognostic impact of intratumor heterogeneous HER2 gene amplification in patients with breast cancer. Presenting Author: Carmen Criscitiello, Division of Medical Oncology, European Institute of Oncology, Milan, Italy

618


When less is better: Safety and efficacy of combination of trastuzumab and continuous low oral dose chemotherapy (HEX) as first-line therapy for HER2-positive advanced breast cancer (ABC)—First early results from a phase II trial on behalf of Gruppo Oncologico Italia Meridionale (GOIM). Presenting Author: Laura Orlando, Medical Oncology & Breast Unit, Brindisi, Italy

Background: There is increasing recognition of the existence of intratumoral heterogeneity of the human epidermal growth factor receptor (HER2), which affects interpretation of HER2 positivity in clinical practice and may have implications for patient prognosis and treatment. Only patients (pts) with HER2 positivity - defined as 3⫹ by IHC or FISH amplified defined as a HER2 gene to chromosome 17 (HER2/CEP17) ratio ⱖ 2.0 - are eligible to receive trastuzumab treatment. Limited information is available on the prognosis of pts with HER2 2⫹ or FISH test with a HER2/CEP17 ratio ⬍ 2.0. Methods: We retrospectively analyzed data from 455 consecutive early BC pts with HER 2⫹ and HER2/CEP17 ratio ⬍ 2.0 who underwent surgery after 2007. The association between HER2/CEP17 ratio and other known prognostic factors was evaluated with multivariable linear regression models. The role of HER2/CEP17 ratio on recurrence free survival was assessed with multivariable Cox regression models. Results: Fifty-one percent of the evaluated pts were node negative, 51% were postmenopausal, 93% had ER positive BC and 85% had Ki-67 ⱖ14%. The mean HER2/CEP17 ratio was 1.27 (SD⫽0.3). A significant positive relationship between HER2/CEP17 ratio and Ki-67 was observed (p⬍0.01). During a median follow-up time of 2.7 years, 40 recurrences were observed (15 locoregional events and 25 distant metastases). Overall, the association between HER2/CEP17 and the risk of recurrence was not significant. From subgroup analysis, a significant interaction between HER2/CEP17 ratio and nodal involvement emerged (p⫽0.02). Among pts with node-negative disease, pts with HER2/CEP17 ratio ⱖ1.27 were at higher risk of recurrence with respect to pts with HER2/CEP17 ratio ⬍ 1.27 (adjusted HR 4.0, 95% CI 1.01-15.9). Conclusions: Among pts with BC and HER2 intratumoral heterogeneity, HER2/CEP17 ratio ⱖ1.27 could have a strong prognostic role in node negative HER2 2⫹ BC, thus suggesting potential future therapeutic approaches in this setting of pts.

Background: Clinical activity of the combination of chemotherapy plus trastuzumab in HER2⫹ ABC has been well documented. We report the first results in terms of activity and safety of the combination of trastuzumab plus metronomic capecitabine and cyclophosphamide as first line therapy in HER-2 positive ABC. Methods: Patients (pts) at first relapse or with synchronous metastasis, were treated with trastuzumab (4 mg/kg, loading dose 6 mg/kg) plus oral capecitabine (1500mg/daily) and cyclophosphamide (50 mg/daily). Primary end-point was overall response rate (ORR), secondary end-points time to progression (TTP), clinical benefit rate (CBR; PR⫹ CR ⫹ prolonged SD for ⱖ 24 weeks) and tolerability. The optimal two-stage design was applied. Results: A total of 31 pts with measurable ABC, tumors scored as ⫹3 positive for HER-2 or FISH ⫹, no pretreated with chemotherapy or trastuzumab for advanced disease have been enrolled, 28 actually valuable for response and toxicity. Median age was 59 years (range 42-87), visceral metastases were present in most patients (61%). Median number of cycles was 12 (range 1-37⫹). The ORR was 61 % (95% CI, 41-78%), with 1 CR (3.6 %) and 16 PR (57.1%). 9 patients had prolonged SD (32%). The CBR was 82.1% (95% CI , 63%-94%). Five progressions were observed (18%). Median TTP was 7 months (range 2- 19 ⫹ months). Ten pts received more than 20 courses. Worst toxicities were grade 2 hand-foot syndrome in 4 pts, grade 2 anemia in 4 pts, grade 2 nausea in 2 pts and diarrhea grade 3 in 1 pt. Cardiac toxicity grade 2 in 1 pts. Alopecia was not reported. Conclusions: Combination of trastuzumab and low dose metronomic oral chemotherapy in HER-2 ⫹ breast cancer has shown clinical activity. The tolerability was excellent and allowed the prolonged delivery of the combination. Thus, the patients accrual is ongoing to the pre-set target of 66 patients. Clinical trial information: 2009-017083-16.

619

620


Multicenter phase II trial of neoadjuvant carboplatin, weekly nabpaclitaxel, and trastuzumab in stage II-III HER2ⴙ breast cancer: A BrUOG study. Presenting Author: Natalie Faye Sinclair, Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI Background: Patients (pts) with human epidermal growth factor receptor-2 amplified (HER2⫹) breast cancers (BrCa) who achieve a pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) ⫹ trastuzumab (T) have an excellent prognosis (Cortazar, SABCS 2012). We tested a novel NAC ⫹ T regimen, designed to avoid potential cardiac and other toxicities associated with anthracyclines (A) and eliminate steroid premedication by replacing standard paclitaxel with nab-paclitaxel (nP). Methods: Clinical stage IIA-IIIC HER2⫹ BrCa pts received single agent either nP or T, with research biopsies and MRIs obtained before and after, then carboplatin (Cb) AUC 6 q3wks, nP 100 mg/m2and T 2 mg/kg weekly x 18 wks. If present, residual tumor was collected at surgery. Post-op pts complete a year of T; other adjuvant treatment is at MD discretion. Endpoints include clinical ⫹ pathologic response (pCR is defined as no invasive BrCa in breast ⫹ axillary nodes), residual cancer burden (RCB), treatment delivery and toxicities. Results: 53 pts (of 60 planned) are evaluable for response, median age 51 (34-72). Median delivered dose intensity for nP was 89 mg/m2/week; nP doses were omitted or reduced for neutropenia (ANC) (in 20% of pts) and neurotoxicity (Nt) (5%). Cb was reduced for thrombocytopenia (tcp) in 15%. Grade 3-4 toxicities: ANC 65%, tcp 22%, anemia 37%, Nt 7%. Serious adverse events: febrile neutropenia (5 pts), infections w/o neutropenia (4), vomiting, diarrhea or dehydration (7), thrombosis (2). LVEF fell by ⬎10% in 3 pts with no clinical CHF. Response data are tabulated below: 28 pts (53%) achieved pCR or RCB class I; 15/21 who did not received A-based adjuvant chemotherapy. Of 38 clinically nodepositive pts, 26 (68%) were node-negative at surgery. Conclusions: The Cb/nP/T regimen was well tolerated, with pCR rates comparable to those reported with A-containing regimens. Final treatment and response data will be presented; correlative studies will be reported separately. Clinical trial information: NCT00617942. Cohort All patients ERⴙ ERStage IIA-IIIA Stage IIIB-C

N

pCR

pCRⴙ RCB I

Clinical CR

Clinical CRⴙPR

53 28 25 47 6

24 (45%) 11 (39%) 13 (52%) 22 (47%) 2 (33%)

28 (53%) 13 (46%) 15 (60%) 26 (55%) 2 (33%)

35% 32% 38%

76% 72% 79%


The potential of miR-630, an IGF1R regulator, as a predictive biomarker for HER2-targeted drugs. Presenting Author: Claire Corcoran, School of Pharmacy and Pharmaceutical Sciences & Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland Background: Innate or acquired resistance to current HER-targeting drugs indicates that their use for HER2-overexpressing breast cancer (BC) treatment may be compromised. miRNAs may have potential as diagnostic, prognostic and predictive biomarkers for treatment response, as well as therapeutic targets and replacement therapies. We aimed to investigate miR-630 as a predictive biomarker for response to a range of HER-drugs and as a potential target for increasing sensitivity to the same. Methods: Following global miRNA profiling using taqman low density arrays, the reduced expression of miR-630 in cells and corresponding conditioned medium (CM) of HER2-positive BC cell lines with acquired/innate lapatinib (L) resistance (SKBR3-LR, HCC1954-LR, MDA-MB-453) was confirmed by qPCR. miR-630 mimics and inhibitors were used to assess cell response to current (L, trastuzumab (T)) and emerging (neratinib (N), afatinib (A)) HER-targeting drugs. Targetscan prediction software and immunoblotting were used to determine miR-630 regulated proteins. Results: miR-630 levels were significantly decreased in cells and CM with acquired lapatinib resistance compared to their age-matched controls. Decreased miR-630 was also observed for innately resistant MDA-MB-453 compared to innately sensitive SKBR3.Administration of miR-630 mimic significantly sensitised resistant cells to all 4 drugs tested. Specifically, miR-630 mimic increased the anti-proliferative effects of L by 31% (SKBR3-LR), 9% (HCC1954-LR) and 9% (MDA-MB-453). Similarly, miR-630 mimic improved the efficacy of T (11-35%), N (4-17%) and A (9-25%); (range for different cell lines). Inhibition of miR-630 in sensitive parent cells induced an insensitive/ resistant phenotype, significantly reducing the efficacy of all 4 drugs tested. Interestingly, miR-630 also significantly regulates cell motility, invasion and anoikis resistance implicating this miRNA in overall cell aggressiveness. Conclusions: This data suggests a potential role for miR630 as a predictive biomarker for HER-targeting drugs as well as an additional therapeutic target for HER2-overexpressing BC. Acknowledgements: MTCI SFI SRC (08/SRC/B1410), MKF and HEA’s PRTLI Cycle 5 to TBSI.




Phase II study of lapatinib in combination with vinorelbine, as first- or second-line therapy in women with HER2-overexpressing metastatic breast cancer. Presenting Author: Helen K. Chew, University of California, Davis Cancer Center, Sacramento, CA Background: Lapatinib (L), an inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2) is approved in combination with capecitabine for second-line treatment of HER2⫹ metastatic breast cancer (MBC). Vinorelbine (V)is a semi-synthetic vinca alkaloid approved for use in patients (pts) with MBC. A previous phase I trial provided a maximum tolerated dose of L plus V. Methods: This was a multicenter, phase II study (LPT111110; NCT00709618) to evaluate the efficacy and safety of L plus V in women with histologically confirmed stage IV HER2⫹ MBC, ⱕ1 prior chemotherapeutic regimen (no prior L or V was allowed; prior trastuzumab was permitted) and a Zubrod performance status of 0-2. Pts received L (1500 mg daily) plus V (20 mg/m2IV on Days 1, 8, 15) in a 4-week treatment cycle until disease progression or study withdrawal. Primary endpoint: overall response rate (ORR). Secondary endpoints: progression-free survival (PFS), overall survival, time to response (TTR), duration of response (DOR), time to progression, and safety assessments. Results: The study was terminated after three years due to slow enrollment; 60 pts were planned and 44 enrolled and were treated. The ORR was 41% (95% CI: 26.4%-55.4%; 4 complete responses, 14 partial responses). Investigator-assessed median (95% CI) PFS, TTR, and DOR were 24.1 (16.9-36.7), 7.5 (7.1– 8.1), and 32.0 (18.0-42.3) weeks, respectively. Survival data are not available since data collection was terminated after discontinuation of study treatment. All pts experienced at least 1 adverse event (AE). Conclusions: The combination of L plus V resulted in a 41% ORR and was generally well tolerated. However, definitive conclusions could not be drawn as the study was terminated early and not powered for inference testing. Further exploration of L plus V is warranted to clearly define the role of this novel combination in the treatment of HER2⫹ MBC. Clinical trial information: NCT00709618. AEs of interest

Grade 2

N (%) Grade 3

Grade 4

Diarrhea Nausea Neutropenia Fatigue Rash Febrile neutropenia

9 (20) 8 (18) 6 (14) 8 (18) 9 (20) 0

5 (11) 2 (5) 7 (16) 2 (5) 1 (2) 1 (2)

0 0 15 (34)* 0 0 2 (5)

623


Correlation between poly (ADP-ribose) polymerase (PARP) and phosphop65 expression in human breast cancer. Presenting Author: Lisa Caroline Klepczyk, University of Alabama at Birmingham, Birmingham, AL Background: Despite the efficacy of targeted agents in patients with HER2⫹ breast cancer, resistance often develops necessitating novel treatment strategies. Poly (ADP-ribose) polymerase inhibitors (PARPi) are known to target tumors with aberrant DNA repair. We previously reported sensitivity of HER2⫹ breast cancer cells to PARPi independent of a DNA repair deficiency but rather due to attenuation of NF-kB signaling. In this study, we investigated the expression of PARP and the active NF-kB subunit phospho-p65, indicators of activity for these pathways, in human HER2⫹ breast tumors and compared to HER2- tumors. Methods: Patients with breast cancer treated at the University of Alabama at Birmingham between the years 1999 and 2012 were identified. Formalin-fixed, paraffinembedded tissue blocks were stained for PARP and phospho-p65 and evaluated independently by two blinded physicians, including a boardcertified pathologist. An H-score was calculated by multiplying the percent of tumor cells with staining intensity of 0, 1, 2, and 3 and subsequently adding these together for a final score of 0-300. Nuclear and cystosolic staining were scored separately for both proteins. Results: Forty-six HER2⫹ and 38 HER2- patients with available tissue were identified; however, only 41 HER2⫹ and 32 HER2- cases had tumoral tissue at the time of analysis. PARP and phospho-p65 were found to be almost exclusively nuclear in both groups. The mean nuclear PARP score was 122.3 in HER2⫹ cases compared to 61.6 in HER2- cases (p value ⬍0.0001). Mean nuclear phospho-p65 scores were 89.0 and 59.4 in HER2⫹ and HER2- groups, respectively (p value 0.0008). Additionally, a significantly positive correlation was observed between PARP and phospho-p65 levels. Conclusions: Our study suggests that HER2⫹ breast cancers have elevated PARP and NF-kB activity compared to HER2- cancers. Furthermore, a direct correlation between PARP and phospho-p65 levels was found. When combined with our previously published preclinical findings, the current research supports the potential clinical utility of PARPi in patients with this aggressive form of breast cancer.

622


Elevated pretreatment serum biomarkers and correlation with progressionfree (PFS) and overall survival (OS) in first-line trastuzumab-treated metastatic breast cancer. Presenting Author: Suhail M. Ali, Penn State Hershey Medical Center, Hershey, PA Background: Approximately one-half of HER2-positive breast cancer patients will respond tofirst-line trastuzumab-containing therapy. However, in those patients with an initial trastuzumab response, most will progress within a year with acquired resistance. Since trastuzumab treatment is also now used in the HER2-positive adjuvant breast cancer setting, trastuzumab resistance will continue to be a recurring clinical problem, and better predictive and prognostic biomarkers are urgently needed. Methods: Seven serum biomarkers (carbonic anhydrase 9 (CA9), endoglin, HER2, IGF-1R, tissue inhibitor of metalloproteinase-1 (TIMP-1), urokinase-type plasminogen activator (uPA), and VEGF-A (isoform 165) were measured using ELISA assays in 81 metastatic breast cancer patients before starting first-line trastuzumab-containing therapy. The endoglin and IGF-IR ELISAs were from R&D Systems; others were from WILEX/Oncogene Science, Cambridge, MA. PFS and OS were analyzed using the Kaplan-Meier method and Cox modeling with continuous pretreatment serum biomarker variables. Results: For univariate PFS analysis, higher pretreatment serum biomarkers (except IGF-1R and VEGF-A) predicted reduced PFS (p⬍0.05) to first-line trastuzumab-containing therapy. In multivariate PFS analysis, only serum CA9 (p⫽ 0.038) remained a significant independent covariate. In univariate OS analysis, higher pretreatment serum biomarkers (except IGF-1R and VEGF-A) were prognostic for reduced OS (p⬍0.05). In multivariate analysis for OS, TIMP-1 (p⫽0.001) and CA9 (p⫽0.04) remained significant independent prognostic factors, as well as line of chemotherapy (3 vs. 2 or 1 line)(p⫽0.005), and hormone receptor status (ER and/or PR positive vs. negative)(p⫽0.013). Conclusions: Higher pretreatment serum CA9 (a marker of hypoxia) predicted reduced PFS, and higher serum CA9 and TIMP-1 predicted reduced OS in metastatic breast cancer patients treated with first-line trastuzumab-containing therapy. These serum biomarkers deserve further study in larger trials of HER2-targeted breast cancer treatment. Supported by a grant from Komen for the Cure.

624


Cardiac toxicity in breast cancer patients treated with dual HER2 blockade: A meta-analysis of randomized evidence. Presenting Author: Antonis Valachis, Department of Oncology Sörmland Mälarsjukhuset, Eskilstuna, Sweden Background: The dual antiHER2 blockade has been shown promising results in patients with HER2-positive breast cancer. Whether this treatment strategy jeopardizes the risk for cardiac adverse events is unclear. We conducted a meta-analysis of randomized trials to investigate the risk of cardiac adverse events when a combination of anti-HER2 therapies is used. Methods: We searched Medline, the Cochrane library, as long as the electronic abstract databases of the major international congresses’ proceedings to identify randomized trials that evaluated the administration of anti-HER2 monotherapy (lapatinib or trastuzumab or pertuzumab) versus anti-HER2 combination therapy with or without chemotherapy in breast cancer. Study outcomes were the congestive heart failure (CHF) grade ⬎/⫽ 3 and left ventricular ejection fraction (LVEF) decline ⬍ 50% or more than 10% from baseline. We calculated pooled odds ratios (ORs) and 95% Confidence Intervals (CI) with the Peto method. Results: Six trials were considered eligible. Overall incidence results for CHF in the combined antiHER2 therapy and the antiHER2 monotherapy were 0.88 % (95% CI: 0.47% - 1.64%) and 1.49 % (95% CI: 0.98% - 2.23%). The incidence of LVEF decline was 3.1 % (95% CI: 2.2% – 4.4%) and 2.9% (95% CI: 2.1% - 4.1%) respectively. The OR of CHF was 0.58 (95% CI: 0.26-1.27, p-value⫽ 0.17) while the OR of LVEF decline was 0.88 (95% CI: 0.53-1.48, p-value⫽ 0.64). In subgroup analyses, there were no significant differences in CHF or LVEF decline among different treatment settings or types of antiHER2 therapy. Conclusions: This meta-analysis offers substantial randomized evidence from trials with well-defined cardiac evaluations that a dual anti-HER2 therapeutic approach does not increase the risk for cardiac toxicity.


38s 625


Estimated life years saved with trastuzumab in first-line HER2ⴙ metastatic breast cancer from 1999 to 2013. Presenting Author: Mark Danese, Outcomes Insights, Inc., Westlake Village, CA

626


What are NCI-designated cancer centers using for breast cancer HER2 testing? Presenting Author: Kalliopi P. Siziopikou, Northwestern University, Feinberg School of Medicine, Chicago, IL Background: After 15 years of HER2 testing in breast cancer, various testing methods are used in practice. Studies comparing methods are published but no consensus exists on which method is best. Our study provides a benchmark on the use of breast HER2 testing methods in leading U.S. cancer centers. Methods: We conducted an IRB-approved web survey of 58 NCI cancer centers (pathologists and oncologists) providing adult breast cancer care. The survey included 14 questions on breast HER2 testing methods, and reflex and retest practices. We analyzed results using simple frequencies and Fisher’s exact test. Results: We achieved a response rate of 98% (57/58 sites). In this cohort, 42% (24/57) of sites conduct HER2 testing for breast cancer using an IHC method with reflex to FISH. Of these, all sites reflex IHC 2⫹ results and 54% (13/24) automatically reflex IHC results beyond 2⫹ (see table, results are not mutually exclusive). Concurrent primary FISH and IHC testing is conducted at 32% (18/57) of sites; FISH only testing at 18% (10/57); concurrent primary SISH and IHC testing at 5% (3/57); concurrent primary CISH and IHC testing at 2% (1/57), and CISH only testing at 2% (1/57) of sites. The choice of testing protocol had no correlation with the size of institution, metro vs rural location, NCCN membership, or whether the site acts as a reference lab. However, sites where oncologists always or often request a specific test method were more likely (75%, 21/28) to use FISH as a primary method vs as a reflex method (38%, 9/24), p⫽.0108. Repeat HER2 testing on surgical tumor samples, after the core biopsy, was reported by 47% of sites (27/57); retesting of relapsed patients by 63% (36/57); and retesting for progressive metastatic disease by 56% (32/57). Conclusions: For HER2 breast biomarker testing, concurrent FISH and IHC testing and expanded reflex testing, beyond IHC 2⫹ results, have become a common practice at the NCI designated cancer centers. Automatically reflex Reflex based on Primary HER2 based on primary order from medical test result test result oncologist

Background: Trastuzumab was approved in the United States (US) in September 1998 for the treatment of HER2⫹ metastatic breast cancer (MBC). This model estimates the total number of life years saved (LYS) in US women treated with trastuzumab over a 15-year period (1999-2013). Methods: Using US population estimates and cancer registry-based incidence data, we estimated the number of women with recurrent stage I-III or de novo stage IV HER2⫹ MBC by year, age, hormone receptor, and nodal status. Trastuzumab utilization was based on published studies of HER2 testing rates, true positive rates in the community, and treatment initiation rates. Survival was estimated by extrapolating survival data pooled across 5 trials and 2 observational studies separately for women treated with trastuzumab and with chemotherapy alone. Few studies reported survival in women with HER2⫹ MBC without trastuzumab (N⫽3). Sensitivity analyses were conducted by estimating overall survival from the initial phase 3 trial (67% of placebo patients crossed over to trastuzumab after progression; HR⫽0.80), and assuming a higher risk reduction to account for crossover effects in clinical trials (HR⫽0.60). Results: In the base case, approximately 83,462 women with HER2⫹ MBC were estimated to receive 1st line trastuzumab over a 15-year period. The pooled median overall survival across studies without and with trastuzumab was 21.2 and 35.5 months, respectively. Patients were projected to live a total of 216,290 life years if trastuzumab had not been available and if they received chemotherapy only. These same patients were estimated to live a total of 294,877 life years with first-line trastuzumab, for an incremental benefit of 78,587 LYS. In sensitivity analysis, total LYS ranged from 48,334-96,360. Conclusions: Real-world evidence supports a median overall survival of approximately 36 months in women with HER2⫹ MBC receiving 1st line trastuzumab. Using a population-based, conservative model, we found that trastuzumab use has resulted in ⬎ 75,000 life years over 15 years in women with HER2⫹ MBC. Future research is warranted to examine the characteristics, experiences, and outcomes among women living longer with HER2⫹ MBC.

IHC 0 IHC 1ⴙ IHC 2ⴙ IHC 3ⴙ Triple positive (ERⴙ, PgRⴙ, HER2ⴙ) Triple negative (ER-, PgR-, HER2-)

627

628


Prognostic and predictive value of a low estrogen receptor expression in breast cancer: A retrospective study from a reference center. Presenting Author: Caroline Diorio, Centre des maladies du sein Deschênes-Fabia, Centre de recherche du CHU de Québec, Faculté de médecine, Université Laval, Quebec City, QC, Canada Background: Threshold of estrogen receptors positivity in breast cancer has been lowered to ⱖ1% of stained cells by immunohistochemistry testing. This change was based on experts’ recommendations from the 2009 St Gallen International Expert Consensus and from the 2010 guidelines of the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP). However few studies support these guidelines and the benefit of treating weakly positive estrogen receptor tumors (1-9%) is unknown. Methods: We identified 2221 breast cancer patients with estrogen receptors tested by ligand-based assay, treated and followed in our institution between 1976 and 2008. Date and cause of death were identified through linkage to Quebec Mortality File. A multivariate Cox proportional-hazards model was used to assess the effect of estrogen receptor levels on breast cancer mortality in patients who received hormonal therapy (tamoxifen). Results: In patients with low estrogen receptors, 17% (383 patients) were within 0-3 fmol/mg of cytosol and 12% (266 patients) were within 4-9 fmol/mg of cytosol. Patients with estrogen receptor levels of 0-3, 4-9, 10-19, 20-49, and ⱖ50 fmol/mg of cytosol had a 20-year breast cancer survival rate of 56%, 56%, 63%, 71% and 60% respectively. From the 2221 patients, 661 (29.8%) received hormonal therapy. In these patients, estrogen receptor levels of 0-3, 4-9, 10-19, 20-49 and ⱖ50 fmol/mg of cytosol were associated with lower breast cancer mortality (HR (p-value) of 1.00 (reference), 0.59 (0.09), 0.19 (⬍0.0001), 0.26 (⬍0.0001) and 0.31 (⬍0.0001) respectively); with significant mortality reduction only for estrogen receptor levels ⱖ10 fmol/mg of cytosol. Conclusions: A weak expression of estrogen receptors (⬍10 fmol/mg) in breast cancer is associated with increase breast cancer mortality. Our results did not show a significant benefit to treat these patients with hormonal therapy as oppose to those with estrogen receptor levels ⱖ10 fmol/mg of cytosol. To further support these findings, a similar study should be repeated in patients with estrogen receptors tested by immunohistochemistry.

13% (3/24) 21% (5/24) 100% (24/24) 25% (6/24) 8% (2/24)

21% (5/24) 25% (6/24) 0 21% (5/24) 4% (1/24)

17% (4/24)

13% (3/24)


Lack of efficacy of adjuvant lapatinib in HER2-negative breast cancer (HER2–ve BC): Analysis of patients in the TEACH trial. Presenting Author: Yanin Chavarri Guerra, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, Mexico, Mexico Background: Benefit from trastuzumab (T) in patients (pts) with HER2–ve tumors by central laboratory FISH testing was shown in an exploratory analysis of the NSABP B-31trial and confirmed by levels of expression of HER2 mRNA. DNA sequencing studies demonstrate that undetected HER2 mutations may drive tumor growth. It is hypothesized that pts with BC deemed as HER2–ve based on amplification may still benefit from anti-HER2 therapy. We undertook an exploratory analysis of disease free survival (DFS) in pts in TEACH whose tumors were HER2–ve or borderline by central FISH testing. Methods: TEACH, a randomized, double-blind, placebo (P)-controlled trial in 33 countries, evaluated lapatinib (L) in reducing relapse risk in T-naive pts pretreated with chemotherapy for HER2⫹ BC. L showed a hazard ratio (HR) for DFS compared with P of 0.83 (95% confidence interval [CI] 0.70-1.00); P⫽.053 in the ITT population (n⫽3147) and in pts with HER2⫹ BC by central FISH [HR: 0.82 (0.67-1.00); P⫽.04]. We conducted an exploratory analysis of DFS in pts with borderline or HER2–ve tumors by central FISH. Estimated DFS times were calculated using a stratified log-rank test. HR was estimated by a stratified Cox regression model. Results: 657 pts (21%) did not have centrally confirmed HER2⫹ BC (L: 341 and P: 316) in the ITT population: 425 had negative (HER2:CEP-17 ratio ⬍1.8) or borderline (ⱖ1.8 –⬍2.0) FISH testing (L: 218 and P: 207), 216 were unevaluable due to insufficient tissue or sample failed to hybridize (L: 114 and P: 102) and 16 were not centrally tested. In the 425 pts with centrally confirmed HER2–ve or borderline FISH results with 27 events in L and 34 in P, the HR for DFS in L compared with P was 0.94 (0.56-1.57). The percentage of pts with DFS at 4 yrs was 85.0% (79.5%-90.4%) in L and 81% (75.1%-87.1%) in P. Conclusions: Although L showed efficacy in pts with centrally confirmed HER2⫹ BC in the TEACH trial, our analysis did not show benefit in pts whose tumors were HER2–ve or borderline by central FISH. The TEACH trial shows once again that quality control of HER2 testing is crucial and central laboratory testing should be considered for non-specialized centers worldwide. Clinical trial information: NCT00374322.




Double-blind, randomized, parallel group, phase III study to demonstrate equivalent efficacy and comparable safety of CT-P6 and trastuzumab, both in combination with paclitaxel, in patients with metastatic breast cancer (MBC) as first-line treatment. Presenting Author: Young-Hyuck Im, Division of Hematology and Medical Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea Background: CT-P6(C) is an anti-HER2 MoAb, a biosimilar to trastuzumab (T). This trial is a global phase III study to compare C with T, both in combination with paclitaxel (P) as first-line treatment in women with HER2⫹ MBC. Methods: 475 patients with centrally confirmed HER2⫹ MBC were randomized to receive either C⫹P (n⫽244) or T⫹P (n⫽231). Patients had to have a baseline LVEF ⱖ50% and no history of serious cardiac disease. Study medication was as follows: C or T 8 mg/kg i.v. (day 1), followed by 3-weekly C or T 6 mg/kg. P (175 mg/m23-weekly) was co-administered. The primary endpoint was overall response rate (ORR) as determined by independent review. Pooled analysis with data from phase I/IIb (NCT01084863) and III studies (NCT01084876) was predefined and endorsed by the EMA. Patient safety was monitored throughout the study by an independent data monitoring committee. Treatment was continued until disease progression, death or patient’s withdrawal. Results: In the pooled ITT population, ORR was 57% for C⫹P and 62% for T⫹P (difference: 5%; 95% CI: -0.14, 0.04) during the first 8 cycles of treatment. The limits of the 95% CIs for the difference in the proportions of responders were contained within the pre-defined range [-0.15, 0.15] required for equivalence. Median time to progression and median time to response were 11.07 vs. 12.52 months (P ⫽0.10), and 1.38 vs. 1.38 months (P ⫽0.37) for C⫹P and T⫹P, respectively. Frequency of treatment-related AEs is shown in the Table. Conclusions: Equivalence of C and T was observed for ORR in patients with HER2⫹ MBC in combination with P as first-line therapy. Secondary efficacy endpoints also supported the comparability between C and T. C was well tolerated with a safety profile comparable to that of T. Clinical trial information: NCT01084876.

Serious AEs All AEs# Infusion reaction/hypersensitivity# Cardiotoxicity# Infection# #

CⴙP (Nⴝ244)

TⴙP (Nⴝ231)

Total (Nⴝ475)

33 (13.5%) 87 (35.7%) 38 (15.6%) 8 (3.3%) 3 (1.2%)

28 (12.1%) 95 (41.1%) 60 (26.0%) 10 (4.3%) 0 (0.0%)

61 (12.8%) 182 (38.3%) 98 (20.6%) 18 (3.8%) 3 (0.6%)

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General Poster Session (Board #12E), Sat, 1:15 PM-5:00 PM

Longer-term cardiac safety and outcomes of dose dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) and trastuzumab (H) with and without lapatinib (L) in patients (pts) with early breast cancer (BC). Presenting Author: Patrick Glyn Morris, Memorial Sloan-Kettering Cancer Center, New York, NY Background: The addition of H to chemotherapy has improved outcomes in HER2-positive early BC. This approach is associated with (w/) an increased risk (⬍4%) of congestive heart failure (CHF). At a median f/u of 36 months, the addition of anti-HER2 Rx to dose-dense (every 2 weeks) anthracyclinetaxane therapy (Rx) was not associated with excess cardiotoxicity. Here we report the incidence of NYHA Class III/IV CHF in 2 phase II studies with longer follow-up. Methods: We conducted a retrospective review of pts w/ HER2 ⫹ early stage BC treated at MSKCC and DF/HCC on two trials: In trial A - pts received dd AC (60/600 mg/m2) x 4 ¡ T (175mg/m2) x 4 (w/ pegfilgrastim) w/ H x 1 year. Trial B differed w/ use of weekly T (80mg/m2) x 12 and the addition of L (1000mg orally daily) x 1 year. In both trials, H was begun after completion of AC and concurrent with T. Left ventricular ejection fraction (LVEF) was prospectively assessed by multi-gated acquisition scan serially throughout Rx. Results: Trial A enrolled 70 pts and Trial B enrolled 95 pts w/ the median age of 46 years (range 27-73 years). Overall, the 5-year distant disease-free survival (DDFS) for trials A and B is 92% (95%Cl; 83-97%) and 89% (95%CI; 81-94%), respectively. The baseline median LVEF was 68% (range 52-81%). In total, 28 of 165 (17%) pts had pre-existing hypertension. Now at a median follow-up of 84 and 57 months respectively, only one (1.4%, 95%CI; 1.36-7.7%) and 4 (4.2%, 95%CI; 4.2-10.4%) pts developed CHF. Since our earlier report, 1 additional CHF event occurred (Trial B) at month 44. Conclusions: Longer follow-up of these 2 studies demonstrate that dd AC ¡ TH with or without L is associated w/ a low risk of CHF. This is consistent w/ the long-term cardiac toxicity reported from the randomized phase III studies of H w/ conventionally scheduled anthracycline-based regimens (with or without taxanes). DDFS outcomes are also encouraging. Clinical trial information: NCT00482391.

Treatment related with C or T.

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Utility of 2D-speckle tracking echocardiography in early identification of left ventricular dysfunction in antineoplastic therapy-induced cardiotoxicity. Presenting Author: Carmela Coppola, National Cancer Institute, Pascale Foundation, Naples, Italy

Effect of afatinib alone and in combination with trastuzumab in HER2positive breast cancer cell lines. Presenting Author: Alexandra Canonici, Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin, Ireland

Background: ErbB2 is overexpressed in about 25% of breast cancers; in the heart, it modulates myocardial development and function. Trastuzumab (T), an anti-ErbB2 inhibitor, has improved the prognosis of patients with breast cancer, but is related to an increased risk of asymptomatic left ventricular (LV) dysfunction (3-34%) and heart failure (2-4%). Conventional measures of ventricular function, such as fractional shortening (FS) and ejection fraction (FE) are insensitive in detecting early cardiomyopathy induced by antineoplastic therapy. Aim of this study is to evaluate whether myocardial strain by 2D-speckle tracking (ST) is able to identify early LV dysfunction in mice treated with doxorubicin (D) and T, alone or in combination (D⫹T) and to relate data of cardiac function with tissue alterations. Methods: Cardiac function was measured with FS, by M-mode echocardiography, and with radial myocardial strain with ST in sedated C57BL/6 mice (8-10 wk old) at time 0, 2 and 6 days of daily administration of D, T, D⫹T and in a control group. In excised hearts, we evaluated TNF␣ and CD68 by immunohistochemistry; interstizial fibrosis was analyzed with picrosirius red staining. Results: FS was reduced in group D and D⫹T at 2 days (52⫹0.2% and 49⫹2% respectively), both p⬍0.001 vs 60⫹0.4% (sham), while in group T it decreased only at 6 days (49⫹1.5% vs 60⫹0.5%, p⫽.002). In contrast, after 2 days, myocardial strain was already reduced not only in D and D⫹T, but also in T alone: 43⫹3%, 49⫹1%, and 44⫹7%, respectively, all p⬍0.05 vs sham (66⫹0.6%). Cardiotoxicity was associated with significant alterations in extracellular matrix remodeling as confirmed by an increase of interstizial collagen with D (4.56%), T (2.17%) and D⫹T (3.77%)at 6 days p⬍0.05 vs sham (1.17%) and by increased cardiac inflammation in fact the myocytes were positive for TNF␣ and CD68 cells/mm2at 6 days in group D (16.46% and 155 respectively), in group T⫹D (12.35% and 74.16) and in group T (5.65% and 72.32) p⬍0.01 vs sham (0.56% and 2.3). Conclusions: Myocardial strain identifies LV systolic dysfunction earlier than conventional echocardiography and can be a useful tool to predict cardiotoxicity in this setting.

Background: Trastuzumab and lapatinib have been shown to significantly improve the prognosis for HER2 positive breast cancer patients. However, resistance is a significant clinical problem. The aim of this study is to assess the activity of afatinib, an irreversible pan-HER tyrosine kinase inhibitor, in HER2 overexpressing breast cancer cell lines, including trastuzumab and/or lapatinib resistant cells. Methods: Using proliferation assays, the effect of afatinib was assessed alone and in combination with trastuzumab in HER2 positive cell lines. The effect of afatinib on HER2, Erk and Akt was determined by immunoblotting. Results: The eight HER2 positive breast cancer cell lines tested, including trastuzumab and/or lapatinib resistant cells, responded to afatinib with IC50values ranging from 5 to 80 nM. The combination of afatinib and trastuzumab was additive in four trastuzumab sensitive cell lines and one model of acquired trastuzumab resistant HER2 positive breast cancer. In the remaining three trastuzumab and/or lapatinib resistant cell lines, combined treatment with trastuzumab and afatinib showed no enhancement compared to afatinib alone. Finally, afatinib decreased the phosphorylation of HER2 and Erk in all cell lines tested. Conclusions: Our results suggest that afatinib has activity in HER2 positive breast cancer, including trastuzumab and/or lapatinib resistant breast cancer. We also demonstrate that afatinib in combination with trastuzumab may be more effective than either agent alone in trastuzumab sensitive breast cancer. Effect of afatinib alone, and in combination with trastuzumab, in HER2positive breast cancer cell lines. Sensitive/resistant

BT474 SKBR3 MDA-MB-361 SKBR3-L SKBR3-T HCC1419 EFM-192A SKBR3-TL

% Growth inhibition

Trastuzumab

Lapatinib

Afatinib IC50 (nM)

Trastuzumab (1 ␮g/ml)

Afatinib

Trastuzumab ⴙ afatinib

S S S R R R S R

S S S R S S S R

4.7 ⫾ 0.9 5.9 ⫾ 2.4 6.0 ⫾ 1.0 6.3 ⫾ 2.1 9.3 ⫾ 3.2 10.5 ⫾ 0.3 12.6 ⫾ 2.1 80.4 ⫾ 5.2

60.4 ⫾ 3.4 44.5 ⫾ 3.1 41.6 ⫾ 6.1 23.3 ⫾ 8.7 1.9 ⫾ 3.3 0.5 ⫾ 8.6 31.7 ⫾ 10 17.5 ⫾ 7

2 nM - 29.7 ⫾ 3.1 10 nM - 59.7 ⫾ 1.1 10 nM - 49.8 ⫾ 4.9 20 nM - 54.2 ⫾ 7.5 5 nM - 7.7 ⫾ 4.0 5 nM - 41.0 ⫾ 7.4 5 nM - 25.1 ⫾ 7.9 20 nM - 56.1 ⫾ 6.5

80.2 ⫾ 3.7 79.3 ⫾ 2.1 65.1 ⫾ 6.6 58.6 ⫾ 7.9 29.0 ⫾ 4.8 49.4 ⫾ 9.4 65.3 ⫾ 2.7 60.9 ⫾ 5.9


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Identification of patients at high risk of recurrent disease development by detection of HER2-positive disseminated tumor cells in bone marrow of patients with HER2-negative tumors. Presenting Author: Rebecca Aft, Washington University in St. Louis, St. Louis, MO Background: A subpopulation of patients with HER2-negative tumors benefit from HER2 therapy. HER2 expression can be discordant between primary tumors and metastases. We have examined the bone marrow (BM) of early stage breast cancer patients for HER2-expression by disseminated tumor cells (DTCs) and the association with disease recurrence. Methods: BM was collected from clinical stage II-III breast cancer prior to treatment between 2007-2011. Gene expression of ERBB2 was determined by multiplex PCR (Fluidigm Biomark [FB]). Positive expression was defined as at least 1.4 fold above a pool of normal BM. Expression was confirmed by single gene PCR and Nanostring nCounter (NC) assays. Cox proportional model was used to estimate hazard ratios (HR). Results: BM from 74 patients was analyzed. Median follow-up was 3.4 years (range 8 months-84 months). 24% of the patients developed metastatic disease. For ERBB2 detection, there was excellent correlation between NC and the FB assays (kappa⫽0.87, 95% CI [0.62, 1.00]). Nine patients expressed ERBB2 in their BM. Five of the 9 patients had Her2-positive tumors and were treated with trastuzumab. One of 5 (20%) of these patients relapsed whereas 75% (3 of 4) of the patients with HER2-negative tumors but ERBB2-positive DTCs relapsed. Patients with HER2-negative tumors/ERBB2-positive BM were found to have a greater hazard of recurrence than patients with HER2-negative tumors/ERBB2-negative BM or ERBB2-positive DTCs treated with trastuzumab (p⫽.0069; Table). Those patients with ERBB2positive BM who did not receive trastuzumab had a decreased disease free survival (p⫽.016). Conclusions: We have found discordant expression of HER2/ERBB2 in tumors and BM of stage II-III breast cancer patients. The presence of ERBB2 expressing DTCs in patients with HER2-negative tumors identifies a subset of patients at increased risk of recurrence who may benefit from targeted HER2-therapy. HER2 status of tumor and DTCs and risk of recurrence. Tumor

DTCs

No. of patients

P value

Hazard ratio

95% CI

HER2HER2ⴙ

ERBB2ERBB2-

50 15

0.44

1 1.58

(0.495, 5.06)

HER2ⴙ

ERBB2⫹

5

0.60

0.57

(0.072, 4.56)

HER2-

ERBB2⫹

4

.0069

6.24

(1.65, 23.6)

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Predictive factors for pathologic complete response (pCR) to trastuzumab (T)-based neoadjuvant chemotherapy in HER2ⴙ breast cancer (BC) women treated in the National Cancer Institute (NCI) of Mexico. Presenting Author: Erika Sifuentes, Instituto Nacional de Cancerología, Mexico City, Mexico Background: Neoadjuvant treatment identifies subgroups of patients (pts) with different prognosis. In HER2⫹ BC, some tumors have been reported to be more sensitive to anti-HER2 therapy than others. We conducted an exploratory analysis in HER2⫹ BC women who received T-based neoadjuvant chemotherapy. Methods: Clinico-pathologic data from HER2⫹ BC pts who received neoadjuvant chemotherapy and T between January 2007 and May 2012 at the NCI were identified. Estrogen receptor (ER), progesterone receptor (PR) and HER2 expression were determined by immunohistochemistry and/or FISH. pCR was defined as complete absence of invasive tumor in breast and axillary nodes. Proportion differences were tested using the Chi-square test. A generalized linear model was used for multivariate analysis. Results: 243 pts received T-based neoadjuvant chemotherapy for localized HER2⫹ BC tumors. Median age was 49 (26-72) years. 96% had positive axillary nodes at diagnosis and median tumor size was 5.5 (1.5-20) cm. 49.4% had hormone receptor (HR) ⫹ (ER⫹ and/or PR⫹) and 50.6% HR negative (ER- and PR-) tumors. 63.4% pts achieved pCR. HR negative tumors reached significantly higher pCR rates than HR ⫹ tumors (69.9% vs. 56.7%, p⫽0.034). Pts with inflammatory BC (n⫽27) had a trend to achieve pCR less frequently than the non-inflammatory tumors (48.1% vs. 65.3%). Those who received taxane-anthracyline sequence chemotherapy (n⫽20) achieved pCR in 70% of the cases vs. 62.8% with anthracyclinetaxane sequence. Differences among other variables (age, tumor size, nodes and HER2 positivity ⫹⫹/⫹⫹⫹) were not significant. Variables that positively influenced pCR were HR negative status (p⫽0.015), noninflammatory BC (p⫽0.082) and chemotherapy sequence (p⫽0.086). Conclusions: HR negative HER2⫹ BC tumors were associated with higher pCR, consistent with neoadjuvant trial reports. Preclinical data suggest bi-directional crosstalk between HER2 and ER pathways, which might influence anti-HER2 agents and chemotherapy sensitivity for tumors co-expressing both receptors. New strategies are needed to overcome resistance for HER2⫹ HR⫹ BC tumors.

.

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Brain and tumor penetration of carbon-11–labeled lapatinib ([11C]Lap) in patients (pts) with HER2-overexpressing metastatic breast cancer (MBC). Presenting Author: Azeem Saleem, Imanova Centre for Imaging Sciences, London, United Kingdom

The importance of adjusting for treatment crossover bias in oncology clinical trials: An analysis of the EGF104900 trial in metastatic breast cancer (mBC). Presenting Author: Norman Paracha, Oxford Outcomes, Oxford, United Kingdom

Background: About a third of HER2-overexpressing (HER2⫹) breast cancer pts will develop brain metastases in the course of their disease. Drug access to normal brain and brain metastases is therefore key to prevention and treatment of cerebral metastases. To provide direct evidence of Lap drug access and evaluate whether therapeutic doses of Lap act as a substrate for efflux transporters, thereby increasing Lap concentrations, we performed positron emission tomography (PET) studies with [11C]Lap. Methods: Pts with HER2⫹ MBC with an ECOG of ⬍3 were grouped into 2 cohorts: with at least one 1-cm diameter brain metastasis or without brain metastases and underwent 90-minute dynamic cranial PET-CT scans after IV administration of a microdose (⬍1 mg) of [11C]Lap before and after 8 days of oral Lap (1500 mg once daily). Arterial blood samples were performed to assess [11C]Lap radioactivity contribution in blood and plasma, and the fraction of plasma [11C] radioactivity corresponding to metabolites. Tissue timeradioactivity curves (TACs) were generated and [11C]Lap exposure (AUC; area under TAC) derived for normal brain and brain metastases. Signal dissection of the total image activity was performed to remove the contribution of blood volume to the image and the actual tissue contribution due to [11C]Lap obtained. Results: 6 pts (3 with brain metastasis) were recruited. Arterial plasma analysis revealed that [11C]Lap contributed to ⬎80% of activity in plasma at 60 minutes. Tissue data revealed [11C]Lap signal in normal brain was low with no appreciable uptake observed when corrected for blood volume contribution. [11C]Lap uptake was higher in brain metastases compared with normal brain and appreciable, even after correction for tissue blood volume contribution. Uptake was also observed in extra-cranial normal tissue. There was no difference in [11C]Lap uptake in normal brain and metastases between treatment-naïve and posttreatment scans. Conclusions: [11C]Lap uptake in brain metastases was higher than in normal brain. [11C]Lap drug access to brain metastases might therefore indicate possible efficacy against HER2⫹ brain metastases. Clinical trial information: NCT01290354.

Background: EGF104900 is a phase III trial in mBC that compared lapatinib ⫹ trastuzumab (LAPTRZ, n⫽146) with LAP monotherapy (LAP, n⫽145). The trial allowed LAP subjects to switch to LAPTRZ on documented disease progression (following ⱖ4 weeks of LAP). Conventional intent-to-treat (ITT) analysis does not control for potential bias due to treatment crossover. The Rank Preserving Structural Failure Time Model (RPSFTM) estimates event times had patients not switched, and performs re-censoring. The approach preserves randomization and ordering of patients’ observed survival times, assuming that patients switching benefit from the treatment effect seen in those initially randomized to the treatment arm. The method is recognized by NICE, UK, as an appropriate method for adjusting for crossover bias. Methods: 53% of LAP subjects crossed over to LAPTRZ. Analyses were stratified by hormone receptor status and visceral/non-visceral disease. RPSFTM was implemented in Stata (using White’s strbee procedure). Absolute overall survival (OS) was estimated using a parametric survival distribution fitted to the trial data with/without crossover adjustment. The unadjusted ITT Cox hazard ratio (HR) was compared with the crossover adjusted RPSFTM estimate, and the absolute gain in OS evaluated. Results: Median OS in the LAPTRZ and LAP arms was 61 and 41 weeks, respectively (ITT HR 0.74, 95% CI: 0.56, 0.96); RPSFTM crossover-adjusted median OS for LAP was 32 weeks (RPSFTM HR 0.52; 95% CI: 0.29, 0.92). Mean OS for LAPTRZ was estimated under a Weibull distribution as 74 weeks, compared with 57 (ITT) and 44 (RPSFTM) weeks for LAP. Treatment with LAPTRZ was estimated to extend mean OS by 30 weeks controlling for treatment crossover using RPSFTM compared with 17 weeks by ITT. Conclusions: Oncology trials are often subject to treatment crossover. Controlling for potential treatment crossover bias can result in greater estimates of gain in OS compared with ITT analysis. In the context of mBC such differences are of great importance to patients, clinicians, and healthcare payers. Treatment crossover-analyses are therefore also important for estimating costeffectiveness in oncology.




Role of HER3 expression and PTEN loss in patients with HER2overexpressing metastatic breast cancer (MBC) patients who received taxane plus trastuzumab treatment. Presenting Author: Yeon Hee Park, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

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Biomarq: A novel approach to automated HER2-analysis of circulating tumor cells (CTCs). Presenting Author: Aurelia Pestka, Department of Gynecology and Obstetrics. Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany

Background: The HER3 receptor is a key member of ErbB family and preferentially signals through the PI3K pathway. Formation of dimers between HER3 and HER2 seems to be crucial for HER2-driven signals in HER2 overexpressing tumors. Given the fact that HER2-HER3 is considered the most active signalling dimer of the ErbB system, HER3 activity may contribute to the resistance of trastuzumab. PTEN plays a wellestablished role in the negative regulation of the PI3K pathway. Our aim of this study was to investigate the role of HER3 and PTEN expression in patients with HER2 overexpressed MBC. Methods: One-hundred twenty-five MBC patients who were treated with taxane plus trastuzumab chemotherapy as the first line therapy were included in this analysis. Immunohistochemical stainings (IHC) with HER3 and PTEN antibody were conducted retrospectively. Results: Median age was 48 years. HER3 IHC was graded from 0 to 3. PTEN IHC was scored as multiplication of intensity and proportion from 0 to 300. The patients who had negative HER3 stain showed better progression free survival (PFS) to taxane plus trastuzumab chemotherapy than those positive HER3 stain (p⫽0.001, median PFS 21 vs. 11 mo.). The patients who had PTEN score of more than 20 showed longer PFS than those PTEN score of 20 or less than 20 (p⫽0.006, median PFS 13 vs. 9 mo.). The patients who had PTEN score of more than 20 showed longer overall survival (OS) than those PTEN score of 20 or less than 20 (p⫽0.005, median OS 48 vs. 25 mo.). HER3 negativity and PTEN loss were identified as independent risk factors for PFS [Hazard Ratio (HR) 0.4 (95% CI 0.3-0.8 for HER3 negativity; HR 2.1 (95% CI 1.2-3.7) for PTEN loss]. However, PTEN loss (HR 3.1 [95% CI 1.6-6.3]) was identified as an independent risk factor for OS. Conclusions: HER3 and PTEN expression may be predictive markers for trastuzumab treatment in HER2-positive MBCs. PTEN expression may have a potential predictive and prognostic biomarker for trastuzumab treatment.

Background: Targeted treatment approaches directed against CTCs might improve the outcome of metastatic breast cancer patients. Accurate and reproducible assessment of the CTC phenotype is a requirement to use CTCs as treatment targets. The aim of this study was to test the suitability of the automated BioMarQ System (Veridex, USA) – an enhancement of the FDA-approved CellSearch System (Veridex USA) for CTC detection– for assessing the Her2-status of CTCs based on fluorescence and cellmorphology data. Methods: Data on classification of the Her2-status into four groups (0, ⫹, ⫹⫹, ⫹⫹⫹) obtained by visual inspection of CTCs after immunocytochemical staining with the CellSearch System, and of BioMarQgenerated automatic measures on fluorescence and cell morphology via image clips generated from raw images were available for 329 CTCs from 17 metastatic breast cancer patients. A discriminant analysis was performed to test whether linear combinations of the fluorescence and/or cell morphology measures allow a separation of CTCs into four groups according to the visual classification of their Her2-status. Results: The highest concordance with the visual classification was obtained by a set of three discriminant functions based on the five variables mean-, maximum- and integrated fluorescence intensity, cell area (␮m2), and coefficient of variation for the pixel fluorescence values within a cell. All five variables differed significantly among the 17 patients (Kruskal-Wallis-test, all p ⬍ 0.001). Based on the three discriminant functions, 74.5% of all cases were correctly assigned to the four visually obtained categories (6 out of 8 CTCs classified as ⫹⫹⫹; 57 out of 80 as ⫹⫹; 17 out of 65 as ⫹, 165 out of 176 classified as 0). Conclusions: Our preliminary analysis shows that discriminant functions derived from measures on fluorescence and cell morphology generated by BioMarQ correctly assigned the Her2-status of CTCs to the four visually obtained categories in 75% of all cases. Further analysis based on a larger number of Her2-positive CTCs, and cross validation by FISH-analysis will provide deeper insight into the suitability of BioMarQ for objectively assessing the Her2-status of CTCs.

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Second-line treatment of HER2ⴙ metastatic breast cancer (MBC): Trastuzumab (T) beyond progression or lapatinib (L)? A retrospective database study. Presenting Author: Rinat Yerushalmi, Institute of Oncology, Davidoff Cancer Center, Beilinson Hospital, Rabin Medical Center, Petach Tiqva, Israel Background: L and T “beyond progression” (TBP) for MBC pts who progressed on 1st line therapy with T, are both reimbursed in Israel since 1/2010. The relative efficacy of L vs. T when combined with chemotherapy in 2nd line therapy for HER2⫹ MBC is unknown. In this retrospective database study we compared outcomes of 2ndline L or TBP, in the daily practice (⬙real life⬙) in Israel. Methods: Using the computerized databases of Clalit Health Services’ (CHS), Israel’s largest health care provider, we identified all MBC pts that received 2nd line anti HER2 therapy, with either L or TBP after a 1stline protocol containing T, between 1/1/2010 and 31/12/2011. Pts characteristics and treatments were retrieved. The primary end point was overall survival (OS) defined as the time interval between date of initiation of 2nd line anti HER2 therapy and death or last day of follow-up. Secondary endpoint was progression free survival (PFS), defined as duration of 2nd line therapy. Results: The study population included 83 pts (28 L and 55 TBP). Mean age (59.9 vs. 61.4) and average Charlson co-morbidity index score (6.54 vs. 6.13) were similar between the cohorts. The groups differed in rates of prior adjuvant T (32.1% vs. 10.9%, p⫽0.017). The interim cutoff date for analysis was 31/12/2012 (allowing at least 12 months of follow-up). Median OS was 10.0 months for L pts (95% CI: 7.41–12.59) and was not reached for TBP, with a total of 31 deaths: 19 [67.9%] in the L group and 22 [40.0%] in the TBP group. A Cox regression showed an adjusted hazard ratio (HR) of 1.44 (95% CI 0.74-2.81), not significant (p⫽0.28).Prior adjuvant therapy with T was found to be a significant cofounder; HR⫽3.16 (95% CI 1.52-6.56). Median PFS was 6.0 months (95% CI: 4.31–7.69) for L and 7.0 months (95% CI: 4.30-9.70) for TBP, with a Cox regression adjusted HR of 0.87 (95% CI: 0.50-1.52), not statistically significant (p⫽0.87). Conclusions: In this retrospective database analysis, our interim results suggest no statistically significant difference in OS and PFS between L and TBP, as 2nd line therapy for HER2⫹ MBC, however the data showed a strong trend toward a survival benefit with TBP. A longer follow-up is required.


Prognostic value of HER2 on breast cancer survival. Presenting Author: Nora Katzorke, Department of Gynecology and Obstetrics, Heinrich-HeineUniversity Düsseldorf, Düsseldorf, Germany Background: HER2 overexpression and overamplification have originally been described as a prognostic factor indicating a poor prognosis. However the highly effective anti-HER2 treatment was approved in 2006 after several large randomized trials showing that the prognosis in HER2 positive women could be improved. Few data has been generated comparing HER2 positive patients treated with trastuzumab with comparable HER2 negative patients. Aim of this analysis was to investigate the prognostic relevance of HER2 status in a post trastuzumab approval study. Methods: The SUCCESS trial is an open-label, multicenter, randomized controlled, phase III study comparing FEC-docetaxel (Doc) vs. FEC-Doc-gemcitabine (Doc-G) regime and 2 vs. 5 year treatment with zoledronat in 3754 patients with primary breast cancer (N⫹ or high risk). All patients were treated per protocol with trastuzumab, if HER2 status was shown to be positive by local pathology. Furthermore HER2 status was a stratification factor. The prognostic value of HER2 status with respect to overall survival (OS) and progression-free survival (PFS), disregarding the above stated treatment arms, was studied with Cox proportional hazards regression models in univariate as well as multivariate analyses adjusted for age, BMI, tumor size, nodal status, grading, estrogen receptor status and progesterone receptor status. Results: 2628 patients were included into this analysis. Median Follow up time was 4.8 years, 221 deaths and 412 recurrences were recorded until data base closure. HER2 was not a prognostic factor in the univariate analysis (OS: HR⫽ 0.86, 95% CI: 0.63 to 1.19; PFS: HR ⫽ 0.95, 95% CI: 0.76 to 1.19). In the multivariate analysis all of the above stated prognostic factors were of prognostic relevance. HER2 was of prognostic relevance with a HR of 0.67 (OS, 95% CI: 0.48 to 0.92) and 0.79 (PFS, 95% CI: 0.62 to 0.99) indicating that patients with a positive HER2 status had a better prognosis. Conclusions: Patients treated with trastuzumab showed a more favourable prognosis compared to HER2 negative patients in this prospectively randomized trial, possibly due to the therapeutic effect of HER2-targeted treatment.


42s 641


Liposome-encapsulated doxorubicin plus cyclophosphamide followed by trastuzumab plus docetaxel as neoadjuvant therapy for HER2-positive breast cancer (BC): A multicenter single-arm phase II study. Presenting Author: Silvana Saracchini, ⬙S. Maria Degli Angeli⬙ Hospital, Pordenone, Italy Background: Trastuzumab combined to sequential chemotherapy with taxanes and anthracyclines as primary treatment achieved high rates of pathologic complete response (pCR) in HER2 positive BC. Liposomeencapsulated doxorubicin (DLNP) shown equal efficacy but minor cardiotoxicity compared to doxorubicin. This phase II study aimed to evaluate the activity and safety of trastuzumab associated with chemotherapy for early or locally advanced HER2 positive BC. Methods: Primary objective of the study was pCR defined as the absence of residual invasive cancer both in the breast and regional nodes. Preoperative treatment included DLNP (60 mg/mq iv) plus cyclophosphamide (600 mg/mq iv) every 3 weeks for 4 cycles followed by docetaxel (35 mg/mq iv) plus trastuzumab (4 mg/mq loading dose iv, then 2 mg/mq iv) weekly for 16 weeks. Patients (pts) were scheduled to receive adjuvant trastuzumab (8 mg/mq loading dose, then 6 mg/mq iv) every 3 weeks for 12 cycles and radiation and hormonal therapy according to guidelines. Results: From December 2005 to September 2011, 43 pts were treated at 3 centers in Italy. 39 out of 43 pts were evaluable for the purpose of the study. Median age was 53 years (range: 31-78). The majority of pts had cT2 (63%), grade 3 (93%), N⫹ (77%) ER positive (56%) and MIB-1 ⱖ20% (77%). pCR was reported in 19 (49%) of 39 pts. The histological regression score (Von Minckwitz G, J Clin Oncol 2012) is shown in the Table. A significant correlation between MIB-1 ⱖ20% at baseline and pCR was observed (p⫽0.018). Pts with pCR had a time to response (29.4 weeks, 95% CI 28-31) lower than pts without pCR (32.9 weeks, 95% CI 27-39). No cardiac toxicity or discontinuation of trastuzumab was reported. After a median follow-up of 30 months only 2 pts relapsed, both with pCR. Conclusions: This study confirms the high activity of trastuzumab combined with chemotherapy based on anthracyclines and taxanes as primary treatment for HER2 positive BC. DLNP is an active and safe option to minimize cardiotoxicity. Regression grade (RG) No or minimal (RG 0-1) Focal invasive (RG 2) Only noninvasive (RG 3) No residual tumor (RG 4)

643

n (totalⴝ 39)

%

8 12 9 10

20% 31% 23% 26%


A Bayesian meta-analysis of the prognostic value of circulating HER2/neu levels in breast cancer (BC) patients. Presenting Author: Walter P. Carney, WILEX/Oncogene Science, Cambridge, MA Background: Many reports have shown the prognostic value of HER-2 measured in tumor tissue or in blood. In 2009, Finn et.al. showed that in a study of 579 MBC patients whose serum HER-2 levels (sHER-2) were constantly below normal had a longer PFS than patients with a sHER-2 level constantly above normal. Patients who converted from above normal to less than normal during therapy had a longer PFS than the opposite change. Methods: We performed a Bayesian meta-analysis of 12 studies where all sHER-2 levels were measured using an FDA cleared sHER-2 test with a standard cutoff of 15ng/ml. We chose a Bayesian approach because a “meta-analysis” is a natural extension of the Bayesian view that current knowledge is the result of prior knowledge modified by the data. After an in depth literature search, we selected 12 publications based on the following criteria. Baseline levels were available from either early stage or late stage patients who had at least a 2 year disease free or progression free survival as indicated by a Kaplan-Meier (K-M) curve. Results: The analysis included 4030 BC patients of which 1106 patients had baseline levels ⬍ 15ng/ml and 2924 patients had baseline values ⬎15ng/ml. From the K-M curves, we estimated the number of recurrences up to 24 months in each group and prepared a 2x2 table for each study. We determined the odds ratio (OR) for the 12 studies which ranged from 0.57 to 74. A posterior distribution for the aggregated 12 studies can be represented by a Dirichlet distribution. 10,000 estimates of the aggregated OR indicated that there is a 95% credibility that the odds of a woman with baseline sHER-2 ⬎15ng/ml recurring at or before two years is between 3.39 and 4.57 times higher than the odds of a woman whose baseline sHER-2 was ⬍ 15ng/ml recurring at or before two years. Conclusions: This meta-analysis agrees with previous studies that serum HER-2 levels ⬎ 15ng/ml can be a strong prognostic indicator for women with Breast Cancer and that managing therapy regimens to maximize the decrease in serum HER-2 levels could be important target in treating patients.

642


Comparison of discontinuation, health care resource utilization (HRU), and costs between metastatic breast cancer (mBC) patients (pts) who received trastuzumab (T) in an office clinic versus outpatient hospital setting. Presenting Author: Melissa Brammer, Genentech, Inc., South San Francisco, CA Background: T treatment for mBC may be administered in an office clinic or outpatient hospital setting. This study assesses the impact of the site of care on T discontinuation risk, HRU, and costs. Methods: Adult women with mBC who received ⱖ2 T infusions in an outpatient hospital or office clinic setting were selected from the US-based Humana database (2007-2012). Pts were required to be continuous eligible in their healthcare plan for ⱖ6 months prior and ⱖ2 months following the first T infusion (index date). Pts were classified, based on their index site of care, into one of the following cohorts: 1) office clinic, or 2) outpatient hospital. Outcomes were measured from the index date up to the end of continuous eligibility/data availability, a change in the site of care, or 12 months after the index date, whichever occurred first. Treatment discontinuation (gap ⱖ45 consecutive days) was compared between cohorts using multivariate Cox-proportional hazards model. Monthly healthcare costs (2012 USD) and HRU were compared between cohorts using multivariate generalized linear/two-part models, and multivariate negative binomial regression models, respectively. Results: A total of 280 pts met the inclusion criteria; 64% and 36% in the office clinic and outpatient hospital cohort, respectively. Baseline characteristics were similar between cohorts. However, differences were found in terms of insurance plan type, year of index date and comorbid conditions (chronic pulmonary disease and peripheral vascular disorder). After adjusting for confounding factors, the outpatient hospital cohort had a 1.5 time higher risk of treatment discontinuation (p⫽.043) and incurred an incremental monthly cost of $1,954 (p⫽⬍.001), mainly driven by higher office clinic and outpatient hospital costs ($1,483 p⫽.016). No differences were observed in HRU. Conclusions: Pts in the office clinics cohort were less likely to discontinue T and were associated with lower monthly total healthcare costs. Future research should examine the impact early discontinuation may have on clinical outcomes.

644


Exposure– efficacy relationship of trastuzumab emtansine (T-DM1) in EMILIA, a phase III study of T-DM1 versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic breast cancer (MBC). Presenting Author: Bei Wang, Genentech, Inc., South San Francisco, CA Background: T-DM1 is an antibody– drug conjugate composed of trastuzumab (T), a stable thioether linker, and the potent cytotoxic agent DM1. In the phase III study EMILIA, median PFS and OS were significantly prolonged with T-DM1 vs XL in patients (pts) with HER2-positive locally advanced or MBC previously treated with T and a taxane; (PFS hazard ratio [HR]⫽0.65, p⬍0.001; OS HR⫽0.68, p⬍0.001). We report the effects of T-DM1 exposure on efficacy outcomes in EMILIA. Methods: In EMILIA, pts were randomized 1:1 to receive T-DM1 3.6 mg/kg q3w (n⫽495) or XL (n⫽496) in 21-day cycles. Pharmacokinetic (PK) samples were from cycle 1 (n⫽350, T-DM1 arm only). Exposure variables were T-DM1 AUC, T-DM1 Cmin, total T AUC, and DM1 Cmaxcalculated by noncompartmental analysis. A logistic regression model was used to evaluate the relationship between T-DM1 exposure and objective response rates (ORR) in the T-DM1 arm. Multivariate Cox proportional hazards models were used to calculate HRs of OS and PFS for each T-DM1 exposure quartile vs all randomized pts in the XL arm, adjusting for baseline covariates. Results: For ORR, mean T-DM1 AUC was 536 day*ug/mL for responders and 502 day*ug/mL for nonresponders (P⫽0.09); mean DM1 Cmax was 4.55 ng/mL and 4.64 ng/mL, respectively (P⫽0.64). OS and PFS HRs (and 95% CIs) of T-DM1 vs XL stratified by T-DM1 exposure quartiles are shown (Table). Conclusions: In EMILIA, no clear trends were observed between T-DM1 exposure and PFS, OS, or ORR, following administration of T-DM1 3.6 mg/kg q3w. However, there was a suggestion of improved OS HR by stratified T-DM1 Cmin quartiles, albeit with mostly overlapping 95% CIs. Ongoing T-DM1 clinical trials will further evaluate this potential relationship. T-DM1 exposure quartiles

OS HRs (95% CI) AUC Cmin PFS HRs (95% CI) AUC Cmin

Q1 (lowest)

Q2

Q3

Q4 (highest)

0.94 (0.76, 1.17) 0.91 (0.74, 1.12)

0.68 (0.51, 0.89) 0.78 (0.61, 0.99)

0.61 (0.43, 0.86) 0.76 (0.57, 1.00)

0.83 (0.66, 1.06) 0.56 (0.39, 0.81)

0.94 (0.78, 1.12) 0.78 (0.65, 0.93)

0.75 (0.62, 0.91) 0.88 (0.73, 1.05)

0.69 (0.55, 0.87) 0.72 (0.58, 0.89)

0.70 (0.58, 0.85) 0.67 (0.55, 0.83)

⬍1.0 favors T-DM1; ⬎1.0 favors XL




Differential expression of microRNAs induced by trastuzumab emtansine (T-DM1) during megakaryocytopoiesis. Presenting Author: Hirdesh Uppal, Genentech, Inc., South San Francisco, CA

646


Exposure–safety relationship of trastuzumab emtansine (T-DM1) in patients with HER2-positive locally advanced or metastatic breast cancer (MBC). Presenting Author: Jin Jin, Genentech, Inc., South San Francisco, CA

Background: Treatment with the HER2-targeted antibody– drug conjugate T-DM1 resulted in significantly longer PFS and OS vs lapatinib ⫹ capecitabine in patients previously treated with trastuzumab and a taxane in the phase 3 study EMILIA. Thrombocytopenia (TCP) was the doselimiting toxicity for patients treated with T-DM1, although platelets do not express HER2. In EMILIA, grade 3/4 TCP was observed in 12.9% of T-DM1-treated patients. We have previously shown that T-DM1 inhibits megakaryocyte (Mk) production and differentiation. Here, we investigated the effect of T-DM1 on microRNAs (miRNAs) associated with megakaryocytopoiesis. Methods: Human stem cells (HSCs; CD133⫹/CD34⫹) from 8 donors were differentiated into Mks in the presence of T-DM1, trastuzumab, or vehicle. Total RNA was extracted using the miRNeasy MiniKit. cDNA was prepared using the Taqman miRNA RT Kit, FAM-MGB probes, and stem-loop RT primer pool set. miRNA expression was measured using the 96.96 Dynamic Array Chip on the Biomark HD Reader. Data were analyzed using Fluidigm real-time analysis software Spotfire 5, and SAS 9.2. hsa⫺let⫺7g and hsa⫺miR⫺671⫺3p were chosen as reference miRNAs due to their low variation between treatments and time points. Median normalization was also applied. Results: A total of 526 miRNA RT-qPCR assays were used to map miRNA expression during differentiation of HSCs from 8 separate donors to Mks in vitro over 30 days. Several miRNAs demonstrated temporal changes in their expression profiles during maturation, suggesting these miRNAs are potential drivers of Mk differentiation. T-DM1 treatment inhibited Mk production and differentiation. Concomitant modifications in the expression of specific miRNAs were observed. These modifications were not present in trastuzumab- or vehicletreated cells, suggesting these miRNAs may be involved in the development of T-DM1–induced TCP. Conclusions: These results suggest that the miRNAs have the potential to be used as biomarkers for TCP in patients treated with T-DM1 and possibly other DM1 conjugates. Specific miRNA alterations related to T-DM1 treatment will be discussed following investigations using clinical samples to validate these preliminary data.

Background: Trastuzumab emtansine (T-DM1) is an antibody– drug conjugate composed of trastuzumab, the cytotoxic agent DM1, and a stable thioether linker. The effects of T-DM1 exposure on safety in patients with HER2-positive locally advanced or MBC are reported. Methods: The exposure–safety analysis included 618 patients with pharmacokinetic (PK) data who received single-agent T-DM1 3.6 mg/kg q3w from five phase 2 or 3 studies: TDM4258g, TDM4374g, TDM4450g/BO21976, TDM4688g, and EMILIA. Exposure parameters observed in cycle 1 were T-DM1 conjugate AUC, T-DM1 conjugate Cmax, and DM1 Cmax, (no PK accumulation). Safety endpoints were worst grade of thrombocytopenia (TCP) or hepatotoxicity (HPT) by protocol definitions. A multivariate logistic regression analysis was conducted to evaluate the association of exposure and clinically relevant covariates with the probability of experiencing TCP or HPT. Platelet counts (PLT), alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin (TBL) versus time profiles were also evaluated by exposure quartiles to further test exposure effect on lab values. A secondary analysis for patients in the EMILIA study alone (n⫽307) was also conducted. Results: Grade ⱖ3 TCP and gradeⱖ 3 HPT were observed in 72 patients and 45 patients in the exposure–safety data set, respectively. Data from the pooled studies showed no statistically significant association between exposure and the incidence of grade ⱖ3 TCP (T-DM1 AUC P⫽0.99, T-DM1 Cmax P⫽0.97, DM1 Cmax P⫽0.72), or grade ⱖ3 HPT (T-DM1 AUC P⫽0.25, T-DM1 Cmax P⫽0.93, DM1 Cmax P⫽0.95). Additionally, no obvious difference was observed for longitudinal PLT, ALT, AST, or TBL profiles across exposure quartiles, with no exposure–safety relationship for the probability that PLT, ALT, AST, or TBL exceeded grade 3 thresholds. Similar results were observed for the EMILIA analysis. Conclusions: For patients with HER2-positive locally advanced or MBC treated with T-DM1 3.6 mg/kg q3w, no exposure–safety relationship was observed for TCP, HPT, PLT, or liver function based on T-DM1 or DM1 exposure.

647

TPS648


Impact of single and dual neoadjuvant HER2-directed therapy on clinical outcomes among patients with HER2-positive breast cancer (BC). Presenting Author: Kerry Lynn Massman, Massachusetts General Hospital, Boston, MA Background: While the addition of trastuzumab to neoadjuvant chemotherapy (CTX) is well established for HER2⫹ BC, the use of dual agent HER2 blockade in the preoperative setting is not considered standard of care. We conducted a comprehensive systematic review and meta-analysis to evaluate the impact of neoadjuvant dual and single agent HER2 blockade on breast conserving surgery (BCS), pathological complete response (pCR) for estrogen receptor (ER)⫹ and ER- tumors, and impact of pCR on disease-free survival (DFS) and overall survival (OS) for HER2⫹ BC. Methods: Based on QUORUM guidelines, MEDLINE and Cochrane Controlled Clinical Trials Register databases were queried to identify eligible trials. Inclusion criteria were prospective, neoadjuvant trials that had at least one arm with HER2 directed therapy, and reported pCR. Pooled relative risk ratios (RRs) and 95% confidence intervals (CIs) were estimated for endpoints using the random effects model. Results: We identified 34 trials (N ⫽ 4064). High pCR rates (⬎ 40%) were seen with anthracyclinebased CTX and trastuzumab, as well as taxane based CTX alone with dual HER2 blockade. The addition of trastuzumab to CTX did not improve BCS rate (RR 1.40, CI: 0.89-2.22, p⫽.15), but significantly increased rates of pCR (RR 1.91, CI: 1.38-2.64, p⫽.0001). Similarly, dual HER2 blockade compared to trastuzumab alone did not improve BCS rate (RR 1.03, CI: 0.77-1.38, p⫽.84), but significantly increased rates of pCR overall (RR 1.38, CI: 1.24-1.53, p⬍0.00001), in both ER⫹ (RR 1.72, CI: 1.14-2.61, p⫽.01) and ER- subsets (RR 1.91, CI: 1.38-2.64, p⫽.0001). Higher pCR was associated with improved DFS (RR 2.29, CI: 1.27-4.12, p⫽.006) and OS (RR 4.61, CI: 1.46-14.56, p⫽.009). Conclusions: Neither the addition of trastuzumab to CTX, nor the dual-HER2 blockade compared to trastuzumab, improves rates of BCS, but both significantly improve rates of pCR, which is associated with improved DFS and OS. A subgroup of HER2⫹ BC patients can achieve pCR with dual HER2 blockade without dependence on anthracycline-based therapy. Predictive biomarkers are needed to improve patient selection and personalize the optimal regimen for HER2⫹ BC.


Antiemetic efficacy of transcutaneous electrical nerve stimulation (TENS) at pericardium 6 acupuncture point (P6) in the treatment of chemotherapyinduced delayed nausea and vomiting (CINV) in stage I to III breast cancer patients during adjuvant/neoadjuvant chemotherapy (Ad/nAd). Presenting Author: Jean Yared, Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD Background: CINV remain major adverse effects of highly emetic chemotherapy for breast cancer patients (BC). Patients (PT) rate nausea & vomiting as the most feared chemotherapy-related symptoms. There is substantial evidence that P6 (located in the region in the middle of the wrist 3 finger breaths from the juncture of the hand & wrist) acupuncture is an effective antiemetic treatment in a variety of PT including the postanesthesia, obstetrical, and motion sickness PT. We hypothesized that application of TENS at P6 point will reduce:1) the overall incidence of CINV episodes in stage 1-3 BC PT, 2) the severity & duration of CINV, 3) the requirement for rescue antiemetics 4) & that TENS is well tolerated & feasible. Maxima III Transcutaneous Electrical Nerve Stimulation unit is utilized in this study & is self-administered by PT. Patients and Methods: We are conducting a prospective, randomized, double-blinded, controlled trial to determine if self-stimulating P6 may decrease the incidence and severity of delayed CINV in stage 1-3 BC treated with the initial dose of highly emetic Ad/nAd (AC, AC-T, TAC, TC, TCH) and reduce PT’ need for rescue oral antiemetic medications. PT will be randomized in a 1:1 ratio to the active treatment group (TENS self-stimulation at P6) & the control group (TENS self-stimulation at a point on the lateral side of the elbow that does not conform to any known acupuncture points). The assignments are blinded to the PT & the investigators. Subjects self-administer TENS at home q4 hours for 20 minutes during days 2-5 postchemotherapy. The use of conventional antiemetic therapy (corticosteroids, setrons, aprepitant, phenergan & prochlorperazine) is similar for both treatment groups. The severity of nausea symptoms, episodes of emesis, use of rescue antiemetics, and compliance are recorded daily by the PT in diaries. A brief questionnaire is also administered to evaluate PT tolerability of TENS & their ability to comply with the treatment regimen. Twenty six out of 70 planned PT have been enrolled. Recruitment is ongoing.


44s TPS649


Early prediction of efficacy of endocrine therapy in breast cancer (BC): Pilot study and validation with 18F fluoroestradiol (18F-FES) PET/CT. Presenting Author: Alessandra Gennari, E.O. Ospedali Galliera, Genoa, Italy

TPS650^


Ph III randomized studies of the oral pan-PI3K inhibitor buparlisib (BKM120) with fulvestrant in postmenopausal women with HRⴙ/HER2– locally advanced or metastatic breast cancer (BC) after aromatase inhibitor (AI; BELLE-2) or AI and mTOR inhibitor (BELLE-3) treatment. Presenting Author: Hiroji Iwata, Aichi Cancer Center Hospital, Nagoya, Japan

Background: Almost 70% of early BC are endocrine responsive, as defined by estrogen receptor (ER) expression; however roughly 30% of ER⫹ BC patients will relapse despite adjuvant ET. Moreover, 10 to 20% of BC metastases lose ER expression. The upfront administration of ET in ER⫹ women with MBC is recommended by major guidelines. However, the early identification of endocrine resistance might improve systemic treatment options, sparing unnecessary toxicities and inactive drugs. 18F-FES, an oestradiol analogue labeled with 18F, may allow to test the performance of ERs, by testing their in vivo linkage ability. In MBC, 18F-FES uptake has been proposed to be a better predictor of response to ET than ER expression itself. The aim of the ET-FES study is to validate the predictive value of 18F-FES uptake at PET/CT scan in metastatic ER⫹ patients. Methods: This is aphase II, multicentric european comparative study of first line ET vs CT in ER⫹ MBC with low 18F- FES uptake. The primary endpoint is disease control rate (DCR). Correlative studies include: 1. Optimization of 18F-FES production; 2. Association between gene alterations in ESR1/ESR2 genes and 18F- FES uptake; 3. Development of a predictive score of endocrine responsiveness based on 18F-FES SUV value and clinical and biological information. All patients with ER⫹ MBC candidate to first line ET will receive a 18F-FES CT/PET at baseline, in addition to standard staging. Patients with 18F-FES uptake (SUV) ⬎ 2 will receive ET. Patients with 18F-FES SUV ⬍ 2 will be randomized to ET until disease progression (control arm) or CT (single agents) until PD. A total of 220 patients with ER⫹ MBC will be enrolled. Of these, approximately 50% (n⫽110) will show a 18F-FES SUV ⬍ 2 and will be randomized to ET or CT. The study will have 85% power to detect an absolute 20% difference in the DCR between arms after 3 months of therapy, assuming a 5% two-sided alpha level and a 10% drop-out rate. Current status: The ET-FES study was approved for funding by the ist Join TRANSCAN European call. 18F-FES production is currently on final development (GMP), and the clinical protocol is being finalized for EC approval in the different EU countries. Clinical trial information: 2013-000287-29.

Background: The PI3K/Akt/mTOR pathway is commonly dysregulated in BC and linked to resistance to endocrine therapy, including AIs. Buparlisib is an oral inhibitor of class I PI3K isoforms (␣, ␤, ␥, ␦), showing near complete tumor regression in an in vivo model of ER⫹ BC in combination with fulvestrant. Preliminary clinical activity in BC pts has been observed with buparlisib as a single agent and in combination with letrozole (Mayer et al. ASCO 2012). Methods: BELLE-2 (NCT01610284) and BELLE-3 (NCT01633060) are 2 Ph III randomized, double-blind, placebocontrolled trials of oral buparlisib (100 mg/d) in combination with fulvestrant (500 mg) given on D1 and 15 of Cycle 1 and D1 of each 28-day cycle thereafter in postmenopausal women with HR⫹/HER2– locally advanced/ metastatic BC. Additional eligibility criteria: disease progression on/after AI treatment for BELLE-2; prior treatment with AI and progression on mTOR inhibitor in combination with endocrine therapy (as last therapy prior to study entry) for BELLE-3; ⱕ1 previous line of chemotherapy for advanced disease; available archival tumor tissue for PI3K-related biomarker analysis. Randomization to either arm (1:1 for BELLE-2 and 2:1 for BELLE-3) is stratified according to PI3K pathway activation status (activated vs nonactivated vs unknown) and visceral disease status (present vsabsent). Study treatment is given until disease progression or discontinuation for any reason. Co-primary endpoints in both trials: PFS in full and PI3K pathway-activated populations based on local investigator assessment (RECIST 1.1). Key secondary endpoints: overall survival (OS) in full and PI3K pathway-activated populations; other secondary endpoints: PFS and OS in PI3K non-activated/unknown population, overall response rate, clinical benefit rate, safety (CTCAE 4.03), PK, and patient-reported outcomes (EORTC QLQ-C30 and QLQ-BR23). Estimated enrollment is 842 pts for BELLE-2 and 615 for BELLE-3. As of January 2013, 96 pts were randomized to BELLE-2 and 1 pt to BELLE-3. Recruitment is ongoing globally. Clinical trial information: NCT01610284 and NCT01633060.

TPS651

TPS652


Dovitinib plus fulvestrant in postmenopausal endocrine resistant HER2-/ HRⴙ breast cancer: A phase II, randomized, placebo-controlled study. Presenting Author: Fabrice Andre, Institut Gustave Roussy, Villejuif, France Background: Overcoming endocrine resistance (ER) is a critical goal in the treatment of hormone receptor⫺positive (HR⫹) breast cancer (BC). Emerging in vitro evidence suggests that amplification and overexpression of fibroblast growth factor receptor 1 (FGFR1) is associated with ER. Up to 8% pts with HR⫹/ human epidermal growth factor receptor 2 negative (HER2–) BC have amplification of the FGFR1 gene. Dovitinib (DOV), a potent inhibitor of FGFR, vascular endothelial growth factor receptor, and platelet-derived growth factor receptor demonstrated antitumor activity in heavily pretreated BC pts with FGF-pathway amplification (FGFR1, FGFR2, or FGF3). The objective of this study is to determine if DOV plus fulvestrant (FUL) can improve outcomes in postmenopausal pts with endocrine resistant HER2-/HR⫹ BC. Methods: This multicenter, randomized, doubleblind, placebo-controlled, ph II trial (NCT01528345) will enroll postmenopausal pts with HER2–/HR⫹ locally advanced or metastatic BC (N⫽150) progressing within 12 months of completion of adjuvant endocrine therapy or after ⱕ 1 prior endocrine therapy in the advanced setting. Pts will be randomized 1:1 (stratified by FGF amplification and presence of visceral disease) to receive intramuscular FUL (500 mg q4w [with an additional dose 2 weeks after the initial dose]) plus oral DOV (500 mg, 5 days on/2 days off) or matching placebo until disease progression, unacceptable toxicity, death, or discontinuation (any reason). Crossover is not permitted. Primary endpoint is progression free survival (investigator’s assessment; RECIST v1.1). Secondary endpoints include overall response rate (investigator’s assessment; RECIST v1.1), duration of response, overall survival, time to deterioration of ECOG performance status, pt-reported outcome scores over time, safety, and assessment of plasma pharmacokinetic concentrations of FUL and DOV. Additionally, the pharmacodynamic effect of DOV on FGFR-associated angiogenic pathways in tumor specimens and potential predictive biomarkers of response to DOV will be explored. As of 21 Jan 2013, 128 pts had molecular screening; 73 pts are enrolled (of these 9 pts are FGF amplified). Clinical trial information: NCT01528345.


A randomized, multicenter, double-blind phase III study of palbociclib (PD-0332991), an oral CDK 4/6 inhibitor, plus letrozole versus placebo plus letrozole for the treatment of postmenopausal women with ER(ⴙ), HER2(–) breast cancer who have not received any prior systemic anticancer treatment for advanced disease. Presenting Author: Richard S. Finn, University of California, Los Angeles, Geffen School of Medicine, Los Angeles, CA Background: Palbociclib (PD-0332991) is an orally bioavailable selective inhibitor of CDK4/6 that prevents DNA synthesis by prohibiting progression of the cell cycle from G1 to S phase. In a randomized phase II trial comparing palbociclib (PD-0332991) plus letrozole (P ⫹ L) to letrozole (L) in postmenopausal women with ER(⫹), HER2(–) advanced breast cancer (ABC) who had not received any prior systemic anticancer therapy for their advanced disease, P ⫹ L demonstrated significantly longer progressionfree survival (PFS) vs L (26.1 vs 7.5 mo; HR ⫽ 0.37, P ⬍ .001) and was generally well tolerated, with uncomplicated neutropenia as the most frequent adverse event (Finn et al SABCS 2012). Methods: Based on phase II data, a global, randomized, double-blind, phase III clinical trial was designed to demonstrate that P ⫹ L provides superior clinical benefit compared with L ⫹ placebo in postmenopausal women with ER(⫹), HER2(–) ABC who have not received any prior systemic therapy for their advanced disease. The study aims to assess whether P ⫹ L improves median PFS over L at HR of at least 0.7. Approximately 450 eligible patients with locoregionally recurrent or metastatic, pathologically confirmed ABC who are candidates to receive L as first-line treatment for their advanced disease will be randomized 2:1 to receive either P (125 mg QD 3 wk on, 1 wk off) ⫹ L (2.5 mg QD) or L (2.5 mg QD) ⫹ placebo. Patients who received anastrozole or letrozole as part of their (neo)adjuvant regimen are eligible if their disease progressed more than 12 months from completion of adjuvant therapy. Tumor tissue is required for participation. Secondary endpoints include overall survival, objective response, duration of response, clinical benefit, safety and tolerability, and patient-reported outcomes of health-related quality of life and disease- or treatment-related symptoms. Clinical trial information: NCT01740427.


Breast Cancer—HER2/ER TPS653


UNIRAD: Multicenter, double-blind, phase III study of everolimus plus ongoing adjuvant therapy in ERⴙ, HER2- breast cancer. Presenting Author: Thomas Denis Bachelot, Centre Léon Bérard, Lyon, France Background: Advances in adjuvant treatment and highly effective endocrine therapies have resulted in better prognosis and survival among patients (pts) with hormone-receptor-positive (HR⫹; ER⫹ and/or PgR⫹) breast cancer (BC). Despite this, high risk pts (⬎3N⫹ and/or T3/4) are likely to relapse during/after adjuvant therapy. In a pivotal phase 3 trial (BOLERO2), everolimus (EVE, an oral mammalian target of rapamycin [mTOR] inhibitor), plus exemestane demonstrated clinical efficacy in postmenopausal pts with HR⫹, human epidermal growth factor receptor-2–negative (HER2–) advanced BC progressing on non-steroidal aromatase inhibitors. Administering EVE earlier, concurrent with adjuvant endocrine therapy (ET) may lower relapse rates, especially in pts with high and/or persistent nodal involvement after neoadjuvant therapy. This study (UNIRAD) will evaluate the safety and effectiveness of adding EVE to adjuvant ET in pts with ER⫹, HER2–non-metastatic BC, who are disease-free following 3y of adjuvant ET. Methods: This multi-center, double-blind, phase 3 study will randomize adult (ⱖ18y) women with non-metastatic ER⫹, HER2- BC, any T, pN⫹(ⱖ4 if initial therapy and ⱖ1 after neoadjuvant therapy), who are disease-free following 3y of adjuvant ET to EVE (10mg/d) plus ongoing ET versus placebo (PBO) plus ongoing ET for a total adjuvant therapy duration of 5y. Stratification is by country, ET (tamoxifen or aromatase inhibitors), previous adjuvant versus neoadjuvant therapy, and age (ⱕ70 versus ⬎70y). Follow-up will continue for 5y after treatment. The primary endpoint is disease-free survival (DFS) with EVE versus PBO. Secondary endpoints include overall survival (OS), event-free survival, distant metastasis-free survival, DFS and OS in selected subgroups, safety, incidence of secondary cancers, quality of life, and predictive value of mTOR activation markers on DFS. Results: Accrual to the UNIRAD study will begin in March 2013 (planned N ⫽ 1984). Updated information will be presented. Clinical trial information: 2012-003187-44.

TPS655^


ADAPT: Adjuvant dynamic marker-adjusted personalized therapy trial optimizing risk assessment and therapy response prediction in early breast cancer. Presenting Author: Nadia Harbeck, Breast Center University of Munich, Munich, Germany Background: Indication of (neo-)adjuvant therapy is based on risk profile, hormone receptor and HER2 status at time of primary diagnosis. Data indicate dynamic proliferation changes after short-term induction therapy are superior to static initial biopsy results in predicting outcome and tumor response following neoadjuvant CTx in distinct BC subtypes. First generation trials such as TAILORx, MINDACT, NNBC-3, WSG planB utilize information of new prognostic/predictive tests to reduce overtreatment by CTx. Results still pending. ADAPT is a second generation trial addressing individualization of adjuvant decision-making in early BC by utilizing optimized pre-therapeutic biomarker information and early biomarker changes in a second core biopsy after 3-week subtype specific induction therapy. It aims at reducing over-/undertreatment in luminal tumors and optimizing therapy in HER2⫹ (T-DM1, pertuzumab) / TNBC (nabpaclitaxel ⫹ platinum/gemcitabine). Methods: Design: ADAPT combines static prognosis assessment by conventional markers (nodal status) and Recurrence Score (HR⫹) with dynamic measurement of proliferation changes after a short 3-week induction therapy, using the baseline diagnostic and repeat core biopsy following induction. ADAPT is a prospective, multi-center, controlled, non-blinded, randomized phase II/III trial, comprising an umbrella trial and 4 sub-trials (HR⫹/HER2-, HR⫹/HER2⫹, HR-/HER2⫹, TNBC). Eligibility criteria: Pre-/postmenopausal women with histologically confirmed unilateral primary invasive BC. Pts requiring CTx/targeted therapy with no contraindications. Statistics: Assumption across sub-protocols: CTx spared in 1120 HR⫹/HER2-, pCR achieved in 170 HER2⫹/TNBC pts. Outcome of good-proliferation responders/pCR pts will be compared to reference group (n⫽640 HR⫹/HER2- pts: low RS, no CTx, 94% 5yr survival). One-sided test of non-inferiority (3.2% margin, 90.8%) with alpha⫽0.05 will have 80% power. Present/target accrual:By 01/2013: 16/35 sites initiated. ADAPT HR⫹/HER2-: 161/4000 pts recruited. ADAPT HER2⫹/HR⫹: 9/380 pts recruited. ADAPT HER2⫹/HRor TNBC: start of recruitment planned for Q2 2013. Clinical trial information: NCT01781338.

TPS654


N-SAS BC06: A phase III study of adjuvant endocrine therapy with or without chemotherapy for postmenopausal breast cancer patients who responded to neoadjuvant letrozole (LET): The New Primary EndocrineTherapy Origination Study (NEOS). Presenting Author: Hiroji Iwata, Aichi Cancer Center Hospital, Nagoya, Japan Background: It is uncertain whether adjuvant chemotherapy is required in the treatment of postmenopausal women with hormone-responsive and intermediate risk breast cancer. The TAILORx and MINDACT trials are ongoing and utilize gene expression profiling in order to answer this question. We have initiated a new study to address this matter by using response to initial neoadjuvant endocrine therapy. The primary aim of this phase III study is to evaluate the necessity of using adjuvant chemotherapy for the treatment of postmenopausal breast cancer patients with nodenegative, ER-positive and HER2-negative tumors who responded to neoadjuvant LET. Methods: Inclusion criteria are T1c-T2N0M0, ER-positive by IHC (⬍10%), HER2-negative, postmenopausal women under 75 years old and written informed consent. Lymph node positive patients as assessed by SLNB are excluded. Neoadjuvant LET is administered for 24-28 weeks before surgery. CR, PR or SD patients are then randomized into two arms receiving either chemotherapy plus LET for 4.5-5 years or LET alone for 4.5-5 years after surgery. If the primary tumor response is defined as PD before surgery, the treatment will be changed at the investigator’s discretion (surgery, chemotherapy or other endocrine therapy, but these patients will be followed up). The primary endpoint is disease-free survival (DFS), and secondary endpoints are overall survival (OS), response rate of LET, pathological response, breast conserving surgery rate, DFS/OS by response rate of LET, safety, QOL and cost-effectiveness. This study utilizes a randomized selection design. The objective of this design is to select the arm with the better outcome. We also conduct an additional translational research and central pathological review of ER, PgR, HER2, and Ki67.Patient recruitment commenced in May 2008 and 803 patients were enrolled at the end of 2012. A total of 850 patients will be enrolled at the end of May 2013. This study is supported by Public Health Research Foundation. Clinical trial information: UMIN000001090.

TPS656


OPTIMA prelim: Optimal personalized treatment of early breast cancer using multiparameter tests. Presenting Author: Rob Stein, University College London Hospitals NHS Foundation Trust, London, United Kingdom Background: Chemotherapy may have little effect on some subtypes of early breast cancer, identified as being hormonally responsive tumours without HER2 gene amplification and with a low or intermediate grade. Multiparameter genomic tests such as Oncotype DX are increasingly used to identify patients for whom the addition of chemotherapy may confer little additional benefit. OPTIMA has an adaptive design seeking to advance development of personalised medicine in breast cancer by assessing the value of multi-parameter tests in a UK population of intermediate risk. Methods: OPTIMA prelim, the feasibility phase, has 3 objectives: (1) To evaluate performance and health-economics of multi-parameter tests to determine which test(s) will be used in the main trial; (2) To establish efficient and timely sample collection and analysis essential to deliver multi-parameter test driven treatment; (3) To establish the acceptability to patients and clinicians of randomisation to test-directed treatment assignment. OPTIMA prelim aims to recruit 300 patients with ER⫹ve HER2-ve tumours with involved nodes (pN1-2). Patients are randomized to the standard arm of chemotherapy with endocrine therapy, or to the “testdirected treatment” arm assigned to either the same chemotherapy with endocrine therapy or endocrine therapy only according to the result of an Oncotype DX test. The decision to continue to a main trial will be determined by concordance, cost and willingness of patients to be randomized to test guided treatment. Cost-effectiveness models will be based on the model developed in preparation for the OPTIMA trial, updated with contemporary evidence from the feasibility study and appropriate external data, e.g. the Ontario prospective cohort study. Results: Optima opened in Sept 2012 with 25 centres involved. To date 22 patients are registered, of which 17 have been randomised. Patient focus groups show the trial design is acceptable and has potential to reduce need for chemotherapy. TSC and DMEC agree that this is an important trial testing the feasibility within this patient population. Decision rules are challenging for this study but employment of adaptive designs gives the flexibility needed for the main trial. Clinical trial information: ISRCTN42400492.


46s TPS657


Phase III randomized, placebo-controlled clinical trial evaluating the use of adjuvant endocrine therapy with or without one year of everolimus in patients with high-risk, hormone receptor- (HR) positive and HER2-neunegative breast cancer: SWOG/NSABP S1207. Presenting Author: Mariana Chavez-Mac Gregor, Breast Medical Oncology Department, The University of Texas MD Anderson Cancer Center, Houston, TX

TPS658


MotHER: A registry for women with breast cancer who received trastuzumab (T) with or without pertuzumab (P) during pregnancy or within 6 months prior to conception. Presenting Author: Vikki Brown, INC Research, Raleigh, NC

Background: Abnormalities of the PI3kinase/AKT/mTOR signaling pathway are common in breast cancer. This pathway has been associated with endocrine resistance. Everolimus, an mTOR-inhibitor, has been shown to increase the biological activity endocrine therapies. S1207 proposes to evaluate the role of everolimus in combination with endocrine therapy in the adjuvant setting. Methods: S1207 is randomized phase III doubleblinded, placebo-controlled clinical trial. The primary objective is to assess whether the addition of one year of everolimus to standard adjuvant endocrine therapy improves DFS. Secondary objectives include OS, DRFS, safety, adherence, and quality of life. Submission of tissue specimens/ blood samples is required. Patients will be randomly assigned to receive standard adjuvant endocrine therapy in combination with one year of everolimus (10 mg PO daily) or in combination with one year of matched placebo. Eligibility Criteria: Patients with histologically confirmed invasive breast cancer HR-positive and HER2-negative with a) node-negative disease with tumors ⬎2cm and a recurrence score (RS) ⬎25; b) 1-3 positive lymph nodes RS ⬎25; c) ⬎4 positive lymph nodes are eligible after they have completed adjuvant chemotherapy; d) Patients with ⬎4 positive lymph nodes after neoadjuvant chemotherapy are also eligible. Patients must have completed surgery, chemotherapy, and radiation therapy (if indicated) before registration. Statistical methods/ target accrual: Parallel randomization design with equal allocation to the two treatment groups with stratification by 4 risk groups. All analyses are intent-to-treat. The study plans to randomize 3,500 patients over a 3.5-year accrual period. All patients will be followed for 10 years to assess survival and late adverse events. The first interim analysis would be after 39% of the expected events (n⫽295) have been observed or approximately 3.5 years after initiation of the study. Support: NCI U10-CA-37377, -12027, -69651; Breast Cancer Research Foundation; Novartis. Clinical trial information: NCT01674140.

Background: T and P are monoclonal antibodies that target different HER2 epitopes. T is approved for treatment of early and metastatic HER2⫹ BC while P is approved in combination with T for previously untreated HER2⫹ MBC. Oligohydramnios has been reported in patients (pts) who received T during pregnancy, and also in P-treated pregnant monkeys. Although both antibodies are FDA Pregnancy Category D, indicating evidence of fetal harm, some physicians and pts accept this risk and continue treatment. The MotHER registry was established in 2008 as an FDA postmarketing commitment to evaluate the effects of T therapy on pregnancy outcome; P was included in the study following its approval in 2012. MotHER is the first prospective study of the effects of a targeted cancer therapy on pregnancy outcome. Methods: MotHER is a US registry study of women exposed to T⫾P during pregnancy or within 6 months prior to conception. Women enroll voluntarily and are followed until pregnancy outcome; infants are followed through the first year of life. Medical information is primarily collected from healthcare providers. Information on potential birth defects noted at birth or during the pediatric follow-up is classified by a birth defect evaluator/clinical geneticist. Enrollment must be initiated before pregnancy outcome. Pts with known prenatal testing results may enroll, but to reduce the potential for bias these pts will be analyzed as a subset. Primary outcomes: number and nature of pregnancy complications, including oligohydramnios, pregnancy outcomes, fetal/infant outcomes and fetal/ infant functional deficits. Secondary outcomes: preterm births, elective/ therapeutic abortions, miscarriages, fetal growth abnormalities and delivery complications. The study is descriptive and not for formal hypothesis testing; event proportions with CIs will be calculated. The registry will accrue in the US from 2009 to 2019 for T-treated pts and from 2012 to 2022 for P⫹T-treated pts. The number of potential pts is small therefore physicians are encouraged to refer any eligible pt to increase knowledge about the safety of T⫾P in pregnancy. herceptinpregnancyregistry.com. Clinical trial information: NCT00833963.

TPS659

TPS660


Phase I/II study of neoadjuvant carboplatin, eribulin mesylate, and trastuzumab (ECH) for operable HER2 positive (HER2ⴙ) breast cancer. Presenting Author: Lee Steven Schwartzberg, ACORN Research and The West Clinic, Memphis, TN Background: Carboplatin, docetaxel and trastuzumab (TCH) regimen yields substantial pathologic complete response (pCR) in operable HER2⫹ breast cancer. Eribulin mesylate (E) is a tubulin inhibitor recently shown to improve overall survival compared to taxanes and other agents in heavily pretreated metastatic breast cancer patients. This trial was designed to determine the maximum tolerated dose (MTD) of E in combination with CH (Phase I) and to determine efficacy and safety of the ECH regimen (Phase II) given as neoadjuvant therapy to early stage HER2⫹ breast cancer with pathologic complete response the primary endpoint. Methods: This is a multicenter prospective open label single arm trial. Eligible patients were operable stage IIA – IIIB HER2⫹ breast cancer, ECOG 0-1, normal LVEF, QTc ⬍ 480 msec, ⬍ grade 1 neuropathy and no history of invasive cancer within the past 3 years. Phase I planned up to 12 patients from 4 centers to 1 of 3 E dose cohorts, with pts treated at the MTD also evaluable for Phase II. Starting dose level 0 was 1.1 mg/m2 with escalation to dose level ⫹1 at 1.4 mg/m2 and de-escalation to dose level -1 at 0.9 mg/m2 if necessary. ECH was given IV for six 3-week cycles with E d1 and d8; C AUC 6 d1; and H 8 mg/kg loading dose d1C1 and 6 mg/kg d1C2-C6. H is scheduled to continue after surgery to complete 1 year of treatment. C1 dose limiting toxicities (DLTs) were defined as: grade 4 thrombocytopenia, anemia, or neutropenia lasting ⬎ 5 days; any grade 3-4 non-hematologic toxicity attributable to E, C, H, or the combination; inability to deliver all three agents at assigned dose and schedule. Standard 3⫹3 dose escalation design was used. At present, 6 patients have been enrolled at dose 0 and 6 have been enrolled at dose ⫹1. The MTD for E has not yet been determined. Phase II has planned enrollment of 44 additional patients from 8 centers with primary endpoint rate of pCR at surgery to be performed 4-8 weeks after completion of ECH and secondary endpoints of safety to include peripheral neuropathy and cardiac toxicity at treatment completion and 1 year follow up. Clinical trial information: NCT101388647.


BOLERO-6: Phase II study of everolimus plus exemestane versus everolimus or capecitabine monotherapy in HRⴙ, HER2- advanced breast cancer. Presenting Author: Bent Ejlertsen, Danish Breast Cancer Cooperative Group Statistical Center Department of Oncology, Copenhagen University Hospital, Copenhagen, Denmark Background: Everolimus (EVE), an orally bioavailable inhibitor of the mammalian target of rapamycin (mTOR), has shown clinical activity as monotherapy and in combination with endocrine therapy (ET) in hormonereceptor–positive (HR⫹; estrogen and/or progesterone receptors) advanced breast cancer (ABC). In a pivotal phase 3 trial in patients with HR⫹ ABC progressing on ET, EVE ⫹ exemestane (EXE) significantly prolonged median progression-free survival (PFS) vs EXE alone per local (7.8 vs 3.2 months; log-rank P⬍.0001) or central (11.0 months for EVE⫹EXE vs 4.1 months for EXE alone; log-rank P⬍.0001) assessment. Capecitabine, an orally administered fluoropyrimidine carbamate indicated as monotherapy in paclitaxel and/or anthracycline-refractory ABC, has shown clinical benefit in patients with HR⫹, human epidermal growth factor receptor 2-negative (HER2-) ABC. The BOLERO-6 study in patients with HR⫹, HER2 ABC progressing on prior anastrozole or letrozole will compare PFS following EVE⫹EXE combination therapy vs EVE or capecitabine monotherapy. Methods: In this multicenter, open-label, randomized, 3-arm, phase 2 study, 300 patients will be randomized to receive either EVE (10 mg/d) ⫹ EXE (25 mg/d) combination therapy, or EVE (10 mg/d) alone, or capecitabine (1,250 mg/m2twice daily for 14 d/3-wk cycle) alone, until disease progression. Patients will be stratified based on the presence of visceral disease. Key eligibility criteria include age ⱖ18 years, postmenopausal status; histologic or cytologic confirmation of estrogen-receptor– positive, HER2- ABC; radiologic or objective evidence of recurrence or progression on prior aromatase inhibitors; Eastern Cooperative Oncology Group (ECOG) performance status ⱕ2. The primary endpoint is PFS with EVE⫹EXE vs EVE, based on local radiologic assessment (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1). The key secondary endpoint is PFS with EVE⫹EXE vs capecitabine. Other secondary endpoints include overall survival, objective response rate, clinical benefit rate, safety, quality of life, and patient satisfaction with treatment. Enrollment will start in Q1 2013. Estimated study completion in Q1 2015. Clinical trial information: NCT01783444.


Breast Cancer—HER2/ER TPS661


BOLERO-4: Multicenter, open-label, phase II study of everolimus plus letrozole as first-line therapy in ERⴙ, HER2- metastatic breast cancer. Presenting Author: William John Gradishar, Northwestern University, Chicago, IL

TPS662


Denosumab versus placebo as adjuvant treatment for women with earlystage breast cancer at high risk of disease recurrence (D-CARE): An international, placebo-controlled, randomized, double-blind phase III clinical trial. Presenting Author: Paul E. Goss, Massachusetts General Hospital Cancer Center, Boston, MA

Background: Endocrine therapy (ET) is the standard of care for postmenopausal women with hormone receptor positive (HR⫹; typically, estrogen receptor [ER] positive) advanced breast cancer (ABC). However, women with HR⫹ ABC can progress while on ET. Crosstalk between ER signaling and the mammalian target of rapamycin (mTOR) pathway enhances tumor progression. Co-targeting these signaling pathways with the combination of everolimus (EVE), an orally bioavailable mTOR inhibitor, and ET (letrozole [LET] or tamoxifen) has been shown to significantly improve clinical outcomes in the neoadjuvant setting and in patients with HR⫹ ABC progressing on/after nonsteroidal aromatase inhibitors. In a pivotal phase 3 trial in women with HR⫹ ABC progressing on ET, EVE ⫹ exemestane (EXE) prolonged progression-free survival (PFS; local/central assessment: 7.8/ 11.0 mo [P ⬍ .0001]) compared with EXE alone (3.2/4.1 mo [P ⬍ .0001]). This study (BOLERO-4) will extend previous investigations to evaluate the safety and effectiveness of EVE⫹LET as first-line therapy in ER⫹ HER2– metastatic BC (mBC), and the potential benefits of continuing EVE⫹ET beyond initial progression. Methods: In this multicenter, open-label, international, single-arm, phase 2 study, 200 postmenopausal women age ⱖ18 y with ER⫹ HER2– mBC or locally ABC without prior therapy for advanced disease will receive EVE (10 mg/d) ⫹ LET (2.5 mg/d) until first disease progression. Upon disease progression, patients continuing in the trial will receive EVE⫹EXE (25 mg/d) until further disease progression. Patients who discontinue therapy in the first-line metastatic setting because of unacceptable toxicity will not be offered second-line therapy. The primary endpoint is PFS with EVE⫹LET in the first-line setting. Secondary endpoints include PFS in the second-line setting, overall survival, objective response rate, clinical benefit rate, safety, and the efficacy of oral dexamethasone solution to reduce the severity and/or duration of stomatitis using Oral Stomatitis Daily Questionnaire (OSDQ). Accrual across Europe, Asia, and the Americas begins Q1 2013. Estimated study completion is Q4 2015. Clinical trial information: NCT01698918.

Background: In women with early-stage breast cancer, bone is a common site of distant recurrence and represents approximately 40% of all first recurrences. Preclinical studies demonstrated that inhibition of RANKL significantly delays skeletal tumor formation, reduces skeletal tumor burden, and prolongs survival of tumor-bearing mice. Denosumab is approved for the prevention of skeletal-related events (SREs) in patients with established bone metastases from solid tumors. The D-CARE trial is designed to assess if denosumab treatment prolongs bone metastasis-free survival (BMFS) and disease-free survival (DFS) in the adjuvant breast cancer setting. The primary endpoint of this event-driven trial is BMFS. Secondary endpoints include DFS and overall survival. Additional endpoints include safety, breast density, time to first on-study SRE (following the development of bone metastasis), patient reported outcomes, and biomarkers. Methods: In this international, randomized, double-blind, and placebo-controlled phase 3 trial, 4509 women with stage II or III breast cancer at high risk for recurrence and with known hormone and HERE2 receptor status were randomized. High risk was defined as biopsy evidence of breast cancer in regional lymph nodes, tumor size ⬎ 5 cm (T3), or locally advanced disease (T4). Standard-of-care adjuvant or neoadjuvant chemo-, endocrine, or HER-2 targeted therapy, alone or in combination, must be planned. Patients with a prior history of breast cancer (except DCIS or LCIS) or distant metastasis, oral bisphosphonate (BP) use within 1 year of randomization, or any intravenous BP use, were not eligible. Patients were randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 months, then every 3 months for a total of 5 years of treatment. Supplemental vitamin D (ⱖ 400 IU) and calcium (ⱖ 500 mg) were required. The trial, sponsored by Amgen Inc., began enrolling patients in June 2010 and completed enrollment in late 2012. Clinical trial information: NCT01077154.

TPS663

TPS664



PIKHER2: A phase Ib/II study evaluating safety and efficacy of oral BKM120 in combination with lapatinib in HER2-positive, PI3K-activated, trastuzumab-resistant advanced breast cancer. Presenting Author: Anthony Goncalves, Institut Paoli Calmettes, Marseille, France

Human epidermal growth factor receptor 2 (HER2) suppression with the addition of lapatinib to trastuzumab in HER2-positive metastatic breast cancer (HALT: LPT112515). Presenting Author: Nancy U. Lin, DanaFarber Cancer Institute, Boston, MA

Background: Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. BKM120 is an oral pan-class I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110␣. PIKHER2 study will evaluate safety and efficacy of oral, daily lapatinib-BKM120 combination in HER2-positive, trastuzumab-resistant advanced breast cancer (ABC) with activated PI3K/AKT/mTOR pathway. Methods: This open label, single arm, multi-center study includes a phase Ib dose-escalation part and a phase II expansion part at the recommended dose (RP2D). Primary objectives include determination of the maximum-tolerated dose (MTD) of BKM120 in combination with lapatinib in trastumuzab-resistant HER2positive ABC (phase Ib part) and evaluation of the activity of BKM120lapatinib combination at RP2D as measured by objective response rate (ORR) in patients with activated PI3K/AKT/mTOR pathway, as defined by PTEN-negative by IHC and/or somatic mutations (exons 9 and 20) of PIK3CA and/or overexpression of phospho-AKT by IHC (phase II part). Secondary objectives include safety and tolerability of the combination, clinical benefit and progression-free survival, pharmacokinetic profiles, biological and pharmacodynamic correlates. Main eligibility criteria are PS ⱕ 1, HER2-positive ABC resistant to trastuzumab, documented activated PI3K/AKT/mTOR pathway (phase II part only). A modified CRM using an adaptive Bayesian model guides the dose escalation of both agents with a maximum of 24 patients planned to be enrolled in phase Ib part. Efficacy will be tested according to a standard 2-stage Simon design under the following unacceptable and desirable hypotheses: H0, ORR ⬍⫽ 10% (unacceptable rate) vs. H1, ORR ⬎⫽30% (desirable rate). A maximum of 35 patients with activated PI3K/AKT/mTOR pathway is planned to be enrolled in phase II part with an interim look after 18 evaluable patients will have been recruited. Clinical trial information: NCT01589861.

Background: Evidence supports the concept of dual HER2 blockade as a treatment strategy for HER2⫹ breast cancer (BC). In patients with prior trastuzumab (T)-treated HER2⫹ metastatic BC (MBC), treatment with T plus lapatinib (L) was associated with longer progression-free survival (PFS) and overall survival (OS) compared with L alone, and had an acceptable safety and tolerability profile. In patients with stage II/III BC, preoperative treatment with T plus L plus paclitaxel (P) resulted in significantly higher pathologic complete response rates compared with P combined with either agent alone. This study is designed to evaluate whether the addition of L improves PFS among women with HER2⫹ MBC receiving T as maintenance therapy. Methods: In this open-label, Phase III study, 280 patients will be stratified by line of treatment (first/second) and hormone receptor status (positive/negative), then randomized 1:1 to receive maintenance treatment with either L (1000 mg qd, continuously) in combination with T (6 mg/kg once every 3 weeks [q3w]), or T (6 mg/kg q3w) alone until disease progression, death, discontinuation due to adverse events, or other reasons. The primary endpoint is PFS; secondary endpoints are OS, clinical benefit rate, and safety. Eligible patients are females, aged ⱖ18 years with HER2⫹ MBC who have completed 12-24 weeks of first-/second-line treatment with T plus chemotherapy with an objective response or stable disease at chemotherapy discontinuation. Patients with stable brain metastases are eligible if entering the study on second-line treatment. Efficacy endpoints will be analyzed in the intent-to-treat population. A total of 193 PFS events is required to detect a 50% increase in median PFS from 18 weeks (T alone) to 27 weeks (L⫹T) with an associated hazard ratio of 0.667, an 80% power and a 1-sided type I error of 0.025. One interim analysis is planned for futility when ~97 PFS events (50% of required events) have been observed. Safety endpoints will be analyzed in all randomized patients who receive ⱖ1 dose of study medication. The trial is currently open for accrual in the United States and Canada. Clinical trial information: NCT00968968.


48s TPS665

Breast Cancer—HER2/ER General Poster Session (Board #17A), Sat, 1:15 PM-5:00 PM

TPS666


PAM50 HER2-enriched (HER2E) phenotype as a predictor of earlyresponse to neoadjuvant lapatinib plus trastuzumab in stage I to IIIA HER2-positive breast cancer. Presenting Author: Maria Vidal, Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, Spain

NSABP B-43: A phase III clinical trial to compare trastuzumab (T) given concurrently with radiation therapy (RT) to RT alone for women with HER2ⴙ DCIS resected by lumpectomy (Lx). Presenting Author: Melody A. Cobleigh, Rush University Medical Center, Chicago, IL

Background: Combinations of two different anti-HER2 therapies without chemotherapy have generated great expectations. However, it is unclear which group of patients benefits the most from this strategy. Within HER2-positive breast cancer, the PAM50 assay identifies a HER2Enriched HER2-E intrinsic subtype characterized by high activation of the EGFR/HER2 pathway. Trial Design: This non-randomized, open label multi-centre translational research study will evaluate the ability of the HER2-E subtype to predict pathological complete response (pCR) to dual HER2 blockade with lapatinib and trastuzumab for a total of 18 weeks. Patients with hormone receptor (HR)-positive disease will also receive endocrine therapy. Eligibility Criteria: Operable primary Stage I-IIIa HER2⫹ breast cancer. Specific Aims: The primary objective is to evaluate the ability of the PAM50 assay to predict pCR in the breast at the time of surgery.Secondary objectives are to (1) assess the correlation of HER2-E with pCR in the breast and axilla, (2) assess the correlation of HER2-E with Residual Cancer Burden (RCB) (3) evaluate the gene expression changes from Day 0 to Day 14 and the correlations with Ki67-IHC at Day 14, (4), identify additional gene expression signatures predictive of pCR, and (5) evaluate safety and tolerability. Methods: The statistical plan is based on the assumption that breast pCR rate will be 35.0% for HER2-E tumors and 8.0% for non-HER2E. The study will have a 95% power with a significance level of 5% (two-sided) and an assumed drop-out rate of 15%. Biomarker Analyses: Baseline, 14-day treated and post-treatment (surgical) formalin– fixed, paraffin– embedded tissues will be obtained. The expression of 547 genes will be explored with the nCounter platform. Subtype will be identified using the PAM50 predictor (Parker et al. J Clin Oncol 2009). Ki-67-IHC will also be evaluated on pre-treatment and Day-14 samples. Target Accrual: 150 patients with a maximum of 75 HR-positive patients across Spain and Portugal. Patient enrollment will begin in May 2013.

Background: A significant amount of DCIS is ER-negative and/or overexpresses HER2. This study will test HER2-targeted therapy in DCIS. Among T-treated HER2⫹ patients (pts) with DCIS treated with a single dose of T, T is found in ductal aspirates and antibody-dependent cell-mediated cytotoxicity activity for HER2 is increased. T boosts the effectiveness of RT in breast cancer xenograft models and cell lines. T given during whole breast irradiation (WBI) may improve results for HER2⫹ DCIS treated with lumpectomy (Lx). A trial to examine this question will enhance the understanding of breast tumor biology, the prevention of such tumors, and could possibly extend breast-conserving surgery benefits for women with DCIS. Methods: After Lx for pure DCIS, each pt’s DCIS lesion is centrally tested for HER2 using ASCO/CAP guidelines. HER2⫹ pts are randomly assigned to receive 2 doses of T, 3 weeks apart during WBI or to WBI alone. Women ⱖ18 yrs with a margin-clear Lx for pure DCIS, with ECOG status 0/1 who are clinically or pathologically node negative are eligible. ER and/or PR status must be known before random assignment. Primary aims are to determine if T decreases ipsilateral breast cancer (IBC) recurrence, ipsilateral skin cancer recurrence, or ipsilateral DCIS. Secondary aims are to determine the benefit of T in preventing regional or distant recurrence and contralateral invasive breast cancer or DCIS. B-43 will determine if DFS, recurrence-free interval, and/or overall survival can be improved with the use of T. 2000 pts will be accrued over 7.9 yrs, with a definitive analysis of primary endpoints performed at163 IBC events (7.5 - 8 yrs after protocol initiation) with an 80% power to detect a hazard reduction of 36%, from 1.73 IBC events per 100 pt-yrs to 1.11 events per 100 pt-yrs. The 36% observed reduction in the hazard of IIBCR-SCR-DCIS on the T arm is based on a projection of 40% hazard reduction if the compliance were perfect, with a 10% noncompliance rate. As of 1-1-13, 1,127 pts have been randomized into the study. Support: PHS NCI-U10-CA-69651, -12027, and -P30-CA-14599 from the US NCI, and Genentech, Inc. Clinical trial information: NCT00769379.

TPS667


PERSEPHONE: Duration of trastuzumab with chemotherapy in women with HER2-positive early breast cancer—Six versus twelve months. Presenting Author: Helena Margaret Earl, University of Cambridge, Department of Oncology, Cambridge, United Kingdom Background: PERSEPHONE is a randomised controlled trial comparing six months of trastuzumab to the standard 12 months in patients with HER2 positive early breast cancer. Methods: 4000 patients (pts) will be randomised into the two arms (1:1). The power calculations assume that the disease-free survival (DFS) of the standard treatment (12 months trastuzumab) is 80% at 4 years. Randomisation of 4000 pts will allow the trial to prove non-inferiority of six months trastuzumab (5% 1-sided significance and 85% power). Non-inferiority is defined as ‘no worse than 3%’ below the control arm (12 month) 4 year DFS. Primary outcome is DFS, and secondary outcomes are overall survival (OS) non-inferiority; cost effectiveness; cardiac function and quality of life. Tumour blocks are collected to research molecular predictors of survival with respect to duration of trastuzumab treatment. Blood samples are analysed for single nucleotide polymorphisms (SNPs) as pharmaco-genetic determinants of prognosis, toxicity and treatment outcome. PHARE, a similar trial from the Institut National du Cancer in France, closed to recruitment in 2010 and presented early data at ESMO 2012. Following this an unplanned interim analysis of PERSEPHONE was presented to the Data Monitoring and Safety Committee (DMSC). PERSEPHONE is funded by the NIHR HTA programme in the UK. Results: PERSEPHONE commenced recruitment in October 2007. At abstract submission, 2593 pts (65%) had been randomised from 144 UK sites. Recruitment is due to complete in September 2014 with the first planned interim analysis of the primary outcome mid-2016. The iDMSC reviewed all data available on HERA and PHARE as well as a PERSEPHONE interim analysis. There were no safety findings or signals that would warrant a change of the study plan and the high quality of data returns was noted. Conclusion: PERSEPHONE continues the active recruitment phase as planned. Preliminary but inconclusive PHARE data have reinforced interest in the PERSEPHONE trial both nationally and internationally. There has been full support from the Breast International Group (BIG) and the international breast cancer community to answer this important shorter duration question. Clinical trial information: 52968807.


Breast Cancer—Triple-Negative/Cytotoxics/Local Therapy 1000

Oral Abstract Session, Mon, 9:45 AM-12:45 PM

10-yr follow-up results of NSABP B-32, a randomized phase III clinical trial to compare sentinel node resection (SNR) to conventional axillary dissection (AD) in clinically node-negative breast cancer patients. Presenting Author: Thomas B. Julian, National Surgical Adjuvant Breast and Bowel Project; The Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA Background: NSABP B-32, the largest surgical prospective randomized phase III trial was designed to compare overall survival (OS), disease-free survival (DFS), and morbidity between SNR alone vs SNR ⫹ AD in SN negative (-) pts. We present 10 yr outcome data for primary endpoints as well as updated data on the effect of occult metastases, found later in the SN by central, detailed pathologic analysis. Methods: 5,611 women with operable, clinically N0, invasive breast cancer were randomized to SNR ⫹ AD (Group [Grp] 1) or to SNR alone with AD only if SNs were positive (Grp2). 3,989 (71.1%) of 5,611 pts were SN-. 3,986 (99.9%) of these SN- pts had follow-up information: Grp 1: 1,975, Grp 2:2,011. Median time on study was 9.4 yrs. Cox proportional hazard models adjusting for study stratification variables were used to compare OS and DFS between the two groups. Two-sided p values were used. HR values ⬎ 1 indicate a more favorable outcome in Grp 1 Results: At 10 yrs, there continues to be no significant difference in OS between the two groups (HR: 1.11, p ⫽ 0.27). 10 yr Kaplan-Meier (K-M) estimates for OS are 87.8% for SNR alone and 88.9% for SNR ⫹ AD. There continues to be no significant difference in DFS between the two groups (HR: 1.01, p⫽0.92). 10-yr K-M estimates for DFS were 76.9% for both groups. Occult nodal disease was originally detected in 3,884 pts (15.8%) with SN- on initial H and E analysis. Comparisons between the groups with and without occult disease yielded an adjusted HR for OS: 1.25 (p ⫽ 0.08) with an absolute difference at 10 yrs of 2.8% and a HR for DFS: 1.24 (p ⫽ 0.018) with an absolute difference of 4.1%. The cumulative incidences of local-regional events were low (10-yr values: SNR 4.0%, SNR⫹AD, 4.3%) and not significant (HR: 0.95, p ⫽ 0.77). Conclusions: At 10 yrs there continues to be no significant differences in OS and DFS between SNR and SNR ⫹ AD in pts with negative SN. The relative increase in risk of DFS and OS for pts with occult SN metastases remains stable. Support: PHS grants: NSABP: U10CA-12027, U10CA-37377, U10CA-69651, U10CA-69974; VT Ca Cntr: P30 CA22435; DNK: 5RO1CA074137 NCI Dpt HHS. Clinical trial information: NCT00003830.

1002


The effect of surgery type on survival and recurrence in very young women with breast cancer. Presenting Author: May Lynn Quan, Foothills Medical Centre, Calgary, AB, Canada Background: Young age has been identified as an independent predictor of recurrence and mortality in women with breast cancer. The equivalence of breast conserving surgery (BCS) with mastectomy remains unclear in this population in an era of multimodal therapy. We sought to determine the effect of surgery type on the risk of recurrence and survival in a large, population based cohort of very young women. Methods: All women diagnosed with breast cancer aged ⱕ35 between 1994 and 2003 in Ontario were identified from the Ontario Cancer Registry, a population based registry of all incident invasive breast cancers in the province. A retrospective chart review was undertaken to identify patient, tumor and treatment variables, as well as locoregional, distant recurrences and death. Univariable and multivariable Cox proportional hazards regression models were fit to determine the effect of primary surgery type on overall survival while controlling for known confounders. To examine time to recurrence in a multivariable analysis, the proportional subdistribution hazards model (Fine and Gray) was used to account for death being a competing risk. Results: A total of 1,381 patients were identified; the median age was 33 (range 18 – 35), median follow up was 11 years. Primary surgical treatment was BCS in 793 (57%) patients of which 89% had adjuvant radiotherapy. Of the 588 (43%) having mastectomy, 53% underwent post mastectomy radiation. Overall, 38% of patients sustained a recurrence of any type and 31% had died. After controlling for tumor size, margin status, node status, grade, LVI, ER/PR, HER2 and treatment (chemotherapy, radiation, hormones) there was no difference in overall survival (HR 0.99, 95% CI 0.79,1.26) or recurrence (HR 0.96, 95% CI 0.73,1.26) among women treated with BCS or mastectomy. Predictors of recurrence were size ⱖ2 cm, ⱖ 1 positive node, neoadjuvant chemotherapy, and lack of radiation. Predictors of death were similar and included high grade and presence of LVI. Conclusions: Very young women selected for BCS had similar outcomes to those selected for mastectomy after controlling for known prognostic factors for recurrence and death.

LBA1001

49s


Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer patients: Final analysis of the EORTC AMAROS trial (10981/ 22023). Presenting Author: Emiel J. Rutgers, Netherlands Cancer Institute, Amsterdam, Netherlands


1003


PrECOG 0105: Final efficacy results from a phase II study of gemcitabine (G) and carboplatin (C) plus iniparib (BSI-201) as neoadjuvant therapy for triple-negative (TN) and BRCA1/2 mutation-associated breast cancer. Presenting Author: Melinda L. Telli, Stanford University, Stanford, CA Background: TN and BRCA1-deficient breast cancer (BC) cell lines exhibit enhanced sensitivity to DNA damaging agents. This study was designed to assess efficacy, safety and predictors of response to iniparib in combination with GC in early-stage TN and BRCA1/2 mutation-associated BC. Methods: This single-arm, phase II study (NCT00813956) enrolled pts with clinical stage I-IIIA (T ⱖ 1cm by MRI) ER-negative (ⱕ 5%), PR-negative (ⱕ 5%), and HER2-negative or BRCA1/2 mutation-associated BC. Neoadjuvant G (1000 mg/m2; IV; D1, 8), C (AUC 2; IV; D1, 8), and iniparib (5.6 mg/kg; IV; D1, 4, 8, 11) were given every 21 days for 4 cycles, until the protocol was amended to increase the treatment duration to 6 cycles, with enrollment of 80 pts at multiple PrECOG institutions. The primary endpoint is pathologic complete response (pCR), defined as no invasive carcinoma in the breast and axilla. Pathologic response was centrally assessed by the residual cancer burden (RCB) index. Assuming 76/80 eligible and treated pts, the regimen would be deemed effective if the lower bound of a 90% exact binomial CI on the pCR rate exceeded 25%. Secondary endpoints are safety, MRI response, and breast conservation. Results: Among 80 eligible pts treated with 6 cycles, median age is 48 years, 19 pts have germline BRCA1/2 mutations (90% tested to date) and clinical stage is I (13%), IIA (36%), IIB (36%), IIIA (15%). Pathologic response data (ITT population) are detailed below. 69 pts completed treatment per protocol: 5 progressed, 5 discontinued due to an AE and 1 mutation carrier was lost to follow-up. Most common G3/4 adverse events are neutropenia (49%), elevated ALT/AST (14%), and anemia (10%). Conclusions: Preoperative GC plus iniparib is active in the treatment of early-stage TN and BRCA1/2 mutation-associated BC. Clinical trial information: NCT00813956. All pts n ⴝ 801

BRCA 1/2 wt n ⴝ 612

BRCA 1/2 mutant n ⴝ 193

TN BRCA 1/2 mutant n ⴝ 164

pCR (RCB 0), n (%) 90% CI

29 (36%) 27 – 46%

20 (33%) 23 – 44%

9* (47%) 27 – 68%

9* (56%) 33 - 77%

RCB 0/1, n (%) 90% CI

45 (56%) 46 - 66%

31 (51%) 40 - 62%

14 (74%) 52 - 89%

12 (75%) 52 - 91%

Completed treatment per protocol: 169, 252, 317, 414. * One pt with bilateral BC had pCR in both tumors.


50s

Breast Cancer—Triple-Negative/Cytotoxics/Local Therapy

1004


A randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). Presenting Author: Gunter Von Minckwitz, German Breast Group, Neu-Isenburg, Germany Background: Use of carboplatin in neoadjuvant chemotherapy (NACT) has never been prospectively examined in breast cancer. Cohort studies suggest a high sensitivity to DNA-damaging agents (e.g., carboplatin in triple negative breast cancer [TNBC]), which have a high prevalence of BRCA mutations. Two trials examining carboplatin in HER2⫹ metastatic disease have shown conflicting results, but one was biased by different dosage of docetaxel in treatment arms. GeparSixto investigates the impact of carboplatin in addition to an identical, optimized cytotoxic-targeted regimen on pathological complete response (pCR) in these two breast cancer subtypes. Methods: In GeparSixto trial (NCT01426880) patients were treated for 18 weeks with paclitaxel 80mg/m² q1w and non-pegylated-liposomal doxorubicin (NPLD) 20mg/m² q1w. HER2⫹ patients received concurrently trastuzumab 6(8) mg/kg q3w and lapatinib 750mg daily. TNBC patients received concurrently Bevacizumab 15mg/kg i.v. q2w. All patients were randomized 1:1 to receive concurrently carboplatin AUC 1.5-2 q1w vs not, stratified by subtype. Primary objective is pCR rates (ypT0 ypN0), secondary objectives are pCR rate in predefined subgroups or by other definitions, clinical response rate, compliance and tolerability of carboplatin. Carboplatin dose was reduced from AUC 2.0 to 1.5 by an amendment after 330 patients due to carboplatin-related toxicity at pre-planned safety analyses. Results: 595 patients were recruited (8/2011 - 12/2012) in 51 German centers, 299 did not receive carboplatin. Median age was 47/48 years (no carb/carb), 36.8/36.5% were postmenopausal; 14.0/13.3% had T3, 5.0/3.7% T4, 41.8/37.6% N⫹, 93.0/92.9% ductal invasive, 64.5/65.3% G3 tumors; 46.2/46.3% had HER2⫹, 53.8/53.7% TNBC. 225 patients had a SAE (149 no carb/177 carb) and 3 died (postoperative pneumonia; reduced general condition; acute myocardial infarct), all in no carb arms. Final analysis on primary endpoint will be presented. Conclusions: This is first study, evaluating efficacy and safety of the addition of carboplatin to anthracycline-taxane containing NACT in patients with primary HER2⫹ and TNBC. Clinical trial information: NCT 01426880.

1006


Time trends in the use of adjuvant chemotherapy (CTX) and outcomes in women with T1N0 breast cancer (BC) in the National Comprehensive Cancer Network (NCCN). Presenting Author: Ines Maria Vaz Duarte Luis, Dana-Farber Cancer Institute, Boston, MA Background: The role of adjuvant CTX in women with small BC is controversial. Here we analyze time trends of CTX use and outcomes in women with T1N0 BC treated at NCCN cancer centers. Methods: 8917 women were identified who received surgery or systemic therapy at an NCCN center with T1a, T1b or T1c N0 M0 BC between 2000-09. Tumors were grouped by biologic subgroups by hormone receptor (HR) and HER2 status and T subgroups (T1a, T1b, T1c). Primary endpoints were receipt of adjuvant CTX (⫾ trastuzumab) and BC specific survival (BCSS). Chisquare, Cochran Armitage trend, Kaplan Meier estimates, log-rank test and Cox hazard proportional regression were used for analysis. In this report we focus on T1a/b results (N⫽4113). Results: Median follow up time was 5.5 years (range, 0.7-12.7). CTX use differed according to biologic and T subgroups, with significant changes over time (Table). In 2009, more than 50% of patients (pts) with HER2⫹ and HR-2- T1a/b breast cancers received CTX (⫾ trastuzumab). The table lists use of CTX by year and subset and the 5 year BCSS for pts treated and not treated with CTX. Conclusions: A high proportion of pts with HER2⫹ and HR-HER2- T1N0 breast cancers received adjuvant CTX, with a sharp increase in use of CTX among HER2⫹ over the past decade. Use of CTX is higher in T1b compared to T1a tumors. In this study, women with T1a and T1b tumors have an excellent prognosis without CTX at 5 Yr. Careful examination of cutoffs for absolute benefit sufficient to recommend CTX is warranted. Percent of adjuvant CTX (ⴞ trastuzumab) (%) HRⴙHER2(T1a, b, c) Nⴝ6789

Year of diagnosis

T1a Nⴝ984

T1b Nⴝ2246

P 1 ALN positive for metastasis

1119

Number (%)

1118


A phase I-II study of tipifarnib plus weekly paclitaxel (P) followed by dose-dense doxorubicin/cyclophosphamide (AC) in stage IIb-IIIc breast cancer (BC). Presenting Author: Eleni Andreopoulou, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY Background: Tipifarnib (T) is an orally bioavailable farnesyl transferase inhibitor (FTI) that has activity in metastatic BC (J Clin Oncol 2003; 21:2492-9). We previously showed that adding T (200 mg PO BID days 2-7) to preoperative AC was associated with a higher pathologic complete response (pCR) than expected compared with historical data (Clin Cancer Res. 2009;15;2942-8), and preclinical data suggest that FTIs enhance the antineoplastic effects of P (Cancer Res 2005; 65:3883-93). Methods: Eligible pts with HER2-negative clinical stage IIB-IIIC BC received 12 weekly doses of P (80 mg/m2) followed by AC (60/600 mg/m2 every 2 weeks and pegfilgrastim), plus T 100 mg or 200 mg on days 1-3 of each P dose in cohorts of 3-6 pts in the phase I (and T 200 mg PO BID on days 2-7 each AC cycle in both the phase I and II). Simon two-stage design used for the phase II in two strata generally resistant to neoadjuvant chemotherapy. The trial was powered to detect an improvement in breast pathologic complete response (pCR) from 15% to 35% in each stratum (alpha 0.10, beta 0.10), which required breast pCR in at least 4/19 eligible pts in stage I to proceed to stage II, and at least 8/33 pts in stage I and II to be considered promising. Results: Sixty patients accrued in both the phase I and II. Two patients were non evaluable. There were no DLTs in the first 6 evaluable patients treated at dose level 1 and 2.The recommended phase II dose of T identified in the phase I trial was 200 mg BID.All protocol therapy was completed in 43/55 pts (78%) in the phase II, and one pt died of pneumonitis during therapy of uncertain cause. The prespecified efficacy endpoint was not met for either stratum. Conclusions: The addition of the FTI tipifarnib to neoadjuvant sequential weekly paclitaxel followed by dose-dense AC did not result in a higher breast pCR rate compared with historical data. Clinical trial information: NCT00049114. Stratum A

14 (61) 7 (30) 2 (9) 6 (26) 6 (26) 3 (13)


Sentinel node biopsy in patients with microinvasive breast cancer: A systematic review and meta-analysis. Presenting Author: Helene Gojon, Department of Oncology, Mälarsjukhuset, Eskilstuna, Sweden Background: The aim of this meta-analysis is to evaluate the role of sentinel lymph node biopsy (SLNB) in patients with microinvasive breast cancer. Methods: We searched MEDLINE and ISI Web of Science to identify studies including patients with microinvasive breast cancer who underwent SLNB and reported the rate of sentinel-node positivity. We performed proportion meta-analysis using either fixed or random-effects model based on the between-study heterogeneity. Results: A total of 23 studies including 952 patients met the eligibility criteria. The summary estimate for the sentinelnode (SN) positivity rate was 3.1% (95% Confidence Interval (CI): 2.0%-4.4%), 4.1 % (95% CI 2.8%-5.6%), and 2.8% (95% CI : 1.6%4.5%) for macrometastasis, micrometastasis and isolated tumor cells (ITC) respectively. Significant between-study heterogeneity was observed only in the meta-analysis of ITC positivity rate. Conclusions: The amount of positive sentinel node in patients with proven microinvasive breast cancer is relatively low. As a result, the indications for SLNB in these patients should be probably individualized.

Definition

ER and/or PR-positive Non-inflammatory Breast pCR/treated 18% (N⫽6/33) 95% confidence intervals 7%, 36% Residual Cancer Burden Class (RCB) 0 5 I 1 II 14 III 11 Unknown 2 No surgery

1120

Stratum B Inflammatory Any ER/PR status 4% (N⫽1/22) 0%, 8% 1 2 9 5 2 3


Intraoperative versus external beam boost for breast cancer: A matchedpair analysis. Presenting Author: Elena Sperk, Department of Radiation Oncology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany Background: After breast conserving surgery, radiotherapy leads to a better overall survival. In addition to whole breast radiotherapy (WBRT) a boost to the tumor bed leads to a better local control. The tumor bed boost is usually added after WBRT or can be done intraoperative (IORT). Belletti et al. (Clin Cancer Res., 2008) described positive effects, an antitumoral effect and modulation of microenvironment after IORT with 50kV x-rays. A matched pair analysis was performed to investigate the impact of IORT boost on overall survival compared to standard external beam boost. Methods: Between 2002 – 2009, 370 patients were treated for breast cancer with WBRT ⫹ boost (external beam (EBRT) boost n ⫽ 146, IORT boost n ⫽224). A matched pair analysis (1:1 propensity score matching for age, TNM, grading, hormonal treatment and chemotherapy) for overall survival and local recurrence free survival could be done for 53 pairs. All patients underwent breast conserving surgery and WBRT with 46-50Gy. 53 patients received an EBRT boost with 16Gy (2Gy/fraction, dedicated linear accelerator) and 53 patients received an IORT boost with 20Gy (INTRABEAM system, 50kV x-rays). Median follow-up was 6 months (range, 1-77 months) for the EBRT boost patients and 56 months (range, 2-97 months) for IORT boost patients. Kaplan Meier estimates were performed for overall survival and local recurrence free survival. Results: IORT boost patients had a longer follow-up than EBRT boost patients. Despite the difference in follow-up times, there was a strong trend towards better overall survival after IORT boost (90.2% vs. 62.3%, p ⫽ 0.375). One local recurrence was present in each group (EBRT boost after 15 months, local recurrence free survival 95%; IORT boost after 12 months, local recurrence free survival 98.1%). Conclusions: IORT given as a boost seems to have a positive impact on overall survival in breast cancer patients after breast conserving surgery. To identify such an effect a prospective randomized trial should be conducted.




TARGIT-A trial: Updated results for local recurrence and survival for the German centers. Presenting Author: Frederik K. Wenz, Department of Radiation Oncology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany Background: In 2010, we reported data on local control and early toxicity for the TARGIT-A trial of intraoperative radiotherapy after lumpectomy for early breast cancer. The updated results and first analysis of survival of the whole cohort (n ⫽ 3,451) were presented at San Antonio Breast Cancer Symposium in December 2012. We analysed the German cohort of patients, which was supposed to be more homogeneous (prepathology IORT only, homogeneous treatment in EBRT arm) and lower risk (older, smaller tumors, larger margin) than the international cohort of patients due to legal restrictions for radiotherapy studies in Germany. Methods: TARGIT-A was a randomised trial in patients ⬎⫽50 years with invasive ductal carcinoma (⬍⫽ 2cm) undergoing breast conserving surgery comparing standard fractionated whole breast EBRT (56 Gy) with single dose TARGIT (20 Gy) immediately after tumor excision / at the time of the primary operation. The experimental arm mandated additional EBRT (46 Gy, excluding a boost, n ⫽ 126) if adverse features were detected on final pathology (EIC, N⫹, margin ⬍ 1 cm) making this a “risk-adapted policy”. Median follow-up was 2 years and 5 months. Results: 734 patients recruited from 7 centres in Germany. Patient’s ages were ⬍⫽50y 3%, 51-60y 33%, 61-70y 51%, ⬎70y 12%. Tumour sizes were 0-1cm 35%, 1.1-2cm 55% and ⬎2cm 11%. Grade I 29%, II 59%, III 12% and nodes negative 81%, 1-3 nodes 16%, ⬎3 nodes 3%. At 5-years, the absolute number of events in TARGIT vs. EBRT were as follows: Primary outcome: IBR 4 vs. 1, Exploratory outcome: All recurrences (breast ⫹axilla⫹contralateral⫹distant recurrence) 11 vs. 7, Secondary outcome: All deaths 6 vs. 12, Breast Cancer deaths 3 vs. 5, Non-Breast Cancer deaths 3 vs. 7. Conclusions: Patients in the TARGIT-A trial have excellent 5 year outcomes (local control ⬎ 97%, overall survival ⬎⫽ 94%) in both arms of the trial. Clinical trial information: protocol 99PRT/47.

1123


Propensity-score matched pair comparison of accelerated partial breast irradiation (APBI) and whole breast irradiation (WBI) for ductal carcinoma in situ (DCIS). Presenting Author: John Ben Wilkinson, Oakland University William Beaumont School of Medicine, Beaumont Cancer Institute, Royal Oak, MI Background: DCIS remains a cautionary criterion for APBI by the ASTRO APBI consensus statement. We performed a matched analysis to compare the efficacy of WBI and APBI for patients with DCIS. Methods: Women with DCIS treated with APBI or WBI were reviewed. APBI (n⫽102) patients with ⱖ2 y follow-up were matched 1:3 to WBI (n⫽546) patients with ⱖ5 y follow-up by age, tumor size, nuclear grade, ER status, margin status, and laterality. Ipsilateral breast tumor recurrence (IBTR), distant metastasis (DM), contralateral breast cancer (CLBC) and cause-specific survival (CSS) were compared by cumulative incidence (Gray’s) and competing risks regression (Fine and Gray’s), and overall survival (OS) and disease-free survival (DFS) by Kaplan-Meier (log-rank test). Results: Median follow-up was 4.6 y (2.0-14.7) for APBI and 9.0 y (5.4-27.0) for WBI. Median (range) or percentages are shown (Table). Patients did not differ by match criteria. There were 17 LR, 1 DM, 19 CLBC, 2 CSS, 22 OS, and 19 DFS events during follow-up. The patient groups had similar rates of cancer-related events including ipsilateral and contralateral breast recurrences at both five and eight years. Treatment type, age, tumor size, nuclear grade, ER status, and hormone therapy (HT) were not prognostic of LR or CLBC on uni- and multi-variate analyses. Conclusions: APBI provides equivalent and exemplary outcomes compared to WBI following breast-conserving surgery for DCIS. These findings support previous reports on the efficacy of APBI in the treatment of noninvasive breast carcinoma. Prospective randomized comparison of APBI to WBI for DCIS is needed. Age (y) Tumor size (mm) Nuclear grade 1 2 3 ER status Positive Margin status Clear (>2mm) Adjuvant HT Detection by Mammogram Patient Other Laterality Left-sided Race Caucasian African American Other Outcomes 5y / 8y IBTR DM CLBC DFS CSS OS

APBI (nⴝ102)

WBI (nⴝ306)

62 (43-84) 6 (0-28)

62 (29-88) 5 (1-30)

28% 54% 17%

31% 45% 24%

88%

86%

88% 54%

93% 55%

93% 6% 1%

91% 5% 4%

60%

61%

78% 14% 8%

90% 6% 4%

2% / 2% 0% / 0% 1% / 5% 98% / 98% 100% / 100% 96% / 96%

2% / 3% 0% / 0% 3% / 4% 98% / 97% 100% / 100% 100% / 98%

P 0.83 0.85 0.24

0.76 0.09 0.91 0.63

0.82 0.02

0.96 0.93 0.63 0.98 0.93 0.04

1122

79s


Sentinel lymph nodes before chemotherapy: The Besançon experience. Presenting Author: Loic Chaigneau, Institut Regional Du Cancer En Franche-Comté - University Hospital, Besançon, France Background: It is debatable whether sentinal lymph node (SLN), before chemotherapy in locally breast cancer (LBC) is feasible. Impact on survival and locoregionally recurrence are unknown. Methods: 256 consecutive patients with LBC treated in Franche Comté (France) between 2004 and 2010 by standard neoadjuvant chemotherapy were retrospectively studied. 177 patients underwent axillary lymph node (ALN) dissection after chemotherapy (cohort A) and 79 patients underwent SLN before chemotherapy (cohort B). The aim of this study was designed to confirm the feasible of SLN before neoadjuvant chemotherapy without negative impact of recurrence and survival. Disease-free survival (DFS) and overall survival (OS) were calculated using Kaplan-Meier method. Differences in OS and DFS according ALN exploration were tested for significance using the Log-Rank test. Results: No statistically significant differences were observed in terms of median age (respectively 59 and 48 years in cohort A and B), tumor size, histological type, grading score, estrogen receptor, progesteron receptor and human epidermal receptor-2 status. No difference of breast conserving surgery was observed between cohort A and B (56.25 vs. 64.56%, p ⫽ 0.21). In cohort B, 38 patients (48.10%) of patients underwent SLN alone. For others patients (n ⫽ 41, 51.90%), secondary complete axillary lymphadenectomy was performed in the same time of breast surgery. After a median follow up of 57 months (range: 38-105), there was no significant difference in termsof local and axillary recurrences (1.13 vs. 1.27%), metastatic recurrence (11.30 vs. 11.40%). Five-year DFS (76 vs 81%, p ⫽ 0.55) and 5-year OS (91 vs. 97%, p ⫽ 0.76) did not differ between patients in cohort A and B. Conclusions: SLN before neoadjuvant chemotherapy is feasible and allows to avoid ALN dissection in nearly 50% of patients without impact on recurrence and survival.

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Volume-based parameters on FDG-PET/CT as early predictors of disease recurrence in postmastectomy breast cancer patients with one to three positive axillary lymph nodes without adjuvant radiotherapy. Presenting Author: Naomi Nakajima, National Hospital Organization Shikoku Cancer Center, Department of Radiation Oncology, Matsuyama, Japan Background: The indication for postmastectomy radiotherapy (PMRT) in patients with 1-3 lymph node metastases in the axilla have been controversial, despite the recommendation that PMRT should be applied. In the current study, we focused our study on volume-based parameters of pretreatment FDG-PET/CT, with the aim of investigating a measurement that could help identify high-risk populations for recurrence. Methods: We retrospectively analyzed 88 patients of breast cancer treated with modified radical mastectomy and were found to have 1-3 metastatic axillary lymph nodes between 2006 and 2010. All of them were studied with FDG-PET/CT for initial staging. We evaluated the relationship between clinicopathologic factors or PET parameters including the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) and recurrence. MTV and TLG of the primary tumor and metastatic lymph node were measured by using semi-automatically delineated volume of interest (VOI) with an isocontour threshold of 40 % of the SUVmax. The optimal cutoffs of PET parameters were determined by ROC curve analysis. Results: The median follow up duration was 39 months. Median MTV was 21.1and median TLG was 42.7. Recurrence was observed in 10 patients. The area under the ROC curve of MTV and TLG for DFS was 0.82 and 0.85, respectively. In Cox univariate analysis, estrogen receptor status (HR ⫽ 6.8, p ⫽ 0.003), triple negativity (HR ⫽ 10.4, p ⫽ 0.0008), SUVmax (HR ⫽ 71.1, p ⫽ 0.001), MTV (HR ⫽ 130.3, p ⬍ 0.0001), and TLG (HR ⫽ 234.1, p ⫽ 0.0001) were significantly related to disease free survival (DFS). The estimated 3-year DFS rates were 96.4 % for the lower MTV group (⬍ 31.8) and 71.4% for the higher MTV group (ⱖ 31.8, p ⫽ 0.0005). The estimated 3-year DFS rates were 95.8 % for the lower TLG group (⬍ 109.6) and 50.0 % for the higher TLG group (ⱖ 109.6, p ⬍ 0.0001). On multivariate analysis, TLG was an independent prognostic factor of DFS (HR ⫽ 8.5, p ⫽ 0.005). Conclusions: Volume-based parameters on FDG-PET/CT were significant predictors of DFS in postmastectomy breast cancer patients with 1-3 metastatic axillary lymph nodes.


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Breast Cancer—Triple-Negative/Cytotoxics/Local Therapy General Poster Session (Board #31H), Sat, 1:15 PM-5:00 PM

PTEN-deficient breast cancer in neoadjuvant treatment. Presenting Author: Juan de la Haba-Rodriguez, Medical Oncology Department University Reina Sofia Hospital. Biomedical Research Institute Maimonides, Cordoba, Spain Background: Loss of function mutations in the tumour suppressor gene PTEN or lack of PTEN expression have both been observed in a wide range of human tumours. PTEN encodes a phosphatase, whose activity antagonizes PI3 kinase signal pathway by dephosphorylation the plasma membrane lipid, phosphoinositide-3,4,5-trisphosphate (PIP3). Loss of PTEN phosphatase activity is thought to foster tumorigenesis, at least in part, by causing downstream constitutive activation of AKT. In addition to this role, PTEN has been suggested to have a nuclear function in maintaining genomic stability[2]. Our proposal is to identify those tumours without expression of PTEN, their characteristics and response to treatment. Methods: We have studied PTEN expression by immunohistochemistry in tumours samples from 86 patients treated with neoadjuvant treatment. Normal breast epithelium or vascular endothelium were used as positive control. PTEN was evaluated by inmunoreactive stain score, taking into account staining intensity and percentage of positive cells, PTEN deficiency (PTEN -) has been stablished by a IRS⫽0[1]. We analyzed the PTEN localization (nuclear vs citoplasmatic). Results: In our serie, 38 (44.2%) of the tumours samples were PTEN deficient. Taking into account as reference PTEN ⫹ tumours, we have found that PTEN deficient tumours are more frequently; ductal carcinoma (94.2% vs 81.8%), G3 (72% vs 48.7%), ER negative (47% vs 30.4%), Triple negative (24.2% vs 15%) and higher Ki67 expression (⬎20%) in the 100% of PTEN deficient tumours. The pathological rate response was PTEN -:18.4% vs PTEN ⫹:19.1% p:ns, and the recurrence rate was higher in PTEN- (26,3% vs 8,3%) p:0.025. Conclusions: The PTEN deficient breast tumours is associated to more histological aggressive profile, and we have not found relations with the pathological rate response to neoadjuvant treatment.

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Clinicopathologic features of multiple phyllodes tumors of the breast. Presenting Author: Fumi Yoshidaya, St. Luke’s International Hospital, Tokyo, Japan Background: Phyllodes tumor of the breast is one of the rare neoplasm accounting for 0.3-0.5% of all breast tumors. It is difficult to diagnose the histological type of phyllodes tumors preoperatively by radiological and even pathological findings. The aim of this study is to clarify the clinicopathological features of phyllodes tumors. Methods: We retrospectively reviewed records from 116 patients with phyllodes tumors who underwent surgery between 2003 and 2011. We determined the clinicopathological characteristics, including the presense of multiple lesions and the type of surgical procedure, of each histological type of phyllodes tumors which were classified as benign, borderline, and malignant. Results: The median follow-up time was 23.3 months. Benign phyllodes tumors were presented in 91 patients (78.4 %), borderline were in 17 patients (14.6 %), and malignant were in 8 patients (6.9 %). Ten patients (8.6 %) had multiple phyllodes tumors; 9 for ipsilateral and one for bilateral breasts. One hundred two patients underwent lumpetcomy and 14 patients underwent mastectomy. No patients received chemotherapy or radiation therapy. Noteworthy, all multiple tumors were diagnosed histologically benign. The median age at operation were 41 years (range, 12-72 years) for benign tumors, 44 years (26-67 years) for borderline, and 47 years (39-60 years) for malignant. The size of malignant tumors was significantly large (a median, 11.3 cm; range, 6-27 cm) compared to benign (a median, 4.4 cm; range 1-21 cm) and borderline (a median, 4.7cm; range 1-16 cm) (p ⫽ 0.001, and 0.03, respectively). Local recurrence developed in 14 of the 91 patients (15.4 %) with benign, 2 of the 17 patients (11.8 %) with borderline, and 2 of the 8 patients (25 %) with malignant tumors. Four patients (50 %) with malignant tumors but none with benign and borderline developed distant metastasis. Of the 4 patients, 3 had undergone mastectomy and one had lumpetcomy for initial treatment. No benign and borderline tumor had malignant change when tumors recurred. Conclusions: Our new findings indicated that multiple phyllodes tumors may be histologically benign. Furthermore, patients with benign or borderline phyllodes tumors had good prognosis regardless of surgical procedure.

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Does radiation therapy increase late cardiac death in patients with left breast cancer? Presenting Author: Chi Lin, University of Nebraska Medical Center, Omaha, NE

Nomogram for predicting breast-conservation surgery after neoadjuvant chemotherapy. Presenting Author: Min Kyoon Kim, Department of Surgery, Seoul National University Hospital, Seoul, South Korea

Background: The objective of this study was to evaluate the effect of external beam radiation therapy (RT) on late cardiac death (CD) in patients with left breast cancer. Methods: A total of 529,246 patients who were diagnosed with adenocarcinoma of the breast between 1983 and 2004 and survived ⱖ 5 years were identified from the SEER database. After excluding patients who were male, had right breast cancer, received brachytherapy or had missing data, 163,894 patients remained. Examined risk factors for CD include age (ⱕ49/50-59/60-69/70-100), race (white/non-white), stage (In situ/local/regional/distant), breast subsite (nipple and areola/inner quadrant/outer quadrant), diagnosis year (1983-1993/1994-2004), surgery status (none/less than mastectomy/mastectomy) and RT. Time to CD was evaluated using the Kaplan-Meier method. A multivariate logistic regression model was used to evaluate factors associated with the use of RT and the Cox Proportional Hazards model was used to evaluate risk factors for CD. Results: A multivariate logistic regression model revealed that patients who received RT tended to be younger, white, more recently diagnosed, have inner quadrant and more advanced disease and undergo less than mastectomy. Median overall survival for patients with RT was significantly longer than those without RT (263 vs. 226 months, Log-Rank p ⬍ .0001). RT group had a lower risk of CD than no-RT group (Log-Rank p ⬍ .0001). Median time to CD was not reached in either group. The probability of CD was increased with increasing age and stage, and decreased with more recent diagnosis year and after mastectomy. Cox model found RT to be associated with lower probability of CD (HR 0.66, 95% CI 0.62-0.70), after adjusting for age, stage, surgery status and diagnosis year. Race and breast subsite were not associated with CD. Conclusions: Patients with left breast cancer who survived ⱖ 5 years and received RT had a lower risk of cardiac death than those who did not. The cause of this difference is unclear but suggests influence from an uninvestigated factor, potentially the increased use of cardiotoxic chemotherapy or other cardiovascular comorbidity in those patients not receiving RT. Continued study, accounting for such factors, is warranted.

Background: The indications for neoadjuvant systemic treatment (NST) have broadened to early breast cancer patients and more patients can undergo breast conservation with results in better cosmetic outcomes. However, a significant number of patients with operable breast cancer still require mastectomy after NST with a small number of patients experiencing disease progression which may hinder complete surgical resection. Therefore, accurate prediction of each patient’s likelihood of achieving breast conservation after NST is important for establishing a treatment plan for patients with operable breast cancers. Methods: We identified 534 women from the Seoul National University Hospital Breast Care Center, who were stage II and III, and treated with neoadjuvant chemotherapy and surgery from Jan. 2001 to Dec. 2010. Breast conservation surgery (BCS) and tumor size reduction to less than 3cm were clinical outcome variables for nomograms, and we analyzed the various clinicopathologic factors best predicting these outcomes. To develop well-calibrated and exportable nomograms for BCS and for residual tumor size, we built each model in a training cohort and validated it in an independent validation cohort. Results: Of the 513 patients, pCR was observed in 10.5% and BCS was performed in 50.1%. The nomogram for predicting BCS and tumor size reduction to less than 3cm were constructed using logistic regressing model. Initial tumor size(p⬍0.001), the distance between the lesion and the nipple (p ⬍ 0.001), the presence of suspicious calcifications in the mammography (p ⫽ 0.0127) and multicentricity (p ⫽ 0.0146) were independently associated with breast conservation surgery. ER status (p ⫽ 0.001), initial tumor size (p ⬍ 0.001), histologic type (p ⫽ 0.012) were independently associated with a residual tumor size ⬍3cm. Mastectomy rate in the larger than 3cm tumors were 72.7%, and breast conservation surgery in smaller than 3cm tumors were 63.2%. (p ⬍ 0.001). Conclusions: In conclusion, we have established a new model to predict BCS and residual tumor size after NST. The model showed the outperformed prediction accuracy compared with previous similar models with reflecting novel factors impacting on surgical decision making.




Clinicopathologic analysis of a large series of microinvasive breast cancer. Presenting Author: Joseph W. Leach, Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Minneapolis, MN Background: Microinvasive breast cancer (Tmic) is defined by the AJCC as extension of cancer cells beyond the basement membrane with no single focus larger than 1 mm. The clinical behavior of this entity is unclear. Most series suggest that prognosis is similar to non-invasive cancer although the literature is mixed. Surgical management typically reflects invasive breast cancer including lymph node sampling. Published incidence of nodal involvement is also variable with some small series reporting incidence as high as 20%. We present a clinicopathologic review of a large series from a community practice setting. Methods: Using the AJCC definition of Tmic, we retrospectively identified all cases treated within Allina Health System from 2001-2011. Inclusion criteria included no prior history of breast cancer and available follow-up data. Data collected included ER/PR and HER2 status (when available), margin status and surgical and adjuvant therapy. Results: 118 eligible cases were identified with a mean follow-up of 3.65 years and mean age of 56.8 years (34-88). 39 were triple negative and 29 were HER2⫹. ER/PR data was available on all cases, HER2 on 60. 72 were treated with mastectomy. All patients underwent axillary staging. Lymph node metastasis was identified in 2 cases (one triple negative, one HER2⫹). In one case the metastasis measured 0.25 mm, in the other 0.4 mm. Complete axillary dissection performed on both cases demonstrated no additional lymph node involvement. Isolated tumor cells were also identified in 9 cases. 2 cases developed local recurrence following lumpectomy and radiation, both in the ipsilateral breast. One recurred with microinvasive disease, the second with DCIS only. There were no cases of metastatic recurrence and no breast cancer associated deaths. Conclusions: The clinical behavior of microinvasive breast cancer in this series is similar to DCIS. The incidence of lymph node metastasis was low (1.7%) and there were no cases of distant metastasis. Our data supports management of microinvasive breast cancer as a subset of DCIS and suggests that the benefit of routine lymph node sampling is questionable.

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Incidence and characteristics of breast cancer following a diagnosis of ductal carcinoma in situ. Presenting Author: Xiudong Lei, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Recent data indicate that the incidence of DCIS is rising. The purpose of this retrospective population based study was to examine incidence of and factors that contribute to the development of a subsequent breast primary. Methods: Using the SEER registry we identified female pts with a primary DCIS diagnosed between 1990 to 2005. Pts who had an invasive or in situ malignancy diagnosed prior to a diagnosis of DCIS were excluded. Cumulative incidence of a subsequent breast primary (invasive/non invasive) was estimated and compared across groups using the Chi-square test. Multivariable logistic regression models were then fitted to determine factors that could predict for the development of a subsequent breast primary. Results: 96,130 pts were identified of whom 14,573 (15.2%) had subsequent primaries. 9,037 (62%) pts had a subsequent primary in the breast of which 5,915 (65.5%) pts had an invasive breast cancer. Among pts who developed an invasive breast cancer 68% had hormone receptor positive disease, 59% had grade I/II disease and 80% had stage I/II disease. 2 and 5-year cumulative incidence of developing a subsequent breast primary was 3.2% and 5.9% respectively. 2 and 5-year cumulative incidence of developing a subsequent invasive breast primary was 1.6% and 3.4% respectively. 5-year cumulative incidence of developing a subsequent breast primary among pts who were of white, black and other race was 5.8%, 6.8% and 6.1% respectively (P⬍0.001). In the multivariable logistic model the probability of developing a subsequent breast primary decreased with each increasing year of diagnosis of DCIS (OR 0.91, 95%CI 0.91-0.92, p⬍0.001). Other factors that predicted for the development of a subsequent breast primary included younger age at diagnosis, non-white race and lack of surgical or radiation therapy for DCIS. Conclusions: Our results indicate that a significant proportion of pts with a diagnosis of DCIS go on to develop invasive breast cancer and may warrant further investigation to determine biological risk factors, appropriate screening procedures and possible interventions to decrease incidence. Target groups that may benefit include pts who are young and of non white race at the time of diagnosis of DCIS.

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Influence of guideline-concordant adjuvant therapy on all-cause and disease-specific survival among breast cancer patients in rural Georgia. Presenting Author: Gery P. Guy, Emory University, Rollins School of Public Health, Atlanta, GA Background: This study examines whether receipt of chemo-, radiation, and hormonal therapy regimens that are jointly guideline concordant improve survival outcomes among women diagnosed with breast cancer in a rural region of the United States. Methods: All women identified by the state cancer registry residing in rural southwest Georgia diagnosed with early stage breast cancer during 2001-2003 were included. Medical chart abstraction and registry data were used to determine treatment concordance with the 2000 NIH consensus development conference guidelines on breast cancer treatment. Patients were Concordant versus NonConcordant according to whether their receipt (or non-receipt) of each adjuvant therapy type was according to guidelines. To examine the effects of concordance on all-cause and breast cancer-specific survival, Cox models were developed that used both propensity score weighting and 2-stage residual inclusion instrumental variable techniques to adjust for patient selection effects. Results: In all-cause analyses, Concordance versus Non-Concordance was associated with significantly better survival (hazard ratios (HRs) 0.41 (95% CI: 0.24-0.72) to 0.54 (95% CI: 0.33-0.87). Similar findings emerged in breast cancer-specific survival analyses, with HRs significantly less than 1.0 in most cases. Diagnosis at older age or later disease stage strongly predicted poorer survival outcome; being not married was significant in all-cause but not breast cancer-specific models. Survival was not generally associated with surgical treatment delay, insurance status, socioeconomic status, rural/urban status, comorbidities, tumor grade, or hormonal status. HR for black women versus white was greater than 1.0 across models but never significant (p⫽0.05). Conclusions: Breast cancer patients in rural Georgia who received guidelineconcordant adjuvant therapy had significantly better all-cause and breast cancer-specific survival, based on Cox model analyses that attempted to control for multiple clinical and demographic factors, as well as selection effects. These findings extend the evidence that guideline bundles of care improve outcomes.

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Distinctive lipid profiles of human breast cancer and adjacent normal tissues by desorption electrospray ionization mass spectrometry imaging. Presenting Author: Diana L. Caragacianu, Brigham and Women’s Hospital/ Dana-Farber Cancer Institute, Boston, MA Background: Routine intra-operative distinction between normal breast tissue and tumor is currently not possible in breast conserving surgery (BCS). This limitation affects the success of surgery, resulting in up to 40% requiring more than one operative procedure. Desorption electrospray ionization mass spectrometry (DESI MS) has been successfully used to discriminate between normal and cancerous human tissues from anatomical sites such as the liver and brain. The aim of this proof of concept study was to determine the feasibility of using DESI MS imaging for tissue identification and differentiation of breast cancer versus normal tissue. Methods: DESI MS imaging was carried out on 14 human invasive breast cancer samples. Breast cancer and adjacent normal paired human tissue sections (margin of tumor, 2cm and 5 cm from tumor) from 14 patients undergoing mastectomy were flash frozen in liquid nitrogen, sectioned, and thaw mounted to glass slides. All samples were imaged using DESI MS at 200 ␮m imaging resolution. DESI MS images were overlaid and compared with hematoxylin and eosin (H&E) images of the same sections. Results: Discrimination between cancer and adjacent normal tissue was achieved on the basis of the spatial distribution and varying intensities of particular fatty acids and lipid species. Several fatty acids such as oleic acid (m/z 281) and arachidonic acid (m/z 303) displayed much greater signal intensities in the cancer specimen compared to low or undetectable intensities in normal tissue. The cancer margins delineated by the DESI MS images of these molecules were consistent with H and E images of the tumor edge. Cancerous tissue was distinguished from normal tissue based on the qualitative assessment of molecular signatures and the distinction was in agreement with expert histopathology evaluation in 85% of samples. Conclusions: Our findings offer proof of concept that examination and classification of breast normal and cancer tissue by mass spectrometry imaging is highly accurate. The results are encouraging for development of a MS-based method that could be utilized intra-operatively for rapid detection of residual cancer tissue in the lumpectomy bed in BCS.


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Immediate tissue expander breast reconstruction following mastectomy in pregnancy-associated breast cancer. Presenting Author: Katherina Zabicki Calvillo, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, MA

TPS1134


Phase II study of ruxolitinib in patients with pStat3ⴙ breast cancer. Presenting Author: Nancy U. Lin, Dana-Farber Cancer Institute, Boston, MA

Background: Management of pregnancy-associated breast cancer (PABC) requires balancing benefits of therapy with potential risks to the developing fetus. Surgical management can be influenced by gestational age of fetus and tumor stage. Minimal data describe surgical and obstetrical outcomes after mastectomy with immediate breast reconstruction (IR) in a pregnant patient (pt). Methods: Pts who underwent IR after mastectomy were identified within a multi-institutional PABC cohort. Retrospective chart review was performed for outcomes including adverse intraoperative events, immediate postoperative complications, gestational age at delivery and fetal weight. Other parameters evaluated included stage at presentation, duration of surgery, and use of delayed reconstruction in pts who did not receive IR. Results: Within a cohort of 79 PABC pts, 25 (32%) had mastectomy while pregnant, 8 (32%) of whom had IC; 17 (68%) did not undergo IR. Mean gestational age at time of IR was 16.6 weeks (range 10-30) and all IR utilized tissue expander (TE) placement followed by permanent implant placement in 7 pts. In the IR cohort, 1 (12.5%) pt was stage 0, 3 (37.5%) stage I and 4 (50%) stage IIB. There were no intraoperative or immediate postoperative surgical complications. The mean duration of surgery was 198 min with IR (7 pts) vs. 157 min without IR (available for 12 pts). All women who underwent IR delivered at, or close to, term infants of normal birthweight. One pt had pre-term labor after surgery at 29 weeks which resolved with tocolysis. Mean gestational age at delivery was 37.3 weeks in the IR cohort vs. 36.3 weeks in the non-IR cohort. No fetal abnormalities or major obstetrical complications were seen after IR. Post-mastectomy radiation (PMRT) was provided after pregnancy in 2 pts (25%) in the IR cohort and cosmetic outcome was not adversely affected. Conclusions: This report represents one of the largest series describing IR after mastectomy in PABC. Results suggest immediate tissue expander placement after mastectomy may increase duration of surgery but does not lead to adverse obstetrical or fetal outcomes. IR with tissue expanders may preserve reconstructive options when PMRT is indicated.

Background: Multiple lines of evidence implicate the IL-6/JAK2/Stat3 signaling pathway in metastatic progression and therapeutic resistance in breast cancer (Marotta et al, JCI2011; Britschgi et al, Cancer Cell 2012). Ruxolitinib, an oral inhibitor of JAK1 and JAK2, is approved for the treatment of intermediate or high-risk myelofibrosis, but has not been extensively tested in solid tumors. Methods: Pts with triple-negative breast cancer or inflammatory breast cancer of any subtype are eligible for prescreening of archival tumor tissue for pStat3 expression by immunohistochemistry. Pts with high (Cohort A; T-score ⬎5) or low (Cohort B; T-score 3-4) pStat3 expression, measurable disease, adequate organ function, ECOG PS 0-2, and progression through ⬎ 1 line of prior therapy may proceed to receive ruxolitinib, 25 mg orally twice daily. Staging studies are performed at baseline (BL) and every 8 weeks (wk). Baseline tumor biopsy is required for pts who have accessible disease, with an optional biopsy at progression. Blood for IL-6, CRP, and circulating tumor cells are collected at BL, Wk 4, and off-treatment. Patient reported outcomes including EORTC QLQ C-30 and the M.D. Anderson Symptom Inventory are collected at BL, Wk 4, Wk 8, and off-treatment. Statistical Considerations: The primary endpoint of this open-label phase 2 trial is objective response by RECIST 1.1. The study is designed to distinguish between a response rate of 5% versus 20% in each cohort, separately. If ⬎ 2 responses out of 21 pts are observed in the first stage of Cohort A, a further 20 pts will be entered on that cohort; the agent will be deemed worthy of further study if ⬎ 5 of the total 41 pts achieve an objective response (power 0.90, type I error 0.046). Cohort B will open to accrual if Cohort A passes the first stage. If ⬎ 2 responses out of 21 pts are observed in the first stage of Cohort B, a further 20 patients will be entered into Cohort B, and the agent will be deemed worthy of further study if ⬎ 5 of the total 41 pts achieve an objective response (power 0.90, type I error 0.046). Study Status: A total of 85 patients have consented for prescreening of tumor tissue. As of January 3, 2013, 5 of a planned 41 patients with high pStat3 IHC scores have been treated with ruxolitinib, and accrual is ongoing. Clinical trial information: NCT01562873.

TPS1135

TPS1136



An adaptive randomized phase II trial to determine pathologic complete response with the addition of carboplatin with and without ABT-888 to standard chemotherapy in the neoadjuvant treatment of triple-negative breast cancer. Presenting Author: Tiffany P. Avery, Thomas Jefferson University, Philadelphia, PA

The ENCHANT-1 trial (NCT01677455): An open label multicenter phase II proof of concept study evaluating first-line ganetespib monotherapy in women with metastatic HER2-positive or triple-negative breast cancer (TNBC). Presenting Author: Ahmad Awada, Medical Oncology Clinic, Jules Bordet Institute, Brussels, Belgium

Background: Inhibition of poly (ADP-ribose) polymerase (Parp) is a potential targeted therapy for triple-negative breast cancer (TNBC). Clinical trials of Parp inhibitors in metastatic TNBC have shown conflicting results. Issues regarding the use of Parp inhibitors in TNBC include choosing a selective Parp inhibitor and selecting an appropriate chemotherapy backbone. The current trial addresses these questions by combining a validated Parp inhbitor, ABT-888, with carboplatin and paclitaxel. Platinum agents have shown synergy with Parp inhibitors in preclinical models and efficacy in clinical trials. The combination of paclitaxel and carboplatin with Parp inhibitors has shown efficacy in phase I trials. Methods: This is a phase II, two-arm neoadjuvant trial of women with TNBC. Eighty patients will be enrolled. Randomization will follow a 1:1 allocation initially, then will follow a Bayesian adaptive allocation in which each prior response will be evaluated and patients assigned preferentially to the better responding arm. The primary endpoint is pathologic complete response (pCR). Secondary endpoints include correlation of pCR with biomarkers, imaging, and circulating tumor cells (CTCs). Treatment: Arm 1: Paclitaxel 80 mg/m2 ⫹ carboplatin AUC⫽2 (12 weekly cycles) ⫹ filgrastim followed by doxorubicin 60 mg/m2 ⫹ cyclophosphamide 600 mg/m2 (4 cycles every 3 weeks) ⫹ pegfilgrastim. Arm 2: ABT-888 (150mg PO bid) ⫹ paclitaxel 80 mg/ m2 ⫹ carboplatin AUC⫽2 (12 weekly cycles) ⫹ (filgrastim) followed by doxorubicin 60 mg/m2 ⫹ cyclophosphamide 600 mg/m2 (4 cycles every 3 weeks) ⫹ (pegfilgrastim). Eligibility: Women ⱖ 18 years old with clinical stage IIB or stage IIIA, IIIB, or IIIC untreated TNBC (ER ⬍1% , PR ⬍1% , Her-2/neu 0, 1⫹ on IHC or 2⫹ and FISH ratio ⬍ 1.8) are eligible. Correlative Studies: Correlation of pCR with tissue expression of CK5, EGFR, ERCC1, Ki-67, Parp1, and longitudinal enumeration of CTCs will be done. Exploratory tissue biomarkers with prognostic and predictive value will be correlated with pCR. Enrollment: The trial will begin accrual in February 2013.

Background: Hsp90 is a molecular chaperone protein required for the stabilization and activation of many proteins, referred to as Hsp90 ‘clients’, including those commonly implicated in breast tumorigenesis such as HER2, EGFR, ER, PI3K, AKT, P53 and VEGFR. Ganetespib is a novel triazolone inhibitor of Hsp90 being studied in over 20 clinical trials, with over 700 patients treated to date. Ganetespib is ~50x more potent than 1st-generation Hsp90 inhibitors, and has been well tolerated in clinical trials with a favorable safety profile. Mild to moderate, transient diarrhea is the most common adverse event associated with ganetespib infusion and is manageable with appropriate supportive care. Ganetespib has shown activity in preclinical models of HER2⫹, ER⫹/PR⫹ and triple negative breast cancer (TNBC). In a phase I trial, ganetespib demonstrated single-agent clinical activity in HER2⫹ disease with an objective response rate (ORR) of 15% and a disease stabilization rate of 46% in heavily pretreated patients. This efficacy-screening study is designed to provide further evidence of ganetespib activity and identify potentially predictive biomarkers in metastatic breast cancer. Methods: The ENCHANT-1 trial is an international, first-line Phase II study in two cohorts of breast cancer patients: Cohort A, HER2 amplified (n⫽35), and Cohort B, TNBC (n⫽35). HER2⫹ patients must have received prior anti-HER2 therapy in the adjuvant setting. Patients are treated with ganetespib at 150 mg/m2 twice weekly on a three out of four-week regimen. Primary endpoint: ORR assessed using RECIST1.1 criteria. Key secondary endpoints include metabolic effects as assessed by PET/CT at week 3. Tumor genetic signature and proteomic profiling are performed on patient’s tumors in an effort to develop biomarkers of response. At the time of submission 6 patients have been enrolled into this study. Clinical trial information: NCT01677455.


Breast Cancer—Triple-Negative/Cytotoxics/Local Therapy TPS1137


Adjuvant phase III trial to compare intense dose-dense adjuvant treatment with EnPC to dose dense, tailored therapy with dtEC-dtD for patients with high-risk early breast cancer (GAIN-2). Presenting Author: Volker Moebus, Klinikum Frankfurt Hoechst, Frankfurt, Germany Background: Intense dose-dense (idd) chemotherapy (CT) significantly improves overall survival in breast cancer patients. Two preceding trials explored iddETC vs a dd combination of EC-TX (GAIN) and dtEC-dtD vs conventional dosed FEC-D (Panther). Nab-paclitaxel (nP) provides a better toxicity profile and higher efficacy compared to solvent based taxanes and might be preferred in an idd regimen. Methods: This is a multicenter, prospective, randomized, open-label phase III trial comparing iddEnPC or dtEC-dtD as adjuvant CT. Pts with uni- or bilateral primary high risk node-positive (N⫹) breast cancer (BC) and centrally confirmed ER/PR/ HER2 and Ki-67 status can be included. Luminal A pts are only recruited with N⫹ ⱖ4. Randomization to iddEnPC or dtEC-dtD will be stratified by biological subtype defined by hormone receptor, HER2 and Ki-67. The iddEnPC arm will receive epirubicin (150mg/m2) q2w x3 followed by nP (260-330mg/m2, dose to be determined in run-in phase) q2w x3, followed by cyclophosphamide (2g/m2) q2w x3. The dtEC-dtD arm will receive EC (38-120/450-1200 mg/m2) q2w x4 followed after 1 wk rest by docetaxel (60-100mg/m2) q2w x4. GAIN-2 will compare toxicity and efficacy of an idd regimen (EnPC) vs a dd regimen with modification of single doses depending on individual hematological and non-hematological toxicities. Primary objective is invasive disease-free survival (IDFS). Secondary objectives are survival by other definitions, compliance, safety, side effects of taxanes and subgroup analyses (by 0-3, 4-9 or 10⫹ involved nodes and Ki-67). Efficacy analyses are planned 60 mths after end of accrual, safety interim analyses after 200 and 900 pts have completed CT. It was assumed that dtEC-dtD will achieve a 5-yr IDFS of 75% and ddEnPC will improve IDFS to 79% (HR 0.819) with a power of 80% (␣⫽0.05, ß⫽ 0.2).GAIN-2 is registered under NCT01690702 Results: 75pts were recruited since 1stOct 2012. Recruitment (in total 2886 pts) is planned for 36 mths in 80-100 sites in Germany. Run-in safety data to be presented. Conclusion: GAIN-2 will compare the efficacy of adjuvant iddEnPC and dtEC-dtD in pts with early N⫹ BC. Clinical trial information: NCT01690702.

TPS1139


NSABP B-47: A randomized phase III trial of adjuvant therapy comparing chemotherapy alone to chemotherapy plus trastuzumab in women with node-positive or high-risk node-negative HER2-low invasive breast cancer. Presenting Author: Louis Fehrenbacher, National Surgical Adjuvant Breast and Bowel Project and Kaiser Permanente Northern California, Vallejo, CA Background: Adjuvant trastuzumab trials in HER2⫹ breast cancer (BC) demonstrated a large reduction in recurrence and death. Central testing showed HER2 non-amplified participants derived similar benefit. Among HER2-amplified patients (pts), multiple studies showed no effect on benefit by degree of amplification. Blinded internal and external review confirmed the non-amplified nature of the HER2 normal group. Based on these findings, NSABP B-47, sponsored by the NCI, was activated January 2011 and is actively accruing. The study is NCI central IRB approved, open via the CTSU, and endorsed by SWOG, ECOG, and RTOG. Methods: Study: Chemotherapy treatment is by physician choice: The non-anthracycline regimen is TC (docetaxel 75 mg/m2, cyclophosphamide (C) 600 mg/m2) IV q 3 wks for 6 cycles; the anthracycline regimen is AC ¡ WP (doxorubicin 60 mg/m2 and C 600 mg/m2 IV either q 3 wks or q 2 wks [investigator discretion] for 4 cycles ¡ paclitaxel 80 mg/m2 IV wkly for 12 doses). Pts are randomly assigned to chemotherapy with or without trastuzumab for 1 year. Pts receive adjuvant radiation therapy and endocrine therapy, as clinically indicated. Detailed menstrual history, concurrent medications, weight changes, and biomarkers (estrogen, stress, inflammation), are being collected. Eligibility: Eligibility includes: node positive or high risk node negative BC pts; HER2 IHC 1⫹ or 2⫹ scores, but non amplified by FISH; normal cardiac, renal, and liver function. Detailed eligibility will be provided. Statistical Design: The primary aim is to determine whether the addition of trastuzumab to chemotherapy improves invasive disease-free survival (IDFS). 3,260 pts will be enrolled to provide statistical power of 0.9 to detect a 33% reduction in the hazard rate of IDFS using a one-sided alpha level of 0.025. Progress: Protocol was activated in January 2011. First pt was entered in February 2011. As of January 23, 2013, 1,416 of 3,260 (43.4 %) pts have been enrolled. Updated information on enrollment and study background will be provided. Support: NCI U10-12027, -37377, 69651, 69974, and Genentech, Inc. Clinical trial information: NCT01275677.

TPS1138

83s


Randomized, open-label, phase II study comparing the efficacy and the safety of cabazitaxel versus weekly paclitaxel given as neoadjuvant treatment in patients with operable triple-negative or luminal b/HER2 normal breast cancer (GENEVIEVE). Presenting Author: Stefan Paepke, TU München, München, Germany Background: Cabazitaxel is a new taxoid promoting the tubulin assembly in vitro and stabilizing microtubules against cold-induced depolymerization as efficiently as docetaxel. It has shown superior survival against mitoxantrone plus prednisone in docetaxel pre-treated hormone refractory metastatic prostate cancer pts leading to its registration. It showed a favorable toxicity profile with a low rate of alopecia. In the GENEVIEVE study it will be compared to weekly paclitaxel, which is currently most widely used in breast cancer (BC) pts. Methods: This is a prospective multicenter, randomized, open label study investigating efficacy and safety of cabazitaxel. Pts with uni- or bilateral primary BC (stage cT3/T2/T1c and cN⫹/T1c and pNSLN⫹), tumor lesion ⱖ 2cm (palpation) or ⱖ 1cm (sonography) and centrally confirmed TNBC or luminal B/HER2- can be included. Pts will be randomized to four q3w cabazitaxel (25mg/m² i.v.) vs. 12 q1w paclitaxel (80mg/m² i.v.). Randomization will be stratified by nodal status and subtype. Treatment will be given until surgery, disease progression, unacceptable toxicity or withdrawal of consent. The primary objective is pathologic complete response (pCR) (ypT0/is ypN0/⫹). Secondary objectives are pCR in stratified subgroups and by other definitions, objective response rate, pCR and local recurrence free survival in pts with clinical complete response and neg. core biopsy before surgery, breast conservation rate, toxicity, compliance, survival rates, biomarkers predicting response. Assuming 15% pCR in controls and targeting a smallest clinical improvement of 10% (i.e. pCR ⫽ 25% in experimental arm), a total of 326 pts (163/arm) are required for the one-sided proportion comparison test (␣⫽0.1) with 80% power. The trial is registered under NCT01779479. Results: Recruitment is planned for 12 mths in 45 (⫹10 back-up) sites in Germany. 1st pt in is planned for Feb 2013. Conclusion: GENEVIEVE will rapidly and precisely compare efficacy and tolerability of cabacitaxel vs. paclitaxel to decide if further development in BC is reasonable. Clinical trial information: NCT01779479.

TPS1140


Phase II study of eribulin mesylate as first- or second-line therapy for metastatic HER2-negative breast cancer. Presenting Author: Mitsuhiko Iwamoto, Osaka Medical College, Osaka, Japan Background: Eribulin mesylate is a nontaxane microtubule dynamics inhibitor that is approved in patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens (including an anthracycline and a taxane) for metastatic breast cancer. In a previous phase III study, eribulin mesylate demonstrated to significant improvement in overall survival in patients with heavily pretreated, locally recurrent or metastatic breast cancer when compared to treatment of physician’s choice. The majority of patients were HER2-negative and all had previously failed 2 or more regimens. Overall, the tolerability and positive phase III findings in this patient population suggest eribulin mesylate may provide a treatment advantage when given earlier in the course of therapy for HER2-negative, metastatic breast cancer. Methods: This study is phase II, multicenter, open-label, single-arm in patients with HER2-negative metastatic breast cancer who have been treated with chemotherapeutic regimens including an antheracycline and a taxane. Eribulin mesylate (1.4mg/m2) will be given on days 1 and 8 of each 21-day cycle. The primary endpoint is objective response rate, and secondary endpoints include duration of response, progression-free survival, overall survival, the safety of the treatment, and quality of life. Eligibility Criteria: Patients must have confirmed HER2-negative metastatic breast cancer with at least 4 weeks since prior neoadjuvant or adjuvant chemotherapy, and have not received over 2 chemotherapeutic regimens for metastatic disease. Additional eligibility criteria include adequate performance status (ECOG PS:0-2) and end organ/marrow function, and ejection fraction ⬎ 50%. Accrual: This study began in December 2012. The expected end of accrual of 35 patients will be the last quarter 2015.


84s TPS1141


A randomized phase III trial comparing nanoparticle-based paclitaxel with solvent-based paclitaxel as part of neoadjuvant chemotherapy for patients with early breast cancer (GeparSepto): GBG 69. Presenting Author: Christian Jackisch, Klinikum Offenbach, Offenbach, Germany Background: Anthracyclines (A) followed by taxanes (T) are standard of care for neoadjuvant therapy in breast cancer (BC). A reverse sequence of T followed by A was suggested to achieve higher pCR rates. Previous studies have shown that dual anti-HER2 blockade is superior to trastuzumab (H) alone and thus can increase the pCR rate by 20%. Nab-paclitaxel (nP) is a solvent-free formulation of P encapsulated in albumin and might also improve the pCR rate with eventually lower toxicity. Methods: The GeparSepto study (NCT01583426) will randomize 1200 patients to either nP (150 mg/m²) q1w or P (80mg/m²) q1w for 12 weeks followed by 4 cycles conventionally dosed EC (E 90mg/m², C 600 mg/m²) q3w for 4 cycles. Primary objective is to compare the pCR rate (ypT0⫹ ypN0). Patients with untreated, histologically confirmed cT2- cT4d BC can be included. HER2⫹ patients receive H (loading dose 8mg/kg; 6 mg/kg) plus pertuzumab (loading dose 840 mg; 420 mg) q3w concomitantly. Biomaterial including FFPE from core biopsy, serum, plasma and full blood is collected. HER2, ER, PgR, Ki67 and SPARC status will be centrally assessed prior to randomization for stratification. P was assumed to achieve a pCR rate of 33% which will be increased to 41% when using nP, corresponding to an odds ratio of 1.41. To investigate resistance to anti-HER2 treatment, patients with HER2⫹ BC are randomized prior to start of chemotherapy to receive either 6 weeks H, pertuzumab or the combination as biological window with biomaterial collection prior to start of therapy and after week 6 prior to start of chemotherapy. Results: After been approved by ethics committees and authorities recruitment started in 7/2012 in 56 sites. 293 patients were recruited (53 HER2⫹; 240 HER2-) by 1st Feb 2013. A first safety interim analysis is planned after 60 patients have finished therapy. Conclusions: GeparSepto investigates the efficacy of neoadjuvant nP compared to solvent-based P given weekly with a dual blockade of the HER2 receptor in HER2-pos BC. Interim safety results for nP will be presented. The window-substudy is funded within the EU-FP7 project RESPONSIFY No 278659. Clinical trial information: NCT01583426.

TPS1143


Randomized controlled phase II trial of simvastatin as prophylaxis against radiation-induced skin toxicity in breast cancer patients. Presenting Author: Shibu Joseph, Waikato Hospital, Hamilton, New Zealand Background: Most women receiving adjuvant radiation (RT) for breast cancer (BC) have significant acute skin toxicities ranging from erythema to moist desquamation. Late skin toxicities include fibrosis and telangiectasia. The inflammatory response to RT is mediated by RT-induced endothelial cell expression of the cell adhesion molecule E-selectin, to which neutrophils and monocytes adhere and then infiltrate into tissues. Blockade of this mechanism could interrupt the inflammatory cascade at an early stage. Preclinical studies have shown that statins can inhibit RT-induced E-selectin expression and skin and intestinal inflammation in vivo without impairing DNA damage or tumour response to RT. Retrospective clinical studies have shown reduced relapse rates with statins in breast cancer patients. Thus statins have the potential to reduce the acute RT-induced inflammatory component without compromising the DNA-damaging effects essential to cancer cell death. This is the only registered trial evaluating the effects of statins on acute RT toxicity. Methods: Randomised open controlled phase II trial of simvastatin 40mg daily during and for 3 weeks after RT. Eligibility: women with invasive or in-situ BC receiving wholebreast ⫹/- lymphatic RT; dose fractionation schedules include 50Gy/25 #, 45Gy/20#, 42.5Gy/16 # or 40Gy/15#, with or without a boost; may have had prior chemotherapy, and be on hormonal or Trastuzumab therapy during RT; no prior statins within 6 weeks of starting RT. Stratification by breast conserving surgery vs mastectomy, use of boost and fraction size (⬍2 Gy vs ⬎2 Gy). Primary endpoint: incidence of ⬎ grade 2 acute RT-related skin toxicity. Secondary endpoints: time to onset of skin toxicity, proportion requiring additional topical treatment, compliance with trial medication, statin-related toxicities and subjective RT-related toxicities (breast discomfort and fatigue). Statistical design: 130 randomised patients gives 90% power (one-sided a 0.20) to detect a reduction in ⬎ grade 2 acute skin toxicity from 55% to 35%. Enrolment opened January 2013, planned to complete by April 2014. Clinical trial information: ACTRN12612000662864.

TPS1142^


MERiDiAN: A phase III, randomized, double-blind study of the efficacy, safety, and associated biomarkers of bevacizumab plus paclitaxel compared with paclitaxel plus placebo, as first-line treatment of patients with HER2-negative metastatic breast cancer. Presenting Author: David Miles, Mount Vernon Cancer Centre, Northwood, United Kingdom Background: Bevacizumab (BV), a humanized monoclonal antibody targeting the angiogenic VEGF, has demonstrated activity in patients with metastatic breast cancer (MBC). Plasma VEGF-A levels ([VEGF-A]p) appear to positively correlate with the effect of BV on progression-free survival (PFS) in MBC, metastatic pancreatic, and advanced gastric cancers. The MERiDiAN study will prospectively investigate (1) whether baseline [VEGFA]ppredict treatment benefit with BV, (2) efficacy of BV with weekly paclitaxel (P), based on previously observed differences in the magnitude of benefit compared with BV ⫹ non-P chemotherapies. Methods: MERiDiAN is a global, randomized, double-blind, phase III study enrolling patients with HER2-negative MBC (first patient was enrolled in August 2012). The co-primary endpoints are PFS by investigator assessment in the intent-totreat (ITT) population, and PFS in the subgroup with high baseline [VEGF-A]p. Secondary endpoints are overall survival (OS), 1-year survival, objective response rate and duration, and safety. Exploratory objectives include assessing the predictive or prognostic potential of blood, DNA and tumor tissue markers, and genetic variants involved in angiogenesis and tumorigenesis, with regard to BV efficacy and safety.Patients will be randomized 1:1 to either P 90 mg/m2 IV weekly (qw) for 3 weeks followed by a 1-week rest and BV 10 mg/kg every 2 weeks (q2w) until disease progression (PD); or P 90 mg/m2IV qw for 3 weeks followed by a 1-week rest and placebo 10 mg/kg q2w until PD. An interim analysis of OS will be performed at the time of the primary PFS analysis. Clinical Trial Registry Number NCT01663727. Clinical trial information: NCT01663727.

TPS1144


Digoxin as an inhibitor of global hypoxia inducible factor-1␣ (HIF1␣) expression and downstream targets in breast cancer: Dig-HIF1 pharmacodynamic trial. Presenting Author: Aditya Bardia, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA Background: Unlike normal cells, tumor cells thrive in a hypoxic microenvironment, and intratumoral hypoxia correlates with increased tumor invasiveness, metastasis, and poor prognosis in cancer. The hypoxic microenvironment is primarily mediated through HIF1␣, a transcription factor for over 200 genes involved in cellular metabolism, proliferation, and angiogenesis. In pre-clinical models, cardiac glycosides, including digoxin, act as potent inhibitors of HIF1␣ protein synthesis and expression of HIF1␣ target genes (Zhang et al, PNAS 09). Methods: Trial design: The proposed study is a randomized, controlled, two arm, pre-surgical study. Eligible patients include women with stage I-III carcinoma of the breast scheduled to undergo definitive surgery, tumor size ⱖ 1cm, grade 2/3 or Ki-67 ⱖ 10%, normal organ function, and no known cardiac arrhythmias. Participants will receive oral digoxin daily, or no therapy, for 14 days (⫾4 days) prior to scheduled surgery. Trial Objectives: 1) To evaluate whether daily oral digoxin therapy, as compared to no study drug, reduces HIF1␣ expression by IHC and mRNA or its target genes (VEGF, CA-9, and GLUT1) in breast cancer tissue. 2) To evaluate whether daily oral digoxin therapy, as compared to no study drug, reduces levels of serum VEGF & PAI-1, reduces tissue Ki-67 expression, and modulates proteomic profiles of breast cancer tissue. 3) To assess safety and tolerability of digoxin therapy in the pre-surgical setting. Statistical methods: The primary hypothesis is that 2 weeks of digoxin therapy will reduce the level of HIF1␣ expression in breast cancer tissue assessed by pathologists blinded to the treatment assignment. Our preliminary study shows the mean HIF1␣ expression level is 2.43. A 33% reduction would be considered clinically relevant. Allowing for up to 20% attrition, a total sample size of 64 will provide more than 85% power to detect 33% reduction with a two-sided significance level of 0.05. Target accrual: 64 (32 each arm). Funding and Acknowledgement: Dept. of Defense, Commonwealth Foundation, ASCO YIA. Contact Person: Dr. Vered Stearns, Email: [email protected] Identifier: NCT01763931. Clinical trial information: NCT01763931.


Breast Cancer—Triple-Negative/Cytotoxics/Local Therapy TPS1145

85s


SHAVE: A randomized controlled trial of routine shave margins versus standard partial mastectomy. Presenting Author: Anees B. Chagpar, Yale University, New Haven, CT Background: It is well known that partial mastectomy for breast cancer is associated with a positive margin rate of 20-40% in most series. This has led some surgeons to advocate for routine cavity shave margins as a means of reducing re-excision rates. Others, however, feel that such a practice may be unwarranted and question the volume of tissue removed, cosmetic outcome and increase in operative time. It is unclear which of these two approaches is optimal; therefore, a prospective randomized controlled trial was proposed. Methods: Given the primary endpoint of positive margin rates (defined as a margin of ⬍ 1mm), the study was powered to find a difference between 30% in the standard partial mastectomy group and 15% in the routine shave margin group. To reach a power of 80% with alpha of 5%, 122 patients were required in each arm; we therefore set N⫽250 with a 1:1 randomization scheme. Patients are evaluated preoperatively and all patients undergoing a partial mastectomy for stage 0-III breast cancer are eligible; including those who have completed neoadjuvant chemotherapy. Patients are stratified according to stage and randomized within strata. After informed consent, patients undergo a standard partial mastectomy (including specimen radiography as needed). Surgeons may resect additional tissue at that time according to their standard practice. At the completion of this procedure, the randomization envelope is opened in the operating room and surgeons are instructed to either shave (ie., take additional circumferential margins) or close (no shave). Patients will be followed for five years. Outcome measures include: positive margin/reexcision rate, local recurrence, volume of tissue resected, cosmetic outcome, and intraoperative time. To date, over 130 patients have accrued to this trial. Initial results are expected to be reported in 2014. Clinicaltrials.gov identifier: NCT01452399


86s 1500

Cancer Prevention/Epidemiology Oral Abstract Session, Mon, 8:00 AM-11:00 AM

Breast cancer risk prediction using the novel germ-line signatures in epigenome regulatory pathways. Presenting Author: Christina Adaniel, Department of Hematology and Oncology, New York University, New York, NY Background: Epigenetic regulatory pathways are intensely studied for their involvement in breast tumorigenesis, however little is currently known about the genetic variation in epigenome components contributing to the risk and/or prognosis of breast cancer. In this study we have tested how the novel germline genetic signatures identified in epigenetic regulatory genes (ERGs) may potentially contribute to clinical prediction of breast cancer risk. Methods: We have genotyped 711 SNPs tagging 87 ERGs in 1985 breast cancer cases and 1609 controls, using Sequenom i-Plex. The samples were of white European origin with the fraction of Ashkenazi Jewish (AJ) ancestry (n⫽1642). The association of SNPs with breast cancer risk was assessed using logistic regression, adjusted by age, AJ status and estrogen-receptor (ER) status. The predictive ability of SNP signatures was tested by ROC curves using logistic regression fitting the SNP/clinical covariate models, and the area under the curve (AUC) was used to assess their utility in the classification of breast cancer risk. Results: We have identified the signature of 20 SNPs tagging 13 ERGs, significantly associated with breast cancer risk. The strongest association has been observed for RUNX1 (rs7280097, OR⫽0.83, CI 95%: 0.71-0.94, p⫽0.006) and PRDM16 (rs12135987, OR⫽1.22, CI 95%: 1.06-1.42, p⫽0.007). The inclusion of predictor variables (age, AJ status, ER status) and 20 associated SNPs in logistic regression ROC curve analysis yielded in best fitting model involving 10 SNPs tagging 8 ERGs with AUC of 0.723, compared to 0.660 with predictor variables alone (p⫽0.003). Conclusions: We have identified a signature of 20 SNPs in epigenetic regulatory genes (20-SNP-ERG) significantly associated with breast cancer risk. In addition, the incorporation of 10 SNPs from 20-SNP-ERG into risk prediction model increases the ability to classify breast cancer risk in addition to other clinical and demographic covariates. The results suggest the promising clinical potential of 20-SNP-ERG signature in identification of high-risk individuals in the population, and point to possible biological implication of germline patterns in epigenetic enzymes in breast tumorigenesis.

1502

Oral Abstract Session, Mon, 8:00 AM-11:00 AM

Efficacy of risk-reducing mastectomy (RRM) on overall survival (OS) in BRCA1/2-associated breast cancer (BC) patients. Presenting Author: Bernadette Anna Maria Heemskerk-Gerritsen, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, Netherlands Background: RRM in BRCA1/2 mutation carriers with a history of unilateral BC significantly reduces the risk of developing contralateral BC (CBC). However, the outcome regarding OS is insufficiently known. Methods: The efficacy of RRM on CBC incidence and OS was studied in a Dutch multicenter cohort consisting of 515 BRCA-associated BC patients (399 BRCA1, 116 BRCA2) of whom 177 BRCA1 and 48 BRCA2 carriers underwent RRM. Data on patient, tumor and treatment characteristics were collected up to June 30, 2012. Women contributed person-years of observation (PYO) to the Non-RRM group from the date of primary BC (PBC) diagnosis or DNA diagnosis (whichever came last) to the date of death, RRM, or last contact. Contribution of PYO to the RRM group started at the date of RRM until similar endpoints as described for the Non-RRM group. Results: Regarding PBC, no significant differences in size, nodal status, differentiation grade, hormone and Her2Neu receptor, and endocrine therapy were observed between the Non-RRM and RRM group. Median age of PBC diagnosis was 42 years for Non-RRM and 38 for RRM women (p⬍0.001). Median time period between PBC and RRM was 2.3 years (range 0.02-20.1). PBC treatment included radiotherapy for 68% of Non-RRM versus 50% of RRM women (p⬍ 0.001). Compared to NonRRM, chemotherapy was more often given to RRM women (66% versus 49%; p⬍0.001), and more RRM women underwent risk-reducing salpingooophorectomy (81% versus 67%; p⬍0.001), while ovarian cancer incidence was not different. With a median FU of 11.7 years after PBC diagnosis, 58 CBC cases were observed in Non-RRM women, while 4 CBC cases occurred after RRM, yielding incidence rates (per 1000 PYO) of 30.6 and 2.5, respectively (adjusted HR 0.09, 95% CI 0.03-0.24). In the Non-RRM group 45 women died during 2408 PYO versus 17 women in the RRM group during 1756 PYO, yielding mortality rates (per 1000 PYO) of 18.9 and 9.7, respectively (adjusted HR 0.56, 95% CI 0.32-0.99). 10 year OS was 80% for the Non-RRM and 90% for the RRM group (p⫽0.008). Conclusions: RRM in BRCA mutation carriers with unilateral BC reduces CBC incidence and is associated with improved OS. Further research is needed to identify potential prognostic factors for this survival benefit.

CRA1501


Inherited mutations in breast cancer genes in African American breast cancer patients revealed by targeted genomic capture and next generation sequencing. Presenting Author: Jane E. Churpek, The University of Chicago, Chicago, IL


1503


Pregnancy outcome and survivorship in cancer patients. Presenting Author: Nir Pillar, Department of Oncology, Sheba Medical Center, Ramat Gan, Israel Background: Advances in cancer detection and treatment have resulted in increased prevalence of female cancer survivors at childbearing age. While the association between cancer treatment and fertility has been thoroughly investigated, data regarding pregnancy outcome of cancer survivor are scarce. The aim of this study is to determine whether cancer survivors and sufferers have increased risk of obstetric complications. Methods: A population-based cohort study using data from the NIS of the Healthcare Cost and Utilization Project, focusing on 2000-2006. The rate of maternal and fetal obstetric complications was determined in pregnant women with and without diagnosis of cancer. Results: A total of 6,732,293 births were included in the analysis, of these 15,191 had maternal cancer diagnosis (0.2%). Pregnant women with cancer diagnosis had increased risk for premature labor, ectopic pregnancy, and need for blood transfusion. Moreover, the rate of maternal (3.6/ 1000 births) and fetal (8.3/1000 births) mortality was higher amongst women with cancer compared to non-cancer bearing women- (0.12/ 1000 births) and (3.9/ 1000 births) respectively. Multivariate logistic regression revealed that both age and cancer diagnosis were significantly and independently associated with pregnancy complications. Conclusions: This is the first large-scale study to determine the prevalence of obstetric complications in cancer patients. Pregnant women with a diagnosis of cancer are at increased risk of major obstetric complications, including maternal and fetal death, although the absolute risk is relatively low. It may therefore be prudent to define such pregnancies as “high-risk” and advocate intense prenatal care for these patients. No cancer – Gynecologic Reference group pelvic tumor Premature labor Ectopic Oophorectomy Hysterectomy Transfusion Not discharged home Death

613,567 29,497 7,309 6,257 50,263 38,271 821

512 34 133 176 88 30 1

RR

Nongynecologic solid pelvic tumor

RR

Hematologic cancer

RR

Nonpelvic solid tumor

RR

1.43* 1.98* 31.25* 48.32* 3.007* 1.34 2.09

62 3 7 3 18 9 2

1.92* 1.93 18.26* 9.14* 6.82* 4.48* 46.45*

379 21 11 1 111 65 15

1.47* 1.69* 3.58* 0.38 5.26* 4.05* 43.57*

664 35 31 18 123 74 9

1.29* 1.42* 5.07* 3.44* 2.93* 2.31* 13.12*

* P value ⬍ 0.05.


Cancer Prevention/Epidemiology 1504


1506

87s Oral Abstract Session, Mon, 8:00 AM-11:00 AM

Active and passive smoking in relation to lung cancer incidence in the Women’s Health Initiative prospective cohort study. Presenting Author: Ange Wang, Stanford University, School of Medicine, Stanford, CA

Breast cancer surveillance in high-risk women with magnetic resonance imaging every 6 months. Presenting Author: Rodrigo Santa Cruz Guindalini, The University of Chicago Medical Center, Chicago, IL

Background: The relationship between both active and passive smoking and lung cancer incidence in post-menopausal women was examined in theWomen’s Health Initiative Observational Study (WHI-OS). Methods: The WHI-OS, a prospective cohort study conducted at 40 U.S. centers, enrolled women ages 50-79 from 1993-1998.Among 93,676 participants, 76,304 women with complete smoking and covariate data comprised the analytic cohort, in which the association of lung cancer incidence with active and passive (childhood, adult home, and work) smoking exposure was studied. Results: Over 10.5 meanyears of follow-up with 901 lung cancer cases, lung cancer incidence was higher in current smokers (HR 13.44, 95% CI 10.80-16.75) and former smokers (HR 4.20, 95% CI 3.48-5.08), compared to never smokers. This relationship was dose-dependent for both current and former smokers. Risk of all lung cancer subtypes, particularly small cell lung cancer (SCLC) and squamous cell carcinoma (SqCC), was higher in smokers. Among never smokers, any passive smoking exposure (HR 0.88, 95% CI 0.52-1.49) and most passive smoking categories did not significantly increase lung cancer risk, compared to no passive exposure; however, passive exposure as an adult at home for ⬎⫽30 years was associated with increased risk, of borderline significance (HR 1.61, 95% CI 1.00-2.58). Current smokers had an annualized lung cancer incidence rate of 472.9 cases/100,000 person-years, compared to 158.1 for former smokers and 36.2 for never smokers (112.3 overall). Conclusions: To our knowledge, this is the first study to examine both active and passive smoking in relation to lung cancer incidence in a complete prospective cohort of U.S. women. Active smoking is associated with significant increases in incidence of all lung cancer subtypes in post-menopausal women, particularly SCLC and SqCC. Smoking cessation decreases lung cancer risk. Prolonged exposure as an adult at home may be the strongest passive smoking contributor to lung cancer risk in this cohort. The findings support continued need for investment in smoking prevention and cessation, research on passive smoking, and understanding of lung cancer risk factors other than smoking.

Background: Surveillance with mammography (MMG) and magnetic resonance imaging (MRI) is recommended for women at high-risk for breast cancer, but there is no consensus on screening strategy. Aim of this study was to evaluate the efficacy of semi-annual MRI in high-risk women. Methods: A multi-modality surveillance program was initiated in 2004. Yearly MMG was supplemented with semi-annual MRI. After 5 years, an additional 5 years of follow-up with yearly MMG and MRI was offered to mutation carriers. Defining positive screening as BIRADS 0, 4 and 5, sensitivity, specificity, NPV, and PPV of semi-annual MRI were analyzed. Results: From 2004 to 2012, 226 patients underwent 1467 MRI and 851 MMG with a mean follow-up of 3.6 yrs. Median age at entry was 43 yrs (range 21-73), 48% were mutation carriers (105 BRCA1/2, 2 CDH1, 1 P53) and 19% had personal history of breast cancer. Eleven cancers were screen-detected, of which 6 (55%) were detected only by MRI, 1 (9%) only by MMG, and 4 (36%) by both. Of these tumors, 4 were detected in the first round of MMG/MRI screening and 7 (64%) in mutation carriers (5 BRCA1, 1 BRCA2, 1 CDH1), and 3 tumors (27%) were detected due to the additional MRI during semi-annual screening. No interval cancers occurred. Sensitivity, specificity, PPV and NPV of MRI were 91%, 97%, 18%, 99%, respectively. Of the incident cancers, 3 (27%) were stage 0 (ductal) and 8 (73%) were stage 1 (7 ductal and 1 lobular). Mean size of the invasive cancers was 0.78 cm (range 0.1-1.6; only 2 tumors ⬎ 1.0 cm), none had lymph node metastasis, and 75% were high grade and hormone receptor positive. The largest tumor detected was invasive lobular in a 73 year old CDH1mutation carrier. Conclusions: To our knowledge, this is the first surveillance protocol with repeated screening rounds that detected mean size of invasive tumors less than 1 cm. Absence of interval cancers, high sensitivity/specificity, and detection of all tumors in early stages (stages 0 or 1) support this screening strategy as a viable alternative to prophylactic mastectomy. Ongoing work will examine quality of life, cost effectiveness and impact on overall survival of this screening approach. Clinical trial information: NCT00989638.

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MRI volumetric analysis of fibroglandular tissue to assess risk of the spared nipple in BRCA 1/2 patients who are considering prophylactic nipplesparing mastectomy. Presenting Author: Heather Baltzer, Division of Plastic Surgery, University of Toronto, Toronto, ON, Canada Background: Prophylactic nipple sparing mastectomy (NSM) in BRCA 1/2 mutation carriers is an option for risk reduction but is controversial over concern that residual fibroglandular tissue (FGT) with malignant potential remains in the spared nipple. Since the volume of FGT in the nipple has not been formally evaluated, the objective of this study is to measure the residual volume of FGT in the spared nipple at a standard retroareolar margin (5mm) and identify sources of variability, including a greater margin and patient factors. Methods: A segmentation protocol was applied to breast MRIs from 105 consecutive BRCA 1/2patients. The MRI segmentation quantified volumes for total breast and nipple FGT. The nipple FGT volume was determined by setting the retroareolar margin (depth on MRI). The proportion of FGT in the nipple with 5mm retroareolar margin relative to the breast was calculated as the primary outcome and compared to 10mm margins. Associations between the proportion of FGT in the nipple (5mm) and patient characteristics were examined using uniand multivariable analyses. Effect size was measured where appropriate. Results: At 5mm and 10mm retroareolar thickness, residual FGT comprised 0.24% (0.02-0.9%) and 0.42% (0.0.2-01.2%), respectively, of the total breast FGT (p ⬍ 0.001, Cohen d ⫽ 0.03). Smaller breast volume, lower BMI and parity (p ⬍ 0.001, p ⬍ 0.009, p ⬍ 0.009 respectively) were predictive of greater proportion of residual FGT on univariate analysis, while breast volume and parity were predictive with multivariate (R2 ⫽ 0.28, F ⫽ 16.5, p ⬍ 0.0005). Conclusions: The proportion of FGT remaining in the spared nipple with a 5mm margin is extremely small, suggesting very little added risk over a skin sparing mastectomy. This proportion may be influenced by breast volume and childbearing. Doubling the retroareolar margin statistically increases the proportion, yet this likely does not translate into a clinically meaningful increase and may support a slightly thicker retroareolar margin. Overall, our findings support safety of the current trend toward increased rates of prophylactic NSM performed in the BRCA 1/2 patient population.

Poster Discussion Session (Board #1), Sun, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

Time-related changes in yield and harms of screening breast MRI. Presenting Author: Holly Jane Pederson, Cleveland Clinic, Cleveland, OH Background: MRI has been accepted as a useful adjunct to screening mammography in high-risk women. Concerns remain over false positive findings, however, and little is known about harms and yield over time. Such information will help women decide about enhanced surveillance. Methods: Of 350 high risk patients offered MRI screening, 320 underwent 757 screens with a 1.5 Tesla magnet from 2008 to 2012 alternating (q 6 mo.) with digital mammography. Data collected included patient characteristics, mammographic density, estimated lifetime risk, and need for additional imaging and/or biopsy. Harms were defined as second look ultrasounds, US or MRI guided core biopsies, surgical biopsies or recommendation for short interval follow up. Estimates of harms over time were modeled by logistic regression. A significance level of 0.05 was used for all testing. Results: Compliance with MRI screening as recommended was 91% with the first MRI, and was not associated with age, race or level of risk. Harms were highest with the first MRI and decreased significantly with subsequent MRIs. Of 59 biopsies, 7 were malignant. Two were found in MRI 1, 3 in MRI 3 and 2 in MRI 4. Women with biopsies resulting from false positive findings were significantly younger (median age 44.5 as compared with 48; p⫽0.049) and were more likely to have extremely dense breast tissue (36% vs 17%; p⫽0.028.) Conclusions: This study of highly compliant high risk patients supports the use of MRI as an adjunct to mammography for early detection. The rate of harmful events decreased over time, yet cancer detection did not. This information is critical in counseling women who are considering annual screening breast MRI, particularly younger women and those with dense tissue. N

Second look US

US biopsy

MRI biopsy

Surgical biopsy 6-mo follow-up

MRI 1 320 72/302 (23.8%) 23/319 (7.2%) 8/314 (2.5%) 9/317 (2.8%) MRI 2 221 27/219 (12.3%) 11 (5%) 3 (1.4%) 2 (0.9%) MRI 3 139 13/137 (9.5%) 3 (2.2%) 6 (4.3%) 3 (2.2%) MRI 4 77 7/75 (9.3%) 4 (5.2%) 0 3 (3.9%)

Any harm

316 (15.8%) 83 (25.9%) 28 (12.7%) 41 (18.6%) 8 (5.8%) 14 (10.1%)* 7 (9.1%)*

* p ⬍0.05.


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Cancer Prevention/Epidemiology Poster Discussion Session (Board #2), Sun, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

Preliminary analysis of risk factors associated with peritoneal carcinomatosis (PC) after prophylactic bilateral salpingoophorectomy (PBSO) in patients with a BRCA mutation. Presenting Author: Neda Stjepanovic, Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain Background: Women with a BRCA1 or BRCA2 mutation are at high risk of developing ovarian carcinoma (OC) and a residual risk of PC after PBSO has been reported. We aimed to analyze the incidence of PC after PBSO and the clinical, pathological and molecular risk factors associated to PC in our series. Methods: Between April 2005 and December 2012, 100 patients with BRCA1 or BRCA2 mutation (50 each) underwent PBSO and were followed in the High Risk Clinics for the development of PC. PBSO pieces were submitted to pathological examination for presence of pathological and molecular risk factors like in situ or invasive Fallopian Tube Carcinoma (isFTC, inFTC) and p53 signature. Patients’ medical charts included in the High Risk Clinics Database were revised retrospectively for clinical, pathological and molecular characteristics. We analyzed the incidence of PC and the odds ratio (OR) for PC after PBSO in univariate analysis. Results: Overall, 2 patients (2%, 1 BRCA1, 1 BRCA2) were found to have isFTC, while 5 out 34 had a positive p53 signature (15%, 1 BRCA1, 4 BRCA2). With a median follow-up of 40 months (1-90) since PBSO, 2 patients developed PC (2%, both BRCA2). They underwent PBSO at age of 63 and 64 years and developed the PC 2 and 9 years after. One had a history of isFTC with p53 signature and 5 children, while the other had a prior history of bilateral breast cancer and no children. None had a family history of OC. Performing PBSO at an age older than 50 years was associated with an OR 8.56 (3.29-22.27) of PC. Conclusions: Fifteen and 2% percent of our patients had a positive p53 signature or an occult isFTC in the PBSO piece. Our analysis suggests that delaying PBSO to women older than 50 years may be associated with a higher risk of PC. Further analysis in a larger cohort is warranted.

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Impact of bilateral oophorectomy on contralateral breast cancer risk in BRCA negative women from site-specific hereditary breast cancer kindreds. Presenting Author: Kara C Long, Gynecology Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY Background: BRCA negative (BRCAneg) women from site-specific hereditary breast cancer (SSB) kindreds have been shown to have an increased risk of breast cancer (BC), but not ovarian cancer (OC). It is hypothesized that, as in women with BRCA mutations, bilateral salpingo-oophorectomy (BSO) will decrease the risk of developing future BCs in women from these BRCAneg SSB kindreds. Methods: Since 5/1995, all women undergoing genetic counseling and testing for BRCA mutations at our institution were offered participation in an IRB-approved prospective cohort study. This sub-study examines the impact of BSO on contralateral BC risk in BRCAneg SSB kindreds. Inclusion criteria were: a personal history of unilateral invasive BC ⱕ age 60, at least one 1st or 2nd degree female relative with BC ⱕ age 60, testing BRCAneg between 1/1/2002 and 2/28/2011. Exclusion criteria were: bilateral mastectomy (BM) or BSO prior to genetic testing, family history of OC, ⬍6 months of followup (F/U). Demographic data and pedigrees were collected at the start of F/U, which was defined as the date of genetic testing. F/U data was obtained via mailed questionnaire and medical record review. Participants were censored at the time of BM, OC, or last F/U. Data were analyzed using a Cox proportional-hazards model with time from genetic testing as the time variable and BSO as the time dependent covariate. Results: 328 living participants met the inclusion criteria and F/U was obtained on 301 (208 via questionnaire, 93 via record review). Median age at genetic testing was 49.0 years (27.4-73.2 years). Median F/U time was 5.1 years (0.5-10.5 years). During the course of F/U, 43 women underwent BSO and 21 women underwent BM. There were 12 contralateral BCs (8 invasive, 4 DCIS) identified: 3 in the BSO group and 9 in the no-BSO group. After controlling for age, parity, prior hormone use, and estrogen receptor status of the original BC, the risk of contralateral BCs was not decreased in women who underwent BSO vs those who did not (HR 2.07, 95% CI 0.51 – 8.35, P⫽0.31). Conclusions: In BRCAneg women from SSB kindreds with a personal history of early onset BC, BSO does not decrease the risk of developing contralateral BC.

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The mutational spectrum of breast and ovarian tumors from BRCA1 and BRCA2 mutation carriers. Presenting Author: Kara Noelle Maxwell, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA Background: Individuals who carry one mutated copy of the BRCA1 or BRCA2 genes have elevated lifetime risks of breast and ovarian cancer. A number of studies have investigated the somatic mutational spectra of breast and ovarian tumors; however, BRCA1/2mutated tumors are underrepresented. Methods: Sixty-eight formalin-fixed paraffin embedded samples from BRCA1/2patients have been identified. Massively parallel sequencing using 48 gene capture is in process, whole exome sequencing of tumor and matched germline DNA is planned. Data are analyzed using a custom bioinformatics pipeline. Results: In analysis of data from the first 26 breast (4 BRCA1, 6 BRCA2) and ovarian (8 BRCA1, 8 BRCA2) tumors, the majority (23/26, 88%) had 0-2 variants in 48 cancer genes. Known deleterious TP53 mutations were the only variants identified in 2/4 BRCA1 and 2/6 BRCA2 breast tumors. Of those remaining, 2 BRCA1 and 1 BRCA2 breast tumors had no identified deleterious mutations. Two BRCA2 breast tumors with no TP53 mutations had known deleterious mutations in a single gene each - FGFR2 and PI3KCA. One BRCA2 breast tumor with no TP53 mutation had a variant of uncertain significance in FLT3. Finally, one BRCA2 breast tumor had a very high mutational rate, with one deleterious TP53 mutation and 7 other small deletion and single nucleotide variants. For the ovarian tumors, 15/16 BRCA1 and BRCA2 tumors had known deleterious TP53 mutations; the ovarian tumor with no TP53 mutation had no other variants. TP53 mutations were the sole identified mutations in 8 ovarian tumors. One ovarian tumor carried a known JAK3 activating mutation and 4 ovarian tumors carried one variant of uncertain significance in a single gene - SMO, PDGFRA, GNA11 and NRAS. Finally, two ovarian tumors were found to have high mutational rates. Conclusions: Using a targeted resequencing panel, we confirmed the high rate of TP53 mutations in BRCA1/2 breast tumors and observed a higher than expected rate in BRCA1/2 ovarian tumors. Importantly, we have identified mutations in other known driver genes using FFPE samples, allowing generalizability to other sites. These analyses may uncover novel mutations that could be exploited in the development of targeted therapeutic agents for BRCA1/2 carriers.

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Comparison of false positive rates for screening breast MRI in high risk women when studies are done stacked versus alternating. Presenting Author: Edress Othman, University of Vermont, Burlington, VT Background: Screening breast MRI added to mammography increases screening sensitivity for high risk women. However, false positive rates are high for MRI and the optimal screening schedule is unclear. In this study we compare rates of false positive MRI when studies were performed on a stacked or alternating schedule. Methods: We reviewed charts for women at increased risk for breast cancer who had screening breast MRI between 2004 - 2012 at the University of Vermont. Eligible women had at least 1 MRI and 1 mammogram performed within one year. Charts were abstracted for clinical, radiological, and biopsy data. Screening was considered stacked if both studies were performed within 90 days and alternating if studies were 4-8 months apart. False positive was defined as MRI result of BI-RADS 3-4-5-0 with additional negative imaging within 12 months or benign biopsy. Results: 143 women had screening which met inclusion criteria; 45 per stacked schedule, 52 alternating, 40 mixed and 6 neither. Women in this study had similar characteristics with respect to age, ethnicity, menopausal status and indications for MRI (i.e. family history, BRCA mutation, biopsy history and prior chest irradiation). 371 MRIs were reviewed (165 stacked and 206 alternating). The overall false positive rate was higher in the stacked group vs. alternating [30(18.2%) vs. 21(10.2%), p⫽0.0264]. Using only BI-RADS 4-5-0 as a positive result that difference was lost. There were significantly more BI-RADS category 3 interpretations in the stacked vs. alternating MRIs [16(9.7%) vs. 6(2.9%), p⫽0.006]. The rate of BI-RADS category 4-5-0 was not different between the two groups [16(9.7%) vs. 17(8.3%), p⫽ 0.6272]. A similar number of biopsies were performed in both groups Conclusions: MRI added to mammography for women at increased risk for breast cancer was associated with higher rates of false positive interpretations when studies were done on a stacked compared to alternating schedule. In this study the greater number of BI-RADS 3 interpretations with a stacked schedule accounted for this difference. Further studies are needed to identify the optimal screening schedule when adding MRI to mammography.




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The role of statins for primary prevention in non-elderly colorectal cancer patients. Presenting Author: Amikar Sehdev, University of Chicago, Chicago, IL

Breast cancer mortality among users of cholesterol-lowering drugs. Presenting Author: Teemu Johannes Murtola, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

Background: There is conflicting evidence for the effect of statins in primary prevention of colorectal cancer (CRC). We conducted a case control study (N⫽357,702) in non-elderly adult US population (age 18-64 years) to investigate the role of statins in primary prevention of CRC. Methods: We used MarketScan claims database to identify patients with CRC using ICD-9 codes. A case was defined as having an incident diagnosis of CRC. Up to ten controls (matched for age, sex, and geographical region) were selected per case. Statins exposure was assessed from prescriptions in the 12 months prior to the earliest date of CRC diagnosis. The primary objective was to assess the incidence of CRC in statin users and nonusers. Conditional logistic regression was used to adjust for multiple potential confounders and calculate adjusted odds ratios (AOR). Results: The mean age of CRC patients was 54 years, 52% were males.Statins were prescribed to 19.1% (68,461/357,702) patients.A total of 8.3% (5,704/68,461) patients developed CRC in statin exposed group compared to 9.3% (26,912/289,241) patients in non-statin exposed group. In a multivariate model, any statin use was associated with 25% reduced risk of CRC (AOR 0.75, 95% CI, 0.73-0.78, p⬍0.001). An age-stratified analysis showed more benefit in patients aged 55 years or less than those above age 56 years (AOR 0.68 and AOR 0.79 respectively; p⬍0.001 for interaction between age group and statin exposure). Variables associated with increased incidence of CRC in the multivariate model were obesity (AOR 1.3, 95% CI, 1.2-1.4, p⬍0.001); DM (AOR 1.2, 95% CI, 1.1-1.2, p⬍0.001); IBD (AOR 3.1, 95% CI, 2.8-3.5, p⬍0.001); use of insulin (AOR 1.2, 95% CI, 1.1-1.3, p⬍0.001) and sulfonylureas (AOR 1.2, 95% CI, 1.1-1.3, p⬍0.001). Prescribed NSAIDs showed modest reduction in CRC incidence (AOR 0.94, 95% CI, 0.91-0.97, p⫽0.002). There was no significant relationship between CRC incidence and other oral hypoglycemic drugs. Conclusions: Statins appears to reduce the incidence of CRC in non-elderly adult US population. A randomized controlled trial is needed to validate this finding.

Background: Breast cancer is a common malignancy and cause of cancer death. Recent studies have suggested that statins, an established cholesterol-lowering drug group used in the prevention of cardiovascular mortality, could have beneficial effects against recurrence and progression of breast cancer. We evaluated breast cancer-specific mortality among users of statins and other cholesterol-lowering drugs (fibrates and bile-acid binding resins) in a cohort of breast cancer patients. Methods: Our study cohort included all newly diagnosed breast cancer patients in Finland during 1995-2003 (31,236 cases), identified from the Finnish Cancer Registry. Information on cholesterol-lowering medication use was obtained from a national prescription database.We used Cox proportional hazards regression method to estimate mortality among medication users. Results: A total of 4,169 participants had used statins, while 313 had used fibrates or resins. Despite similar median age, tumor and treatment characteristics, only statin use was associated with decreased breast cancer mortality (participants with localized tumors: HR 0.33, 95% CI 0.24-0.42; metastatic tumors: HR 0.52, 95% CI 0.31-0.86). Fibrate and resin use were associated with increased overall mortality (HR 1.70, 95% CI 0.96-2.99 for participants with localized disease, HR 2.65, 95% CI 1.18-5.96 for participants with metastatic disease). Conclusions: Decreased breast cancer mortality among users of statins, but not other cholesterol-lowering drugs despite similar population characteristics suggests that this drug group may have benefit in prevention of cancer progression. Clinical trials testing statins’ efficacy in breast cancer patients are warranted.

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High-dose omega-3 fatty acid supplementation to modulate breast tissue biomarkers in premenopausal women at high risk for development of breast cancer. Presenting Author: Carol J. Fabian, University of Kansas Medical Center, Kansas City, KS Background: We conducted a pilot study of high dose omega-3 fatty acid (FA) supplementation in pre-menopausal women to determine if risk biomarkers for breast cancer in benign breast tissue sampled by random peri-areolar aspiration (RPFNA) could be favorably modulated and to acquire preliminary data on possible mechanism of action. Methods: 36 pre-menopausal women at increased risk for breast cancer were accrued to a trial of 6-month intervention with 4 g daily of omega-3-acid ethyl esters [1.86 g eicosapentaenoic acid (EPA), 1.5 g docosahexaenoic acid (DHA)]. To date, 31 subjects have completed study with RPFNA performed pre- and post-intervention in the follicular phase of the menstrual cycle and specimens evaluated for cytomorphology and proliferation (Ki-67). FA composition was determined in plasma, red blood cells, and RPFNA specimens. Additional specimens were frozen for assessment of hormones, a panel of 11 adipokines and cytokines, and gene expression. Results: The ratio of (EPA⫹DHA):Arachidonic Acid (AA) levels increased significantly in plasma and erythrocytes by a median of three-fold. There was a significant decrease in blood EPA⫹DHA between discontinuation at 6 months and 2 weeks later when RPFNA was performed. Despite that, there was favorable modulation for cytologic evidence of atypia (81% at baseline to 42% at off-study; p⫽0.003), Masood score (medians of 15 to 14; p⫽0.001), number of epithelial cells recovered (p⫽0.004) and Ki-67 expression (p⫽0.025 for 30 women with any Ki-67 at baseline, medians of 1.9% to 0.9%). Serum assays have been completed for 24 subjects. No statistically significant changes were observed for estradiol, testosterone, progesterone, SHBG, IGF-1, IGFBP-3. There was a trend (p⫽0.056) towards a decrease in resistin. To date, only two subjects have discontinued the study early; grade 2 or greater gastrointestinal side effects have been reported by only two subjects. Conclusions: Favorable modulation of tissue risk biomarkers, cytologic atypia and proliferation along with good tolerability suggests that high dose omega-3 FA esters should be tested further in a placebo controlled trial. Clinical trial information: NCT01252277.


Chemoprevention of cancer with metformin: A meta-analysis. Presenting Author: Sara Gandini, European Institute of Oncology, Milan, Italy Background: Previous meta-analyses have shown that the anti-diabetic agent metformin is associated with reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models and recent epidemiological studies. Here we update the metaanalyses of observational studies with a focus on confounders and biases. Methods: We identified 47 articles published between 1966 to August 2012 that were related to metformin and cancer incidence or mortality. Study characteristics and outcomes were abstracted for each study that met inclusion criteria. Results: The analysis is based on a total of 32,647 cancer events and 1,198 cancer deaths. Cancer incidence was reduced by 34% (SRR⫽0.66, 95%CI: 0.42-1.03) in subjects taking metformin compared with other antidiabetic medications. Cancer mortality was reduced by 49% (SRR⫽0.51, 95%CI: 0.30-0.86). The SRR estimates for liver (SRR⫽0.40, 95%CI: 0.20-0.80) and lung cancer incidence (SRR⫽0.87, 95%CI: 0.83-0.93) were significant. Adjustment for BMI and exclusion of studies with time-related biases showed a significant reduction in cancer incidence of 26% (95%CI: 1% to 45%) or 10% (95%CI: 9% to 11%), respectively (Table). Breast cancer was significantly reduced by 24% (95%CI: 7% to 38%) in BMI-adjusted studies and the reduction remains significant in prospective studies and in studies without timerelated biases. Conclusions: Metformin is a promising agent for cancer prevention, although it may not benefit all populations equally. Clinical trials are needed to determine if the observations seen in diabetic populations apply to pre-diabetic or non-diabetic populations and to optimize the benefit/risk ratio. Summary risk estimate (SRR) and 95%CI for BMI-adjusted and timerelated unbiased studies. Endpoint Overall incidence Breast Prostate Colon Pancreas Liver Lung Cancer mortality

BMI-adjusted

Time-related unbiased

0.74 (0.55-0.99) 0.76 (0.62-0.93) 0.89 (0.53-1.47) 0.79 (0.44-1.42) 0.42 (0.08-2.15) . . 0.58 (0.37-0.92)

0.90 (0.89-0.92) 0.94 (0.89-0.99) 1.00 (0.88-1.15) 0.91 (0.85-0.98) 0.77 (0.38-1.56) 0.65 (0.39-1.09) 0.88 (0.81-0.95) 0.45 (0.16-1.27)


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Metformin effects on cancer adjacent breast preneoplasia in a randomized PRE-surgical trial. Presenting Author: Andrea De Censi, E.O. Ospedali Galliera, Genoa, Italy

Aspirin use in prostate cancer and the risk of death and metastasis. Presenting Author: Jonathan Assayag, Department of Experimental Medicine, McGill University, Montreal, QC, Canada

Background: Metformin has been associated with a significant reduction in cancer incidence and mortality in diabetic patients, including positive results in breast cancer. In a window-of-opportunity trial in 200 nondiabetic women with breast cancer, we showed a heterogeneous effect of metformin on breast cancer proliferation (Ki-67) depending on insulin resistance, with a trend to a decreased proliferation in women with insulin resistance (HOMA⬎2.8) and an opposite trend in women with normal insulin sensitivity (Bonanni et al. JCO 2012). Here we determined whether metformin has antiproliferative effects on adjacent lobular or ductal intraepithelial neoplasia (LIN or DIN) and on distant ductal hyperplasia and whether these effects are different according to specific host and tumor characteristics. Methods: Baseline core biopsies of tumor tissue and blood samples were obtained at study entry and before surgery for pre/posttreatment comparisons. Patients were randomly assigned to metformin, 850 mg or placebo once daily on day 1-3 followed by two 850 mg tablets from day 4 to 28. At surgery, three to five specimens of adjacent (ⱕ1 cm from the tumor) and distant (⬎1 cm from the tumor) grossly normal tissue were obtained to assess systematically the prevalence, grade and proliferation of LIN or DIN and ductal hyperplasia. Results: Overall, the prevalence of LIN, DIN and ductal hyperplasia was 4.5% (9/200), 66.5% (133/200) and 35% (69/200), respectively. Ki-67 was positively associated with DIN grade (p-trend⬍0.001). The median (and IQ range) Ki-67 LI distribution of LIN⫹DIN was 12% (8-20) and 10% (6-22) on metformin and placebo, respectively (p⫽0.6). Compared with placebo, metformin exhibited different effects on Ki-67 according to DIN grade (delta⫽⫹4.4% in DIN1 vs -27.9% in DIN3, p-interaction⫽0.09), cancer HER2 status (median 12% vs. 10% in HER2-ve; 28% vs. 35% in HER2⫹ve, p⫽0.03), abdominal circumference (p⫽0.08), and BMI (p⫽0.17). Conclusions: Metformin had no overall significant effect on breast preneoplasia proliferation but exhibited heterogeneous effects depending upon host and tumor characteristics. The significant reduction of HER2⫹ve, DIN3 proliferation under metformin warrants further studies. Clinical trial information: 16493703.

Background: There has been recent interest in the role of aspirin in preventing prostate cancer outcomes, but data remain limited. The objective was to determine whether the use of aspirin after prostate cancer diagnosis is associated with a decreased risk of prostate cancer mortality, distant metastasis and all-cause mortality in men newly-diagnosed with prostate cancer. Methods: A population-based cohort of men diagnosed with non-metastatic prostate cancer between 01/04/1998 and 31/12/ 2009 was identified using the UK Clinical Practice Research Datalink, including the Cancer Registry. All men were followed until death, distant metastasis, or 01/10/2012. A nested case-control analysis was performed where, for each case with an incident outcome event, up to 10 controls were matched on age, year of diagnosis and duration of follow-up. Exposure was defined as aspirin use during the matched follow-up period. Rate ratios (RR) and 95% confidence intervals (CI) were estimated using conditional logistic regression, adjusted for covariates and considering effect modification by aspirin use prior to prostate cancer diagnosis. Results: The cohort included 13,396 prostate cancer patients, followed for 3.9 (SD⫽2.4) years during which 4,425 deaths occurred, including 2,315 from prostate cancer, and 2,344 cases of distant metastasis. Aspirin use was associated with an increased risk of prostate cancer mortality (RR 1.36, 95% CI 1.18-1.55) and all-cause mortality (RR 1.33, 95% CI 1.21-1.47), but not distant metastasis (RR 1.09, 95% CI 0.94-1.27). The increased risks were limited to patients who did not use aspirin before diagnosis, for both prostate cancer mortality (RR 1.69, 95% CI 1.43-2.00) and all-cause mortality (RR 1.62, 95% CI 1.44-1.82), while those who used aspirin before diagnosis did not have increased risks (RR 0.93, 95% CI 0.76-1.15 and RR 0.98, 95% CI 0.85-1.13, respectively). Conclusions: The use of aspirin after prostate cancer diagnosis is not associated with a decreased risk of prostate cancer outcomes. Although increased risks were observed for all-cause and prostate cancer mortality, these effects were exclusively driven by new-users of aspirin, suggesting that aspirin use in these patients was likely related to disease progression.

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Overview of meta-analyses and pooled analyses of nutrition and breast cancer risk. Presenting Author: Patrick Mullie, International Prevention Research Institute, Lyon, France Background: Twenty years ago, recommendations for prevention of breast cancer by dietary modification were based on decreased fat consumption, and increased consumption of dietary fibre, fruits, vegetables and vitamins. Subsequent literature is replete with reports of studies of diet and nutrition often containing widely varying advice for women regarding reducing their breast cancer risk. Methods: A systematic search in PubMed of the published literature was conducted to identify meta-analyses and pooled analyses relating breast cancer risk to a wide variety of nutritional components including intake of coffee, dairy, dietary fibre, eggs, fat components, fruits and vegetables, glycaemic index and load, meat components, minerals, seafood, soy, tea, and a variety of vitamins. Inclusion criteria were: published in English, time period 2000-2011, and restricted to studies with a prospective design. All published relative risks and confidence intervals were abstracted. Results: The search retrieved 2 pooled analyses and22 meta-analyses concerning alcohol (1), coffee (2), dairy (3), dietary fibre (2), eggs (1), fat components (3), fruits and vegetables (2), glycaemic index and load (3), meat (3), minerals (1), seafood (1), soyfood (1), tea (3), and vitamins (5). In total 256 relative risks were computed by meta- and pooled analyses, with 195 (76%) statistically not significant, 16 (6%) showing an increased risk and 45 (18%) showing a decreased risk of breast cancer. 18 relative risks were less than 0.90 and 5 were greater than 1.25. Of the 5 estimates for alcohol, 2 (40%) showed statistically significant increased risk for breast cancer. For other food items, proportions associated with non-significant risk were for dairy (85%), total fat consumption (83%), dietary fibre (56%), fruits and vegetables (96%), glycaemic index/load (77%), meat (95%) and vitamins (78%). Conclusions: Other than accepted dietary risk factors alcohol, obesity and physical activity, no individual nutritional item has been consistently related to breast cancer risk. Energy balance seems to be an essential element in breast cancer prevention.


Cardiorespiratory fitness and risk of cancer incidence and cause-specific mortality following a cancer diagnosis in men: The Cooper Center longitudinal study. Presenting Author: Susan G. Lakoski, University of Vermont, Colchester, VT Background: Few studies have examined the prognostic importance of cardiorespiratory fitness (CRF) to predict cancer incidence or causespecific mortality following a cancer diagnosis in men. Accordingly, we examined the relationships between baseline CRF and incidence of prostate, lung, or colorectal cancer in men at Medicare age and subsequent cause-specific mortality among men diagnosed with cancer. Methods: The Cooper Center Longitudinal Study (CCLS) is a prospective observational cohort study of participants undergoing a preventive health examination including CRF assessment at the Cooper Clinic in Dallas, Texas. We studied 17,049 men with a complete CCLS medical exam and cardiovascular risk factor assessment at a mean age of 50⫾ 9 years. Cancer incidence was defined using Medicare claims data. Cox proportional models were used to estimate the risk of adjusted primary cancer incidence and cause-specific mortality after cancer according to baseline age-specific CRF quintiles (Q). Results: The mean times from CRF assessment to cancer incidence and death were 20.2 ⫾ 8.2 years and 24.4 ⫾ 8.5 years, respectively. During this period, 2885 men were diagnosed with prostate, lung, or colorectal cancer and 769 died. Compared with men in lowest CRF quintile, the adjusted hazard ratio (HR) for incident lung, colorectal, and prostate cancer incidence among men in the highest CRF quintile was 0.32 (95% CI: 0.20 to 0.51, p⬍0.001), 0.62 (95% CI: 0.40 to 0.97, p⫽0.05), 1.13 (95% CI: 0.97 to 1.33, p⫽0.14), respectively. In men developing cancer, both cancer-specific mortality and cardiovascular-specific mortality declined across increasing CRF quintiles (p’s ⬍0.001). A 1-MET increase in CRF was associated with a 14% reduction in cancer-specific mortality (HR 0.86, 95% CI: 0.81-0.91, p⬍0.001), and 23% reduction in cardiovascularspecific mortality (HR 0.77, 95% CI: 0.69-0.85, p⬍0.001). Conclusions: Fitness is a strong independent predictor of incident lung and colorectal cancer and remained a robust predictor of cause-specific mortality in middle-aged and older men diagnosed with lung, prostate, or colorectal cancer.




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The relationship between serum vitamin D levels and breast cancer prognosis: A meta-analysis. Presenting Author: April Ann Nicole Rose, Faculty of Medicine, McGill University, Montreal, QC, Canada

Changes in early- and late-stage colorectal cancer incidence during the era of screening: 1976-2009. Presenting Author: Daniel X Yang, Yale School Of Medicine, New Haven, CT

Background: Vitamin D (VitD) is a circulating hormone known to regulate gene transcription in breast cancer (BC) cells. The association between VitD and BC risk has been extensively studied. Until recently, however, the role of VitD in BC progression and its association with clinical outcomes among BC patients was poorly understood. To assess these new developments, a systematic review and meta-analysis was performed. Methods: A systematic review and meta-analysis by searching MEDLINE (1982 – 2012), ASCO, and SABCS for abstracts (2009 – 2012), with the following keywords: “breast cancer” and “prognosis” or “survival”, and “vitamin D” or ”calcitriol.” Abstracts were scrutinized for reports correlating serum VitD levels with breast cancer clinical outcomes, including: disease-free survival (DFS) and overall survival (OS). Studies were included if serum VitD samples were taken shortly after diagnosis and survival data were reported. Meta-analyses were performed using an inverse-variance weighted fixedeffects model. Results: We identified 7 studies reporting correlative data between serum VitD levels and BC survival. These data included 4,885 patients evaluated for DFS and 3858 patients evaluated for OS. VitDdeficiency was defined as ⬍30ng/mL, ⬍20ng/mL, and ⬍14ng/mL in 3, 3, and 1 studies, respectively, and was identified in an average of 48.1% of patients (range: 17.9-87.8%). VitD deficiency was associated with a pooled hazard ratio (HR) of 2.13 (CI: 1.64 - 2.78) and 1.76 (CI: 1.35 2.30) for DFS and OS, respectively. Conclusions: To our knowledge, this is the first report of a meta-analysis of the relationship between serum VitD and BC prognosis. The prevalence of VitD-deficiency varied widely across studies and may reflect differences in geographic location, race, and rates of supplementation across patient populations. These findings support the hypothesis that VitD-deficient breast cancer patients have poorer clinical outcomes than VitD sufficient patients; but do not establish whether this relationship is causative. Further studies are warranted to investigate the possible protective effects of VitD supplementation on survival among VitD-deficient BC patients.

Background: Ideally, screening detects cancer at a more curable stage, and as a result decreases the incidence of subsequent diagnosis at a late stage. Whereas breast cancer screening is suggested to have led to a substantial increase in the number of early-stage cancers diagnosed in the United States with only marginal reductions in the number of late stage cancers, the impact of colorectal cancer screening on cancer incidence is unknown. Methods: Colorectal cancer incidence data spanning over three decades, 1976 —2009, were collected from the Surveillance, Epidemiology, and End Result (SEER) database. Screening utilization data spanning 1986 — 2010 were collected from the National Health Survey (NHS) progress reports. We examined trends in the incidence of early-stage (in situ, local) and late-stage (regional, distant) colorectal cancer among adults 50 years or older. Results: Over the past three decades, the incidence of late-stage colorectal cancer decreased significantly, from 118 to 74 cases per 100,000 people—a 37% decrease. The incidence of early-stage colorectal cancer also decreased, from 77 to 67 cases per 100,000 people. There was also an associated increase in the utilization rates of screening colonoscopy. From 1987 to 2010 —the years for which NHS data were available— the percentage of adults 50 and older who received screening colonoscopy rose from 27% to 63%. After adjusting for trends in cancer incidence in non-screened populations, we estimated that colorectal screening was associated with a reduction of approximately 550,000 cases of colorectal cancer over the past three decades in the United States. Using the most conservative assumption of constant cancer incidence during the past three decades, 235,000 cases of colorectal cancer were prevented. Conclusions: There has been a significant decline in both early and late stage colorectal cancer diagnoses, during a time of increasing rates of increased screening.

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Variation in the efficacy of low-dose computed tomographic lung screening based on risk of lung cancer mortality in the National Lung Screening Trial. Presenting Author: Hormuzd A. Katki, Division of Cancer Epidemiology and Genetics, NCI/NIH/DHHS, Rockville, MD Background: Low-dose computed tomography (LDCT) screening reduced lung cancer mortality by 20% in the National Lung Screening Trial (NLST). The efficacy of LDCT screening could be improved by targeting smokers at highest risk of lung cancer death, provided that the efficacy of LDCT screening increases with lung cancer mortality risk. Methods: We evaluated the efficacy of LDCT screening as compared to chest radiography in the NLST across groups defined by participants’ 5-year risk of lung cancer mortality at randomization, which was estimated using a validated prediction model. Across quintiles of 5-year lung cancer mortality risk [Q1: 0.15%-0.55%, Q2: 0.56%-0.84%, Q3: 0.85%-1.24%, Q4: 1.24%2.0%, Q5: ⬎2.0%], we estimated the number of participants with false positive screens, the number of prevented lung cancer deaths, and their ratio. Results: The number of prevented lung cancer deaths due to LDCT screening increased in tandem with lung cancer mortality risk (Q1⫽0.2, Q2⫽3.5, Q3⫽5.1, Q4⫽11.0, Q5⫽12.0 per 10,000 person-years; Ptrend⫽0.01). The number of participants with false positive screens per lung cancer death prevented, a measure of screening efficiency, significantly decreased with increasing risk (Q1⫽1,648, Q2⫽181, Q3⫽147, Q4⫽64, Q5⫽65, P-trend⬍0.001). The 60% of participants at highest 5-year lung cancer mortality risk (0.85% or greater) accounted for 88% of LDCT-preventable lung cancer deaths and included only 64% of participants with a false positive screen. The 20% of participants at lowest lung cancer mortality risk (0.15%-0.55%) accounted for only 1% of LDCTpreventable lung cancer deaths. Conclusions: In the NLST, LDCT screening prevented the most lung cancer mortality among those at highest lung cancer mortality risk and prevented almost no mortality among those at lowest risk, providing empirical support for risk-based targeting of smokers to improve the efficacy of LDCT screening.


Smoking and estrogen plus progestin (EⴙP) and lung cancer incidence and mortality. Presenting Author: Rowan T. Chlebowski, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA Background: In the Women’s Health Initiative (WHI) randomized, placebocontrolled clinical trial, E⫹P increased deaths from lung cancer (those cancer-attributed) and after lung cancer (regardless of cause) (Lancet 2009:374:1243). To examine smoking status influence on this process, a cohort combining WHI clinical trial (CT) and observational study (OS) participants, the latter meeting criteria as in the CT, was identified to examine E⫹P associations with lung cancer incidence and outcome. Methods: 31,966 postmenopausal women (12,299 CT, 19,668 OS) with no prior hysterectomy and no prior hormone therapy use were classified at baseline as not hormone users or E⫹P users and as current or never smokers. Lung cancers were verified by medical record review. Multivariant adjusted Cox proportional hazards regression, including pack-year use, calculated hazard ratios (HRs, 95% confidence intervals [CI]) for groups defined by smoking status and E⫹P use for lung cancer incidence, deaths from lung cancer and deaths after lung cancer. Results: After 12 years mean follow-up, 664 lung cancers were diagnosed with 444 deaths from lung cancer and 513 deaths after lung cancer. Analyzed from cohort entry; see Table. In nonusers of E⫹P, lung cancer incidence, deaths from lung cancer, and deaths after lung cancer were significantly and substantially greater in current smokers vs never smokers (p⬍ .0001 for all comparisons). In current smokers, lung cancer incidence, deaths from lung cancer and deaths after lung cancer were significantly and substantially greater in E⫹P users vs non-users (p⫽.0021, .0005 and .0002, respectively). Conclusions: E⫹P use in current smokers nearly doubles their already high risk of death from and after lung cancer. Based on this risk, current smokers should not use E⫹P. Group EⴙP use No No Yes

Lung cancer HR (95% CI) Smoking status

Incidence

Deaths from

Deaths after

Never Current Current

1.00 reference 15.00 (11.23, 20.05) 24.18 (17.21, 33.99)

1.00 reference 17.79 (12.42, 25.49) 35.89 (21.93, 49.34)

1.00 reference 18.49 (13.19, 25.94) 34.32 (23.43, 50.27)


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Can microsatellite status of colorectal cancer (CRC) be reliably assessed after neoadjuvant therapy? Presenting Author: Eduardo Vilar Sanchez, The University of Texas MD Anderson Cancer Center, Houston, TX

APC I1307K polymorphism as a predictive factor for colorectal neoplasia recurrence. Presenting Author: Ben Boursi, Sheba Medical Center, Ramat Gan, Israel

Background: Universal testing of resected CRC for Microsatellite Instability (MSI) status has been widely advocated. While PCR-based MSI analysis is the current gold standard test, immunohistochemistry (IHC) of mismatch repair (MMR) proteins is more commonly performed. At present, it remains un-established whether PCR-based MSI analysis remains reliable when performed on post-neoadjuvant treated specimens. Our goal was to examine the effect of neoadjuvant therapy on MSI analysis using both in vitro and clinical data. Methods: MSI analysis was performed using the standard panel of 7 markers. In vitro, MMR deficient (HCT116) and proficient (HCT116⫹Ch3) isogenic cell lines were exposed to 3 cycles of single agent 5-Fluorouracil, Oxaliplatin and Irinotecan and MSI analysis was tested after each cycle. To evaluate the induction of genomic instability, 3 additional coding microsatellite tracts in ATR, BLM and CHK1 were assessed by fragment analysis. In parallel, clinical data from 238 CRCs that were resected after neoadjuvant chemoradiation (n⫽191) or chemotherapy (n⫽47) between 9/2009 and 8/2011 were queried for MSI results. MSI analysis performed on paired pre-treatment and posttreatment resection tissues was compared. Results: No changes in MSI status were detected and there was no increase in genomic instability post-treatment in cell line models. In the clinical setting, pre-neoadjuvant MSI testing was limited by the availability of pre-treatment biopsy tissue. 3 patients found to be MMR proficient based on MSI analysis performed on pre-treatment biopsy remained microsatellite stable when analyzed on post-treatment resection tissue. 7 patients were MMR deficient based on MSI analysis performed on post-treatment resection tissue but most had strong clinical evidence to expect MMR deficiency. Conclusions: Based on both preclinical in vitro and clinical data, results of the MSI analysis does not appear to be affected by neoadjuvant therapy for both MMR proficient and deficient cases. In addition, preclinical results do not suggest that neoadjuvant chemoradiation induces an increase in genomic instability. Therefore, MSI analysis remains a reliable gold standard test on posttreatment specimens.

Background: The use of surveillance colonoscopy to detect disease recurrence after initial colorectal neoplasia resection has increased significantly in the past decade. Currently, predictive factors at index colonoscopy include only histo-pathologic characteristics such as adenoma number, size, type and dysplasia. The goal of the current study is to identify additional factors (i.e., genetic markers) that increase the risk of subsequent lesions and may optimize the use of surveillance colonoscopies. Methods: A prospective analysis of 383 consecutive Israeli subjects with an initial neoplastic finding in screening colonoscopy. The participants were followed over a period of 10 years, and underwent up to five surveillance colonoscopies. Clinical data regarding potential risk factors for colorectal cancer as well as blood samples were collected. Genetic polymorphisms were detected using real-time PCR from DNA extracted from peripheral mononuclear cells. Results: The overall prevalence of recurrent Colorectal carcinoma and adenoma was 9.4% (36/383) and 69% (268/383) respectively, with a median of 4.8 years from index colonoscopy. In a univariate analysis, subjects with recurrent lesions had significantly higher number of adenomas at index colonoscopy (3.9 Vs 1.1, p⫽0.001), increased rate of high grade dysplasia (65.8% Vs 50%, p⫽0.018), and a non-significant trend for larger adenomas and villous histology. The APC I1307K gene variant was detected in 11.8% of subjects with recurrent lesions compared to 3.8% of subjects with normal follow-up colonoscopies (p⫽0.03). In a multivariate logistic regression (adjusted to age, sex, family history of CR neoplasia, time to recurrence and number of colonoscopies performed), the I1307K variant and the presence of dysplasia were the only significant predictive factors for recurrent neoplasia with an OR of 3.27 (1-11.02, p⫽0.05) and 1.72 (1.02-2.89, p⫽0.04) respectively. Conclusions: The APC I1307K gene variant is an important predictive factor for recurrent colorectal neoplasia after a positive index colonoscopy and should be considered as part of the criteria for high risk subjects among Israeli Jews.

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Second malignant neoplasms (SMN) in Cowden syndrome patients with underlying germline PTEN mutations. Presenting Author: Joanne YY Ngeow, Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH Background: Cowden syndrome (CS) patients with underlying germline PTEN mutations are at significantly increased risks of breast, thyroid, endometrial and renal cancers. Current estimates of lifetime cancer risks do not provide the majority of patients who present after their first cancer a meaningful gauge of their risk of a SMN. Quantification of the risk of a SMN will allow patients to be better informed and provide clinicians a much needed guide to finally address patients’ question of “how likely am I to have a second cancer and will it likely be the same primary?” Methods: We conducted a 5-year, multi-center prospective study of CS and CS-like patients, all of whom had comprehensive PTEN analysis done. Patients’ records were reviewed for prior history of invasive cancers. Invasive SMNs were confirmed by pathology reports or physician reports where possible. All metastatic disease, synchronous primary cancer at the same site and non-melanoma skin cancers were excluded. Incidences of SMNs were compared between patients with pathogenic PTEN mutations (PTENmut⫹) and wildtype PTEN (PTENwt). Standardized incidence ratios (SIR), cumulative incidences and excess absolute risks for SMNs were calculated comparing against SEER-derived data. Results: Of 2,792 CS/CS-like patients who present with 1 or more cancers, there were 100 (4%) PTENmut⫹patients. Compared with PTENwt CS/CS-like patients with SMNs (223/2039; 11%), PTENmut⫹cases (42/100; 42%) were more likely to develop SMNs (p⬍0.0001). PTENmut⫹ cases were also younger at median age of SMN diagnosis (48yrs vs 54 yrs; p⫽0.30). PTENmut⫹ patients were 56-fold more likely to develop any SMN compared with the general population (95%CI 41-55); corresponding to an excess absolute risk of 731/10000 person years. Breast cancer was the most common SMN encountered in PTENmut⫹CS/CS-like patients (SIR 73; 95%CI 45-122) followed by endometrial (SIR 44; 95% CI 18-92), renal (SIR 47; 95% CI 15-113) and thyroid cancers (SIR 222; 95% CI 37-734). Conclusions: Our study shows that PTENmut⫹CS/CS-like patients are significantly more likely to present with a SMN compared to PTENwt CS/CS-like patients and the general population, and should be advised and surveillanced accordingly.


Referral for genetic counseling and testing in BRCA1/2 and Lynch syndromes: A nationwide study based on 240,134 consultations and 134,652 genetic tests. Presenting Author: Pascal Pujol, Centre Hospitalier Universitaire, Montpellier and INSERM 896, Montpellier, France Background: Patients referral to dedicated consultations for cancer predisposition syndrome has become a standard in clinical practice. Based on nationwide data from the French national cancer institute (NCI), we analyzed the evolution of cancer genetics consultations and testing over time, and the uptake of targeted tests in relatives of families with a BRCA1/2 or MMR mutation. Methods: All French cancer genetics centres completed annually a survey collecting standardized parameters for the NCI from 2003 to 2011. We report on the analysis of a total of 240,134 consultations and 134,652 genetic tests that enabled to identify 32,494 mutation carriers. Results: From 2003 to 2011, 141,639 (59 %) and 55,698 (23.2 %) patients were referred for a breast or a colorectal cancer predisposition syndrome, respectively. During this period, we found a dramatic and steadily increase in genetic tests performed for the BRCA1/2 genes (from 2095 to 7393 tests/year, P⬍0.0001) but not for the MMR genes (from 1144 to 1635/year, P⫽NS). The percentage of deleterious mutations identified in the probands tested was 13.8 % and 20.9 % in BRCA1/2 and Lynch syndromes, respectively. In families with a BRCA1/2 or a MMR identified mutation, there was an average number of 3.03 relatives performing target tested. Conclusions: This nationwide study shows a lack of referral and genetic testing in Lynch syndrome as compared to BRCA1/2 syndrome. Only a third of relatives for a proband identified with a BRCA1/2 or MMR gene mutations performed a genetic targeted test. Enhanced information about validated benefit of genetic testing should be given to clinicians and patients particularly for Lynch syndrome and for relatives of a proband carrying an identified BRCA1/2 or MMR genes mutation.




Imaging techniques in pancreatic cancer screening: Preliminary results from the PanGen-FAM registry. Presenting Author: Carmen Guillen-Ponce, Familial Cancer Unit, Medical Oncolgy Department, Ramón y Cajal University Hospital, IRYCIS, Madrid, Spain Background: The incidence of pancreatic cancer (PC) is low, thus screening is recommended for individuals considered to be at high risk. These include members of families with ⱖ 2 relatives with PC (FPC), Peutz Jegher syndrome, hereditary breast/ovarian cancer (HBOC), familial atypical multiple mole melanoma and Lynch syndrome. Previous studies have shown that non-invasive precursor lesions, such as intraductal papillary mucinous neoplasm (IPMN) and pancreatic intraepithelial neoplasia (PanIN) are more common and of a higher invasive grade in patients with a family history of PC. Methods: Baseline screening consisted of endoscopic ultrasound (EUS) and computed tomography (CT) and magnetic resonance imaging (MRI). FNA-EUS was performed when mass lesions or cysts ⱖ1 cm in size were encountered. The possibility of surgical intervention or ongoing clinical observation was discussed by a multidisciplinary team in the case of abnormal findings. Furthermore Circulating Tumor Cells (CTC) in peripheral blood as a diagnostic marker was assessed. Thirty-five individuals from FPC and HBOC families were screened between October 2011and December 2012. Results: The most frequent abnormal findings by EUS were parenchymal changes found in chronic pancreatitis (hyperechoic foci, echogenic strands, lobularity, cysts). Overall 13 (41%) patients showed at least 1 of these changes; of note, 7 patients were from the same FPC family. Four patients were diagnosed with cystic lesions by EUS; two lesions were confirmed by MRI but not by CT, one lesion was confirmed by both MRI and CT and was compatible with a mucinous tumor ⬍ 1cm in diameter and one lesion was detected only by EUS. One patient with cystic lesion ⬎1 cm in size underwent EUS-FNA and the cytology showed benign celularity. One patient has a solid lesion, and it was a neuroendocrine tumor. The remaining patients with cystic lesions were proposed for ongoing close clinical observation. CTC have not been detected in 54 patients tested. Conclusions: A high prevalence of pancreatic abnormalities was found in patients from FPC families. Preliminary data suggest that EUS is the most sensitive method to detect small tumors and premalignant lesions.

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Cancer risks and mutation spectrum of mismatch repair genes in African American families with Lynch syndrome. Presenting Author: Sonia Kupfer, The University of Chicago Medical Center, Chicago, IL Background: Although African Americans (AA) have the highest colorectal cancer (CRC) incidence and mortality of all populations in the United States, no studies have determined cancer risk and mismatch repair (MMR) genes mutation spectrum in LS patients of AA ancestry and the contribution of this syndrome to cancer disparities. Thus, the aims of this study are: (1) to describe LS cancers in AAs; (2) to investigate the mismatch repair (MMR) gene mutation spectrum in AA families with LS; (3) to determine how Amsterdam II criteria, revised Bethesda guideline, and PREMM(1,2,6) model perform for predicting MMR gene mutations in this population. Methods: Pedigrees of AA families with deleterious mutation or suspected deleterious mutation in MMR genes from five US referral centers were analyzed for personal and familial clinical cancer histories. Results: Twenty-four AA families were identified, of which 22 had deleterious mutations (15 MLH1, 4 MSH2, 2 MSH6, 1 PMS2) and 2 had suspected deleterious mutations (1 MLH1, 1 MSH2). Three recurrent mutation were found in MLH1(677G⬎A, IVS1-2A⬎G, IVS4-1G⬎A), accounting for 25% of all mutations. Of 24 probands, 58% were female and 96% had personal history of cancer. The median age at first primary tumor was 42yrs (range 28-57) and 50% developed more than 1 primary tumor. The majority of probands (79%) had CRC (median age of onset – 42yrs [range 31-61]), of which 26% had at least 2 CRC primaries. Endometrial cancer developed in 50% of the women (median age of onset – 51yrs [range 32-57]). Amsterdam II and Bethesda criteria were met in 63% and 88% of the individuals, respectively. Median score by PREMM(1,2,6) model was 54% (range 12.9-99.8). Conclusions: To our knowledge, this is the largest series of AA families with LS reported to date. Earlier age of onset for CRC at 42yrs (previously reported ~45 yrs) is suggested. The majority of mutations were found in MLH1 (67%), including three recurrent mutations. A 10% cutoff for PREMM(1,2,6) predictive model identified all mutation carriers. Larger studies are warranted to confirm the differences observed in age of CRC onset in this population.

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PROFILE: Broadly based genomic testing for all patients at a major cancer center. Presenting Author: Barrett J Rollins, Dana-Farber Cancer Institute, Boston, MA

Telomere length and recurrence risk after curative resection in women with adenocarcinoma of the lung: A prospective cohort study. Presenting Author: Eric S. Kim, University of Rochester Medical Center, Rochester, NY

Background: Genotyping plays an increasingly important role in the management of cancer patients. However, the landscape of genomic abnormalities is unknown for many cancers and the influence of specific genotypes on clinical behavior is often unclear. To address these deficiencies, we developed PROFILE, a project designed to obtain genomic information on all patients who come to our hospitals for cancer-related care. Methods: Clinically acquired specimens were genotyped using a mass spectrometry genotyping test (OncoMap) which assays 471 alleles in 41 cancer-related genes. Because the majority of these alleles currently have no known clinical meaning, we implemented PROFILE as a research test. This required developing an ⬙umbrella⬙ protocol governing PROFILE activity, a highly simplified 2-page consenting brochure, and a centralized consenting process. We created process flows for retrieving clinical specimens and performing OncoMap in a CLIA-certified laboratory. We return results on individual participants to their ordering providers who can use actionable findings to guide management. All results are stored in a database which can be queried using a web-based search tool that returns aggregate results. Approval to link specimen to clinical information can be sought by a streamlined process of User Committee and IRB approval, and linkage is performed by IS acting as honest brokers. Results: From August 2011 through December 2012, we consented 12,980 patients (consent rate ⬎70%). We found that 39% of clinical samples are of sufficient quality to yield OncoMap results. We have reported and stored 3,000 genotyping results. OncoMap mutations were detected in 40% of clinical samples. As expected, mutations in KRAS, PIK3CA, TP53, and BRAF were most commonly observed across all tumor types. However, rarer mutations were also detected in RET, PIK3R1, and ERBB2 among others. Conclusions: Novel operational approaches have permitted enterprise-wide, broadlybased genotyping that serves a combination of research and clinical needs. Early insights from this database will be discussed along with information about their impact on clinical management.

Background: We hypothesized that telomere length in peripheral blood would have significant predictive value for risk of recurrence after curative resection in non-small cell lung cancer (NSCLC). Methods: This prospective study included 473 patients with histologically confirmed early stage NSCLC who underwent curative resection at MD Anderson Cancer Center between 1995 and 2008. Relative telomere length (RTL) of peripheral leukocytes was measured by real-time PCR. The risk of recurrence was estimated as hazard ratios (HRs) and 95% confidence intervals (CIs) using a multivariable Cox proportional hazard regression model. Results: Median duration of follow-up was 61 months and 151 patients (32%) had developed recurrence at time of analysis. Patients who developed recurrence had significantly longer mean RTL compared to those without recurrence (1.13 vs 1.07, P⫽0.046). A subgroup analysis indicates that women had longer RTL compared to males (1.12 vs 1.06, P⫽0.025), and the patients with adenocarcinoma demonstrated longer RTL compared to those with other histologic types (1.11 vs 1.05, P⫽0.042). To determine if longer RTL in women and adenocarcinoma subgroup would predict risk of recurrence, multivariate Cox analysis adjusting for age, gender, stage, pack year and treatment regimens was performed. Longer telomeres were significantly associated with higher risk of developing recurrence in female (HR⫽2.25; 95% CI, 1.02-4.96, P⫽0.044) and adenocarcinoma subgroups (HR⫽2.19; 95% CI, 1.05-4.55, P⫽0.036). The increased risk of recurrence due to long RTL was more apparent in females with adenocarcinoma (HR⫽2.67; 95% CI, 1.19-6.03, P⫽0.018). Conclusions: This is the first prospective study to suggest that long RTL is associated with recurrence in early stage NSCLC after curative resection. Women and adenocarcinoma appear to be special subgroups in which telomere biology may play an important role. (Supported by NCI CA 111646, CA 55769, and CA 70907.)


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Cancer Prevention/Epidemiology General Poster Session (Board #1A), Mon, 1:15 PM-5:00 PM

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General Poster Session (Board #1B), Mon, 1:15 PM-5:00 PM

Comparative study of the efficacy of breast cancer neoadjuvant chemotherapy (NAC) in patients (pts) with BRCA1/2 mutation vs sporadic cancer cases versus pts with a family history but no BRCA1/2 mutation. Presenting Author: Francois P. Duhoux, Institut Curie, Paris, France

Prevalence and differentiation of hereditary breast and ovarian cancer in Japan. Presenting Author: Seigo Nakamura, Division of Breast Surgical Oncology, Department of Surgery, Showa University School of Medicine, Tokyo, Japan

Background: During NAC, impaired DNA repair mechanisms may account for the higher response rate of BRCA mutation carriers (group #1) when compared to sporadic cases with no history of breast/ovarian cancer (group #2). In this study, we investigated whether pts with possible BRCAX mutation (i.e. with a family history but no BRCA1/2 mutation, group #3) treated by NAC exhibit a different efficacy (response rate, survival) pattern. Methods: All pts screened for a BRCA1/2 mutation between 1999 and 2010 were selected from the prospectively registered cancer genetics database of Institut Curie. Pts younger than 36 years old were excluded. Pts who received NAC were classified in groups #1 (n⫽23 mutated pts) or #3 (n⫽64 non-mutated pts). Group #2 (n⫽87 sporadic cancer pts) was built to match groups #1 and #3 according to age (⫹/- 5 years), year of treatment (⫹/- 2 years), hormone receptor status and taxane or trastuzumab use. Results: Median follow-up was 65 months. Fifty % of pts had cytologically proven axillary nodal involvement before NAC. Taxanes were used in 63% of pts and trastuzumab in 9% of pts. Pathological complete response (pCR) rates were 39.1% in group #1, 17.2% in group #2 and 20.3% in group #3 (p⫽0.07). For locoregional relapse (LR), the difference between groups was statistically significant (p⫽0.007). The hazard ratio (HR) for LR was higher in group #1 (HR⫽7.86, p⫽0.002) than in group #2. No significant difference was seen between group #3 and group #2 (HR⫽2.37, p⫽0.15). The difference between groups was also statistically significant for distant metastasis relapse (DMR) (p⫽0.009). The HR for DMR was higher in group #1 than in group #2 (HR⫽4.57, p⫽0.01) and in group #3 than in group #2 (HR⫽2.81, p⫽0.01). Conclusions: While pts with BRCA1/2 mutations have a trend towards higher pCR rates with NAC, they have higher rates of LR and DMR than sporadic cases. Pts with a positive family history but no BRCA1/2 mutation have similar pCR and LR rates than sporadic cases, but they have higher rates of DMR. Whether these differences translate into overall survival differences remains to be studied.

Background: Breast cancer is the most common female cancer, according to the Center for Cancer Control and Information Service in Japan. However, the lifetime breast cancer risk in Japan is markedly lower (one in 16) than in the U.S. or Europe. We assembled needed data on the prevalence and characteristics of BRCA1/2 in Japan. Methods: Our study of BRCA 1 and 2 (BRCA1/2) collected data at 8 institutions in Japan on 320 individuals with a strong family history of breast cancer, according to the NCCN guidelines, by the end of March, 2012. Results: Among 260 proband cases, 46 (17.7%) were positive for BRCA1 and 35 (13.5%) were BRCA2 positive. Therefore, the total pathological mutation rate was 30.7%. Pathology data after breast surgery were obtained from 35 cases of BRCA1 mutation, 22 (62.9%) of which were triple negative and 10 (29.4%) were Luminal type. On the other hand, 24 cases (85.7%) of BRCA2 mutations were Luminal type. The most prevalent BRCA1 mutation site was L63X, found in 10 families. L63X was reported previously by studies in Japan, and it may be a founder mutation. We found 2 cases of large deletion detected by MLPA, comprising the first two reported cases in Japan. One was an entire deletion of exon 20 and the lacked exons 1-9. Eight cases of BRCA1 (3.1%) and 12 (4.6%) BRCA2 were uncertain variants. TN with a family history ovarian cancer were 14/20 (70%), TN under 40 y/o 17/23 (73.9%) and TN with one or more breast cancers in family history 19/32 (59.4%) showed higher incidences of BRCA1/2, especially BRCA1. Conclusions: HBOC may have nearly the same prevalence in Japan as in the U.S. or Europe. If TN cases are taken into account, the ratio of BRCA1 is higher. L63X may be one of the founder mutations in Japan. A nationwide database of HBOC is important to address these challenges: (1) To develop risk models for BRCA1/2 carriers in Japan (2) To identify the proper methods to detect cancer occurrence among Japanese BRCA1/2 carrier early (3) To differentiate whether uncertain mutation variants found in Japan are deleterious.

1535

1536

General Poster Session (Board #1C), Mon, 1:15 PM-5:00 PM

Inadequate family history assessment by oncologists as a physician barrier to referral for cancer genetics evaluation. Presenting Author: Samuel Guan Wei Ow, Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore Background: Cancer genetics programs have been established in tertiary cancer centers in Asia for more than a decade. However, the proportion of high-risk patients who are referred for genetic evaluation remains low, and may be attributed to physician and patient barriers. Methods: We reviewed 3-generation genograms of 6301 cancer (CA) patients constructed by a trained cancer genetics counselor at our centre between 2001 and 2012, and identified 1092 (17.3%) patients with suspected hereditary cancer syndromes. 618 patients were estimated to have ⱖ10% chance of carrying a BRCA1/2 mutation. Their case records were reviewed to determine the referral pattern to the cancer genetics clinic. Results: Of the 618 high risk patients, 420 (68%) had young onset CA (age ⬍40), 112 (18.1%) were breast CA families, and 58 (9.4%) were breast and ovarian CA families; only 164 (26.5%) were seen in the cancer genetics clinic. Of the 391 records reviewed so far, 132 cases (33.8%) were referred for genetic evaluation. A good family history (FH), defined by obtaining CA history in 3 consecutive generations, was obtained by the primary oncologist in 52.2%, compared to adequate smoking and drinking history in 64.7% of cases (p⬍0.001). Taking a good FH increased the likelihood of oncologists suspecting hereditary breast and ovarian CA syndrome (50% vs 32.1%; p⬍0.001), with 79% (128/162) of physician-suspected cases referred for genetic counseling. Young onset CA was more likely to arouse physician suspicion (46.9%) compared to other indications (30.5%, p⫽0.002). Of the 259 high-risk cases that were not referred, lack of FH evaluation by the oncologist was the most common reason (41.3 %), followed by lack of suspicion despite taking a FH (34.7 %), patient refusal (8.6%), and planned but no formal action (1.6%). Conclusions: Failure to take a good FH and failure to recognize high-risk CA patients despite taking a FH are important physician barriers that resulted in only a third of high-risk breast or ovarian CA patients being referred for cancer genetics evaluation at a tertiary cancer center in Asia. Systematic FH screening by genetic counselors, clinic-based protocols, and continued physician education may rectify this barrier.

General Poster Session (Board #1D), Mon, 1:15 PM-5:00 PM

Next-generation sequencing for genetic cancer risk assessment: Critical needs and perceptions of community clinicians. Presenting Author: Kathleen R. Blazer, City of Hope, Duarte, CA Background: Current standard-of-care practice for genetic cancer risk assessment (GCRA) focuses on single-gene testing for specific hereditary cancer syndromes. Next-generation sequencing (NGS) technologies recently became available for clinical applications. This study explored the perspectives and experiences of community-based clinicians regarding NGS testing for personalized GCRA. Methods: A 27-item survey was developed and administered online to 325 members of an interdisciplinary nationwide clinical cancer genetics community of practice. Results: Of 94 (29%) respondents, 25 (27%) have ordered at least one multi-gene panel and only 2 (2.1%) have ordered a whole exome or genome test from a commercial vendor for GCRA. Concerns about clinical utility, the challenge of interpreting and communicating results, lack of knowledge about and potential costs were most often cited as reasons for not pursuing NGS testing. Respondents were significantly more confident about their ability to interpret and counsel about single gene test results compared with multi-gene panels or whole exome/genome sequencing; and about multigene panels over whole exome/genome sequencing (p⬍.0001 for all comparisons). Conclusions: Findings suggest that while NGS tests are entering the realm of GCRA, multidisciplinary genomics education and clinical support resources are needed to address barriers to utilization and promote successful integration of NGS testing into community-based GCRA practice settings.



General Poster Session (Board #1E), Mon, 1:15 PM-5:00 PM

Structural variations in mammary carcinomas and their detection in cell-free plasma DNA in a clinical dog model. Presenting Author: Silvia Hennecke, Institute of Veterinary Medicine, Goettingen, Germany Background: Mammary tumors are the most frequent cancers in female dogs exhibiting a variety of histopathological differences to which a dearth of information about their genomic status exists. Massive parallel sequencing (MPS) of tumor, white blood cell and associated cell-free DNA from plasma revealed the utility of the dog in modeling the dynamics of cell-free cancer DNA. Methods: Five tumors of three different histological subtypes were evaluated. MPS of tumors was performed in comparison to the respective white blood cell DNA of each animal. Copy number and structural variations were evaluated and those only present in tumors were validated using digital droplet PCR (ddPCR). Results: Using mate-pair sequencing chromosomal aneuploidies were found in two tumors, frequent smaller deletions were found in one, inter-chromosomal fusions in one other, whereas noteworthy one tumor was devoid of any of these anomalies. The detected structural variations affect several known cancer associated genes such as BRCA1, cMYC, and KIT. One deletion of the proximal end of CFA27, harboring the tumor suppressor gene PFDN5 was detected in four of the five tumors. Using ddPCR, this deletion was validated and detected in 50% of tumors (N⫽20).One breakpoint specific ddPCRs was established for each of four tumors. In all cases tumor specific DNA was detected in the plasma prior to surgery and accounted for 1 to 24 % of the cfDNA. In one animal the ddPCR detected tumor specific DNA in cfDNA still present ⬎1 year after surgery; subsequently a lung metastasis was found as cause. Furthermore, paired-end sequencing of extracted cfDNA and subsequent depth of coverage analysis proved that copy-number variations of the tumor are reflected by the cfDNA. Conclusions: The similarities of patterns of copy-number imbalances (e.g. chromosomal and segmental aneuploidy subtypes) of canine and human mammary cancers and their correlation in cfDNA supports the use of the dog as a model for using MPS for screening and discovery of individual cancer biomarkers. The ddPCR technology offers rapid, cost effective and sensitive confirmation and monitoring. The possibility exists that ddPCR can be expanded to screening for common cancer related variants.

1539

General Poster Session (Board #1G), Mon, 1:15 PM-5:00 PM

1538

95s General Poster Session (Board #1F), Mon, 1:15 PM-5:00 PM

A randomized trial of telephone versus in-person disclosure of BRCA 1/2 results. Presenting Author: Angela R. Bradbury, University of Pennsylvania, Philadelphia, PA Background: While some providers use telephone to share genetic test results, there is limited data on the efficacy and impact on patient cognitive and emotional responses. Methods: Patients who completed in-person genetic counseling for BRCA 1/2 testing were randomized to telephone (TD) or in-person (IPD) disclosure. Baseline (BL) and post-disclosure (PD) surveys assessed knowledge, satisfaction and psychological factors. We used T-tests and multiple linear regressions. Results: 179 patients (68% of approached),126 (72%) agreed to be randomized; 36 (28%) declined randomization (Self-select IPD). Patient characteristics did not differ between arms. Change in knowledge, satisfaction and psychological factors did not differ between TD and IPD (Table). Self-select IPD participants had greater declines in depression and state anxiety (Table). In multivariable models, history of cancer was associated with greater declines in general anxiety (coef -1.4, p⫽0.01). BRCA⫹ results were associated with greater increases in knowledge (coef 3.2, p 0.02) and state anxiety (coef 12.0, p⬍0.01), and declines in satisfaction (coef -6.6, p⬍0.01). Having a mutation in the family was associated with greater declines in intrusive thoughts (coef -4.8, p⬍0.01). Conclusions: In general,telephone disclosure of BRCA1/2 results does not appear to negativelyimpact psychological outcomes but outcomes among carriers (BRCA⫹) differ. Larger studies are needed to understand the impact among subgroups and more diverse populations. Some patients preferred in-person communication and had different outcomes, suggesting more data is needed before telephone disclose is universally adopted. Outcome General anxiety BL PD Depression BL PD State anxiety BL PD Intrusive thoughts BL PD Knowledge BL PD Satisfaction BL PD

TD (nⴝ63)

IPD (nⴝ52)

Self-select IPD (nⴝ36)

7.1 (3.9) 6.9 (4.0)

6.7 (4.4) 6.6 (3.9)

6.8 (4.3) 5.5 (4.2)

5.5 (2.8) 5.9 (2.6)

5.4 (2.7) 5.7 (2.0)

6.0 (2.4) 5.6 (2.6)

35.8 (11.8)a 36.5 (13.2)b

39.3 (13.7) 37.7 (12.4)

36.9 (13.2)c 33.3 (13.4)d

9.4 (8.3) 8.7 (8.5)

10.0 (9.2) 11.1 (9.2)

11.2 (10.2) 9.5 (8.5)

23.4 (2.8) 23.5 (2.9)

23.5 (3.2) 22.9 (2.8)

22.8 (3.1) 23.2 (2.8)

38.4 (3.9) 40.3 (4.6)

37.8 (4.6) 39.1 (5.1)

38.4 (3.7) 40.2 (4.2)

ab v. cd ⫽ p ⬍ 0.05.

1540

General Poster Session (Board #1H), Mon, 1:15 PM-5:00 PM

Screening of CHEK2 and TP53 p.R337H germ-line mutations in high-risk patients for hereditary breast and ovarian cancer from northeast of Brazil. Presenting Author: Ivana Lucia Oliveira Nascimento, Federal University of Bahia, Salvador, Brazil

R497K of EGFR and BIM deletion polymorphisms as predictive biomarkers to EGFR TKIs in NSCLCs harboring wild-type EGFR. Presenting Author: Jin Hyoung Kang, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, South Korea

Background: CHEK2 is a molecular messenger that interacts with a checkpoint network of other susceptibility genes like ATM, BRCA1, TP53, MDM2, Cdc25A and Cdc25C. The mission of these checkpoints is to preserve the genome integrity during the cell division by regulating the cellular response to DNA damages. The TP53 p.R337H germline mutation was studied in patients with Li-Fraumeni Syndrome, breast cancer and Choroid plexus carcinomas in Southern of Brazil, but never in the Northeast. In the hereditary breast cancer the mutation frequencies of susceptibility genes of low penetrance like CHEK2 is 1-10%, while for genes of high penetrance as TP53 is ⬍1%. Thus, the aim of this study was to screening for CHEK2 and TP53 most common germline mutations in high-risk patients for hereditary breast and ovarian cancer (HBOC) from Northeast of Brazil. Methods: It was analyzed 100 high-risk patients for HBOC from Bahia, Brazil. The genomic DNA was extract from peripheral blood. The CHEK2 mutations, c.1100delC, c.444⫹1G⬎A and p.I157T, and TP53 p.R337H mutation were genotyped by Allelic Specific-PCR or PCR-RFLP. Results: Most of the subjects had only breast cancer (86.0%), followed by ovarian (7.0%) and both breast and ovarian cancer (7.0%). Among the breast cancer cases the most common histological type was the ductal (71.0%), while among the ovarian cancer cases were the serous (57.14%). The mean age at diagnostic was 42 yrs (⫾ 9.99). Any of the patient presented c.1100delC, c.444⫹1G⬎A and p.I157T mutations. But, two have the p.R337H mutation. Conclusions: Though there is the hypothesis that mutations of low penetrance genes, such as CHEK2, are more likely to be found than high penetrance genes, such as TP53, here it was demonstrate that three of most predisposing variants of CHEK2, c.1100delC, c.444⫹1G⬎A and p.I157T, do not have major contribution in HBOC in the population studied. While, the p.R337H, though presented in low frequency compared with the Southern of Brazil (Ashton-Prolla et al., 2012), seems to have a significant contribution in HBOC.

Background: Activating EGFR mutations are strongly predictive of EGFR tyrosine kinase inhibitor (TKI) activity in NSCLCs, however, some patients having wild type EGFRdo not infrequently show clinically favorable outcome to EGFR TKIs. The key proapoptotic proteins have been reported to be involved in TKI-induced cell death. The up-regulation of BIM, a proapoptotic protein of BCL2 family, is required for TKIs to induce apoptosis in cancers. Methods: For 150 advanced or metastatic NSCLC pts. receiving gefitinib or erlotinib, we assayed mutation status of EGFR in paraffin embedded tumor tissue using PNA clamping (PANAGENE, Korea) and direct sequencing. Six different genetic variants of EGFR (-191C⬎A, -216 G⬎T, CA repeat number, R497K, 2607G⬎A, and D994D) and BIMdeletion in genomic DNA extracted from peripheral blood were analyzed. Results: M:F ratio was 72:78 and median age was 63 (35~82). Histological subtypes are as follows: 131 adenocarcinoma (87.3%), 16 squamous cell ca. (10.7%) and 3 large cell ca. (1.3%). Objective tumor response (CR⫹PR) was observed in 60 pts. (40.0%) and SD in 44 pts. (29.3%). Median PFS and OS were 4.3 (0.4~67.4) and 18.6 (0.9~78.1) months, respectively. Of 129 pts. in whom EGFR mutation could be analyzed, 41 pts. (31.8%) had activating EGFR mutation. In univariate analysis, only gender was associated with objective response to EGFR TKI in activating EGFR mutant group (P⫽0.048). In wild type EGFR group (n⫽88), R497K (P⫽0.04) and BIM (P⫽0.04) as well as gender (P⫽0.05) were significantly correlated with objective response. In addition, multivariate analysis demonstrated that gender, R497K and BIM were associated with objective response to EGFR TKIs in wild type EGFR group with statistical significance (P⫽0.023, 0.027 and 0.018, repectively). Neither six EGFR polymorphisms nor BIM was correlated with PFS and OS in activating EGFR mutant group. Meanwhile, in wild type EGFR group, R497K was significantly associated with OS (P⫽0.028). Conclusions: Taken together, our data suggest that R497K of EGFR and BIM deletion polymorphisms are useful pharmacogenetic biomarkers to predict objective tumor response for EGFR TKIs in advanced NSCLC pts. harboing wild type EGFR.


96s 1541

Cancer Prevention/Epidemiology General Poster Session (Board #2A), Mon, 1:15 PM-5:00 PM

Unique genetic characteristics of BRCA mutation carriers in a cohort of Arab American women. Presenting Author: Seerin Viviane Shatavi, Oakland University William Beaumont School of Medicine, Royal Oak, MI Background: Worldwide ethnic variations in the distribution of BRCA1 and BRCA2 mutations of breast cancer patients have been recently recognized. This has led to investigations of the epidemiology, genetics and clinical characteristics of BRCA positive individuals within specific populations. This study aims to describe the findings of BRCA genetic testing in a cohort of Arab American women. Methods: A total of 73 women of Arab ancestry were evaluated in the Beaumont Cancer Genetics Program from Jan 2008 to Jan 2013. Criteria for genetic testing included a personal or family history suggestive of Hereditary Breast and Ovarian Cancer Syndrome (HBOC). Patients underwent comprehensive genetic counseling, followed by full sequence analysis for germline mutations in BRCA1 and BRCA2. Results: 63 women of Arab ancestry underwent genetic testing for BRCA1 and BRCA2. 13 (21%) patients were found to be mutation carriers, of whom 10 (16%) of the 63 had deleterious mutations (7 in BRCA2, and 3 in BRCA1), and 3 (5%) had variants of undetermined significance (VUS) in BRCA2. Of the 10 patients with deleterious mutations, 4 (40%) unrelated individuals had the same mutation, 5804del4, in exon 11 of BRCA2. The remaining patients had deleterious mutations in exon 2, exon 20, and exon 13 of BRCA2; one patient had a BRCA1 and BRCA2 mutation (exon 18). 7 of 10 patients with deleterious mutations had a cancer diagnosis, of which 5 had breast cancer, 1 had ovarian cancer, 1 had pancreatic cancer, and 3 were unaffected. Conclusions: This study demonstrates that BRCA mutations (predominantly in BRCA2) were seen in a significant proportion of Arab American women undergoing genetic testing for HBOC. A mutation in BRCA2, 5804del4, was seen in nearly half (4/10) of the carriers of deleterious mutations. This mutation, in exon 11, has not previously been associated with Arab ethnicity and may represent a founder mutation. Knowledge of the genetic spectrum, frequency, and clinical characteristics of BRCA mutation carriers will lead to greater understanding of hereditary cancer in Arab American women.

1542


Investigating parent of origin effects (POE) and anticipation in Irish Lynch syndrome kindreds. Presenting Author: Michael P. Farrell, Mater Private and Mater Misericordiae University Hospital, Dublin, Ireland Background: Genetic diseases associated with dynamic mutations often display parent-of-origin effects (POE) in which the risk of disease depends on the sex of the parent from whom the disease allele was inherited. Genetic anticipation describes the progessively earlier onset and increased severity of disease in successive generations of a family. Previous studies have provided limited evidence for and against both POE effect and anticipation in Lynch syndrome (LS). We sought evidence for a specific POE effect and anticipation in Irish LS families. Methods: Affected parent-child pairs (APCPs) (N ⫽ 53) were evaluated from LS kindreds (N ⫽ 20) from two hospital-based registries and one cancer genetic centre. POE were investigated by studying the ages at diagnosis in the offspring of affected parent-child pairs. Anticipation was assessed by a paired t-test, and bivariate Huang and Vieland model. Results: See Table. Paired t-test revealed anticipation with children developing cancer mean 11.8 years earlier than parents, and 12.7 years using the Huang and Vieland model (p ⬍ 0.001). Conclusions: These data demonstrate a similar age at diagnosis among all offspring of affected mothers that was indistinguishable from affected fathers. Affected sons of affected mothers were diagnosed with cancer almost 3 years younger than female offspring; however, this finding failed to reach statistical significance. Evidence of anticipation was suggested in this cohort, emphasizing the importance of early-onset screening. Addition LS families are under review and updated data will be presented at the meeting. POE effect: Comparison in age at diagnosis in 53 affected parent-child pairs with Lynch syndrome-associated malignancies. Affected

Affected

Mothers N ⫽ 14 Mean ⫽ 48.8 Range ⫽ 27-73

Fathers N ⫽ 13 Mean ⫽ 53.6 Range 36-85

All offspring

N ⫽ 24 Mean ⫽ 40.4 Range ⫽ 23-72

N ⫽ 30 Mean ⫽ 41.6 Range 23-60

0.67

Female offspring

N⫽6 Mean ⫽ 42.5 Range ⫽ 31-64

N ⫽ 15 Mean ⫽ 41.06 Range ⫽ 27-58

0.75

Male offspring

N ⫽ 18 Mean ⫽ 39.77 Range ⫽ 23-72

N ⫽ 15 Mean ⫽ 40.07 Range ⫽ 20-60

0.94

0.604

0.95

Unique parent

P value female v male offspring

1543


Prospective correlation between clinical and pathologic criteria identification of Lynch syndrome (LS) in endometrial carcinoma (EC) patients and relapse. Presenting Author: Ignacio Romero, Area Clinica Oncologia Ginecológica. Instituto Valenciano de Oncologia, Valencia, Spain Background: Prospective comparison of different methods for recognition of LS associated EC is lacking. Microsatellite instability (MSI) has been observed to be inconsistent as a prognostic factor in EC. The aim of this study was to analyze the impact of MSI and Mismatch Repair (MMR)deficiency on LS identification and prognosis in a prospective series of EC treated in one single institution. Methods: Consecutive and prospective EC patients were included. Clinical data, family history of cancer and criteria for LS were evaluated. MSI and MMR protein expression were performed. When loss of MMR proteins and/or high MSI (MSI-H) was observed, complete sequencing and large genomic rearrangement analysis of germline MLH1, MSH2, MSH6 or PMS2 was done once MLH1 methylation was excluded. Results: Seventy-seven women diagnosed with EC were enrolled from 2009 to 2012 with a median age of 62 (31-87), 84% histological type I, 16% type II and FIGO stages I 83%, II 2.8%, III-IVA 7% and IVB 7%. Among which, 6.6% fulfilled revised Bethesda criteria (rBC), 5.3% criteria defined by the Society Gynecologic Oncology (⬎20%-to-25% risk of LS) (SGO) and 5.3% Amsterdam II criteria (AII). Seventy-four underwent surgery with curative-intent. Tumor tissue was unavailable in 5 cases for molecular analysis. MSI-H was observed in16 cases (22%) and 18 (24%) had loss of expression of MLH1 (14), MSH2 (2), MSH6 (1) or PMS2 (1). Nine MLH1 hypermethylation, 10 K-RAS and no BRAF mutations were identified. Four (5.5%) pathogenic MMR germline mutations were recognized: 2 MSH2, one MSH6 and one PMS2. One patient (25%) with MSH6 mutation did not fulfil rBC, SGO nor AII criteria and was identified both by MSI-H and loss of MSH6 expression. Median follow-up was 23.4 (0.276.3) months. No correlation between MSI-H, MMR gene mutation and relapse was observed in stage I-IVA EC. Conclusions: Based on these results, rBC, AII and SGO criteria for identification of LS in EC do not identify 25% of germline MMR gene mutations. No correlation with relapse and MSI-H could be identified.

1544

P value

0.28


BRCA1/2 mutation prevalence among triple-negative breast cancer patients from a large commercial testing cohort. Presenting Author: Kristilyn Dillman Zonno, Myriad Genetics and Laboratories, Inc., Salt Lake City, UT Background: BRCA1/2 deleterious mutation identification among triplenegative breast cancer (TNBC) patients has gained importance due to cancer-risk management implications for patients and their relatives, and also has an emerging role in guiding treatment selection for therapies such as PARP inhibitors. The National Comprehensive Cancer Network (NCCN) currently recommends BRCA1/2 testing for TNBC patients diagnosed at age ⬍60. Mutation prevalence among TNBC patients has previously been studied only in small regionalized cohorts. A recent study in unselected patients using the updated definitive criteria for TNBC reported mutation prevalence as 10.6%. Methods: Following the 2011 NCCN Hereditary Breast and Ovarian Cancer (HBOC) Testing Criteria update, serial cohorts of ⬎ 5,000 Ashkenazi Jewish and ⬎ 65,000 non-Ashkenazi Jewish breast cancer patients undergoing commercial BRCA1/2 testing were analyzed. Age at diagnosis, ethnicity, and provider-reported TN status were obtained from test requisition forms completed by ordering providers, and correlated with test results. Neither the accuracy nor definitive criteria used for TN status reported was independently verified. Results: Incidence of TNBC was reported as 9.7% among non-Ashkenazi patients and 16.5% within the subset with African ancestry. Incidence of TNBC was reported as 4.5% among Ashkenazi patients, but this is likely affected by test ordering for this population. The Table displays the BRCA1/2mutation rates classified by ethnicity and age-group. Conclusions: This study provides the most robust estimate to date of BRCA1/2 mutation prevalence among TNBC patients of all ages. The mutation rates seen among TNBC patients diagnosed after age 60 also illustrate the importance of testing such patients who may not meet the current NCCN HBOC testing criteria. BRCA1/2 mutation rates among TNBC patients by ethnicity and age. BRCA1/2 mutation rates among TNBC patients

Ethnicity Ashkenazi Jewish Non-Ashkenazi Jewish African

All ages 19.9% 11.3% 12.0%

Age ⬍ 60 23.9% 11.7% 12.4%

Age ⬎60 8.7% 6.8% 2.7%




1546

97s General Poster Session (Board #2F), Mon, 1:15 PM-5:00 PM

Timing of referral to genetic counseling among women with gynecologic or breast cancer. Presenting Author: Amy J Bregar, Women and Infants Hospital of Rhode Island, Providence, RI

Lynch syndrome testing in ethnically diverse patients: Mutation spectrum and performance of prediction models. Presenting Author: Y. Nancy You, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: The National Comprehensive Cancer Network (NCCN) has established guidelines delineating appropriate candidates for genetic counseling. While genetic predisposition is responsible for a small percentage of cancer, genetic referral at diagnosis may effect treatment decisions. We aim to determine factors associated with timing of referral in women with breast and gynecologic cancers. Methods: Patients from an academic women’s oncology program were identified who met a subset of NCCN referral criteria for genetic evaluation between 2004-2010 (ovarian cancer at any age, breast cancer ⱕ 50 years of age, or uterine cancer ⬍ 50 years of age). A retrospective chart review was conducted. Statistics were analyzed using SAS v. 9.2 (SAS Institute, Cary, NC); categorical variables were compared by chi-square or Fisher’s exact test and continuous variables were compared by ANOVA. The study was approved by the hospital Institutional Review Board. Results: 820 women with cancer (26% uterine, 38% breast, 35% ovarian) were included. The overall referral rate was 22%; more breast than gynecologic cancer patients were referred (34% vs. 28%, p⬍0.0001). Breast cancer patients were more often referred at diagnosis compared to women with uterine (p⬍0.0001) and ovarian cancer (p⫽0.007). Early stage breast cancer patients were more often referred at diagnosis compared to women with late stages (p⫽0.03). Among ovarian cancer patients, those with late stages were more often referred at diagnosis compared to women with early stages (p⫽0.02). Age at diagnosis, family history, and parity were not associated with timing of referral. Among women with breast cancer, 26% of referred patients had a prophylactic contralateral mastectomy compared to 8% of those not referred (p⬍0.0001). Conclusions: Genetic counseling is underutilized in breast and gynecologic malignancies. The timing of referral varies widely and genetic counseling may impact treatment decisions. Breast cancer diagnosis, early stage breast cancer, and late stage ovarian cancer are associated with earlier referral for genetic evaluation. Further research is needed to determine additional factors that may increase referral rates and impact timing of referral.

Background: Lynch syndrome (LS) is characterized by deficiency in DNA mismatch repair (MMR). Several models can predict the probability of MMR gene mutations, but all were derived from populations in Northern Europe and America. We aimed to characterize MMR mutations and to evaluate the performance of 4 models (Leiden, MMRpredict, MMRpro, and PREMM1,2,6) in an ethnically diverse high-risk population. Methods: Mutation and pedigree data from 387 distinct probands tested for germline MMR mutations at a single center between 2003-2012 were analyzed. Mutation testing was triggered by suggestive tumor microsatellite results and/or clinical/family history. Race/ethnicity was self-reported: 84 (22%) were ethnically-diverse (African American, 19; Hispanic, 29; Asian/Arabic, 34; and other, 2) and 303 (78%) were white. Area under the receiver operating curve (AUC) for all 4 models was analyzed by logistic regression. Results: Pathogenic mutations were detected in 152 patients (39%; MLH1 in 37, MSH2/EPCAM in 84, MSH6 in 21, and PMS2 in 10). The detection rate was significantly lower in ethnically-diverse patients when compared to white patients (30 vs. 42%; p⫽0.04). The mutation frequency of the major MMR genes MLH1 and MSH2 differed, although the overall mutation distribution did not reach statistical significance (MLH1, 40 vs. 22%; MSH2: 36 vs. 59%; MSH6: 20 vs. 13%; and PMS2: 4 vs. 7%; p⫽0.10 vs. white). The Leiden, MMRpredict, MMRpro, and PREMM1,2,6 models trended toward inferior discrimination for the ethnically diverse patients, with AUCs of 0.63, 0.64, 0.63, and 0.66 respectively (vs. AUCs of 0.71, 0.69, 0.72, and 0.76 for white patients), but the difference was not statistically significant(p⫽0.11, 0.17, 0.09, and 0.08, respectively). Adjusting for family size did not significantly alter results. Conclusions: In ethnicallydiverse patients, the overall detection rate for pathogenic MMR mutations is significantly lower, with associated differences in mutation frequencies and in predictive model performance. We caution against relying solely on predictive scores, as high-risk ethnically-diverse patients without an identified mutation may deserve to be followed as clinical LS patients.

1547

1548


A prospective comparison study on EGFR mutations by direct sequencing and ARMS in completely resected Chinese non-small cell lung cancer with adenocarcinoma histology (ICAN). Presenting Author: Xuchao Zhang, Guangdong Lung Cancer Institute, Medical Research Center of Guangdong General Hospital, Guangzhou, China Background: ICAN study investigated EGFR mutation (M) status, clinical outcomes and recurrent risk factors in Chinese lung adenocarcinoma (ADC) patients (pts) after complete resection. Here we report analysis results for the overall EGFR M rate and the consistency between two EGFR M detecting methods, ARMS and PCR⫹direct sequencing (Seq). Methods: Pts were aged ⱖ18 years, with histological diagnosed lung ADC, and received surgical complete resection. Tumor sample EGFR M status (primary endpoint; positive [M⫹]) was determined according to clinical routine practice by whatever methods, including ARMS, Seq, liquid chip and mutant-enriched PCR. For the pts whose tissue was adequate after EGFR M testing by single method of either ARMS or Seq, the other method was applied. Results: Of 571 pts from 26 sites, 315 (55.2%) pts were EGFR M⫹. 420 pts’ tissues were tested by both ARMS and Seq. EGFR M⫹ rates were 58.1% and 54.5% respectively without statistical significance (p⫽0.0548). The total consistent rate (both M status and M types) between two methods was 76.7%. The following Table showed individual EGFR M types by two methods. Conclusions: The overall EGFR M⫹ rate in operable Chinese ADC was 55.2%. For resection samples, two common methods, ARMS and Seq, didn’t show statistical significance on EGFR M⫹ rate. Regarding EGFR M types, Seq found some rare mutations which ARMS kit could not detect, while ARMS seemed more sensitive for exon 20 and 21 mutations, especially for S768I and L861Q. Clinical trial information: NCT01106781. Individual EGFR M types by methods (chi-square test). Exon 18 G719X L692F/P694L Exon 19 deletion L747S S752F Exon 20 insertion T790M S768I L788F R776H T794S Exon 21 L858R L861Q L833V P848L V821I

Sequencing (%)

ARMS(%)

P value

12(2.9) 11(2.6) 1(0.2) 125(29.8) 122(29.0) 2(0.5) 1(0.2) 13(3.1) 6(1.4) 2(0.5) 0(0.0) 1(0.2) 3(0.7) 1(0.2) 91(21.7) 89(21.2) 1(0.2) 1(0.2) 1(0.2) 1(0.2)

13(3.1) 13(3.1) 0(0.0) 118(28.1) 118(28.1) 0(0.0) 0(0.0) 22(5.2) 6(1.4) 6(1.4) 10(2.4) 0(0.0) 0(0.0) 0(0.0) 115(27.4) 108(25.7) 9(2.1) 0(0.0) 0(0.0) 0(0.0)

0.839 0.679 1.000 0.594 0.760 0.479 1.000 0.120 1.000 0.287 0.002 1.000 0.247 1.000 0.054 0.122 0.011 1.000 1.000 1.000

General Poster Session (Board #3A), Mon, 1:15 PM-5:00 PM

Decreased TGFBR1 signaling and breast cancer. Presenting Author: Clark Henegan, University of Alabama at Birmingham, Birmingham, AL Background: We previously identified TGFBR1*6A (rs11466445), a hypomorphic TGF-beta type 1 receptor variant that is associated with cancer risk, has impaired TGF-beta signaling capability, and enhances the migration and invasion of breast cancer cells (Cancer Res 2008, 68:1319). Two recent large meta-analyses of case control studies have found a significant association between TGFBR1*6A and risk of breast cancer (Mol Biol Rep 2010 37:3227; PLoS One 2012,7(8). Rs7034462 is a single nucleotide polymorphism (SNP) in a noncoding region more than 9 kilobases upstream of TGFBR1 exon 1, which has been shown to be associated with decreased TGFBR1 expression similar to TGFBR1*6A (J Exp Clin Cancer Res 2010, 29:57). In this study we tested the hypothesis that rs7034462 may be associated with breast cancer risk. Methods: rs7034462 was genotyped in DNA obtained from patients with breast cancer and their unaffected sisters recruited by the Breast Cancer Family Registry (B-CFR). Results: The median age of cases and controls was 48.8 and 47.6 years, respectively. Using a simple case-control genetic association analysis for this family-matched population, rs7034462 was found to be associated with breast cancer risk. Conclusions: TGFBR1 rs7034462 is emerging as a low penetrance breast cancer susceptibility allele suggesting that two distinct TGFBR1 SNPs, each associated with decreased TGFBR1 expression, may modulate breast cancer risk. SNP rs7034462 (nⴝ1,962)

Cases

Controls

Heterozygous vs. common homozygous

95% CI

P value

833

1128

1.29

1.01-1.64

0.037


98s 1549

Cancer Prevention/Epidemiology General Poster Session (Board #3B), Mon, 1:15 PM-5:00 PM

Genomic alterations in matching primary tumors and metastasis in breast cancer. Presenting Author: Tingting Jiang, Yale University, New Haven, CT Background: We examined DNA sequence alterations in matching normal tissues, primary breast cancers and metastatic lesions to study the genomic evolution of breast cancer. We also assessed technical reproducibility. Methods: DNA was extracted from formalin fixed paraffin embedded tissues obtained during autopsies from 3 patients including 12 specimens. We performed paired-end whole exome sequencing with SOliD V4 Genome Analyzer using the Agilent Sure Select All Exon Kit including technical replicates. Nucleotide variants (NV) were detected by Varscan V2.2 and functional impact was predicted by ANNOVAR. Results: After 4 QC steps (duplicate and strand bias removal, base quality and minor allele frequency filters) that removed 98.81% of variants per sample (range 96.50%99.99%). We observed on average 2648 new NVs per cancer sample (range 10-5541) at a mean coverage of 72 (range 19-283) and mean library size of 48270660 base (range 7764034 base - 60752085 base). Concordance for high quality NVs reached 95% (range 92%-98%) in replicates. Mutation rate in the primary cancer differed from patient to patient (range 10.41per Mb to 18.29 per Mb) with more mutations seen in patients with longer disease history and extensive prior therapy. We also observed more differences in mutations between primary tumors and metastasis than expected by technical nose alone. On average, 234(83.53%) mutations were shared between a primary tumor and a metastasis (range 4 – 947; 62.5%-97.63%) and the number of site-specific mutations ranged from 0 to 251. An index for assessing mutational heterogeneity was greater in primary cancers compared to their metastasis. Mapping of variants with predicted functional impact yielded different targetable anomalies for different tumor sites. Conclusions: Mutation rates differed among patients according to their disease history. Difference of mutation between primary tumor and metastatic lesion were larger than technical noise and the heterogeneity of primary cancers was larger than that of metastasis. Metastasis often differed from the primary tumor in the spectrum of potentially targetable anomalies.

1550


The first 10 years experience with genetic testing (GT) for BRCA1/2 mutations in a publicly funded program at a tertiary care teaching hospital in Ontario, Canada. Presenting Author: Sherry Athena Doroja Ruste, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada Background: Publicly funded testing for BRCA1/2 mutations in Ontario has been available for high-risk individuals since 2000. The criteria are based on personal and/or family cancer history and ethnicity. We reviewed the results of the first 10 yrs of testing at our institution, a regional cancer centre in an academic, tertiary care teaching hospital. Methods: This REB-approved, retrospective study included individuals who had GT from 2001-2011. Sociodemographic, clinical, and GT results were collected. Results: 2,305 individuals met criteria and underwent GT between Jan. 2001and Dec. 2011. Of all tested subjects, 93% were female, median age was 55 yrs., 23% were of Ashkenazi Jewish (AJ) ancestry and 80% lived in an area with family income $50-100K/yr. BRCA1/2 mutations were present in 16%, 8% had unclassified variant (UCV), 76% had normal sequence. We excluded 460 individuals who had predictive GT for a familial mutation, and results are shown in the Table. For each carrier, an average of four additional relatives had GT. The most common criteria for GT was at least three cases of ovarian or breast cancer at any age on the same side of the family. BRCA mutations were most common among those AJ, Italian, Asian Oriental and English ancestry. Wait time for GT result improved from 107 wks. in 2001 to 8 wks. in 2011. Conclusions: In our tested population, the prevalenceof BRCA1/2 mutations was high. Over time wait times improved and more relatives were tested. Prevalence of mutations excluding predictive testing (Nⴝ1,845). Mutation BRCA1 BRCA2 UCV only Normal sequence Cancer history in carriers No cancer Breast cancer Ovarian cancer Breast and ovarian cancer Other cancer Median age breast cancer diagnosis Ancestry in carriers* Ashkenazi Jewish Italian Asian-oriental Eastern European Asian-other

N

%

100 74 171 1,500 BRCA1 N 18 63 9 5 5 42 BRCA1 N 26 16 4 5 6

6 4 9 81 BRCA2 N 12 53 2 3 4 44 BRCA2 N 10 8 8 5 4

% 18 3 9 5 5 % 26 16 4 5 6

% 16 72 3 4 7 % 13 11 11 7 5

Abbreviations: BRCA, breast cancer; UCV, unclassified variant. *Same ancestry on paternal and maternal side.

1551


Risk of hospital-related morbidity among survivors of breast cancer in British Columbia, Canada. Presenting Author: Christine E. Simmons, BC Cancer Agency, Vancouver, BC, Canada Background: Long-term consequences of cancer diagnosis and treatment are of increasing concern, as therapeutic interventions improve survival. Various survivorship programs exist; few address the importance of bridging oncology and primary care. This study assesses risk of late hospital-related morbidity among a population-based cohort of 39,436 3-year survivors of female breast cancer in British Columbia, Canada and compares the risk of morbidity to a similarly-aged comparison group. Methods: Demographic and clinical records of breast cancer survivors diagnosed between 1986 and 2005 were linked to inpatient records from provincial administrative databases. A comparison group from the provincial health insurance plan registry, frequency-matched by birth cohort was identified. Morbidity was ascertained from diagnosis codes listed on hospital records, and categorized by organ system. Poisson regression was used to assess the relative risk of morbidity, adjusting for sociodemographic factors. Results: Compared to controls, non-relapsed survivors diagnosed age 18-39 (N⫽1158) had more than twice the risk of morbidity (RR 2.57, 95%CI 2.21-2.98); those with a relapse (N⫽580) had eight times the risk (95% CI 6.78-9.44). Among those diagnosed age ⱖ40, non-relapsed survivors (N⫽20473) had a 62% increase in risk RR 1.62, 95% CI 1.57-1.68; relapsed survivors (N⫽5223) had triple the risk of morbidity (RR 2.89, 95% CI 2.78-3.01). In both cohorts, excess risks were statistically significant for most types of non-neoplastic morbidity, with highest rates seen for disorders of the blood, endocrine, skin and circulatory systems. Among survivors, those diagnosed with a higher stage cancer had increased risk of morbidity. Type of treatment received did not correlate with increased risk of morbidity (RR 1.05, 95% CI 1.00 –1.11 for combination of surgery, radiation and systemic therapy vs surgery alone); majority of the risk increase is likely related to the impacts of cancer itself rather than treatment. Conclusions: Survivors of breast cancer are at an increased risk of a wide range of morbidities years after diagnosis. This underscores calls for improved models of survivorship care and continued survivorship research.

1552


Genome sequencing of multiple primary tumors to reveal underlying germline cancer susceptibility. Presenting Author: Kasmintan A. Schrader, Clinical Genetics Service, Department of Medicine, Memorial SloanKettering Cancer Center, New York, NY Background: Apart from germline mutations in BRCA1 and BRCA2, the basis for genetic susceptibility to breast and ovarian cancer is heterogeneous, and can necessitate sequential or multiplex genetic testing. In addition, examination of germline DNA alone may not be conclusive. Information regarding both primary and secondary genetic events can be obtained from genomic analysis of tumors in conjunction with germline DNA. Methods: To determine the underlying cause of multiple primary malignancies in an Ashkenazi Jewish individual, whole genome sequencing was performed on DNA from the patient’s germline, invasive ductal carcinoma of the breast, and ovarian high-grade serous carcinoma. After identifying a structural variant of interest in this patient, germline DNA of 1846 Ashkenazi Jewish individuals who had a personal history of either breast, pancreatic, or ovarian cancer or a history of both breast and/or ovarian cancer and a similar family history, were screened using a TaqMan copy number assay or a specific PCR breakpoint assay to determine if this structural variant is a founder mutation. Results: A novel germline complex structural variant of PALB2 creating a 3790 base-pair deletion encompassing exon 11 associated with a 68 base-pair insertion was identified and confirmed by Sanger sequencing and a TaqMan copy number assay. The germline deletion was retained in both tumors. In addition, both tumors acquired second hits that led to inactivation of the wild-type allele of PALB2. The germline PALB2 structural variant was not identified in any of the additional 1846 Ashkenazi Jewish individuals genotyped. Conclusions: Whole genome sequencing of multiple primary tumors enabled identification and characterization of a novel germline structural variant in PALB2 as the basis for the individual’s susceptibility to breast and ovarian cancer. The variant does not appear to be a founder mutation in Ashkenazim.



General Poster Session (Board #3F), Mon, 1:15 PM-5:00 PM

1554

99s General Poster Session (Board #3G), Mon, 1:15 PM-5:00 PM

Personalized cancer tests and services on the Internet: A website content analysis. Presenting Author: Stacy W. Gray, Dana-Farber Cancer Institute, Boston, MA

Transcriptional regulation and prostate cancer risk loci. Presenting Author: Robert J. Klein, Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY

Background: The Internet may facilitate the use of guideline endorsed “personalized” cancer tests and services by increasing awareness of and access to new technologies; however limited regulation over Internet marketing may also lead to the promotion of tests and services of unproven benefit. Methods: We identified 51 websites that sell personalized cancer medicine (PCM) tests and/or services by searching Google, Bing, and Yahoo (53 search terms per site, 30 results per search term), reviewing the medical literature, and abstracting information from the exhibitor list from a national oncology conference. Two independent coders evaluated website content. Discrepancies were resolved by consensus. Results: Sites most commonly promoted physicians/institutions selling PCM (49%), tumor analysis (47%, e.g., DNA, RNA, or protein analysis) or offered interpretive services (12%, e.g., cloud-based analytical systems to select personalized cancer therapies). Eighty-six percent of sites included information on the benefits of PCM whereas only 24% of the sites included information on the limitations of PCM (McNemar’s chi square ⫽32, p⬍0.001). Forty-three percent of sites included general cost information; of those sites, 23% provided an exact dollar figure and 24% included information on insurance reimbursement. Commercial sites were more likely to include cost information than educational and organizational sites (56% vs. 23%, chi square ⫽ 4.1, p⫽0.04). Cancer-related germline testing was offered by 27% of sites. Websites marketed guideline endorsed tests such as EGFR and KRAS mutation testing as well as tests that are not guideline endorsed such as in vitro and in-vivo (mouse) chemotherapy sensitivity testing, EMSY, ZNF703, and whole-exome sequencing. Conclusions: The clinical utility of “personalized” cancer tests and services marketed and sold over the Internet is highly variable. Patients and physicians need to evaluate PCM Internet sites with caution given the fact that benefit information is more common than limitation information and that unproven technologies are commonly promoted.

Background: While genome-wide association studies (GWAS) have identified numerous loci at which common single nucleotide polymorphisms (SNPs) are clearly associated with the risk of developing prostate cancer, the mechanism by which these variants influence disease is not clear. Based on the observation that regions of the genome with marks of transcriptional regulatory elements harbor SNPs that are more likely to be under negative selective pressure, we hypothesized that many prostate cancer associated SNPs, or their correlated proxies in linkage disequilibrium, function by altering regulation of nearby genes through alteration of transcription factor binding sites. Two predictions of this hypothesis are that there will be an enrichment of prostate cancer risk SNPs or their proxies in regulatory elements in prostate tissue and that some of these SNPs will correlate with the expression levels of nearby genes. Methods: To test the first prediction, we compared the number of prostate cancer risk SNPs (or their proxies) that overlap with DNase hypersensitive sites in the LNCaP prostate cancer cell line with randomly selected SNPs matched for allele frequency, distance from nearby genes, and local gene density. To test the second prediction, we asked if any of the known prostate cancer risk SNPs are associated with mRNA expression levels of nearby genes. Results: We found a four-fold enrichment of real prostate cancer risk SNPs overlapping with DNase hypersensitive sites versus the random set (p⫽0.03) at an r2 threshold of 0.95. In both tumor and benign prostate tissue, we found that a recently identified prostate cancer risk SNP is associated with expression levels of IRX4, a transcription factor previously implicated only in cardiac development. Conclusions: These data support the hypothesis that many GWAS-identified risk SNPs alter transcriptional regulation of nearby genes.

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1556


Characterization of colorectal cancer (CRC) in Lynch syndrome (LS) patients with MSH6 or PMS2 mutations. Presenting Author: Jean Kyung Lee, Memorial Sloan-Kettering Cancer Center, New York, NY Background: The majority of LS patients harbor germline mutations in the MLH1 or MSH2 genes. However, ~10% have MSH6 and ~⬍5% PMS2 mutations. An attenuated form of LS has been suggested in MSH6/PMS2 carriers with decreased CRC risk and older age of disease onset. As recent guidelines suggest that initiation of CRC screening may be delayed in such patients, we characterized our patients with MSH6/PMS2-associated CRC. Methods: We obtained an IRB waiver to identify all LS patients with CRC, defined as the presence of a deleterious germline mutation in a MMR gene, from the Clinical Genetics database at MSKCC. Clinical, pathologic, and genetic features were extracted from medical records and Progeny software. Results: Of 147 LS patients with CRC, 23 had mutations in the MSH6 (n⫽16, 11%) or PMS2 (n⫽7, 5%) genes. Mean age at CRC diagnosis was 48.5 yrs (range 32-70) in MSH6 and 40.7 (range 22-57) in PMS2 carriers. 16 (70%) and 5 (22%) were diagnosed at age ⱕ50 or ⱕ35, respectively. 4 (17%) had metachronous and 3 (13%) synchronous primary CRCs, and 5 (22%) had additional LS-associated cancer. Although all 23 LS patients met Revised Bethesda guidelines, only 50% of MSH6 and 0 of the PMS2 carriers met Amsterdam I/II criteria (AC). Of 32 independent primary CRCs, 18 (56%) were stage I/II, 9 (28%) stage III, and 1 (3%) stage IV. 9/9 MSH6 and 4/4 PMS2 CRCs had high-frequency microsatellite instability. In MSH6 carriers, 11/13 had absence of MSH6protein expression only on IHC, 1 had inconclusive MSH6 staining, and 1 had absence of both MSH6 & MSH2 proteins. In PMS2carriers, 7/7 had absence of PMS2 on IHC, 2 also had equivocal/focal MLH1 staining. Right-sided CRC was present in 50% and at least 40% had mucinous features. 26/29 (90%) of tumors underwent segmental resection. 6/11 stage II patients received adjuvant chemotherapy including 2 with pT4N0 tumors. With a mean follow-up of 5.6 yrs to date, 1 patient is known to have developed recurrent CRC. Conclusions: Although the majority of MSH6/PMS2 CRC patients do not meet AC, 70% of CRCs were diagnosed at age ⱕ50, 22% at age ⱕ35, and 30% had synchronous/metachronous CRCs. These findings have important implications for CRC surveillance and may not support delaying colonoscopy initiation in MSH6/PMS2 LS families.


Differences in outcome between colorectal cancer (CRC) patients (pts) with Lynch syndrome (LS) versus MLH1 hypermethylation (MLH1 HM). Presenting Author: Sigurdis Haraldsdottir, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH Background: In ~15% of CRC tumors mismatch repair deficiency (dMMR) is observed and is usually caused by LS (germline mutations in MLH1, MSH2, MSH6 or PMS2) or sporadic inactivation of MLH1 (hypermethylation [HM] of MLH1 gene promoter). The objective of this study was to retrospectively compare clinical factors and outcomes in pts with dMMR with LS to those without LS. Methods: This cohort includes pts with CRC diagnosed between 5/98 and 5/12 with dMMR on immunohistochemistry (IHC) staining. Prior to 2006 pts came from the Columbus area HNPCC study. After 2006, we included all CRC pts at OSU as universal IHC was initiated. Chi-square was used to compare nominal parameters and log-rank to compare overall survival (OS). Results: A total of 189 pts had dMMR per IHC staining (see characteristics in table). In 36 pts (19.0%) a diagnosis of LS was made after germline testing, in 59 pts (31.2%) a diagnosis of MLH1 HM was made with methylation or BRAF testing, in 65 pts (34.4%) a LS or MLH1 HM diagnosis was assumed based on clinical criteria. Median OS was 159 mos in the LS group and 49 mos in the MLH1MH group (p⫽0.003) and OS was significantly longer in the LS group across all 4 stages (p⫽0.002) (see Table). Conclusions: Pts with LS-associated CRC had longer OS than pts with MLH1 HM-associated CRC, even in the setting of a higher incidence of other cancers (44.1% vs. 28%). This is likely related to younger age in the LS group. The MLH1HM group was older at diagnosis and more often female. There are a number of limitations to our study including the potential for survivorship bias and lack of a definitive diagnosis in ~50% of patients despite using clinical criteria to define these pts. Age (median; Q1,Q3) Sex Male Female Race Caucasian AA Hispanic Stage I II III IV Location Right Left Rectum Synchronous Metachronous Other cancer dx (%)

Lynch (nⴝ60)

MLH1 (nⴝ100)

49 (36,56)

73 (66,80)

36 (60%) 24 (40%)

41 (41%) 59 (59%)

p⫽0.02

53 (88.3%) 6 (10.0%) 1 (1.7%)

82 (89.1%) 9 (9.8%) 1 (1.1%)

p⫽0.95

5 (9.4%) 22 (41.5%) 22 (41.5%) 4 (7.6%)

13 (13.1%) 49 (49.5%) 27 (27.2%) 10 (10.2%)

p⫽0.016

41 (69.5%) 9 (15.3%) 9 (15.3%) 6 (10%) 13 (21.7%) 26 (44.1%)

81 (81.8%) 11 (11.1%) 7 (7.1%) 6 (6.0%) 2 (2.0%) 28 (28.0%)

p⫽0.16

p⫽0.35 p⬍0.01 p⫽0.039


100s 1557


Assessment of cancer screening practices after BRCA testing in Michigan. Presenting Author: Julie Zenger Hain, Oakwood Healthcare System, Dearborn, MI Background: Women who harbor BRCA1/2 mutations are at increased risk for breast and ovarian cancer and are advised to undergo high risk surveillance and/or preventative surgery. The compliance with screening guidelines in these women is not well known. This study aims to evaluate the uptake and screening practices of women with known deleterious BRCA mutations and BRCA true negatives who received genetic counseling in the state of Michigan. Methods: A telephone survey coordinated by the Michigan Department of Community Health was conducted on pts seen at 8 genetics clinics between 10/07 to 10/09. Each center was staffed by board certified genetics professionals who provided pre and post-test genetic counseling. Pts who were found to carry a deleterious BRCA mutation, or to be negative for a known familial mutation, were queried regarding adherence to NCCN guidelines. Results: 138 of 253 (55%) pts responded to the phone survey, with an elapsed time of 1.7 to 4.6 years from post-test counseling session. Among BRCA mutation carriers over age 25 years with no cancer history or mastectomy, 11 of 21 pts (52%) adhered to MRI screening guidelines, 3 pts (14%) reported two MRIs, and 7 (33%) pts had no MRI screening in the preceding year. 18 of 21 pts (86%) reported having a screening mammogram in the preceding year and the remaining 3 had two or more. 8 of 20 (40%) pts had two clinical breast exams. Of the women who had breast cancer and no mastectomy, 5 of 9 (56%) pts did not have MRI screening. Of the BRCA true negatives with no cancer history, CA-125 or transvaginal ultrasound was performed in 7 (19%) and 8 (20%) of 37 pts, respectively. Conclusions: This study reveals sub-optional compliance with screening guidelines in women who were identified to be carriers of BRCA mutations or those who were true negatives, despite pre and post-test genetic counseling and communication of established management guidelines. Some recommended screening measures were underutilized in BRCA mutation carriers, and some were over-utilized in the true negatives. Additional interventions are needed to improve adherence to evidence-based screening guidelines aimed at promoting early detection, with an emphasis on appropriate utilization of limited healthcare resources.

1559


Assessing breast cancer risk in primary care: What can we learn from cardiovascular disease? Presenting Author: Kelly-Anne Phillips, Peter MacCallum Cancer Center, Melbourne, Australia Background: Routine assessment of breast cancer (BC) risk by primary care clinicians (PCCs) might improve uptake of BC prevention and screening interventions, thus reducing morbidity and mortality as has occurred for cardiovascular (CV) disease. Methods: Australian PCCs were recruited through local professional networks. Facilitated focus group discussions about current practice of assessing and managing BC risk were audiotaped, transcribed verbatim and managed using QSR NVivo qualitative data management software. A coding framework was developed based on the transcripts, data were coded and each code further analyzed to identify key themes. Results: 17 PCCs (12 doctors, 5 practice nurses) participated in 2 focus groups. 41% were male, median age 49 years, median number of years in practice was 15. Approaches to assessment and management of BC risk differed markedly from that of CV risk. PCCs see assessment and management of CV risk as an intrinsic, expected part of their role. Practice software prompts trigger CV risk assessment and PCCs often use an online tool (www.knowyournumbers.co.nz) to provide personalized risk estimates and to discuss management options for CV risk. Conversely, assessment of BC risk is not routine or prompted by practice software, is generally patient (not clinician) initiated, and management, beyond routine BC screening (e.g. chemoprevention), is considered outside the PCCs domain. Most PCCs are not familiar with, or using, BC risk assessment tools. PCCs suggested they could potentially routinely assess and manage BC risk. Such an approach would need to be widely endorsed as within the remit of primary care and would be enhanced by an online tool that is accessible, quick, visual (graphs and pictograms), evidence-based and regularly updated. Ideally, its use would be prompted by their practice software. Conclusions: There is a clear opportunity in primary care to enhance the capacity and motivation of clinicians to assess and manage BC risk. A risk assessment and decision aid tool, integrated into primary care software, might facilitate routine appropriate management of BC risk in the Australian primary care setting, modelling what has already been achieved for CV disease.

1558


Increasing dietary rice bran consumption for colorectal cancer prevention and control. Presenting Author: Erica Borresen, College of Veterinary Medicine and Biological Sciences, Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO Background: Emerging evidence supports that dietary rice bran (RB) exhibits colorectal cancer (CRC) control and prevention activity, yet a significant knowledge gap exists for feasibility of increased RB intake in humans. BENEFIT (Bran Enriching Nutritional Eating For Intestinal health Trial), is a community-academic partnership for dietary chemoprevention research. Our main objectives were to pilot the feasibility of increased RB consumption in healthy adults, with and without a history of CRC, and to examine changes in gut microflora and fecal metabolite profiles following RB consumption. Methods: Seven meals and six snacks were developed for inclusion of dietary RB (30g/day). A total of 15 adults (7 non-cancer and 8 CRC survivors) completed the randomized-controlled, dietary intervention trial. Participants were blinded to their study group (placebo-control or RB) and consumed one study meal and snack daily for 28 days. Blood, urine, saliva and stool samples were collected at baseline, 2-week, and 4-week timepoints for metabolomic and microbiome analyses. Participants recorded weekly 3-day dietary food logs. Results: Adding RB (30g) into prepared foods provided 4-8% daily caloric intake with 95.5% intervention compliance. Inclusion of RB or control diet intervention in our non-cancer cohort did not result in a major shift of the fecal microbiome after 2- and 4-weeks. For CRC survivors, we observed that 19% of the total variation in the fecal microbiome was due to the rice bran intervention. At the genus level, we saw changes in Bacteroides, Bifidobacterium, and Ruminococcus. Principal Components Analyses of fecal metabolome detected using liquid-chromatography mass spectrometry revealed 16% variation between time points and 8% variation when comparing RB and control groups at 4 weeks. Candidate metabolites from ~50 features will be determined by spectral libraries and database matches. Conclusions: The accessibility, affordability, and availability of RB support the global public health impact potential for novel RB “phytochemical teamwork” based CRC control and prevention strategies. These findings warrant further evaluation of increased RB intake in a larger cohort for CRC control and prevention.

1560


Plasma adiponectin to predict incident cancer in a large multiethnic population-based cohort study. Presenting Author: Muhammad Shaalan Beg, Division of Hematology/Oncology, The University of Texas Southwestern Medical Center, Dallas, TX Background: Previous retrospective studies have suggested an inverse relationship between cancer and markers of insulin resistance, including adiponectin. Whether circulating levels of adiponectin are associated with future cancer incidence has not been well demonstrated. As such, we examined the association of adiponectin on the risk of future cancer development in a large population based cohort study. Methods: The Dallas Heart Study (DHS) is a multiethnic population based study of 3,531 Dallas County residents with an intentional oversampling of minorities which are underrepresented in other population studies. Incident and prevalent cancer cases were identified in the DHS by the Texas Cancer Registry. Cases were defined as ‘incident’ if they were diagnosed 24 months after enrollment into DHS. Fasting blood samples were obtained from DHS participants between 2000 and 2002, and used for biomarker analysis. Univariate and multivariate analysis was performed to test the association of incident cancer and adiponectin after adjusting for age, diabetes status, gender, ethnicity and body mass index (BMI). Results: Of 3,531 individuals, 150 incident cancer cases were diagnosed. The study population comprised 55.8% females, 51.5% were black and 39.6% had a BMI above 30 kg/m2. Mean adiponectin was 8.12 ␮g/ml in incident cancer group and 7.46 ␮g/ml in non-cancer group (p⫽0.129). In multivariable analysis, adiponectin was not an independent predictor of cancer incidence after adjusting for age, diabetes status, gender, ethnicity and BMI (p⫽0.167) Conclusions: Previous population based studies have demonstrated conflicting results on the association of markers insulin resistance, including adiponectin, and cancer incidence. In this study of a predominant ethnic minority population, an association between adiponectin and cancer incidence was not seen. Further prospective studies are needed to understand the association between markers of insulin resistance and risk of future cancer risk.




Addressing tobacco use and cessation in cancer patients: Practices, perceptions, and barriers reported by oncology providers. Presenting Author: Graham Walter Warren, Medical University of South Carolina, Charleston, SC

1562


Prostate cancer screening: Rise and fall? Presenting Author: François Eisinger, Institut Paoli Calmettes, Marseille, France

Background: Tobacco use is associated with adverse outcomes in cancer patients, but there are limited data on tobacco cessation support by oncology providers. Methods: Duplicate surveys were sent to the membership of the International Association for the Study of Lung Cancer (IASLC) and the American Society of Clinical Oncology (ASCO) asking about tobacco assessment and cessation practices, perceptions of tobacco use by cancer patients, and barriers to implementing tobacco cessation. The results of 1,507 responses from IASLC and 1,197 responses from ASCO are reported. Results: At initial consult, most respondents asked about tobacco use (90% in both surveys), asked if smokers would quit tobacco use (79-80%), advised patients to stop smoking (81-82%). Most respondents felt that tobacco affects cancer outcomes (87-92%) and that tobacco cessation should be a standard part of clinical care (86-90%). However, few discussed medication options (40-44%) or actively provided smoking cessation assistance (39% in both surveys). Fewer respondents asked about tobacco use at follow-up and few reported adequate tobacco cessation training (29-33%). Dominant barriers to providing cessation interventions included patient resistance to cessation treatment (67-74%) and inability to get patients to quit tobacco use (58-72%), but very few believed tobacco cessation was a waste of time (8-12%). Lack of time, reimbursement, lack of training, and lack of resources were reported as barriers in less than 50% of respondents. Conclusions: Oncology providers feel tobacco affects cancer outcomes and cessation should be a standard part of clinical care. Most assess tobacco use, but few discuss medication options or provide active cessation support. Efforts are needed to improve cessation methods in cancer patients and to improve access to tobacco cessation support for cancer patients.

Background: Our previously published data showed a fast increasing rate of prostate cancer screening in men aged 50-74 from 36% in 2005 to 48% in 2008. According to their expressed wish either to continue to be tested annually or to start prostate cancer screening, the rate of testing was expected to rise to 70% in 2011. We report here the actual rate of prostate cancer screening. Methods: Three nationwide observational surveys (EDIFICE opinion polls) were carried out by telephone (2005, 2008, and 2011). The target was a representative sample of more than 1,500 subjects living in France and aged 40-74. Precision of results for the samples was ⫹ 3.2% with a 95% confidence interval (CI). Results: In this survey population (men aged 50-74), the rate of screening reported remained stable between 2008 and 2011 (48% and 49% respectively). However, there were some differences according to age with a decreasing rate for men aged 50 to 59 years: 44% in 2008 vs 37% in 2011 (p⫽0.11) and an increasing rate for men aged 60 to 74 years: 53% in 2008 vs 62% in 2011 (p⫽0.04). Comparing privileged versus underserved populations, significant differences were found with a relative decrease in attendance of those of higher professional status (p⫽0.034) and from higher income groups (p⫽0.015); the difference was not significant for educational attainment (p⫽0.147). For household with a monthly income above 2500 €, the screening rate decreased from 61% in 2008 to 51% in 2011, while for an income below 2500 €, the rate increased from 36% in 2008 to 44% in 2011. Conclusions: A plateau or even reduction in prostate cancer screening is observed, possibly due to a progressive recognition of the controversy on prostate cancer screening by the population, which previously engaged only the experts. After previously being more likely to take up prostate cancer screening, the backlash is mainly observed in the younger, wealthier groups. This “fall”, according to many health agencies should not be seen as a health threat. Health institutions and medical practitioners should, however, be aware of this trend, to avoid general mistrust of cancer screening as a whole.

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Racial differences in perceived risk in participants enrolled in the American College of Radiology (ACRIN-6654) arm of the National Lung Screening Trial (NLST). Presenting Author: Christopher Lathan, Dana-Farber Cancer Institute, Boston, MA

Patients’ reactions to a decision aid about lung cancer screening with low-dose spiral computed tomography: An uncontrolled trial. Presenting Author: Robert J. Volk, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: Blacks in the U.S. have higher incidence and mortality rates of lung cancer (LC) compared to whites. Previous work in small studies suggests that blacks have lower perceived risk of LC which may influence smoking cessation behavior. However, racial disparities in risk perceptions (RP) of LC and smoking related diseases (SRD) in heavy smokers have not been studied. We examined LC and SRD risk perceptions among black and white ACRIN NLST participants. Methods: The 10-item Smoking Risk Perceptions Scale (SRPS) for LC and SRD was administered to NLST participants, from 4 ACRIN sites, with a minimum 30 pack-year smoking history at 1 year following baseline screening chest x-ray or low dose computerized tomography (LDCT). We 1) validated the SRPS in black and white participants separately using exploratory and confirmatory factor analyses, 2) used 2-way ANOVAs to compare RP of black and white participants and 3) used multivariable linear regression models to identify factors associated with RP. Results: Among 1742 white and 194 black participants, the 10 SRPS items loaded onto two factors (absolute and relative risk; Cronbach’s alpha⫽0.92 and 0.95 for white and black participants, respectively). Black participants had significantly lower RP compared to white participants (SRPS range⫽ 10-50, mean diff. 3.48, 95% CI 2.29-4.68, p⬍0.01). Factors significantly associated with lower RP in a multivariate linear regression were black race (␤⫽4.59, p ⬍ 0.001), former smoking status (␤⫽3.82, p⬍0.001), male gender (␤⫽1.35, p⬍0.001), lower education (␤⫽1.16, p ⫽0.010), and older age (years, ␤ ⫽ 0.15, p⬍0.001). Conclusions: We validated the SRPS in black and white ACRIN-6654/NLST participants. Blacks had significantly lower perceptions of LC and SRD risk compared to whites, even after adjusting for study arm, sociodemographics, and smoking status. Sociodemographic factors and smoking status were independently associated with lower RP. These findings confirm that black current and former smokers are at risk of underestimating their smoking-related risk, which may contribute to lower rates of adherence to screening and smoking cessation recommendations.

Background: Results from the National Lung Screening Trial (NLST) and a recent ASCO-supported systematic review concluded that screening with low-dose spiral computed tomography (LDCT) reduces lung cancer deaths among selected heavy smokers. Yet, this mortality benefit must be weighed against the potential harms of screening (e.g., high false positive rate). In anticipation of LDCT screening becoming a reimbursable preventive health service, we developed and evaluated a brief, video-based patient decision aid designed for use in clinical settings. Methods: Patients from a tobacco treatment program who were 45 to 75 years of age and had no history of lung cancer participated in the study. Measures of acceptability and ratings of the aid were included. We assessed effectiveness of the aid via knowledge about lung cancer and the benefits and risks of screening, and clarity of values using the Decisional Conflict Scale. Results: Fifty-two patients completed the study (mean age⫽58.5 years; mean average years smoking⫽34.8 years). Over 94% of patients watched the entire video, would recommend it to others, felt it held their interest, rated the content favorably, and wanted to view similar video-based aids. Acceptability was high, although 23.3% wanted more information about the NLST findings and evidence base. After viewing the aid, knowledge about lung cancer screening increased significantly (before viewing aid, 25.5% of questions answered correctly; after viewing aid, 74.8%; P⬍.01). The majority of patients continued to have difficulty with the question about whether all current and former smokers should be screened for lung cancer (23.1% answered correctly). Patients reported being clear about which benefits and harms of screening mattered most to them (94.1% and 86.5% were clear, respectively). Conclusions: Our decision aid was rated favorably by tobacco treatment patients. Large gains in knowledge about lung cancer screening were observed, highlighting the important informational function of the aid. Additional features under consideration for the aid include screening eligibility assessment and information about the evidence behind the screening recommendations.


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Clinical experience with exemestane in postmenopausal women at increased risk of breast cancer. Presenting Author: Mia Sorkin, Yale University School of Public Health, New Haven, CT Background: Exemestane has recently been identified as an effective breast cancer chemoprevention agent. This drug may be more appealing to patients than tamoxifen or raloxifene, since it does not increase the risks of thrombosis, cataracts and uterine cancer. Poor patient acceptance of tamoxifen and raloxifene as chemoprevention is well-documented but patient acceptance rates for exemestane have not been reported. The goal of this study was to assess exemestane use in a breast cancer prevention clinic. Methods: A retrospective chart review was conducted to capture patient characteristics, medical history and chemoprevention uptake of all postmenopausal women presenting to the Yale Breast Cancer Prevention Clinic from November 2011-November 2012. Descriptive statistics are presented. Results: Fifty-six postmenopausal women deemed eligible for initiation of chemoprevention were seen during the study timeframe, with a mean age of 58 (range 42-79). Risk categories included: 22 women (39%) diagnosed with breast atypia, 7 with LCIS (12%), 4 with prior DCIS (7%), 41 with family history of breast cancer (73%), and 8 women with a deleterious BRCA 1 or 2 mutation (14%). 22 (39%) of these women had osteopenia or osteoporosis. Of all eligible women, 13 opted to start a chemoprevention medication (23%); 8 of whom opted for raloxifene, 1 for tamoxifen and 4 for exemestane. While exemestane comprised 30.7% (4/13) of chemoprevention medication uptake, only 4 of 56 women eligible for chemoprevention decided to take exemestane (7%). Conclusions: Chemoprevention uptake rates of postmenopausal women in the setting of a breast cancer prevention clinic are higher (23%) than those reported in the general population, but remain low overall. Uptake of exemestane appears lower than that of raloxifene but higher than tamoxifen. A large proportion of postmenopausal women (39%) have osteopenia or osteoporosis which limits exemestane uptake in a breast cancer prevention setting.

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Increasing access to tobacco cessation support for cancer patients: Results of an institution-wide screening and referral program in an NCI-designated comprehensive cancer center. Presenting Author: Mary E. Reid, Roswell Park Cancer Institute, Buffalo, NY Background: Guidelines from ASCO and other national organizations recommend assessment of tobacco use and structured tobacco cessation support for cancer patients. However, most oncology providers fail to provide cessation assistance to cancer patients who use tobacco. Reported are results of a systematic approach to assessing tobacco use and delivering cessation support for cancer patients in a comprehensive cancer center. Methods: A standard set of evidence based tobacco assessment questions were incorporated into an automated electronic medical record based system delivered by nursing at initial consult and follow-up. Patients eligible for tobacco cessation support (i.e. patients self-reporting tobacco use within 30 days) were automatically referred to a dedicated tobacco cessation service providing primarily phone based cessation support. Results: Of approximately 11,900 patients screened over 26 months, 2,978 patients were automatically triaged for cessation support. Contact priority was given to newly diagnosed patients in tobacco related disease sites. Using 1.25 full time cessation specialists, 1,531 received only a standard tobacco cessation mailing and no further contacts were attempted by the cessation service. In 1447 patients with attempted phone contact by the cessation service, 1189 (82.2%) were reached within 5 contact attempts. In 1,189 patients contacted, 52 (4.4%) were inappropriate referrals, 245 (20.6%) were in an active quitting phase, 465 (39.1%) were willing to prepare, and only 24 (2.0%) refused any intervention at initial contact. At the most recent follow-up, 44 patients (3.7%) requested no further contact and 90 additional patients (7.6%) were lost to follow-up. In the 1,045 remaining patients, 338 (32.3%) reported quitting tobacco use. Notably, in the 1,531 patients with no phone contact by the cessation service, only 14 proactively contacted the cessation service for assistance. Conclusions: An institution wide program to automate the delivery of tobacco cessation services was feasible with high patient contact rates, low patient refusal, and moderately high tobacco cessation rates.

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Occurrence of familial malignant tumors in the first-degree relatives of patients with differentiated (non-medullar) thyroid carcinoma. Presenting Author: Rodica Mindruta-Stratan, PMSI Institute of Oncology, Chisinau, Moldova

The effectiveness of ovarian cancer screening in high-risk population and BRCA 1/2 carriers: A systematic review and meta-analysis. Presenting Author: David Fawunmi, Department of Internal Medicine, Mälarsjukhuset, Eskilstuna, Sweden

Background: Family aggregation of thyroid cancer and aggregation of a number of ⬙associated⬙ malignant tumors in one family indicates a possible significant genetic predisposition and an increased risk for developing cancer in blood relatives of these families. Methods: Distribution of malignant tumors in first degree relatives of 1135 patients surgically treated for thyroid tumors during 3 years period was studied. These families don’t refer to hereditary syndromes. Patients were distributed in 3 groups: I group - 453 patients with thyroid carcinoma, II group - thyroid carcinoma on adenoma background (222) and III group - thyroid gland adenoma (460 probands). Results: In the I-st group from 2868 first degree relatives 870(64, 5⫾1.6%) was affected by cancer. From these: 49(3.9⫾2.8%) had thyroid cancer (TC), 39(3.1⫾2.8%) - gastric cancer (GC), 36(2.8⫾2.7%) - colorectal cancer (CRC), 26(2.05⫾2, 8%) - breast cancer (BC) and 20(1.6⫾2.8%) - endometrial cancer (EC). Thyroid adenoma was seen in 86(6, 6%) cases. Incidence of the TC was 23, GC- 11, CRC-5, and BC- 4, EC 12 times higher, respectively in compare with general population. From 1414 relatives (II group) 445(66, 1⫾2.2%) first degree relatives were affected by cancer. From these: 27(4.3⫾3.9%) - TC, 22(3.5⫾4.0%) - GC, 21(3.3⫾3.9%) - CRC, 14(2.2⫾4.1%) – BC and 5(0.8%) - EC. Thyroid adenoma was seen in 45(6.9⫾3.7%) cases. In III group - from 2945 investigated first degree relatives 924(66.6⫾1.5%) relatives were affected by cancer. From these: 44(3.4⫾2.7%) - TC, 37(2, 8⫾2.7%) - GC, 27(2.1⫾2.8%) - CRC, 34(2.6⫾2.7%) – BC and 19(1.5⫾2.8%) - EC. Thyroid adenoma represented 116(8, 6⫾2.6%) cases. Differences between groups are not statistically significant (p ⬍0,05). Conclusions: The results obtained by clinical and genetic research of non-medullar thyroid cancer patients and their first degree relatives are an important reason to direct the monitoring of these families for the risk assessment of hereditary predisposition to cancer, genetic testing, dynamic monitoring and performing of preventive interventions.

Background: The purpose of this study is to assess the effectiveness of different screening modalities in detecting ovarian cancer in high-risk women and BRCA 1/2 carriers. Methods: We searched through MEDLINE and ISI Web of Science, with no language or year restriction, to identify studies that used various screening modalities (Ca125, transvaginal ultrasound (TVUS) or combination) to detect ovarian cancer in high-risk women and BRCA 1/2 carriers. We summarized the sensitivity, specificity, and likelihood ratios of each screening modality. Results: Seven studies including BRCA 1/2 carriers and 12 studies including high-risk women were eligible for analysis. The pooled sensitivity of combined Ca125 and TVUS for BRCA 1/2 carriers was 47.6% (95% Confidence Interval (CI): 36.6%-58.8%). The pooled sensitivity of combined screening modality for high-risk population was 54% (95% CI: 43%-64-8%). The summary negative likelihood ratio for BRCA 1/2 carriers was 0.6 (95% CI: 0.48 – 0.75). In high-risk population (N ⫽ 12398) the rate of advanced stage incident screen-detected cancer was 56% (9 of 16 cancer) which is comparable to the rate of advanced stage in prevalent screening-detected cancer (18 of 32, 56%). In BRCA 1/2 carriers (N ⫽ 2356) no difference in stage distribution between incident screen-detected and interval cancer was found (26 of 31 cancer (84%) versus 24 of 27 (89%)). Conclusions: Despite annual combined screening with TVUS and Ca125, a high proportion of ovarian cancer in both BRCA 1/2 carriers and high-risk women are diagnosed in advanced stage. In addition, all screening modalities have an unacceptably low sensitivity. Therefore, it is unlikely that these screening modalities will reduce mortality from ovarian cancer. Further studies are needed to evaluate if more frequently screening more frequently than annually would offer a better chance of early-stage detection.




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Clinical factors affecting HE4 and CA125 in women at high risk of developing ovarian cancer. Presenting Author: Archana Raamanathan, The University of Texas MD Anderson Cancer Center, Houston, TX

Effect of smoking on survival from non-small cell lung cancer. Presenting Author: Vijaya Raj Bhatt, University Of Nebraska Medical Center, Omaha, NE

Background: CA125 is often used to screen high-risk patients (pts) for ovarian cancer (OC), but levels are affected by many factors, especially in premenopausal pts. In prior studies of low-risk pts, HE4 is more stable than CA125. The objective of this study was to determine how clinical variables affect CA125 and HE4 in pts at high risk for ovarian cancer. Methods: Serum from 373 pts at high risk of OC was collected every 3-12 mo from 2006-2012, for a total of 1081 samples. Serum CA125 and HE4 were measured in duplicate utilizing a commercially available multiplexed sandwich immunoassay (MagPlex). Multilevel regression models were used to examine the associations of clinical factors with CA125 and HE4, while considering the inter-correlated nature of outcomes measured periodically from the same subject. Results: The mean age was 44.6 years, 51.2% were premenopausal, 72.7% were white, 9.1% were Ashkenazi Jewish, 65.2% had a history of breast cancer, and 81.5% had a BRCA mutation. Log transformed CA125 was found to be 0.32 units higher in premenopausal pts compared to postmenopausal pts (p⫽0.0023), and 0.27 units higher in pts with active breast cancer (BC) compared to pts with no active BC (p⫽0.0044). In premenopausal pts, CA125 varied throughout the menstrual cycle, with highest levels noted at menstruation (p⬍0.0001). Age, smoking status, and hormone use did not affect CA125 levels. Interestingly, there was no significant association between HE4 levels and any of the evaluated variables, including age, menopausal status, active BC, smoking status, hormone use, or point in menstrual cycle (all p⬎0.05). Conclusions: In women at high-risk for OC, HE4 levels fluctuate less with the menstrual cycle and are less likely to be elevated in BC than CA125. This finding is important as many high-risk pts that undergo screening are pre-menopausal and have a BC history. HE4 may provide a valuable addition to the current screening regimen of high-risk pts.

Background: Although a well-established risk factor for lung cancer, the impact of smoking on the survival of non-small cell lung cancer (NSCLC) is not well-known. This study evaluated the effects of tobacco exposure on outcomes from NSCLC. Methods: We performed a retrospective analysis of Veteran’s Affairs Comprehensive Cancer Registry of NSCLC patients diagnosed between 1995 and 2009. Data abstracted included age, gender, family history, stage at diagnosis, histology, tumor grade, smoking history, other exposures, treatment received and overall survival (OS). Smoking status was categorized as never-smoker, past-smoker and current-smoker based on the self-reported history at diagnosis. Multivariate analysis was performed using SAS version 10.2. Results: The study population (n⫽61,440) comprised predominantly of males (98%), of which Caucasians (81%) formed the majority. The median age at diagnosis within this cohort was 68 years (range: 22-108 years) and median follow-up was 6 months (range: ⬍1 – 161 months). Squamous cell carcinoma (35%) and adenocarcinoma (30%) were the most common histologies. The majority (71%) presented with stage III or IV disease. Positive family history was identified in one-third. Current smokers were diagnosed with NSCLC at a younger age (65 yrs) compared to never-smokers (71 yrs) and past-smokers (72 yrs) (p⬍0.001). After adjusting for age at diagnosis, grade, histology, family history and treatment, current-smokers (n⫽34613) [Hazard ratio (HR) 1.059; 95% CI, 1.012-1.108], but not past-smokers (n⫽23864) (HR 1.008; 95% CI, 0.962-1.056), had worse OS for Stage III and IV NSCLC, compared to never-smokers (n⫽2963). Smoking status was not prognostic in stage I and II NSCLC. Conclusions: Current smokers were 6 years younger than never-smokers at diagnosis of NSCLC. Although current smoking was associated with worse prognosis, especially in stages III and IV, the impact of smoking status on OS was modest, at least in males. Therefore, primary prevention of smoking cessation is more likely to be meaningful than efforts on smoking cessation after the diagnosis of NSCLC.

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Risk-adapted screening in bladder cancer with the open-access tool RiskCheck Bladder Cancer: Proof of principle by the health service research foundation IQUO. Presenting Author: Goetz Geiges, Interessenverband zur Qualitätssicherung der Arbeit niedergelassener Uro-Onkologen in Deutschland e.V., Schöneiche, Germany Background: The open-access questionnaire RiskCheck Bladder Cancer (RCBC) was proven in daily routine work from German urologists organized in the health services research foundation IQUO on asymptomatic patients to identify BC risk exposure and its relation to detectable tumors. Methods: The open-access RCBC questionnaire checked asymptomatic patients for their BC risk exposure in relation to personal-, smoking-, occupation- and medical induced risk. This resulted in a risk stratification with lowintermediate- and high risk. The intermediate and high risk subjects were checked for tumor presence by routine diagnostics. IBM-SPSS 20 was used for descriptive statistics and effectiveness was proven by classification tree analysis and cross-table analysis with Chi-square test. Results: Out of 303 checked asymptomatic persons 274 (90.4%) were negative for tumor and 29 (9.6%) had a detectable tumor. In the group of NED 176 (68.1%) persons were classified as low risk, and 98 (16.2%) with tumor risk. Out of the 29 detected tumors 20 were at intermediate or high risk (68.9%). This resulted in an over all detection rate of 6.6% and focused on the risk population of 16.9%. The RCBC risk assessment was significant (p ⬍ 0.01). Sensitivity 69.0%, specificity 64.2%, NPV 95.1%, PPV 16.9%, false positive cases 35.8%, false negative cases 31.0%, accuracy 64.7%. Compared to the common incidence (35/100,000) this is an increase in effectiveness of 188.6 in the screened population and 482.8 in relation to the risk population alone. Conclusions: Preventive medical care becomes effective because RCBC is able to condense a population with focusing investigations on people living under risk. A reasonable preventive care by a yearly recall control in urological offices for the risk population (32.3%) can be organized. In consequence the assessment is work effective, aim achieving and in result cost effective. The questionnaire RCBC integrates evidence based bladder cancer inductors, is easy in use and as a open-access tool available in 10 languages via internet to all medical services. www.riskcheck-bladder-cancer.info.


Adiposity post prophylactic oophorectomy in young women at high risk for breast and ovarian cancer. Presenting Author: Kala Visvanathan, Johns Hopkins Bloomberg School of Public Health and Johns Hopkins Sidney Kimmel Comprehensive Cancer, Baltimore, MD Background: Bilateral prophylactic salpingo-oophorectomy (BPSO) is the current standard of care for BRCA1/2 mutation carriers and women with a strong family history of ovarian cancer. We have previously demonstrated an association between early oophorectomy, adiposity and mortality in the general population. Methods: A cross sectional study was conducted between November 2009 and January 2013 in 87 women with a family history of breast and ovarian cancer and/or BRCA1/2 mutation to identify the effect of early BPSO on multiple health outcomes. Twenty-two women who underwent BPSO within 1 to 5 years of enrollment while premenopausal and not on hormone therapy were compared to 44 premenopausal women with intact ovaries and the same age distribution and 21 postmenopausal women with intact ovaries and not on hormone therapy. Multiple anthropometric measures were taken and % body fat assessed by DEXA scan. Linear regression was used to estimate differences in these measures between the three groups. Results: The mean ages were 47, 47, and 54 years in the BPSO, premenopausal and postmenopausal groups respectively. Parity, alcohol intake, smoking and race did not significantly differ between groups. Fewer BPSO women had ever used oral contraceptives (OCP) compared to the premenopausal group (p ⫽0.05). The BPSO group had lower mean physical activity (p ⫽ 0.05) compared to the two other groups. BMI was increased in the BPSO group but was not statistically different across groups. However, mean waist and abdominal circumference and trunk % body fat were significantly higher among women who underwent BPSO compared to both groups. In multivariate analyses adjusting for age, physical activity, and OCP use, the average waist circumference was 7.92 cm (95% CI 1.46, 14.37) higher and 8.98 cm (95% CI 0.40, 17.46) higher in the BPSO group compared to the postmenopausal and premenopausal groups, respectively. A similar pattern was seen for abdominal circumference. Association with % body fat were not statistically significant. Conclusions: This pilot study suggests that increased central adiposity, is a sequelae of BPSO in young women. Longitudinal studies are needed to confirm results and evaluate the efficacy of interventions.


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The impact of family information services on genetic testing uptake among relatives in Lynch syndrome families. Presenting Author: Henry T. Lynch, Creighton University, Omaha, NE Background: A mismatch repair (MMR) pathogenic mutation in an index patient provides a basis for predictive mutation testing in at-risk members of Lynch syndrome (LS) families. Mutation carriers warrant aggressive surveillance. As importantly, non-carriers can safely follow general population screening guidelines. However, penetration of predictive testing has been disappointing in first-degree relatives (FDR), and has been even more limited in second- and more distant-degree relatives, even though the benefits can be as great as in FDRs. Family Information Services (FISs), involve an in-person session in which expert providers and counselors meet with multiple family members in a convenient geographical location. Education and counseling are intended to lead to testing for the family MMR mutation, followed by appropriate surveillance. Methods: LS families with a known MMR mutation (n⫽97) were targeted for this study. Selection for FIS was based on family size and convenient geographic location. Twenty-eight were offered an FIS and 69 received standard care (mailed educational material and invitation for testing). Data were collected on testing rates. Results: In at-risk patients that did receive FIS, 20.4% (std dev ⫽ 11.4%, 95% CI: 16.0 to 24.8%, range: 3 to 57.5%) were DNA tested, whereas in families that did not receive FIS, 12.9% (std dev ⫽ 10.8%, 95% CI: 10.2 to 15.5%, range: 0 to 43.5%) were DNA tested. The difference in proportions tested between the FIS and non-FIS families was statistically significant (p⫽0.003) and was more pronounced in family members whose relationship to the proband was beyond first-degree (p⬍0.0001). Of those individuals that attended an FIS, 81.1% were tested. Conclusions: Genetic counseling in the FIS setting facilitates uptake of predictive mutational testing in FDRs and in more distant at-risk relatives. However, the FIS is time-consuming and labor intensive; more efficient means of disseminating LS risk information and the benefits of predictive testing in more distant relatives are needed. A cost-effectiveness analysis as well as a randomized study that controls for participation bias must be done.

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Public awareness of the HPV vaccine: A national population-based study. Presenting Author: Abigail Shrader, Yale School of Medicine, New Haven, CT Background: Human papilloma virus (HPV) is associated with a number of malignancies. While national guidelines exist for the use of HPV vaccines in men and women up to the age of 26, data are lacking regarding public awareness of these vaccines. Methods: The National Health Interview Survey is conducted annually by the CDC, and is designed to be representative of the US population. Questions regarding the HPV vaccine were fielded in 2010, and formed the basis of this analysis. Results: 9120 men and 10946 women between the ages of 18 and 64 were surveyed. More women than men had heard about the HPV vaccine (68.1% vs. 34.0%, p⬍0.001), and young people (aged 18-26) were more likely to have heard about the vaccine than their older counterparts (54.3% vs. 50.5%, p⫽0.002). Factors associated with awareness of HPV vaccines amongst the younger cohort (eligible for the vaccine) are shown below. On multivariate analysis, race, insurance, and education were significant predictors of HPV vaccine awareness. Conclusions: While over half of young people aged 18-26 are aware of the HPV vaccine, racial/ethnic minorities, along with less educated and uninsured populations lag behind their majority counterparts in their awareness of the HPV vaccine. These data should be useful in directing public health educational programs. Univariate Analysis Factor Race Hispanic White Black Asian Other Insurance Not covered Medicare Medicaid Military Private Region Northeast Midwest South West Education < Grade 12 High school/GED Associates degree Bachelors Masters Professional/doctorate Family income $0- $34,999 $35,000- $74,999 $75,000- $99,999 $100,000ⴙ

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Multivariate Analysis

Proportion (%)

P-value

OR (95% CI)

P-value

32.5 57.8 46.1 36.0 41.7 37.6 36.2 43.3 51.4 57.8 49.7 55.2 51.6 48.2 28.2 40.0 58.6 61.0 66.9 72.2 41.9 50.5 56.0 62.7

⬍0.001

0.45 (0.35 - 0.57) 1.0 0.65 (0.49 - 0.87) 0.33 (0.21 - 0.52) 0.44 (0.17 - 1.13) 1.0 0.87 (0.26 - 2.89) 1.64 (1.21 - 2.12) 1.78 (0.95 - 3.34) 1.77 (1.39 - 2.26) 0.90 (0.62 - 1.29) 1.11 (0.78 - 1.58) 1.05 (0.78 - 1.42) 1.0 1.0 1.30 (0.97 - 1.75) 2.60 (1.95 - 3.45) 3.41 (2.30 - 5.05) 2.38 (1.02 - 5.56) 6.63 (1.36 - 32.25) 1.0 1.04 (0.83 -1.31) 1.05 (0.70 - 1.59) 1.02 (0.70 - 1.49)

⬍0.001

⬍0.001

⬍0.001

⬍0.001

⬍0.001

⬍0.001

0.637

⬍0.001

0.985


Insulin analogues to stimulate cell growth in human cancer initiating cells (CICs). Presenting Author: Esther Holgado, Centro Integral Oncológico Clara Campal, Madrid, Spain

HIV-associated high-risk HPV infection in Nigerian women. Presenting Author: Sally Nneoma Akarolo-Anthony, Harvard School of Public Health, Boston, MA

Background: Conflicting epidemiologic studies have suggested insulin and their analogues currently used in the management of type 2 diabetes to be involved in tumor progression and development. Surprisingly, time of exposure to insulin analogs reported in those retrospective studies is too short for be a carcinogen. We hypothesized that differential affinity that insulin analogs display for insulin receptor and IGF-1R at CICs may account for this possibility. [AspB10]insulin (X10) is a long-acting insulin analog that displays greater affinity for IGF1R than either the long-acting insulin analog GLA or human insulin (HI) in vitro. X10 is tumorigenic in animal models whereas GLA is not. GLA is rapidly metabolized to the metabolites, M1 and M2 that exhibit metabolic and mitogenic profiles similar to that of HI in vitro. CICs are cancer cells with self-renewing, stem cell-like properties with the ability to proliferate and differentiate into specific cells found in tumor types and thus they are able to maintain tumor bulk. Many cancers are thought to be initiated by CICs, and there is evidence that they cause cancer recurrence, metastatic progression and resistance to therapies. Our aim was to compare the mitogenic activity of HI, GLA, X10, M1 and M2 on human CICs in vitro. Methods: CICs derived from 10 human cell lines including glioma, lung, breast, colon, and prostatic cancers were isolated and grown in defined growth medium (no serum) with either HI, GLA, X10, M1 or M2. Growth was estimated using the MTS colorimetric assay. Results: HI, GLA and X10 stimulated CIC growth to a similar extend, whereas M1 and M2 had growth promoting activity similar to medium without HI. Similar results were obtained when measuring diametric sphere growth. Additionally, AKT phosphorylation levels were increased 2-fold after stimulation with HI, GLA or X10, whereas stimulation with M1 or M2 did not produce a significant increase. Conclusions: This is the first study that has explored the biology of CICs treated with insulin analogs. The data show that GLA displays a mitogenic profile comparable to that of human insulin for all CIC lines tested, whereas M1, has even less growth promoting activity.

Background: The incidence of cervical cancer has remained stable in HIV⫹ women but the prevalence and multiplicity of high risk HPV (hrHPV) infection, a necessary cause of cervical cancer, appears different comparing HIV⫹ to HIV- women. Because this has not been well studied in Africa, we conducted this study to identify single and multiple hrHPV infection among HIV⫹ and HIV- women in Nigeria. Methods: We enrolled HIV⫹ and HIV- women presenting at our cervical cancer screening program in Abuja, Nigeria between April 2012 and August 2012. Using a nurse administered questionnaire, we collected information on demographic characteristics, risk factors of HPV infection and cervical exfoliated cells samples from all participants. We used Roche Linear Array HPV Genotyping Test to characterize the prevalent HPV according to manufacturer’s instruction and logistic regression models to estimate the association between HIV infection and the risk of high-risk HPV infection. Results: There were 278 participants, 40% (111) of whom were HIV negative, 54% (151) HIV positive and 6% (16) with HIV status unknown. Of these, 108 HIV⫹ women cases and 149 HIV- women controls were available for analysis. The mean ages (⫾SD) were 37.6 (⫾7.7) for HIV⫹ and 36.6 (⫾7.9) years for HIVwomen (p-value ⫽ 0.34). Cases and controls had similar sociodemographic characteristics. Among HIV⫹ women, HPV35 (8.7%) and HPV56 (7.4%) were the most prevalent hrHPV, while HPV52 and HPV68 (2.8%, each) were the most prevalent among HIV- women. The age adjusted RR for prevalent hrHPV was 4.18 (95% CI 2.05 – 8.49, p-value ⬍0.0001), comparing HIV⫹ to HIV- women. The multivariate RR for any HPV and multiple hrHPV was 3.75 (95% CI 2.08 – 6.73, p-value 0.01) and 6.6 (95% CI 1.49 – 29.64, p-value 0.01) respectively, comparing HIV⫹ to HIV- women, adjusted for age, and educational level. Conclusions: HIV infection was associated with increased risk of any HPV, hrHPV and multiple HPV infections. Oncogenic HPV types 35, 52, 56 and 68 may be more important risk factors for cervical pre-cancer and cancer among women in Africa. Polyvalent hrHPV vaccines meant for African populations should protect against HPV types other than 16 and 18.




Survival rates in patients with primary metastatic breast cancer over a 10-year period: A retrospective analysis based on individual patient data from a multicenter data bank. Presenting Author: Jana Barinoff, Department of Gynecology and Gynecologic Oncology, Klinken-Essen-Mitte, Essen, Germany Background: Approximately 6% of patients with breast cancer have distant metastases at the time of the initial diagnosis. The aim of this analysis was to examine the overall survival rate over time and to investigate the effect of new therapy options. Methods: This retrospective analysis was performed based on the data bank of the Clinic for Gynaecological Oncology/ Dr. Horst Schmidt Klinik, Wiesbaden and the Clinic for Gynaecological Oncology and Senology/ Kliniken Essen Mitte, Essen. The patients with primary metastatic breast cancer (pmBC) who were diagnosed and treated at the accredited breast cancer centres of these clinics were enrolled between 1998 and 2007. The date of diagnosis was used to define 2 specifically chosen 5-year periods: 1998 –2002 and 2003–2007. The follow-up time was on average 76 months. The Breslow Test was used to evaluate changes in the median survival time and to detect factors associated with the increase in survival rates. Results: Two hundred sixteen patients with complete baselines were analysed. Ninety patients were diagnosed between 1998 and 2002, and 126 patients received their diagnosis of pmBC between 2003 and 2007. The tumour-biological factors were the same in both groups, whereas the therapeutic concepts were different—the later group (2003–2007) received more aromatase inhibitors, taxane-based chemotherapy and trastuzumab. This finding resulted in an increased median survival time from 31 months in the years 1998 –2002 to 44 months in the group with the first diagnosis between 2003 and 2007. Conclusions: Primary metastatic breast cancer occurred at constant rates over last 10 years. The tumour findings did not change in the time between the two examined groups; however, the treatment options in the 2003– 2007 group included newly approved therapies. The time period of the first diagnosis was detected as a risk factor for overall survival. Those patients diagnosed in the more recent time frame had a significantly improved survival rate. The establishment of new therapy options may explain this finding.

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Individual insulin use and the risk of breast cancer: An international clinical epidemiology study. Presenting Author: Lamiae Grimaldi-Bensouda, LA-SER, CNAM, and Pharmacoepidemiology and Infectious Diseases Research Group, Pasteur Institute, Paris, France Background: The association between individual insulin use and cancer risk has been previously considered with studies reporting higher breast cancer incidence for insulin glargine. Objective: To assess the relative risk of breast cancer associated with individual insulin use (glargine, human insulin, insulin analogs aspart and lispro). Methods: Systematic casecontrol study of incident breast cancer occurring in women with diabetes from across the United Kingdom, Canada and France. Participants and Settings: 775 case-patients with diabetes and primary invasive or in situ carcinoma of the breast (diagnosed between 1 January, 2008 and 30 June, 2009) selected from 39,958 incident breast cancer patients from 92 large oncology clinics; and 3,050 control-patients with diabetes selected from 580 general practices and matched on country, age, date, type of diabetes (1 or 2), and management by diabetologist or general practitioner. Data on exposure: Data was collected from physicians and patients. Statistical analysis: The main risk model was a multivariable conditional logistic regression including individual insulin use, 8 years preceding the index date, and controlling for past use of any insulin, oral antidiabetic drug use, reproductive factors, lifestyle, education, hormone replacement therapies and contraceptive use, body mass index, comorbidities, diabetes duration, and annual number of physician visits. Results: Adjusted odds ratios of breast cancer were: 1.04 [95% Confidence Interval: 0.76-1.44] for glargine; 1.23 [0.79-1.92] for lispro; 0.95 [0.64-1.40] for aspart; 0.81 [0.55-1.20] for human insulin. Similar results were observed in new insulin users. No effect of dose or duration of use was observed for glargine on the risk of breast cancer. Conclusions: This first international casecontrolled study found no difference in the risk of developing breast cancer among patients according to individual insulin use.

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The impact of body mass index on survival in stage 3 and 4 lung cancer. Presenting Author: Kit Man Wong, University of Toronto, Toronto, ON, Canada

Abnormal bone marrow signal on MRI heralding oncologic diagnoses: A single institution review. Presenting Author: Gunjan L. Shah, Tufts Medical Center, Boston, MA

Background: Obesity is an adverse prognostic factor in several cancers, including colorectal, breast, endometrial and prostate. Studies on body mass index (BMI) and lung cancer outcomes are lacking. Understanding the clinical impact of body weight is important given the high prevalence of obesity globally. We retrospectively evaluated the BMI at diagnosis and its effects on survival in stage 3/4 lung cancer patients. Methods: 1,121 patients with stage 3/4 lung cancer were analyzed. Clinicopathologic data were collected retrospectively. Adjusted hazard ratios (aHR) for overall survival (OS) were generated by Cox regression for each BMI (kg/m2) category (underweight: ⬍18.5, normal: 18.5-24.9, overweight: 25.029.9, obese: ⱖ30), after adjusting for age, gender, Charlson Comorbidity Index, performance status (PS), clinical stage and treatment regimen. Results: In this cohort (n⫽1,121), the frequencies of stage 3A, 3B and 4 lung cancers were 35%, 32% and 33%, respectively. There were 633 (57%) adenocarcinomas, 238 (21%) squamous cell carcinomas, 38 (3%) small cell lung cancers, and 210 (19%) other histologies. Patients had variable BMI: 82 (7%) underweight, 550 (49%) normal weight, 333 (30%) overweight, 156 (14%) obese. Being overweight/obese was associated with older age (p⫽0.002) and stage 3A disease (p⫽0.001); underweight patients were more likely current smokers (p⬍0.001). OS was significantly decreased with age ⱖ65, males, PS 2-3, stage 4, and lack of systemic therapy (p⬍0.001). Median OS in underweight, normal weight, overweight and obese patients were 14, 23, 24 and 26 months, respectively. Compared with BMIⱖ18.5, being underweight was associated with poorer OS (aHR 1.33, 95% CI 1.01-1.77, p⫽0.045), but not progression-free survival (aHR 1.12, 95% CI 0.86-1.46, p⫽0.414). The magnitude of this association was greatest in those aged ⬍65 (aHR 1.57, 95% CI 1.11-2.22, p⫽0.011). Conclusions: Underweight patients with stage 3/4 lung cancer, especially if aged ⬍65, have significantly poorer OS. Lower BMI was mostly observed in current smokers, while above normal BMI was seen in stage 3A. Unlike other cancers, obesity does not increase mortality in this population. The inverse BMI-survival relationship in lung cancer requires further study.

Background: The increased use of magnetic resonance imaging (MRI) has resulted in increased numbers of incidental findings. Oncologists often receive consults for workup of ⬙abnormal marrow signal.⬙ As there is no standard evaluation for such findings and the yield of additional evaluation is unclear, we performed a retrospective study of patients evaluated with MRI at Tufts Medical Center (TMC). Methods: With IRB approval, TMC radiology reports were searched from 5/9/05-12/31/08 with GE Centricity Radiology Information System 2.2. Included patients had MRI reports containing the phrases “abnormal bone marrow” or “heterogeneous bone marrow”, but no clear etiology stated. Further workup, including referral to a subspecialist, laboratory, radiographic, or pathologic evaluations, final diagnosis, and last follow up were collected. Results: 29,508 MRIs were performed and 77 patients met search criteria. Median age was 58 years with a median follow-up of 41 months at TMC after qualifying MRI. 40/77 (52%) of patients had either an MRI of the lumbar spine or hip with 21/77 (27%) undergoing work-up for the marrow findings. Evaluations included CBC (38%), SPEP (24%), quantitative immunoglobulins (14%), free light chains (10%), peripheral blood flow cytometry (5%), bone marrow biopsy (19%), skeletal survey (14%), bone scan (48%), CT scan (24%), biopsy of other site (24%), and subspecialty referal (48%, 29% to oncology). Definitive diagnosis was assigned in 11/21 (52%) cases, with 5 being malignancies (1 follicular lymphoma, 2 multiple myeloma, 2 lung cancer). Three patients were later diagnosed with malignancy (breast cancer, myelodysplastic syndrome, merkel cell carcinoma) at a median of 19 months. Overall, 10% of patients with abnormal marrow on MRI were diagnosed with a malignancy. Conclusions: Incidentally noted abnormal or heterogeneous bone marrow signal on MRI was not inconsequential. Of those patients who underwent evaluation for the finding, 24% were diagnosed with a malignancy. We conclude that abnormal bone marrow findings on MRI should not be ignored, and given the rates of malignancy in our series, oncologists are ideally suited for this task.


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Survival outcomes for patients with equivocal 18FDG-PET CT scan for extrahepatic disease prior to liver resection for metastatic colorectal cancer. Presenting Author: Rajiv Kumar, Department of Medical Oncology, Flinders Medical Centre, Adelaide, Australia

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Late effects among testicular cancer survivors (1994-2011). Presenting Author: Mohammed Hassan Hussain Al-Temimi, University of Utah, Salt Lake City, UT

Background: Patients considered for liver resection (LR) for hepatic metastases from metastatic colorectal cancer (mCRC) have an 18FDG-PET CT scan (PET) to exclude extrahepatic disease (EHD). The prognostic significance of an equivocal PET on overall survival (OS) for patients who proceed to LR is not entirely clear. The aim of the study is to compare OS for patients with equivocal PET prior to LR to those with a PET negative for EHD. Methods: The South Australian Metastatic Colorectal Cancer Registry collects data for mCRC patients diagnosed after February 1, 2006. Patients were included if they had LR and a PET prior to LR. PETs were coded as no EHD and possible EHD. The Cox proportional hazard model was applied to analyse the outcome of patients with an equivocal PET for EHD on OS, adjusting for possible confounders. Results: Of the 2,480 patients on the registry, 273 had had LR. Of these, 183 (67.0%) had a PET prior to LR, with 137 having no EHD and 46 having possible EHD. The no EHD and possible EHD groups were well balanced for patient, tumour and treatment characteristics – mean age: 66.7 yrs-vs-68.4 yrs, male gender: 61.3%-vs63.0%, KRAS wildtype: 11.0%-vs-16.3%, stage IV disease at initial diagnosis: 49.6%-vs-54.3%, colonic primary: 74.4%-vs-65.2%, one LR: 82.5%-vs-89.1%, one line of chemotherapy: 52.4%-vs-48.6% and wellmoderate tumour differentiation: 85.7%-vs-86.4%. The median follow-up was 32.9 months for no EHD and 33.6 months for possible EHD (P-value ⫽ 0.84). The OS for no EHD compared with possible EHD at 1-year was 98.5%-vs-93.5%, at 2-years was 87.6%-vs-88.0%, and at 5-years was 61.5%-vs-59.4%. The unadjusted hazard ratio for OS was 1.22 (95% CI 0.64 –2.34, P-value ⫽ 0.54) for possible EHD. On adjustment for age, gender, stage at diagnosis, primary site, number of LRs, lines of chemotherapy and tumour differentiation, the hazard ratio remained nonsignificant; however lower (HR⫽0.76 (95% CI 0.37–1.59, P-value ⫽ 0.47)), for possible EHD. Conclusions: A PET was only performed in 67.0% of patients who had LR for mCRC. There was no difference in OS between patients with no EHD and possible EHD on PET who proceed to LR.

Background: More than 95% of testicular cancer (TC) patients survive at 10 years; however, they develop many complications following diagnosis. Our study is toassess the risk of developing morbidities among TC survivors. Methods: We used the Utah Population Database to identify TC patients (age⬎13) who 1) were diagnosed between 1994 and 2008, 2) had medical records at the University of Utah and Intermountain Health Care hospitals and 3) survived at least 3 years. Cases were matched to five TC-free patients (controls) from the same hospitals on birth year, birth region and date of residence in Utah. Individuals (cases and controls) with morbidities of interest before the date of TC diagnosis were excluded. Adjusted Cox regression analysis was used to identify the risk of developing ischemic heart disease, renal failure, infertility, hearing loss, peripheral neuropathy, osteoporosis and restrictive lung disease among TC patients relative to controls. The models were adjusted for age, race and other confounders. We also compared the risk of these morbidities among patients with regional/ advanced tumor relative to patients with in situ/localized tumor. The latter was adjusted for age and tumor histology. Results: We identified 955 TC patients and 4775 controls. TC stage was: 73.7 % in situ/localized and 26.3% regional/advanced. The hazard rate (HR) of developing any of the target morbidities was 2.57, 95% confidence interval (CI), 2.2-2.9 for patients with localized cancer, 3.85 (95% CI: 2.9-5.1) for patients with regional cancer and 3.3 (95% CI: 2.3-4.8) for patients with advanced cancer relative to controls. Risk of developing renal failure, infertility, peripheral neuropathy, hearing loss and restrictive lung disease was significantly higher among TC survivors (P⬍0.05). We also identified a significant association (HR 5.2; 95% CI 1.8-15.5) of cancer stage and the risk of developing hearing loss and non-significant positive association of TC stage with the other morbidities. Conclusions: TC survivors were more than twice as likely to develop morbidities following diagnosis when compared to controls. The risk increases when the comparison is stratified by stage, which might be related to the differences in the treatment used for different stages of TC.

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Influence of physical activity on recurrence and survival of colorectal cancer patients: A meta-analysis. Presenting Author: Gaetan Des Guetz, Oncology Department, Bobigny, France

U.S. Preventive Services Task Force (USPSTF) recommendations on breast cancer screening (BCS): Are they justified? Presenting Author: Lori H. Pai, Tufts Medical Center, Boston, MA

Background: Colorectal cancer (CRC) predominates in developed countries among sedentary populations. A meta-analysis (MA) showed that physical activity (PA) decreased the incidence of new cases of CRC. The impact of PA on recurrence and mortality of non-metastatic CRC patients is still controversial. Methods: We performed a literature-based meta-analysis of all published observational studies, using the following keywords (colorectal cancer, physical activity, survival) in PubMed and EMBASE. We searched for a dedicated MA in the Cochrane Library (none found). We cross-checked all references. Pre- and post-diagnostic PA levels were assessed with MET (Metabolic Equivalent Task). Usually, high PA levels corresponded to ⬎ 17 MET hours/week. Overall survival (OS) and cancerspecific survival (CSS) were assessed by means of Hazard Ratios (HRs) with their 95 % Confidence Interval (CI). We pooled adjusted HRs since the variables of adjustment were almost identical between studies (age, sex, BMI, tobacco use, alcohol and red meat consumptions ). By convention, when higher PA levels were associated to an improved survival compared with lower PA levels, HRs for detrimental events were ⬍ 1. We used EasyMA software. We used fixed effect model whenever possible and random effect model only in case of between-study heterogeneity. Results: Eight studies (11298 participants) published from 2006 to 2013 met the inclusion criteria, representing 3110 males and 3710 females, 3072 colon and 1318 rectum cancers. Mean age was 67 years (range 21-82 years). HR CSS for post-diagnostic PA (higher PA level vs. lower) was 0.61 (CI: 0.44-0.86; random effect model). The corresponding HR for OS was 0.62 (CI: 0.54-0.71). HR CSS for pre-diagnostic PA was 0.80 (CI: 0.69-0.92). The corresponding HR for OS was 0.74 (CI: 0.63-0.86). Conclusions: This MA is the first to show that higher PA levels are associated with a better CSS, suggesting that sustained PA should be advised for non-metastatic CRC patients. OS also significantly improved, not surprisingly since PA should reduce risk of cardio-vascular events. These findings should be tempered by the rather small number of studies included.

Background: Nine randomized population trials (RPTs) on BCS with mammography have been reported. Conclusions based upon mortality (MOR) comparisons in RPTs have long led to uncertainty about whether BCS saves lives, especially in women in their 40s. In Nov 2009, USPSTF recommended against BCS in women 40-49 and biennial BCS for women ⬎50. By 2010, BCS fell by ⬎4% in US. Does the evidence support USPSTF recommendations? Methods: MOR quantifies the effect of intervention across an entire population. However, the key issue is whether BCS reduces MOR among those with disease. This is reflected by survival (SUR), not MOR. While SUR is considered flawed due to conventional screening biases, the confounding influence of these biases is misunderstood. In a RPT, randomization provides an opportunity to eliminate these biases, so that (SUR) may accurately reflect screening efficacy. MOR would be biased if randomization fails to produce populations at equal risk for the target disease. Results: Among 9 RPTs, significant MOR reductions were reported only in Swedish Two-County Study in women ⬎50 and in the Gothenburg Study in women 39-49. However, problems with randomization were responsible for MOR overestimating BCS efficacy in these trials. In 7 RPTs, significant MOR reductions were not seen. However, MOR underestimated BCS efficacy in several RPTs. The Canadian National BCS Study, the most influential RPT in women ⬍50 yrs, showed a trend toward increased BC MOR in the screened group. However, randomization failure was likely responsible for significantly more high risk BC in the screening group, which confounded MOR comparisons. Conclusions: It’s never been possible to justify BCS based on MOR comparisons in RPTs. While meta-analyses have been widely utilized, they can be biased when MOR fails to accurately reflect BCS in individual RPTs. Abundant evidence from RPTs supports that BCS leads to significant stage and SUR advantages not attributable to conventional biases, and which more accurately reflect BCS efficacy. The magnitude of benefit is similar for women in their 40s and for those ⬎50. USPSTF recommendations are not supported by the data. If fully implemented, these guidelines can lead to increased BC MOR in US.




Breast cancer subtype variation by ethnicity in a population-based cohort in British Columbia. Presenting Author: Dante Wan, British Columbia Cancer Agency, Vancouver, BC, Canada Background: Reports suggest breast cancer subtypes (BCS) are different in developing countries, often attributed to ethnicity. We assessed BCS in our multiethnic population with access to screening mammography and universal health care. Methods: The Breast Cancer Outcomes Unit database was used to identify women diagnosed with invasive breast cancer in 2006 and referred to the BCCA. Ethnicity was abstracted by chart review from a patient questionnaire completed by all new referrals. Ethnicities were grouped into: Caucasian (CA), East Asian (EA), Aboriginal (A), South Asian (SA), South-East Asian (SEA) and Other (O). BCS were grouped as: ER/PR⫹ HER2-, ER/PR⫹ HER2⫹, ER/PR- HER2⫹, ER/PR- HER2-. Rates of ER and HER2 positivity and BCS were compared by ethnicity using the Chi-square test; age at diagnosis was compared by ethnicity using the Kruskal-Wallis test. Results: 2,222 women were eligible with 2072 having completed questionnaires. Median age was 59 years. The distribution of ethnicities: 73% CA, 8% EA, 4% A, 3% SA, 3% SEA and 9% O. T stage was T1 57%, T2 34%, T3 8% and Tx 1%. N stage was N0 55%, N1 25%, N2 9%, N3 3% and NX 9%. 4.5% were Stage IV at diagnosis. HER2 positivity was significant by ethnicity; 14% CA, 18% EA, 25% A, 29% SA, 26 % SEA, 17% O (p ⫽ 0.0008). Age varied significantly (p⬍0.0001); mean age in SEA was 53 compared to 60 years in CA. Conclusions: Although the subsets are small there appear to be differences in the rates of ER and HER2 positivity by ethnicities. ER negative disease was more frequent in Aboriginal and South Asians. These groups and SE Asians had more HER2 ⫹ disease. Validation on larger populations is pending. Genomics analysis may provide epidemiologic information. Differences in BCS may impact screening and prevention strategies. Ethnicity by breast cancer subtype; N (%). Ethnicity Caucasian East Asian Aboriginal South Asian SE Asian Other/unknown Total

ERⴙ or PRⴙ HER2-

ERⴙ or PRⴙ HER2ⴙ

ER-, PR-, HER2ⴙ

ER-, PR-, HER2-

Total

1,058 (74) 120 (77) 45 (63) 35 (54) 31 (61) 130 (73) 1,419

130 (9) 19 (12) 12 (17) 12 (18) 10 (19) 24 (13) 207

67 (5) 9 (6) 5 (7) 6 (9) 4 (8) 6 (3) 97

180 (13) 7 (5) 9 (13) 12 (18) 6 (12) 18 (10) 232

1,435 155 71 65 51 178 1,955

Missing ⫽ 117; p-value⫽ 0.0013, suggesting different subtype by ethnicity.

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Comparison of adenocarcinoma (ACA) and squamous cell carcinoma (SCC) of the uterine cervix: A population-based epidemiologic study of 60,000 women in Brazil. Presenting Author: Angelica Noguelra Rodrigues, Brazilian National Cancer Institute, Rio de Janeiro, Brazil Background: Most cancers of the uterine cervix are SCC, but the relative and absolute incidence of ACA has risen in recent years, particularly in younger patients, and ACA now accounts for about 20% of invasive cervical cancers in screened populations worldwide. However, the developing world, with sub-optimally screened women, accounts for more than 80% of incident cervical cancers. Our objective was to compare epidemiological, clinical characteristics, and treatment outcome of ACA with those of SCC of the cervix, with respect to ethnic group, age and stage at diagnosis, and pattern of response to first treatment in a sub-optimally screened population. Methods: Data of cervical cancer patients with SCC and ACA (adenosquamous ⫹ adenocarcinoma) treated from 2000 through 2009 were obtained from the Brazilian Hospital Cancer Register databases. Summary odds ratios and chi-square tests were estimated. Results: A total of 60,883 patients were analyzed: 54,425 (89.4%) cases of SCC, and 6,458 (10.6%) of ACA. Compared to ACA, the SCC cohort were younger (49.37 x 51.83 years, p⬍0.001), more frequently black (58.1% x 49.2%, p⬍0.001), presented higher degree of illiteracy (22.7 x 16.1%, p⬍0.001), and alcohol (13 x 9.8%, p⬍0.001) and tobacco dependence (41.5 x 31%, p⬍0.001). Tumor stage at the time of diagnosis was also significantly different (p⬍0.01). Considering prognostic factors, in both subtypes, more than 60% of the patients were stage II or inferior and ACA was associated with a significantly increased risk of inadequate response after the first course of treatment (crude OR⫽1.14 CI95%⫽1.07-1.21; adjusted OR⫽0.94 CI95%⫽0.87-1.01) and of death (crude OR⫽1.26 CI95%⫽1.15-1.38; adjusted OR⫽1.1 CI95%⫽1.00-1.23). Conclusions: Differences between ACA and SCC were found in age at diagnosis, extent of disease and ethnic distribution. In spite of these differences, the inadequate response to treatment seems to be mainly the result of more advanced stage, rather than cell type. Screening strategies with higher sensitivity are necessary, and irrespectively of histological subtype, quality of treatment must be improved in developing countries.

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Effects of obesity and smoking on survival in non-small cell lung cancer. Presenting Author: Damien Mikael Hansra, University of Miami/Jackson Memorial Hospital, Miami, FL Background: Tobacco is the leading cause of preventable death in the US and is linked to many cancers most notably lung cancer. It is established that smoking not only causes lung cancer but is also associated with decreased survival. Obesity is an emerging leading cause of morbidity and mortality in the US and the relationship between obesity, tobacco, and survival in NSCLC is unclear. Methods: Data (n⫽ 87,631) were obtained from linkage of the 1996-2007 Florida Cancer Data System, a populationbased cancer registry, to the Agency for Health Care Administration database providing procedure and diagnoses codes. Survival time was calculated from date of diagnosis to date of death. Smoking status was categorized as never, current, and former. Obesity (yes/no) was determined by body mass index greater than 30. Cox proportional regression models were used to predict survival; demographic, clinical, treatment factors, and comorbidities were included in adjusted models with smoking status and obesity as the main factors. Results: The majority of patients were either former (49%) or current (40%) smokers, and non-obese (93%). There were significant differences between survival curves and median survival (months) for obese vs. non-obese patients (19.9 vs.9.8; P⬍.001). Former and current smokers had shorter median survival than never smokers (10.8 & 9.2 vs. 11.9; P⬍.001). Survival rates (%) at 1-yr (60.0 vs. 44.8; P⬍.001), 3-yr (38.4 vs. 22.1; P⬍.001) and 5-yr (30.2 vs. 15.0; P⬍.001) were better for obese vs. non-obese patients. Independent predictor of worse survival in the unadjusted model was former (HR 1.08; P⬍.001) and current (HR 1.20; P⬍.001) smokers compared to never. Obese patients had better survival vs. non-obese patients (HR 0.64; P⬍.001). In the adjusted model, controlling for extensive variables and comorbidities, former (HR 1.14; P⬍.001) and current (HR 1.22; P⬍.001) smokers still had significantly worse survival vs. never smokers. Obese patients still had better survival (HR 0.84; P⬍.001) vs. non-obese patients. Conclusions: Our results show that being a former or current smoker worsens survival while obesity improved survival regardless of smoking status when compared with non obese patients.

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Frequency of oncogenic alterations in five driver genes in Chinese female lung adenocarcinoma. Presenting Author: Ren Xu, Shanghai Yuanqi Biomedical Technology Co., Ltd., Shanghai, China Background: Currently, 5 driver genes (EGFR, K-RAS, B-RAF, ALK, RET) have been widely explored and become new targets of NSCLC, however no report has been found in Chinese female lung adenocarcinoma, who were prone to EGFR mutations and therefore, are the targets for TKIs therapy. Methods: FFPE-tissues from 310 female lung adenocarcinoma adopted in Hunan or Henan province between 2000 and 2012 were investigated. Oncogenic alterations in newly found 5 driver genes were analyzed. ARMS was used to study EGFR, K-RAS and B-RAF mutation. The reverse transcription and real-time PCR were performed to detect either ALK and RET fusions or ALK and RET gene expression. Sequencing was further applied to confirm the subtypes of fusions. Results: Among 310 samples, 149 (48.1%) EGFR mutations, 16 (5.2%) KRAS mutations, 0 (0%) BRAF mutations, 23 (7.4%) ALK fusions and 5 (1.6%) RET fusions were detected. Only EML4-ALK fusion but no other ALK fusions were found. Further research showed that cases (22, 95.6%) with high ALK expression were often accompanied by EML4-ALK fusion and poorly differentiated adenocarcinoma. Two RET fusions, KIF5B-RET and CCDC6-RET were found, with 2 cases and 3 cases, respectively. The ratio of RET/ABL mRNA levels was significantly higher in CCDC6-RET samples with poorly differentiated adenocarcinoma. However, with KIF5B-RET fusion, relatively high RET/ABL mRNA expression was detected in one KIF5B-RET sample with moderately differentiated adenocarcinoma, while no RET expression was detected in other two KIF5B-RET samples with highly differentiated adenocarcinoma. Conclusions: This is the first research about the oncogenic alterations of 5 important driver genes in Chinese female lung adenocarcinoma, as well as the correlation between ALK fusion and ALK expression or between RET fusion and RET expression, thus laying good foundation for understanding the genetic mutation spectrum in female lung adenocarcinoma.


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Cancer Prevention/Epidemiology

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Association of PIK3CA mutations and age with the occurence of second primary lung cancer (SPLC). Presenting Author: Marc Christiaan Allardt Bos, Lung Cancer Group Cologne, Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany

The incidence, risk factors and prognostic implications of venous thromboembolism in Asian patients with non-small cell lung cancer. Presenting Author: Yun-Gyoo Lee, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea

Background: The incidence of SPLC in Germany was reported to be 1.2 per 100,000 inhabitants in 2007 and the prevalence of second primary cancers reported by the US International Cancer Institute’s Surveillance, Epidemiology and End Results Program has more than doubled over the last 25 years. Recently there has been tremendous progress in the ability to detect driver mutations in lung cancer and large studies presented the frequencies of driver mutations in unselected patient populations. We conducted an association study of known genetic driver events and clinical characteristics with the occurence of SPLC. Methods: Within the Network Genomic Medicine Lung Cancer, a local molecular screening network encompassing hospitals and office-based oncologists in the catchment area of the Center for Integrated Oncology Köln Bonn, we retrospectively reviewed the medical records of 375 molecularly annotated NSCLC patients for their SPLC status and clinical characteristics (age at diagnosis, histology, sex, smoking status). Molecular analysis for lung adenocarcinoma included the EGFR, ALK, BRAF, KRAS and PIK3CA status and for squamous cell lung cancer the FGFR1 and PIK3CA status. Results: 84 of 375 (22,4%) patients were SPLCs. The median age of SPLC diagnosis was 70 yrs. (Range 53 - 85 yrs.) and differed significantly from the rest of the population with a median age of 65 yrs. (Range 28 - 86 yrs.). The frequency of SPLCs was not significantly different between males and females (p ⫽ 0,259). In univariate logistic regression analysis active and former smoking, positive PIK3CA mutation and FGFR1 amplification status as well as age were significantly associated with the occurrence of SPLC. In a multivariate logistic regression analysis including the variables mentioned above only PIK3CA mutations (OR 9,48 95% CI 1,83 - 49,1) (p ⫽ 0,007) and age (OR 1,06 95% CI 1,03 - 1,1) (p ⫽ 0,015) could be confirmed to be independent prognosticators for the occurrence of SPLCs. Conclusions: The occurrence of SPLC was associated with age and PIK3CA mutations in our study population. Further comprehensive investigations on this topic are needed to confirm our findings and to further understand the association between mutation status and SPLCs.

Background: The goal of this study was to describe the incidence, risk factors and prognostic implications of venous thromboembolism (VTE) in Asian patients with non-small cell lung cancer (NSCLC). The association between specific gene mutations and the risk of VTE was also evaluated. Methods: A total of 1998 consecutive patients with NSCLC were enrolled and analyzed retrospectively. To minimize potential confounding, we used propensity score-matching to compare overall survival between patients with and without VTE. Results: The 6-month and 2-year cumulative incidences of VTE were 4.2% and 6.4%, respectively. The risk of VTE increased 2.45-fold with each advancing stage in NSCLC (common hazard ratio [HR] 2.45; 95% CI 1.96 –3.05; P⬍0.001). In multivariate analyses, the effects of therapeutic variables including surgery, chemotherapy, and radiotherapy on the development of VTE were modified by NSCLC stage. Therefore, we calculated stratum-specific HRs by performing stratified analyses for each stage. The independent predictors of VTE were advanced age, pneumonectomy (vs. lobectomy) and palliative radiotherapy (vs. no radiotherapy) in localized NSCLC and no surgery (vs. lobectomy) and palliative radiotherapy (vs. no radiotherapy) in locally advanced NSCLC. Adenocarcinoma histology (vs. squamous cell carcinoma) was the only independent risk factor for increased risk of VTE in metastatic NSCLC. EGFR mutation was independently associated with a 47% lower risk of VTE in adenocarcinoma compared to wild type (HR 0.53; 95% CI 0.29 – 0.99; P⫽0.045). Among both the entire and propensity score-matched cohorts, a significant survival difference was observed between patients with and without VTE in localized NSCLC, but not in locally advanced or metastatic NSCLC. The strong association we observed between VTE and the increased rate of recurrence (risk ratio 2.0; 95% CI 1.28 –3.12; P⫽0.009) can explain the significant difference in survival in localized NSCLC. Conclusions: Approximately 6.4% of Asian patients with NSCLC developed VTE during a 2-year period. The association between VTE and decreased survival was limited to localized NSCLC.

1591

1592


Correlation between anthropometric, pathologic data, and 21-gene recurrence score assay in early-stage breast cancer. Presenting Author: Keith Ian Quintyne, Mid-Western Cancer Centre, Limerick, Ireland Background: Obesity or body mass index (BMI) ⬎ 30kg/m2 is a grave public health concern. Poorer outcome has been documented in obese breast cancer patients. We report the use of the Oncotype Dx Recurrence Score (RS) assay and its correlation with BMI and pathologic data. Methods: Study period: 01/09/08 – 31/05/12. Data was derived from: MWCC database; pathology reports; patient files; RS reports. Statistical analysis was carried out using R. Results: 89 patients were found. Median follow-up: 21.4 months. See Table for data. Conclusions: For this cohort: A skewed pattern in RS assay scores was observed in obese patients, where there were more intermediate and high scores, although this was not significant in multivariate model; tumour size and grade were shown to correlate with the RS assay results; these findings are thought-provoking and certainly can augment to the accruing energy balance data that has been increasingly of interest in oncological research. MWRH data. RS

RS Assay U/k Age (y) < 44 45 – 54 55 – 64 > 65 Size (cm) < 1.00 1.01 – 2.00 > 2.01 Histology Ductal Lobular Mixed

Significance

No.

Range

Median

Low

Intermediate

High

89 2 89 10 31 24 24

0–44

17

45 (51%)

36 (40%)

6 (7%)

30.6–72.3

55.2

0.8–5.0

1.7

7 (70%) 16 (52%) 11 (46%) 11 (46%) 3 (38%) 29 (54%) 13 (48%) 38 (53%) 7 (44%) 0 (0%)

2 (20%) 12 (39%) 12 (50%) 10 (42%) 3 (38%) 23 (43%) 10 (37%) 28 (39%) 7 (44%) 1 (100%)

89 8 54 27 89 72 16 1

Unknown

Univariate

Multivariate

1 (10%) 1 (3%) 1 (4%) 3 (13%) 1 (13%) 1 (2%) 4 (15%) 5 (7%) 1 (6%) 0 (0%)

0 (0%) 2 (6%) 0 (0%) 0 (0%) 1 (13%) 1 (2%) 0 (0%) 1 (1%)1 (6%) 0 (0%)

0.46

0.71

0.02

0.06

0.85

0.86

Grade I II III

89 8 74 7

1 (13%) 42 (57%) 2 (29%)

7 (88%) 26 (35%) 3 (43%)

0 (0%) 4 (5%) 2 (29%)

0 (0%) 2 (3%) 0 (0%)

0.04

0.04

PgR ⴙve – ve

89 78 11

43 (55%) 2 (18%)

29 (37%) 7 (64%)

5 (6%) 1 (9%)

1 (1%) 1 (9%)

0.11

0.09

89 31 57 1

20 (65%) 25 (44%) 0 (0%)

7 (23%) 28 (49%) 1 (100%)

2 (6%) 4 (7%) 0 (0%)

2 (6%) 0 (0%) 0 (0%)

0.56

0.81

19 (61%) 16 (52%) 9 (38%) 1 (33%)

8 (26%) 13 (42%) 13 (54%) 2 (67%)

3 (10%) 1 (3%) 2 (8%) 0 (0%)

1 (3%) 1 (3%) 0 (0%) 0 (0%)

Menopause Pre Post U/k Weight (kg) BMI (kg/m2) < 25 25.1 – 30 > 30.1 U/k

89

51–106

71.0

89 31 31 24 3

20.0–44.1

27.2

0.29 0.02

* Unknown: U/k, PgR: progesterone receptor, ⫹ve: positive, -ve: negative; % have been rounded and might not total 100%.

0.13


A survey of clinical prediction tools in colorectal and lung cancers and melanoma. Presenting Author: Alyson L. Mahar, Division of Cancer Care & Epidemiology, Cancer Research Institute, and Department of Community Health & Epidemiology, Queen’s University, Kingston, ON, Canada Background: Clinical prediction in cancer depends on a myriad of prognostic factors, and relies on sound methodology for model building and validation. Increased understanding of complex tumour biology allows for simultaneous consideration of biological markers and standard clinical and pathological factors for prediction. We evaluated published studies supporting existing prediction tools in three cancers. Methods: Scientific literature and online resources were searched for clinical prediction tools for survival in three cancers: colorectal, lung, and melanoma. A priori criteria determined by the Molecular Modellers Working Group of the AJCC were evaluated and included: defined patient population, consideration of standard prognostic variables, model development approaches, validation strategies, performance metrics, presentation form of prediction tool, and intended clinical use. Results: Seventy-eight tools intended for prediction of survival were identified for the three cancers: 41 in colorectal, 23 in lung, and 14 in melanoma. Clinical presentations varied within each: 23 of the colorectal cancer tools focused on advanced disease with liver metastases and the remaining varied by stage; 16 lung cancer tools focused on NSCLC and 7 on SCLC. Even in narrowly defined situations, there was no consensus on key variables; for example, no variables were common to all 8 prediction tools for metastatic lung cancer. Variable definitions were missing or vague and the form of the model was often not provided, hampering independent validation and usability. Only 32/78 tools were supported by appropriate internal validity statistics and 21/78 with external validation. Often the development of risk scores did not create groups for whom treatment decisions would be similar. Conclusions: The quality of the literature supporting clinical prediction tools is variable, and the accuracy and utility of many existing tools is undetermined. Methodological guidelines for prediction tool development and validation should be adopted and adhered to. Studies developing and validating clinical prediction tools in cancer must be reported in complete and transparent fashion to facilitate proper interpretation and judgment of utility.




1595

109s General Poster Session (Board #8H), Mon, 1:15 PM-5:00 PM

A retrospective study on the role of diabetes and metformin in colorectal cancer disease progression. Presenting Author: Ravi Ramjeesingh, Cancer Center of Southeastern Ontario, Kingston, ON, Canada

Second primary tumors in cancer patients: A retrospective analysis based on institutional tumor registry. Presenting Author: Luca Fumagalli, Division of Medical Oncology, European Institute of Oncology, Milan, Italy

Background: Recent studies have suggested a potential epidemiological role for diabetes as an independent risk factor for the development of colorectal cancer (CRC). These studies have furthermore suggested patients with diabetes who develop colorectal cancer have an increased mortality. Methods: To identify a potential correlation between CRC and diabetes, we are performing a retrospective chart review of CRC patients treated at the Cancer Center of Southeastern Ontario diagnosed from January 2005 to December 2011. 1,300 colorectal cancer patient charts have been identified through Ontario Cancer Registry Data based on confirmed ICD-10 diagnosis codes and the variables of 200 random patients have been extracted into our database thus far. The final analysis will be completed April 2013. Results: Preliminary analysis of the database has indicated that the average age of patients with CRC was 69 years with 55% being women. The incidence of diabetes in our CRC population was 19%, double the rate of diabetes in the general population in Canada. As expected, the rate of co-morbidities excluding diabetes was higher in the diabetic group (92.9% vs 69.3%; p⫽0.004). When we looked at the diabetic population specifically, the rate of death was not significantly different compared to the non-diabetic population (13.2% vs 12.7%, p⫽0.94), however those with diabetes presented with later-stage (stage 2/3/4) disease (92.1% versus 88.6%). The average number of days from the time of diagnosis to death in the diabetic group (200 days) was half compared to the non-diabetic group (420 days, p⫽0.014). However, there was no statistical difference in the percentage of progression, number of different metastatic sites or the burden of metastatic disease amongst the two populations. A subgroup analysis of diabetic patients on metformin illustrated that the death rate (p⫽0.06), rate of progression (33% vs 20%) and those presenting with later stage disease was higher in patients not on metformin compared to those on the drug. Conclusions: Our preliminary work suggests diabetics with CRC may have a worst prognosis however taking metformin may have a positive impact on prognosis.

Background: The relative risk of developing a second tumor by site of primary tumor or gender is still unclear. Methods: We retrospectively analyzed data of 24,224 consecutive patients admitted to the European Institute of Oncology between 2000 and 2006 for a first primary invasive tumor. All the data were extracted from the institutional Tumor Registry. All tumors were registered and indexed within the same patient’s record. We limited the analysis to the patients who were diagnosed and received at least one treatment in IEO for their first primary tumor. Follow-up was based on the last registered patient’s control visit. Cumulative incidence was compared across different subgroups by means of the Gray test. The observed cases of second metachronous primary tumors was compared with the number of cancers we expected from the general Italian population. We used the standardized incidence ratio (SIR), defined as the ratio of the number of second cancers observed to the number of second cancers expected, to estimate the relative risk of second cancers, and we calculated 95% confidence intervals (95% CIs) by applying the Wilson and Hilferty approximation for chi-square percentiles. Results: In this population the 5-year cumulative incidence of a second tumor on the average population was 5.0%, SIR (CI 95%) was 1.3 (1.2-1.4). The Table reports details on observed versus expected second metachronous primary tumors by first tumor site. Conclusions: Cancer patients have a higher risk of a second primary tumor than general population.

1596

1597


First primary

Head and neck

At risk 627 All patients Observed 46 Expected 25.1 SIR 1.8 (95% CI) (1.3-2.5)

Respiratory Digestive and organs and intrathoracic peritoneum organs 1,702 61 73.5 0.8 (0.6-1.1)

2,059 149 97.4 1.5 (1.3-1.8)

Female breast

Melanoma

Skin

Female genital organs

Male genital organs

Urinary organs

Brain

Thyroid and other endocrine glands

Lymphatic and hematopoietic tissues Sarcoma

Total

12,222 797 90 1,540 1,190 502 24 363 792 430 22,338 524 45 9 54 64 53 2 8 51 19 1,085 391.4 26.2 4.8 39.8 77.2 25.5 0.3 8.3 27.2 11.8 808.5 1.3 1.7 1.9 1.4 0.8 2.1 7.4 1.0 1.9 1.6 1.3 (1.2-1.5) (1.3-2.3) (0.9-3.6) (1.0-1.8) (0.6-1.1) (1.6-2.7) (0.8-25.7) (0.4-1.9) (1.4-2.5) (1.0-2.5) (1.2-1.4)


Rapid online feedback to improve clinical trial accrual: CODEL anaplastic glioma (AG) (NCCTG/Alliance N0577) as a model. Presenting Author: Holly Massett, National Cancer Institute, Rockville, MD

Androgen deprivation therapy and survival in patients with lung cancer. Presenting Author: Craig Henry Harlos, University of Manitoba, Department of Internal Medicine, Winnipeg, MB, Canada

Background: Structured feedback from community oncologists regarding trial design rarely occurs. Survey templates were created to assess trial feasibility, design and scientific interest from the community, with the aim of improving accrual. We report results from a survey regarding redesign of the Phase III CODEL trial for newly diagnosed 1p/19q codeleted AG, which employed this approach. Methods: A field-tested, online survey template was tailored for CODEL and emailed to U.S. and international oncologists. The survey assessed (a) practice changes resulting from ASCO 2012 data from RTOG 9402 (abstract # 2008b) and EORTC 26951 (abstract # 2); (b) scientific interest in a redesigned trial; and (c) potential accrual issues. Respondents reviewed a brief trial concept and answered 15 questions anonymously via a web-based system. Results: 173 oncologists completed the survey over 2 weeks in Sept 2012(48% US, 52% Int’l; 35% med oncs, 31% rad oncs, 29% neuro-oncs). Results from the 2 prior studies substantially influenced clinicians’ treatment decisions for patients with newly diagnosed 1p19q codeleted AG--from only 9% recommending RT⫹PCV prior to the ASCO reports, to 46% after the results were presented. Previously, 25% recommended RT alone, and after ASCO, no one did. Most indicated strong interest in the revised CODEL research questions, trial design, randomization arms, and in re-opening the revised trial. The most interesting schema was a 3-arm design (selected by 45% of respondents): (RT ⫹ procarbazine, CCNU and vincristine chemotherapy [PCV]) vs. (RT ⫹ Temozolomide [TMZ]) vs. (TMZ alone), with neuro-oncs (49%) preferring it most, and rad oncs least (36%). The second most interesting choice (27%) was RT⫹PCV vs. RT⫹TMZ; the third choice (20%) was RT⫹TMZ vs. TMZ alone. Most (61%) felt patients would accept any arm. Respondents encountered eligible patients frequently enough to meet projected CODEL accrual goals. Conclusions: Survey findings significantly influenced decisions on how best to redesign the CODEL trial. Rapid, web-based surveys of community oncologists can provide important feedback regarding level of interest, which might facilitate timely accrual and trial completion.

Background: The epidemiology of lung cancer differs between men and women. There exists significant evidence suggesting estrogens influence the pathophysiology of lung cancer, however the role of androgens remains unclear. This study was performed to determine if exposure to androgen deprivation therapy (ADT) has an effect on survival in male patients (pts) diagnosed with lung cancer. Methods: Using the population-based Manitoba Cancer Registry and Manitoba Health Administrative Databases, all pts diagnosed with lung cancer from January 1, 2004 to December 31, 2010 were identified. Information from the Drug Program Information Network (DPIN) and the Aria electronic record at CancerCare Manitoba were used to determine prescriptions filled for anti-androgens, 5-alpha reductase inhibitors and GnRH agonists as a measure of exposure (defined as having filled at least 2 prescriptions and/or bilateral orchiectomy). Multivariable analysis with Cox proportional hazards analysis was used to compare survival. Results: A total of 3018 men with lung cancer were identified between 2004 and 2010. Of these, 339 (10%) were identified as having used a form of ADT. The majority of pts received 5-alpha reductase inhibitors (85%), the most common being finasteride (80% of total). Multivariable analysis revealed that patients who received ADT prior to the diagnosis of lung cancer had no statistically significant difference in survival (HR: 0.97 p⫽0.69) compared to those who did not. Patients exposed to ADT after their diagnosis were found to have a significantly better survival than those not exposed (HR 0.36 p⫽0.0007). This effect was also seen in those who received ADT before and after diagnosis (HR 0.53 p⬍0.0001). Conclusions: In male pts diagnosed with lung cancer, exposure to ADT is associated with significantly better survival when compared with no exposure. This effect is only seen when some or all of the exposure has occurred after the diagnosis of lung cancer. This study supports the hypothesis that the androgen pathway plays a role in lung cancer pathophysiology, and that androgen deprivation may improve prognosis


110s 1598

Cancer Prevention/Epidemiology General Poster Session (Board #9C), Mon, 1:15 PM-5:00 PM

1599


Survival after cancer diagnosis among patients with higher income and education in Israel, a country with highly appreciated health service. Presenting Author: Yakir Rottenberg, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Neurologic, vascular, and endocrine morbidity following childhood exposure to low and moderate doses of ionizing radiation. Presenting Author: Siegal Sadetzki, The Gertner Institute for Epidemiology and Health Policy Research, Ramat Gan, Israel

Background: In recent years, the 5 year survival following cancer diagnosis is about two thirds. Among patients with various chronic diseases, improved survival is known to be associated with higher income and education. The aim of the current study is to assess the influence of income and education on survival following cancer diagnosis in Israel. Methods: Retrospective cohort study, using baseline measurement from the 1995 census conducted by the Central Bureau of Statistics in Israel. Cancer data were obtained from the Israel Cancer Registry. Cox proportional hazards ratios were calculated for mortality among cancer patients and adjusted for age, sex, religious, income and education years. The first model excluded cancers associated with early detection (breast, prostate, colorectal and cervix), and a second model excluded also lung cancer in order to control for smoking which is common in lower socioeconomic status. Results: A total of 3,712 cases of cancer and 1,252 deaths were reported during the study period. Higher income (HR⫽0.985 per 1000NIS, approximately 330$ in 1995’s value, p⫽0.016) and education (HR⫽0.957 per year of education, p⬍0.001) were associated with decreased risk of death after cancer diagnosis. Jews had better prognosis than non-Jews following cancer diagnosis (HR⫽0.62, p⬍0.001), while males (HR⫽1.54, p⬍0.001) and age (HR⫽1.036 per year, p⬍0.001) had been associated with worse prognosis. The association between higher income and education was not changed in a model which excluded lung cancer. Conclusions: Higher income and education are associated with improved survival after cancer diagnosis. In the light of current study, further studies are needed to depict the variation in cancer incidence, stage at diagnosis and treatment disparities related to socioeconomic variables.

Background: While the association between exposure to ionizing radiation and cancer is well known, its possible role in the development of other diseases e.g. in the vascular, neurologic and endocrine systems is limited and inconsistent. The aim of this study was to assess the effect of childhood exposure to low and moderate doses of radiation on the development of chronic diseases (other than cancer) based on a large cohort followed for 55 years. Methods: The study population included an exposed group of 13,158 individuals treated with ionizing radiation for tinea capitis and a comparison group of 16,225 unexposed subjects. The mean dose to the head and the thyroid gland were 1.5 Gy and 0.094 Gy respectively and the mean age at exposure was 7.1⫾3.1y. Data on the outcome variables was obtained through computer linkage of the study database with the largest health care provider registry in Israel. Results: Of the study population, 64% were found to be insured in this heath provider (66.8% among the irradiated and 63.6% among the unexposed group). The two study groups did not differ in current age (mean 62.1⫹4.5 y), gender, marital status, smoking and BMI. Compared to the unexposed group, the irradiated group demonstrated a significantly (p⬍0.001) increased prevalence of epilepsy (1.8% vs. 2.8%), CVA (6.4% vs. 8%), diabetes (26.5 % vs. 28.2%), hyperthyroidism (8.1% vs. 9.4%), hyper/hypoparathyroidism (0.6% vs. 1.2%) and depression (8.1% vs. 9.4%), respectively. There was no statistical difference between the groups in the prevalence of dementia and Parkinson’s disease. Multivariate models accounting for different variables of interest (e.g. age at exposure, gender, SES) will be presented. Conclusions: These results have practical implications for primary prevention and early detection of therapeutic and diagnostic radiation associated morbidity.

1600

1601



Prevalence and patterns of cancer in patients with congenital disease: A national-based cohort study. Presenting Author: Po-Han Lin, Department of Medical Genetics and Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan

Longitudinal comparison of body mass index (BMI) in breast cancer survivors to cancer-free women: A prospective study in high-risk women. Presenting Author: Amy L Gross, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

Background: Association of congenital disease (CD) and malignancy was noted in some studies. However, the cancer risk and patterns of different CD was unclear. In this study, we aimed to assess and quantify the relationships between CD and cancers. Methods: In the National Health System of Taiwan, 2.9 million children were born between 1998 and 2010. Patients with CD were identified using ICD-9-CM 740-759. Cox’s proportional hazards regression analysis was used to assess the cancer risk of CD. Results: A total of 32358 CD patients were identified and 87 of them developed malignancy. The cancer diagnostic age was significantly younger in patients with CD (2.44 ⫾ 2.28 years) than patients without CD (3.97 ⫾ 3.04 years; p⬍0.001). The hazard ratio (HR) of cancer incidence was 2.70 (95% confidential interval (CI) 2.12-3.44). Subgroup analysis showed that significantly increased risk of cancer development was noted among patients with cardiac anomalies (N⫽26, HR⫽1.91, 95% CI 1.28-2.86), digestive anomalies (N⫽8, HR⫽3.32, 95% CI 1.64-6.70), cutaneous anomalies (N⫽2, HR⫽21.5, 95% CI 5.35-86.40) and chromosomal anomalies (N⫽29, HR⫽17.5, 95% CI 12.00-25.70); other congenital diseases did not. Considering cancer types, patients with cardiac anomalies had higher rate of hematological cancers (N⫽12, HR⫽2.09, 95% CI. 1.15-3.79), especially acute myeloid leukemia (AML; N⫽9, HR⫽12.2, 95% CI. 5.36-28.0). Patients with digestive anomalies also had higher rate of hematological cancers (N⫽4, HR⫽3.95, 95% CI. 1.46-10.70), and the dominant type was non-Hodgkin lymphoma (N⫽2, HR⫽14.70, 95% CI. 3.38-64.0). Patients with chromosomal anomalies had superior rate to have retroperitoneal sarcoma (N⫽1, HR⫽8.54, 95% CI. 1.14-63.90), anterior mediastinal tumor (N⫽1, HR⫽8.54, 95% CI. 1.14-63.90), and hematological cancers (N⫽23, HR⫽33.20, 95% CI. 21.20-51.80), especially the AML (N⫽21, HR⫽231, 95% CI. 119-448). Down syndrome patients had extremely high risk of AML (N⫽8, HR⫽388, 95% CI. 164-918). Conclusions: Patients with cardiac, digestive, cutaneous and chromosomal CD were at increased risk and younger age to develop cancer. Hematological malignancies, especially AML, were the most common cancer type among these patients.

Background: Postdiagnosis weight gain in non-familial breast cancer (BC) survivors has been observed in a number of studies, with the reported prevalence and amount of weight gain being highly variable. Most studies did not include a cancer-free comparison group. Change in BMI has not been studied in BC survivors from high-risk populations. Methods: In an ongoing prospective cohort of women at Johns Hopkins with a family history of BC, ovarian cancer, and/or a BRCA1/2 mutation, we identified 249 survivors of stage 0-III BC and 400 cancer-free women who completed a baseline and at least one follow-up questionnaire and were age ⬎ 30 years (yrs) at enrollment. Linear regression was used to estimate % change in self-reported BMI from baseline to follow-up (median 3.7 yrs) for survivors compared to cancer-free women including the effects of time between BC diagnosis and baseline, and differing BC treatment. Results: Mean age at baseline was 54.6 yrs among for survivors and 50.2 yrs among for cancer-free women. Mean age at BC diagnosis was 48.7 yrs with ⬎ 50% diagnosed under 50 yrs, and 23% with ER- tumors. Baseline BMI did not differ between survivors and cancer-free women irrespective of tumor subtype. However, the average change in BMI was 1.79% (95% CI 0.32, 3.26) greater in survivors compared to cancer-free women in models adjusted for age, baseline BMI, menopausal status, physical activity, enrollment yr, and bilateral oophorectomy. The increase in BMI was highest (␤ ⫽ 4.22%; 95% CI 1.74, 6.70) in survivors diagnosed within 1 yr of baseline. Change in BMI in survivors diagnosed ⬎ 5 yrs prior to baseline did not significantly differ from cancer-free women. A significantly greater increase in BMI was also observed in survivors diagnosed at age ⬎ 50 yrs, and in those who received chemotherapy and not hormone therapy. Conclusions: In this study of BC survivors and cancer-free women enrolled from the same source population, we observed a greater percent increase in BMI over time among survivors, particularly those diagnosed within 5 yrs of baseline and/or treated with chemotherapy. Survivors in these categories may benefit from interventions aimed to reduce weight gain post diagnosis.




1603

111s General Poster Session (Board #9H), Mon, 1:15 PM-5:00 PM

Effect of statin and metformin on survival in veterans (V) with B-cell lymphoproliferative disorders (BLD). Presenting Author: Shanthi Srinivas, University of Medicine and Dentistry of New Jersey, Newark, NJ

Evaluation of a dedicated institutional tobacco cessation service for thoracic clinic cancer patients. Presenting Author: Katharine Ann Dobson Amato, Roswell Park Cancer Institute, Buffalo, NY

Background: The incidence of BLD has been increasing in V. As many V are on statin and metformin for comorbid conditions, we evaluated the impact of their use on survival. Methods: In an IRB-approved protocol, we reviewed the records of 332 V diagnosed with BLD from January 1997 to Dec 2011 for demographics, height(H),weight(W), BMI,statin and metformin use, clinical and laboratory data and ECOG PS. Comorbidity was assessed using the Charlson Comorbidity Index (CCI),Kaplan-Feinstein Index (KFI) and Cumulative Illness Rating Scale (CIRS). Cox regression analysis was performed using SAS v 9.2. Results: There were 332 V with a median (M) age of 70 years (27-94). The M for H 70 inches (58-78), W 183lbs (99-356.5) and BMI 26.7 kg/m2 (15.54 -48.45). The M for hemoglobin(Hgb) 12.8 g/dl (7.3-17.4), albumin 3.9(1.2-5.4), lactate dehydrogenase( LDH) 183 IU/L (85-1905), beta 2-microglobulin 2.6 mg/dl (0.8-39) . The M for CCI was 4.7 (0.8-12), KFI 2 (0-3), CIRS15 3 (0-6), CIRS16 6(0 -14), CIRS17 1.9(0-6), CIRS18 0(0-3), CIRS19 0(0-3). M survival was 1297days(4-7468).The number of V receiving statin was 167 (51%) and metformin 46 (14%). Statin use was a predictor of survival by both univariate and multivariate analysis but metformin was a predictor only by univariate analysis. Conclusions: Statin use was an independent and significant predictor of survival in this group of V with BLD and needs to be validated in a larger group of patients.

Background: Tobacco use by cancer patients is associated with poor therapeutic outcomes including increased toxicity, decreased quality of life, and decreased survival. Though recommendations provide for tobacco assessment and cessation for cancer patients, few oncologists provide cessation support. Presented are data from universal tobacco assessment and cessation program for patients presenting at a thoracic oncology clinic in a NCI Designated Comprehensive Cancer Center. Methods: A standard set of evidence based tobacco assessment questions were incorporated into an automated electronic medical record based system delivered by nursing at initial consult and at follow-up. Patients eligible for tobacco cessation support (i.e. patients self-reporting tobacco use within 30 days) were automatically referred to a dedicated tobacco cessation service. All referred patients are sent a standardized packet of cessation materials with telephone-based follow-up by trained cessation counselors. Results: A total of 980 new thoracic clinic patients were referred to the cessation service from January 2011 and October 2012. Two-thirds of the patients referred (n⫽728) referred into the system were current smokers and the remainder had quit in the 30 days prior to assessment. Among the 788 patients with contact attempts by the cessation service, 81.2% (n⫽640) were successfully contacted and only 2.5% (n⫽20) refused the offer of cessation support. At first contact, 75.6% (n⫽484) of patients reported continued current tobacco use. Follow-up calls were placed for 53.1% (n⫽340) of those who participated in the first contact an average of 39 days after the first successful contact. The follow-up had a 93.2% (n⫽317) participation rate which revealed that 33.3% (n⫽106) reported not smoking, an 8.9% increase since the first cessation service telephone call. Conclusions: Data demonstrate that an automated tobacco assessment and cessation service for thoracic oncology patients can effectively generate a large mandatory referral base with high patient interest in cessation, and that cessation support can be implemented and maintained in high risk cancer patients.

Univariate analysis P< Hazard ratio Stage Albumin LDH B2Microglobulin Weight BMI Metformin Statin CCI-1 KFI

1604

0.0001 0.0001 0.0001 0.0261 0.0050 0.0007 0.0274 0.0006 0.0001 0.0001

Multivariate analysis P< Hazard ratio

2.331 2.417 2.003 2.524 0.994 0.946 1.028 1.673 2.455 1.977

0.003 0.0008 0.0003 NS 0.0478 NS 0.0931 0.0232 0.0097 0.044

1.617 1.720 1.736 0.996 1.418 1.418 1.711 1.550


Night work and cancer: A systematic review and meta-analysis. Presenting Author: Lanhua Tang, Central South University, Changsha, Hunan, China Background: The association between night work (or shift work) and cancers has been studied for decades. However, researches investigating the association have yielded inconsistent results. Methods: A systematic review and meta-analysis was performed to investigate whether night work is a risk factor for different kinds of cancer. PubMed and Cochrane library search were independently conducted by two authors from January 1960 to January 2013 using keywords related to night work and cancer. According to between-studies heterogeneity, pooled risk ratios (RR) were estimated with fixed or random effects models by STATA 12.0 software. Sensitivity analysis and publication bias were also analyzed. Results: A total of 33 studies were identified according to the inclusion criteria. The aggregate estimate for all cancers combined was [1.35, (1.24-1.47)] with a similar significant elevation of breast cancer [1.36, (1.21-1.52)], ovary cancer [1.24, (1.08-1.43)] risk among female, and malignant melanoma [1.58, (1.03-2.44)]. No significant risks were observed as regard to patients with prostate cancer, colorectal cancer, cervix cancer and non-Hodgkin lymphoma. Sensitivity analyses indicated no change in all results but malignant melanoma and colorectal cancer. The RRs became significant differences after removing one study from the colorectal cancer [1.60, (1.70-2.18)]. No publication bias was observed in this meta-analysis. Conclusions: The current meta-analysis suggested that night work played an important role in breast cancer, ovary cancer, and malignant melanoma. However, it might be premature to consider night work as a risk factor for prostate cancer, colorectal cancer, cervix cancer and non-Hodgkin lymphoma. The relationship between night work and cancer. Cancer type Breast cancer Prostate cancer Cervix cancer Ovarian cancer Malignant melenoma Colorectal cancer Non-Hodgkin Total

PHeterogeneity

RR

95% CI

P

Model

P (publication bias)

0.026 ⬍0.01 0.87 0.39 0.04 ⬍0.01 0.005 ⬍0.01

1.36 1.90 1.20 1.24 1.58 1.36 1.31 1.35

1.21-1.52 0.92-3.94 0.92-1.58 1.08-1.43 1.03-2.44 0.94-1.99 0.95-1.80 1.24-1.47

⬍0.01 0.08 0.18 0.002 0.04 0.11 0.10 ⬍0.01

Random Random Fixed Fixed Random Random Random Random

0.46 1.00 0.29 1.00 0.37 0.81 0.73 0.09

1605


Identification of the occult tumor in cancer of unknown primary (CUP): A priority based on histology. Presenting Author: Chong Sung Kim, University of Western Ontario, London, ON, Canada Background: The poor prognosis of cancer of unknown primary (CUP) patients is likely to improve with knowledge of the primary site. CUP patients form a diverse clinicopathological group; however, there remains doubt as CUP may indeed represent a unique clinical classification. Methods: We used the Ontario Cancer Registry to identify all patients diagnosed with cancer from January 2000 to December 2005. We linked these patients with the Canadian Institute of Health Information Same Day Surgery and Discharge Abstract Database to identify those who were initially diagnosed with a metastatic tumour. Information on clinical and pathological characteristics including age, gender, primary tumour site, histology, and second primary were available from the Ontario Cancer Registry. We stratified results according to primary tumour site and histology. Five-year survival data were available for all patients and were obtained from the Ontario Cancer Registry. Results: Of 52,619 patients diagnosed with metastatic tumour at the time of their initial cancer diagnosis, 4,866 (9.2%) patients were diagnosed with CUP and 47,753 (90.8%) patients were diagnosed with metastasis of known primary. The 5-year Kaplan-Meier estimate of CUP overall survival (OS) differed significantly with patients diagnosed with metastasis of known primary (median OS⫽ 1.0 versus 10.4 months, respectively, log–rank test p⬍0.0001). In subgroup analyses, the 5-year OS of CUP patients with adenocarcinoma (n⫽1,389, median OS⫽1.83) was significantly worse when compared to metastatic adenocarcinoma of known primary (log-rank test p⬍0.0001). An identical result was obtained with CUP patients of undifferentiated histology (n⫽3,230). The 5-year OS of CUP patients with squamous cell carcinoma (n⫽247, median OS⫽18.5) did not differ significantly with those of other squamous cell carcinoma groups of known primary (log-rank test p⬎0.56). Conclusions: Although CUP patients as a whole have a poor prognosis compared to other metastatic patients of known primary, distinct subsets of CUP patients have similar prognosis. These data suggest that an intensive diagnostic approach for identification of the primary is not justified for all CUP patients.


112s TPS1606

Cancer Prevention/Epidemiology General Poster Session (Board #10C), Mon, 1:15 PM-5:00 PM

TPS1607


Investigating hereditary risk from T790M (inherit): A prospective multicentered study of risk associated with germ-line EGFR T790M. Presenting Author: Geoffrey R. Oxnard, Dana-Farber Cancer Institute, Boston, MA

Evaluation of whole body MRI for early detection of cancers in subjects with germ-line TP53 mutation (Li-Fraumeni syndrome). Presenting Author: Olivier Caron, Institut Gustave Roussy, Villejuif, France

Background: The EGFR T790M mutation, commonly associated with acquired resistance to EGFR kinase inhibitors, has also been seen as a germline mutation in association with familial lung cancer. In collaboration with the Addario Lung Cancer Medical Institute (www.ALCMI.net), we initiated a prospective trial to identify patients and families carrying germline EGFR mutations in order to characterize their cancer risk. Preliminary data: In a prior study (Oxnard et al, JTO, 2012), it was found that patients with lung cancers found to harbor EGFRT790M at diagnosis have a 50% chance of carrying an underlying germline T790M mutation. This suggests that study of patients known to carry T790M in their cancer will enrich for a germline event that otherwise is too rare to study prospectively. Subject eligibility: Three cohorts are eligible: (1) Patients with a cancer (lung or other) harboring EGFR T790M on tumor genotyping; lung cancers that acquire EGFR T790M only after treatment are ineligible. (2) First-degree relatives of patients carrying a germline EGFR mutation. (3) Patients already known to carry a germline EGFRmutation on prior testing. Subjects are referred to cohort 1 based upon routine genotyping results from commercial laboratories (e.g. Response Genetics Inc., Los Angeles, CA). Methods: Subjects may present at a participating cancer center or may participate remotely through a study website (www.DanaFarber.org/T790Mstudy). Eligible patients submit a saliva and/or blood specimen for central testing in a CLIA lab. After counseling, patients carrying germline EGFR mutations have the option of inviting first-degree relatives to participate. Genetic counseling is coordinated at the participating center or offered over the phone. Chest CT scans are collected from germline carriers and analyzed centrally to study nodule characteristics. Patients are clinically followed for 2 years. At time of submission, 6 subjects have enrolled from 3 different families and 4 different US states. (NCT01754025) Funding: Supported by grants from the Conquer Cancer Foundation of ASCO and the Bonnie J. Addario Lung Cancer Foundation. Clinical trial information: NCT01754025.

Background: The TP53 germline mutation carriers have a huge increase of cancer risk. The cancer spectrum is particularly broad (breast, sarcoma, brain tumour, leukaemia, . . .). The clinical management of these people is challenging, mainly concerning sarcoma screening. Moreover, some data let speculate that normal cells of these carriers are particular hypersensitive to X-rays. Among major breakthroughs in radiology, whole-body MRI (WBMRI) may contribute to TP53 carriers surveillance. In order to update the french guidelines on Li-Fraumeni families management, the LIFSCREEN study (NCT01464086) was designed to assess its usefulness in France. Methods: This open, randomized, multicentric trial will evaluate the efficacy and tolerability of two screening schemes, avoiding irradiating exams. In the standard arm, people undergo clinical exam, abdominal sonography, brain MRI, Complete Blood Count, breast MRI, breast sonography, depending on the age) at inclusion, Month 12, Month 24, and a study visit at Month 36. In the experimental arm, people included undergo the same scheme, completed by a diffusion WBMRI at M0, M12, M24. At each round, quality of life and psychological impact will be assessed by self-questionnaires and semi-structured qualitative interviews. In an ancillary study, serums will be collected at each step. Subjects meeting these criteria are eligible: any TP53 germline mutation carrier, with or without personal cancer history, aged ⬎5 and ⬍71. A hundred people will be enrolled and randomized. The primary objective is to assess the efficiency of each scheme, evaluated by the cancer incidence at 3 years. Notably, sensitivity and specificity of each exam will be studied. As a secondary objective, the acceptability of each scheme will be assessed by quality of life / psychological questionnaires interpretation (SF-36, HADS, TAS 20, CBCL, CDI, R-CMAS, depending on subject’s age). Recruitment began in December, 2011. To date, 32 patients have been enrolled on 8 french study sites. The study will soon be implemented in another 12 sites. This academic study is, to our knowledge, the first randomized trial on this topic, and supported by the french “Ligue contre le cancer.” Clinical trial information: NCT01464086.

TPS1608

TPS1609



Change in mammographic density with metformin use: A companion study to NCIC study MA.32. Presenting Author: Marie E. Wood, University of Vermont College of Medicine, Burlington, VT

A pilot chemoprevention study of isopropanolic black cohosh extract in women with ductal carcinoma in situ. Presenting Author: Erin Wysong Hofstatter, Yale Cancer Center, New Haven, CT

Background: Metformin may have growth inhibitory effects on many cancer types including breast cancer. NCIC MA.32 is a randomized placebocontrolled trial examining the effects of 5 years of metformin in women with breast cancer (http://clinicaltrials.gov/show/NCT01101438). This trial offers us the opportunity to explore the effects of metformin on breast cancer biomarkers to gain an understanding of the potential chemo preventive effects of this drug. The primary aim of this companion to MA.32 (Alliance trial # A211201) is to examine the effects of 1 year of metformin vs placebo on breast density for women with Estrogen Receptor negative (ER-) breast cancer. Secondary aims of this study include: evaluation of breast density following 2 years of metformin use, and correlation of density with fasting insulin, glucose and Homeostasis Model Assessment (HOMA). Exploratory aims include examination of the effects of metformin on second cancer rates. Methods: Eligible women must have been enrolled on MA.32 (North America accrual completed January 23, 2013), have hormone receptor-negative breast cancer, and breast composition on mammography ⬎25% glandular density, have a digital mammogram within 12 months of registration on MA.32 and have an intact, unaffected contralateral breast. Women enrolled on this study must provide menstrual cycle data (if premenopausal) and digital mammograms. All other study related information is gathered through participation in MA.32. Mammographic density will be calculated using Cumulus software (the Boyd method). Our accrual goal is 458 patients (229 per arm) and with an assumption of 20% drop out due to drug intolerance and another 20% due to ineligibility. Therefore, with a sample size of 274 (137 per arm) we will have at least 85% power to detect a 4% difference between study arms, i.e., 5% change from baseline to one year of treatment for metformin vs. 1% for placebo, using the two-sided two-sample t-test at a significance level of 5%. This study was activated in the United States on 8/22/2012 and 15 patients have been accrued to date. This study is sponsored by the NCI and the Alliance for clinical trials. Clinical trial information: NCT01666171.

Background: Recent evidence suggests that black cohosh (Cimicifuga racemosa) may be a potential agent for breast cancer prevention. The active ingredients in black cohosh preparations appear to be triterpene glycosides. Recent preclinical data suggest several mechanisms by which triterpenes may prevent and treat breast cancer, including anti-proliferative, pro-apoptotic, anti-estrogenic, and anti-inflammatory effects. Epidemiologic data demonstrate a significant protective effect of black cohosh against the development of breast cancer in healthy women, and prolonged disease-free survival in breast cancer patients. There is also abundant evidence demonstrating the safety and tolerability of black cohosh in several clinical trials studying its use for treatment of hot flashes. We hypothesize that efficacy of black cohosh can be demonstrated in a pilot pre-operative window trial in a cohort of women with ductal carcinoma in situ (DCIS). Methods: In this trial, we treat women with a 2-5 week pre-operative course of commercial standardized isopropanolic black cohosh extract (20 mg orally twice per day). We aim to demonstrate a reduction in breast epithelial cell proliferation as measured by Ki-67 staining in regions of DCIS using traditional IHC staining and AQUA analysis. We also assess safety and tolerability of black cohosh through monitoring of patient adherence, liver function tests and serum hormone levels. 22 patients will be enrolled onto the trial. Sample size is based on power calculations for the specific study aim of determining the mean change in the levels of Ki67, using a targeted effect size. Assuming a 10% drop-out rate, a sample size of 20 patients will achieve 91% power to detect a 0.8 standard deviation of difference with a two-sided significance level at 0.05 using Wilcoxon signed-rank test. Eligible subjects are pre- and post-menopausal women ⱖ 18 years of age newly diagnosed with DCIS histologically confirmed on breast core biopsy, prior to definitive excision. Women who have recently taken any agent known to affect Ki67 levels in the breast (e.g. hormone therapy) are excluded. Enrollment is currently ongoing with 10 of 22 patients accrued. Clinical trial registry number NCT01628536. Clinical trial information: NCT01628536.


Cancer Prevention/Epidemiology TPS1610

113s


Randomized, placebo controlled, phase III trial of low-dose tamoxifen in women with intraepithelial neoplasia. Presenting Author: Matteo Puntoni, E.O. Ospedali Galliera, Genoa, Italy Background: Breast IntraEpithelial Neoplasia (IEN) is associated with a 8-10 fold increased risk of invasive disease, thus representing an important target for chemoprevention. The NSABP-P1 trial showed that tamoxifen (TAM) at 20 mg/day is associated with a 86% reduction of invasive breast cancer (BC) in women with previous atypical ductal hyperplasia (ADH) (RR⫽0.14, 95% IC, 0.03-0.47) and with a 56% risk reduction in women with previous LCIS (RR⫽0.44, 0.16-1.06). However, TAM broad use in chemoprevention has been significantly hampered by the increased risk of endometrial cancer and of venous thromboembolism (VTE). We recently showed that a dose of 5 mg/day does not increase endometrial proliferation, is associated with a decrease of the estrogenic activity of TAM on IGF-I, SHBG and antithrombin-III, and attains at the breast tissue level a concentration 10 times higher than that needed to inhibit cell growth in vitro. The CYP2D6 enzyme mediates oxidation of N-desmethyl tamoxifen to endoxifen, the most active metabolite of TAM. The SNP CYP2D6*4 (1846G⬎A) allele accounts for 75% of poor metabolizer phenotype which have been associated with a higher risk of a breast event compared to wildtype (Pharmacogenomics J. 2011;11:100-7). Methods: A randomized double-blind placebo-controlled phase III trial to assess the efficacy and safety of 5 mg/day TAM vs. placebo for 3 years in women with previous IEN (LIN 2-3 and ER⫹ or unknown DIN 1b-3). In Europe TAM is not registered in women with prior DCIS. 1400 women are needed to detect 50% reduction in the incidence of BC in the TAM arm (80% power, 1-sided 5% ␣ error). Secondary endpoints are: incidence of other non-invasive breast disorders, endometrial cancer, clinical bone fractures, cardiovascular events, VTE events, and clinically manifest cataract. Pharmacogenetic endpoints includes the association between CYP2D6 genotype and modulation of biomarkers of TAM efficacy and safety (circulating IGF-I, hormones, mammographic density, endometrial thickness and hot flashes) and clinical events. As of February 5, 2013, 18 enrolment centers have been activated and n⫽338 women have been randomized. No suspected unexpected serious adverse reactions were registered. Clinical trial information: NCT01357772.


114s LBA2000

Central Nervous System Tumors Oral Abstract Session, Sat, 3:00 PM-6:00 PM

Bevacizumab, irinotecan, and radiotherapy versus standard temozolomide and radiotherapy in newly diagnosed, MGMT-non-methylated glioblastoma patients: First results from the randomized multicenter GLARIUS trial. Presenting Author: Ulrich Herrlinger, Division of Clinical Neurooncology, Department of Neurology and Center of Integrated Oncology Cologne/Bonn, University of Bonn, Bonn, Germany

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Saturday, June, 1, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.

2001

Oral Abstract Session, Sat, 3:00 PM-6:00 PM

A randomized phase II study of bevacizumab versus bevacizumab plus lomustine versus lomustine single agent in recurrent glioblastoma: The Dutch BELOB study. Presenting Author: Walter Taal, Erasmus MC, Rotterdam, Netherlands Background: Bevacizumab (BEV) is widely used in recurrent glioblastoma, alone or in combination with other agents. There is however no wellcontrolled trial to support the use for this indication. Methods: In a three-arm Dutch multicenter randomized phase II study (NTR 1929) patients were assigned to either BEV 10 mg/kg iv every 2 weeks, BEV 10 mg/kg iv every 2 weeks and 110 mg/m2 lomustine every 6 weeks, or lomustine 110 mg/m2every 6 weeks. Eligible were patients with histologically proven glioblastoma, with a first recurrence after chemo-irradiation with temozolomide, having concluded radiotherapy more than 3 months ago, with adequate bone marrow, renal and hepatic function, and WHO performance status (PS) 0-2. Primary endpoint was 9 months overall survival (OS); P0 was set at 35% and P1 at 55%. Progression was defined using RANO criteria. A safety review after the first 10 patients in the combination arm was preplanned. Results: Between December 2009 and November 2011, 153 patients were enrolled of whom 148 were considered eligible. Median age was 57 years (range, 24-77) and median WHO PS was 1. With respect to prognostic factors groups were well balanced. After review of the safety cohort the dosage lomustine in the combination arm was lowered to 90 mg/m2 because of hematological toxicity (predominantly thrombocytopenia without symptoms). At this lower lomustine dose level the combination treatment was in general well tolerated. Outcome: see Table. Conclusions: In this first well-controlled study on BEV in recurrent glioblastoma with a primary OS endpoint, combination treatment with bevacizumab and lomustine met the prespecified criterion for further investigation in clinical trials, whereas both drugs given as single agent failed to meet this criterion. Clinical trial information: NTR1929. Treatment BEV Lomustine BEV/lomustine 90 mg/m2 BEV/lomustine 110 mg/m2

n

% 9 mo OS [95% CI]

Median PFS (mo)

% 6 mo PFS [95% CI]

50 46 44 8

38% [25, 51] 43% [29, 57] 59% [43, 72] 88% [39, 98]

3 2 4 11

18 [9, 30] 11 [4, 22] 41 [26, 55] 50 [15, 77]

n: number of patients, PFS: progression free survival, CI: confidence interval, mo: months.

2002^


Tumor response based on adapted Macdonald criteria and assessment of pseudoprogression (PsPD) in the phase III AVAglio trial of bevacizumab (Bv) plus temozolomide (T) plus radiotherapy (RT) in newly diagnosed glioblastoma (GBM). Presenting Author: Wolfgang Wick, University of Heidelberg Medical Center, Heidelberg, Germany Background: Until recently the primary criteria for assessing response to GBM therapy were those by Macdonald et al. (JCO 1990;8:1277– 80). Advances in imaging technology/targeted therapies exposed limitations, addressed in 2010 by Response Assessment in Neuro-Oncology Working Group. Prior to this, the AVAglio study similarly adapted Macdonald criteria to address anti-angiogenic therapy/corticosteroid use by incorporating non-contrast-enhancing components and integrating a strict algorithm to standardize assessment of possible PsPD. Methods: Randomisedpts (n⫽921) received: T/RT ⫹ Bv or placebo (P), 6 wks; 28-d break; maintenance T ⫹ Bv or P (6 cycles); monotherapy Bv or P until PD/unacceptable toxicity. Tumor response was investigator (inv)-assessed by MRI (adapted Macdonald criteria) at baseline (BL), end of break, every 2nd maintenance cycle, every 9 wks during monotherapy, at PD and 9 wks post-PD. PsPD was inv-assessed at the end of the break. A ⱖ25% increase in index lesions and/or unequivocal progression of existing non-index lesions relative to BL and in the absence of clinical deterioration was assessed as PsPD. Confirmatory PsPD assessment: end of the 2nd maintenance cycle. If progression was confirmed, PsPD was retrospectively designated as PD. If PsPD was confirmed, pts remained on treatment and the 1st post-RT MRI was used as a new BL. Best ORR was evaluated in pts with lesions at BL, excluding pts with confirmed PsPD. Results: Co-primary endpoint of inv-assessed PFS was longer for pts receiving Bv⫹RT/T compared with P⫹RT/T (HR 0.64, 95% CI 0.55– 0.74; p⬍0.0001). Best ORR and PsPD are shown (Table). Conclusions: Addition of Bv to 1st-line T/RT significantly improves ORR. The rate of confirmed PsPD was low in both arms. Clinical trial information: NCT00943826. Best ORR n Responders, n % (95% CI) Difference, % (95% CI) n

Bv⫹T/RT 375 144 38.4 (33.5–43.5)

P⫹T/RT 366 66 18 (14.2–22.4) 20.4 (13.9–26.8) p⬍0.0001 PsPD

458

463 End of treatment break

Potential PsPD, n (%) Confirmed PsPD, n (%) Rejected PsPD, n (%) Missing, n (%)

12 (2.6) 84 (18.1) Post-2nd maintenance cycle 10 (2.2) 43 (9.3) 1 (0.2) 35 (7.6) 1 (0.2) 6 (1.3)

2003


Comparative impact of treatment on patient reported outcomes (PROs) in patients with glioblastoma (GBM) enrolled in RTOG 0825. Presenting Author: Terri S. Armstrong, University of Texas Health Science Center School of Nursing, Houston, TX Background: RTOG 0825 tested if adding bevicizumab (BEV) to standard chemoradiation improves survival (OS) or progression free survival (PFS) in newly diagnosed GBM. While OS was equivalent, PFS was longer with Bev (Arm 2) than with placebo (Arm 1). Patients completed quality of life and symptom PROs to evaluate clinical benefit. Methods: The M.D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) and the EORTC core Quality of life Questionnaire and brain tumor module (EORTC QLQ-C30/ BN20), were completed by pts at baseline (B) and longitudinally (wk 6, 10, 22, 34, and 46) while on study. The difference between treatment arms were compared from B with evaluation in subsequent weeks in those pts without disease progression; and early change (EC) (baseline to wk 10) between those with and without progression as predictors for OS and PFS. Results: 542pts consented to participate on this trial, and 507 randomized pts participated, with completion of forms by 94% at baseline, 75% at wk 10, 61% at wk 22, and 58% at wk 34. There was a trend for all MDASI-BT symptom groupings to be worse in Arm 2, with significant findings in treatment symptoms at wk 22 and wk 34; both affective and generalized disease symptoms were also significantly worse. For EORTCQLQ30/BN20, differential effects varied at each time point, with no persistent differences. For the MDASI-BT, B neurologic symptom grouping and EC in cognitive symptoms were prognostic for both OS and PFS. For the EORTC QLQ30/ BN20, global QOL and motor dysfunction at B as well as EC in communication and leg weakness were prognostic for OS; whereas physical function at B and EC in headaches, seizures, and weak legs were prognostic for PFS. Conclusions: The longitudinal collection of PROs in this phase III trial revealed important treatment-related differences as there was overall more deterioration in symptoms and QOL in Arm 2 as compared to Arm 1, with persistent significant differences in treatment associated symptoms. B and EC tumor associated symptoms on both PRO tools were prognostic for OS and PFS. Longitudinal modeling is ongoing to further assess for differential impact of treatment on symptoms and QOL. Support: U10 CA21661, U10 CA37422 and Genentech, Inc. Clinical trial information: NCT00884741.


Central Nervous System Tumors 2004


Neurocognitive function (NCF) outcomes in patients with glioblastoma (GBM) enrolled in RTOG 0825. Presenting Author: Jeffrey Scott Wefel, The University of Texas M.D. Anderson Cancer Center, Houston, TX Background: RTOG 0825 evaluated overall survival (OS) and progressionfree survival (PFS) differences in patients with newly diagnosed GBM treated with standard chemoradiation, maintenance temozolomide and placebo (Arm 1) or bevacizumab (Arm 2). While OS was equivalent, PFS was longer in Arm 2. Longitudinal NCF testing was performed to evaluate clinical benefit. Methods: NCF was evaluatedat baseline and while on study and progression free with the Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test (TMT) and Controlled Oral Word Association (COWA). Change in NCF from baseline was categorized using the reliable change index. Differences between treatment arms were compared at follow-up evaluations. Additionally, baseline (B) and early changes (EC) (B to week 10) in NCF were examined as prognostic factors. Results: 542 patients consented and 507 randomized patients participated, with test completion rates at weeks 0 (B), 10, 22, and 34 of 94-97, 69-73, 59-64, and 53-58%, respectively. Mean test performance at B was equivalent between arms and ranged from -0.8 to -4.8 SDs below healthy population norms with global NCF on a composite variable at -2.0 SDs. There were no statistically significant between arm differences in frequency of improvement through week 34. Decline on COWA (verbal measure of executive function) at week 34 relative to baseline was more common (16.1 vs 5.7%) in patients in Arm 1 (p⬍0.05); whereas, there were trends for more decline in Arm 2 on a visuomotor measure of executive function (TMT B, p⬍ 0.06; 22.2 vs 35.4%). B performance and EC in global NCF, memory, executive function and processing speed were prognostic for OS. At B, global NCF was prognostic for PFS. EC in global NCF, memory and executive function were prognostic for PFS. Conclusions: There was a statistically significant difference in the frequency of decline on a verbal test of executive function at week 34 favoring Arm 2. However, this was not found at earlier time points and was not found on a visuomotor test of executive function. B and EC in NCF were prognostic for OS and PFS. Longitudinal modeling is ongoing to further evaluate the impact of treatment on patients’ NCF. Support: U10 CA21661, U10 CA37422 and Genentech, Inc. Clinical trial information: NCI-2009-01670.

2006


Phase III randomized, double-blind, placebo-controlled trial of donepezil in irradiated brain tumor survivors. Presenting Author: Stephen R. Rapp, Wake Forest University, School of Medicine, Winston Salem, NC Background: This RCT assessed the effect of 24 weeks of 5-10 mg per day of donepezil, an acetyl cholinesterase inhibitor, on cognitive functioning (primary endpoint) and fatigue, mood and QOL in long-term brain tumor survivors following partial or whole-brain irradiation. Cognitive results are reported herein. Methods: From 2/08-12/11,198 adult primary and metastatic brain tumor survivors ⬎ 6 months post radiation treatment (⬎30 Gray) recruited at 24 sites affiliated with the Wake Forest Community Clinical Oncology Program Research Base, 3 CTSU sites and M.D. Anderson Cancer Center were randomly assigned to receive donepezil (n⫽99) or placebo (n⫽99). Cognitive function was assessed at baseline, 12 and 24 weeks with Hopkins Verbal Learning Test-Revised, ReyOsterreith Complex Figure, Trail Making Test, Digit Span, Controlled Oral Word Association, and Grooved Pegboard. A Cognitive Composite (CC) score was the primary outcome. Results: The sample was 91% White, 54% female, and median age was 55 yrs. 66% had primary tumors, 27% brain metastases and 8% PCI. Median time since diagnosis: 38 mos. 95% had 0-1 ECOG performance status scores. 74% completed the study. CC score improved significantly by 24 weeks in both arms (p ⬍ .01); however, there was not a statistically significant difference between groups (p ⫽ .57). Donepezil group performed better than placebo on HVLT Recognition (p ⫽ .03) and Discrimination (p ⫽ .01) and GP-Dominant Hand (p ⫽ 0.02). Significant interactions were found between treatment arm and baseline cognitive scores for: CC (p ⫽ .01), HVLT Immed. Recall (p ⫽ .03), HVLT %Savings (p ⬍ .01), Digit Span Forward (p ⫽ .01), ROCF Copy (p ⫽ .03), TMT-B (p ⫽ .05) and GP-Dominant (p ⬍ .01). In all cases, the benefit of donepezil, relative to placebo, was greater for those with worse baseline scores. Conclusions: Long-term brain tumor survivors treated with brain irradiation who have cognitive impairment can benefit from 5-10mg of donepezil for 24 weeks. Improvements in verbal memory, working memory, visuo- and psychomotor performance and executive functioning were observed in this group. (Study supported by NIH/NINR grant 5R01NR009675-04, NIH/NCI grant 2 U10 CA 81851-09-13 and Eisai, Inc.) Clinical trial information: NCT00369785.

115s

2005^


Progression-free survival (PFS) and health-related quality of life (HRQoL) in AVAglio, a phase III study of bevacizumab (Bv), temozolomide (T), and radiotherapy (RT) in newly diagnosed glioblastoma (GBM). Presenting Author: Roger Henriksson, Regional Cancer Center Stockholm; Umeå University Hospital, Stockholm/Umeå, Sweden Background: GBM has a high disease burden and poor prognosis, and impacts negatively on HRQoL. Symptomatic therapies for GBM, such as corticosteroids (CS), may impact patient status negatively Methods: AVAglio, a randomized, double-blind, placebo (P)-controlled trial in patients (pts) ⱖ18 yrs with newly diagnosed GBM, evaluated the addition of Bv or P (10mg/kg, q2w) to 6 wks of T (75mg/m2/d) ⫹ RT (2Gy, 5d/wk) followed by 28 treatment-free days, then 6 cycles of T (150 –200 mg/m2/d, 5d q4w) with Bv or P (10 mg/kg, q2w), and then single-agent Bv or P (15 mg/kg, q3w) until disease progression (PD)/ unacceptable toxicity. Co-primary endpoints were investigator-assessed PFS and overall survival. Secondary endpoints included HRQoL (EORTC QLQ-C30 and BN20, with 5 prespecified domains based on relevance in GBM). HRQoL time to definitive deterioration (TDD) was defined as time from randomization to ⱖ10 point deterioration from baseline with no subsequent improvement, PD, or death. Exploratory endpoints included KPS and CS use. Results: Baseline characteristics were well balanced. Bv significantly prolonged PFS (HR 0.64, 95% CI 0.55– 0.74, p⬍0.0001; median 10.6 vs 6.2 mo) and delayed TDD in HRQoL compared with P (p⬍0.0001; Table). Functional independence (KPS ⱖ 70%) was maintained during PFS in both arms (median Bv vs P: 9 vs 6 mo). Among pts on CS (ⱖ 2mg) at baseline, discontinuation (ⱖ 5 consecutive days) was more frequent with Bv than P (66% vs 47%). In pts off CS at baseline (⬍ 2mg), time to CS initiation was significantly longer with Bv than P (HR 0.71, 95% CI 0.57– 0.88; median 12.3 vs 3.7 mo). Conclusions: Addition of Bv to RT/T provided a clinically meaningful and statistically significant PFS improvement associated with stable/improved HRQoL and KPS, and reduced CS requirement. Clinical trial information: NCT00943826. P ⴙ RT/T Bv ⴙ RT/T (nⴝ463 (nⴝ458) HR (95% CI) P value ⬍0.0001

KM-estimated median TDD, mo Global health status 3.9 6.4 Physical functioning 4.2 6.1 Social functioning 4.1 7.4 Motor dysfunction 5.0 8.6 Communication deficit 4.2 6.9

2007

0.64 (0.56–0.74) 0.70 (0.61–0.81) (0.63 (0.55–0.73) 0.67 (0.58–0.78) 0.67 (0.58–0.77)


Temozolomide chemotherapy versus radiotherapy in molecularly characterized (1p loss) low-grade glioma: A randomized phase III intergroup study by the EORTC/NCIC-CTG/TROG/MRC-CTU (EORTC 22033-26033). Presenting Author: Brigitta G Baumert, Department of RadiationOncology (MAASTRO), GROW (School for Oncology), Maastricht University Medical Center, Maastricht, Netherlands Background: Outcome of low-grade glioma (LGG) is highly variable. We investigated whether primary chemotherapy in comparison to standard radiotherapy (RT) prolongs progression-free (PFS) and overall survival (OS), and whether prognostic molecular factors could be defined. Methods: Progressive, symptomatic or high-risk patients with a LGG requiring treatment other than surgery were randomized (after stratification for 1p-status) to either conformal RT (50.4 Gy/28 fractions) or dose-dense temozolomide [TMZ] (75 mg/m² daily x 21 days, q28 days, max. 12 cycles). Primary endpoint was PFS, secondary analyses included OS and impact of 1p status. Results: 477 patients were randomized (2005-2012, median FU 45.5 months). Analysis was performed after 246 progression events. Hematological toxicity ⱖ grade 3 was observed in 9.4% of TMZ patients. PFS was not significantly different, median OS not reached. 1p deletion was a positive prognostic factor irrespective of treatment (p-value stratified by treatment (PFS: 0.0003;HR⫽0.59 95% CI(0.45-0.78)/OS: 0.002; HR⫽0.49 95% CI (0.32-0.77)). Conclusions: First-line treatment with TMZ compared to RT did not improve PFS in high-risk LGG patients. Although interaction test was not significant, there was a trend for inferior PFS in patients treated by TMZ with 1p intact, while OS may be better when 1p-deleted patients receive TMZ upfront. Survival analysis requires further maturation of the data. Clinical trial information: EudraCT number 2004-002714-11.

Age (median, range) WHO PS 0-1 Histology Astrocytoma/Oligoastro. Oligodendroglioma 1p Deleted Undetermined Surgery Debulking / complete Biopsy PFS All patients 1p intact 1p deleted OS All patients 1p intact 1p deleted

RT (nⴝ240)

TMZ (nⴝ237)

44 yrs (18-72) 95% 36 / 24% 39% 41% 15%

45 yrs (19-75) 97% 33 / 25% 41% 41% 14%

60% 40%

61% 39%

(median, CI) (median, CI) 47 mo (40, 56) 40 mo (35, 44) 41 mo (32, 55) 30 mo (24, 40) 58 mo (41, 67) 55 mo (38, N) Interaction test: n.s Not reached 74 (69, N)

TMZ vs RT HR (CI), p value

246 events 1.16 (0.9, 1.5) p⫽0.23 1.41 (0.9, 2.0) p⫽0.06 1.01 (0.7, 1.5) p⫽ 0.95 108 events 0.9 (0.6, 1.3) p⫽0.55 1.03 (0.6, 1.7) p⫽ 0.9 0.47 (0.2, 1.0) p⫽0.05

Interaction test: n.s


116s 2008

Central Nervous System Tumors Oral Abstract Session, Sat, 3:00 PM-6:00 PM

A phase II study of a temozolomide-based chemoradiotherapy regimen for high-risk low-grade gliomas: Preliminary results of RTOG 0424. Presenting Author: Barbara Jean Fisher, Department of Radiation Oncology, London Regional Cancer Program, London, ON, Canada Background: The primary endpoint of RTOG 0424 was to compare the 3-year survival (OS) of a regimen of concurrent and adjuvant temozolomide (TMZ) and radiotherapy (RT) in a high-risk low-grade glioma (LGG) population to the 3 year (yr) OS rate of the high risk EORTC LGG patients (pts) reported by Pignatti et al (J Clin Oncol 2002;20(8):2076-84). Secondary endpoints were: progression-free survival (PFS), toxicity, neurocognitive and quality of life data and molecular analysis. Methods: Pts with LGG’s and ⬎⫽3 high risk factors (age⬎ ⫽ 40, astrocytoma dominant histology, tumor crossing midline, tumor ⬎ ⫽ 6 cm or preoperative neurological function status ⬎1) were eligible and treated with conformal RT (54 Gy/30 fractions) plus concurrent TMZ 75 mg/m2 /day for 6 weeks and post-RT TMZ 150-200 mg/m2/day days 1-5 q28 days for up to 12 cycles. The study was designed to detect a 43% increase in median survival time (MST) from 40.5 to 57.9 months, and a 20% improvement in 3 yr OS rate from 54% to 65%, at a 10% significance level (1 sided) and 96% power. Results: Between January 2005-August 2009 136 pts were accrued, 129 (75 males, 54 females) were evaluable. Median age was 49 years, 91% had a Zubrod score 0-1 and 69%, 25% and 6% of pts had 3,4 and 5 high risk factors respectively. With a median follow-up time of 4.1 yrs, minimum follow-up of 3 yrs, MST has not yet been reached. Three year OS rate was 73.1% (95%CI:65.3-80.8%), significantly improved from historical control with a p-value ⬍0.0001. No difference in OS rates for pts with 3, 4 or 5 high risk factors was seen. 3 year PFS was 59.2% (95% CI:50.7-67.8%). Grade 3 adverse events (AE) occurred in 43% of pts and grade 4 AE in 10%, primarily hematologic, constitutional or gastrointestinal (nausea, anorexia) toxicity. One patient died of herpes encephalitis. Secondary analyses are ongoing. Radiation Quality Assurance was per protocol/ acceptable in 95% and 74% of pts completed chemotherapy per protocol. Conclusions: The 3 year OS rate of 73.1% for these high risk LGG pts is significantly higher than those reported for historical controls (54%, p ⬍ 0.0001, one-sided) and the study-hypothesized 65%. Supported by RTOG U10 CA21661 and CCOP U10 CA37422 grants from NCI and Merck Clinical trial information: NCT00114140.

LBA2010

Clinical Science Symposium, Sun, 8:00 AM-9:30 AM

Molecular predictors of outcome and response to bevacizumab (BEV) based on analysis of RTOG 0825, a phase III trial comparing chemoradiation (CRT) with and without BEV in patients with newly diagnosed glioblastoma (GBM). Presenting Author: Erik P. Sulman, The University of Texas MD Anderson Cancer Center, Houston, TX


LBA2009


Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation: Final results of the multicenter, randomized, open-label, controlled, phase III CENTRIC study. Presenting Author: Roger Stupp, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland


2011


Optimizing the identification of anaplastic oligodendroglioma patients that benefit from adjuvant PCV chemotherapy using the Illumina platform: A further report from EORTC study 26951. Presenting Author: Martin J. Van Den Bent, Erasmus MC, Rotterdam, Netherlands Background: Adjuvant PCV chemotherapy improves overall survival (OS) in 1p/19q co-deleted grade 3 gliomas. Analyses of EORTC 26951 and RTOG 9402 suggest that other molecularly defined subsets of grade III tumors benefit as well. We previously identified a CpG-Island Hypermethylated Phenotype (CIMP⫹) as a candidate biomarker. This was further explored in a larger series using snap frozen (SF) or formalin fixed paraffin embedded (FFPE) tumor material, and compared to the value of 1p/19q, IDH1/2 and MGMT status. Methods: Methylation profiles were assessed using the Infinium HumanMethylation 27 or 450 BeadChip (Illumina). MGMT promoter methylation was re-assessed with a logistic regression model (MGMT-STP27) using probes cg1243587 and cg12981137 of the platform as described (Bady et al, Acta Neuropathol 2012;124:547-60). These probes correspond to area’s of the promoter correlated to MGMT protein expression. Previously, MGMT promoter methylation had been assessed using methylation specific multiplex ligation-dependent probe amplification (MS-MLPA). Results: Methylation profiling was conducted in 115 patients. CIMP status correlation between FFPE and SF was excellent (R2 0.96). In multivariate analysis, 1p/19q co-deletion and CIMP status were independent prognostic factors. Although 1p/19q status and IDH mutational status identify subgroups with more benefit of PCV chemotherapy, tests for interaction remain negative (p 0.25 and 0.33 respectively); MGMTstatus (MS-MLPA) had no impact (p ⫽ 0.70). However, CIMP status was of borderline predictive significance (p⫽ 0.07), and MGMTSTP27 was of statistical significance (p ⫽ 0.003; HR unmethylated 1.61, 95% CI [0.71, 3.66], HR methylated 0.37, 95% CI 0.23, 0.61]. Conclusions: CIMP status and MGMT promoter methylation assessed with Illumina HumanMethylation BeadChips appear the most informative tests for identifying grade III glioma patients benefitting from the addition of PCV to RT. Validation in an independent dataset is required. Clinical trial information: NCT00002840.



Poster Discussion Session (Board #1), Mon, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

Tumor pharmacokinetics (PK) and pharmacodynamics (PD) of SAR245409 (XL765) and SAR245408 (XL147) administered as single agents to patients with recurrent glioblastoma (GBM): An Ivy Foundation early-phase clinical trials consortium study. Presenting Author: Timothy Francis Cloughesy, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA Background: XL765 is a potent pan PI3K inhibitor with activity against mTOR and XL147 is a potent pan-PI3K inhibitor. Inhibition of the PI3K/mTOR pathway may be beneficial in the treatment of GBM. Methods: Patients with GBM who were candidates for a surgical resection were eligible for this exploratory study. Cohorts of 6-10 patients were treated with one of three regimens: Cohort 1: XL765 50mg twice daily (BID), Cohort 2: XL147 200mg once daily (QD), Cohort 3: XL765 90mg QD for ⬎10 days prior to undergoing tumor resection. Tumor tissue was obtained at ~12, 24 and 3 hours after the last dose, respectively. Frozen tumor tissue and blood were analyzed for drug concentration (PK) and pathway modulation was analyzed in post-dose frozen tumor tissue and compared to reference tumor samples from GBM patients not treated with XL765 or XL147. Pharmacodynamic impact (PD) on the pathway, apoptosis and proliferation was examined by immunohistochemistry (IHC) in an FFPE tumor sample from each patient and compared to an archived tumor sample from an earlier surgery. Results: Enrollment is complete with 21 patients enrolled; 6, 6 and 7 were evaluable for the PK/PD analysis in cohorts 1, 2 and 3, respectively. The toxicity profiles for both drugs were consistent with previous studies. PK analyses revealed a mean tumor to plasma ratio of 0.38 and 0.40 in cohorts 1 and 3 and 0.27 in cohort 2. PD analysis by IHC revealed reduction compared to archived tumor in pS6K1 in 4/6 and 7/7 patients in cohorts 1 and 3 and 6/6 patients in cohort 2. Reduction in Ki67 was observed in 6/6 and 5/7 patients in cohorts 1 and 3 and 4/6 patients in cohort 2. Conclusions: XL765 when given on a QD or BID schedule to patients with glioma yields moderately higher distribution of XL765 into CNS tumor compared to XL147 based on tumor to plasma ratios. Decreases in pS6K1, consistent with pathway inhibition, and decreases in Ki67, consistent with inhibition of proliferation, were observed following treatment with both XL147 and XL765. Clinical trial information: NCT01240460.

2014


NCCTG (Alliance) N0572: A phase II trial of sorafenib and temsirolimus in recurrent glioblastoma (GBM) patients who progress following prior RT/ temozolomide (TMZ) and VEGF inhibitors (VEGFi). Presenting Author: Kurt A. Jaeckle, Mayo Clinic, Jacksonville, FL Background: PFS6 is low (2.3%) and med OS brief (4 mos) for recurrent GBM pts who progress after prior RT/TMZ and bevacizumab (Bev), and then receive non-Bev containing regimens (Reardon et al, Br J Canc 2012). Following VEGFi exposure, tumor cell resistance potentially may result from activation of Ras/Raf/MEK/ERK (MAPK) and PI3K/Akt/mTOR signaling pathways. Temsirolimus (mTOR inhibitor) and sorafenib (Raf, PDGFR, VEGFR inhibitor) have previously shown limited single agent activity in GBM. Methods: Recurrent GBM pts who showed radiographic progression despite prior surgery, RT ⫹ temozolomide, and VEGFi (initially or at recurrence) received sorafenib 200 mg PO bid and temsirolimus 20 mg IV weekly (the NCCTG N0572 phase I MTD) until progression. All pts had received ⬍ 2 prior chemo regimens. A two-stage design was used, with 90% power to detect an increase in PFS6 from 8% to 23%, requiring 41 evaluable pts. The primary endpoint was PFS6; secondary endpoints included OS, TTP, and ORR. Toxicity (TOX) was assessed using CTC ver 3.0. Results: 44 evaluable pts were accrued. Four of the first 40 (10%) reached PFS6, but this did not meet the pre-study threshold for success. Median TTP was 1.8 mos. (40 events, 95% CI: 1.5 – 2.3); median OS was 5 mos. (36 events, 95% CI: 6.6 – 3.1), and no objective responses were reported. Eight pts are alive; 4 have not progressed (median F/U 3.1 mos.; max, 12.2 mos.). Grade 3⫹ non-heme AE were observed in 51% (23/45; fatigue-5, hypophosphatemia-7, hypercholesterolemia-5, hypertriglyceridemia-5). One grade 4 hematologic AE (thrombocytopenia) occurred. 13.3% (6/45 pts) went off due to TOX, and 71.1% (32/45) due to disease progression. Conclusions: Sorafenib plus temsirolimus was tolerable, but the primary endpoint threshold for success (PFS6) was not met in post-VEGFi recurrent GBM patients. Nevertheless, PFS6 (10%) and OS (5 mos.) compared favorably to contemporary series of Bev-refractory, recurrent GBM pts who are subsequently treated with a non-Bev containing regimen. Supported by NCI CA-25224. Clinical trial information: NCT00329719.

2013

117s


Interim analysis of a phase I/II study of panobinostat in combination with bevacizumab for recurrent glioblastoma. Presenting Author: Eudocia Quant Lee, Dana-Farber Cancer Institute, Boston, MA Background: Bevacizumab is frequently used to treat recurrent GBM, but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects in GBM and may work synergistically with bevacizumab. We conducted a multicenter phase I/II trial of panobinostat in combination with bevacizumab in patients with recurrent GBM. Methods: In the phase II trial, patients with recurrent GBM were treated with oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. The primary endpoint was 6-month progression-free survival (PFS6) and the study was powered to discriminate between a 35% and 55% PFS6 rate (85% power at an alpha level of 0.07). A planned interim analysis specified suspension of accrual and careful data review if 12 or more of the first 21 patients accrued to the study progress within 6 months of initiating treatment. Patients with recurrent GBM enrolled in the phase I study at the maximum tolerated dose (which is the phase II dose) were eligible for inclusion in the interim analysis. Results: Thirteen of the first 21 patients accrued to the GBM arm of the study had progressed within 6 months of initiating study treatment. The study was closed to further accrual and a planned interim analysis was performed. Median age was 53 (range 22-66) and median KPS was 80% (60%-100%). PFS6 rate was 33.9% [95% CI 12.8, 56.5), median was PFS 5 months [95% CI 3 months, NR], and median OS was 342 days [95% CI 203 days, NR]. Five patients (23.8%) achieved partial responses. Conclusions: Although reasonably welltolerated, this phase I/II study of panobinostat and bevacizumab in recurrent GBM did not meet criteria for continued accrual and the study was closed. Updated outcome and safety data will be presented at the meeting. Study Supported by: Novartis and Genentech Clinical trial information: NCT00859222.

2015


Phase II trial of the phosphatidyinositol-3 kinase (PI3K) inhibitor BKM120 in recurrent glioblastoma (GBM). Presenting Author: Patrick Y. Wen, Dana-Farber Cancer Institute, Boston, MA Background: The PI3K pathway is activated in most GBMs and represents a potential therapeutic target. BKM120 is an oral, pan-Class I PI3K inhibitor that enters the brain at therapeutic concentrations demonstrated to inhibit PI3K pathway, and potently inhibits the growth of U87 GBM tumors and human glioma tumor spheres in vitro and in vivo. Methods: The Ivy Foundation Early Phase Clinical Trials Consortium is conducting a phase II study of BKM120 in recurrent GBM patients with activation of the PI3K pathway (mutation, homozygous deletion or loss of IHC of PTEN, PIK3CA or PIK3RI mutations, or detectable pAKT). Additional eligibility criteria included radiologic progression, 1st or 2nd relapse, ⬎ 18 yrs, KPS ⬎ 60, adequate bone marrow and organ function, controlled blood glucose, and no enzyme-inducing antiepileptic drugs. Patients received BKM120 100mg daily. The study consisted of 2 parts conducted concurrently. Part 1 involved up to 15 patients who received BKM120 daily for 8-12 days prior to surgery for recurrent disease. Patients underwent FDG PET, pharmacokinetic (PK) studies, and tumor was obtained for drug concentrations and pharmacodynamic effects. Part 2 consisted of up to 50 patients with unresectable GBM treated with BKM120. The primary endpoint for Part 2 was 6-month progression-free survival (p0 ⫽15%; p1⫽ 32%). Results: To date 7 patients have been enrolled into Part 1, 33 into part 2. There were 5 women and 35 men. Median age was 54 yrs (29-68). Treatment was fairly well-tolerated. Major grades 3/4 toxicities were asymptomatic lipase elevation (5), fatigue (3), hyperglycemia (3), rash (3) elevated AST (1), and depression (1). Analysis of tumor from Part 1 showed reduction of pAkt by IHC. Genotyping of tumor specimens is ongoing. To date 33 patients had positive pAkt, 21 had PTEN loss by IHC. Of the first 19 patients who underwent whole exome sequencing, 3 had PIK3Ca mutations and 6 had PTEN mutations. Conclusions: BKM120 is generally well tolerated in patients with recurrent GBM and achieves adequate tumor concentration to inhibit pAkt. Updated PK and efficacy data and correlation of the latter with tumor genotype will be presented. Clinical trial information: NCT01339052.


118s 2016

Central Nervous System Tumors Poster Discussion Session (Board #5), Mon, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

Integrated data review of the first-in-human dose (FHD) study evaluating safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor, LY2157299 monohydrate (LY). Presenting Author: Jordi Rodon, Experimental Therapeutics Group, Vall d’Hebron Institute of Oncology, Barcelona, Spain

2017


A randomized phase II study of carboplatin and bevacizumab in recurrent glioblastoma multiforme (CABARET). Presenting Author: Kathryn Maree Field, Royal Melbourne Hospital, Parkville, Australia

Background: Activated TGF-ß signaling has been associated with poor survival in several tumors, including glioma (GM). Hence, we investigated the safety, PK and antitumor responses of the novel TGF-ß inhibitor LY in cancer patients, mainly in GM. Methods: There were 3 study parts: Part A: dose escalation of LY monotherapy in patients with solid tumor (cohorts 1 and 2, continuous dosing) and with GM (cohorts 3 to 5, intermittent dosing 14 days on/14 days off); Part B: intermittent LY dosing in combination with lomustine; Part C: monotherapy of 300 mg/day in solid tumors after completing a relative bioavailability study. Safety, antitumor activity, PK and PD were assessed as previously described (Calvo-Aller, et al. JCO 2008;26:abstract #14554; Rodon, et al. JCO 2011;29:abstract #3011; Azaro, et al. JCO 2012;30:abstract #2042). Results: 79 patients participated in this study (Part A, n ⫽ 39, 7 solid tumor, 32 GM; Part B, n ⫽ 26, all GM; Part C, n ⫽ 14 solid tumor, 9 GM, 2 hepatic cell carcinoma [HCC], 2 gastrointestinal [GI] and 1 melanoma). The integrated safety and efficacy evaluation confirms that LY has a manageable toxicity profile with antitumor activity. For GM patients the median progression-free survival (PFS) in months (range) was: 2.5 (0.0 to 36.9) in Part A; 2.5 (0.0 to 20.5) in Part B; 1.9 (0.0 to 6.4) in Part C. PFS duration in months were (range): 2.1-3.8 for HCC; 1.2-3.9 for GI and 2.2 for melanoma patient. Responders were observed in primary GM (Part A: 3/16; Part B: 2/20) and secondary GM (Part A: 3/14; Part B: 4/6). As of January 2013, 3 GM patients are still on treatment for 54, 36, and 31 months. P450-inducing medications including proton pump inhibitors or enzyme-inducing anti-epileptic drugs did not influence the PK parameters. Approximately, 90 biomarkers have been assayed and the results will be presented during the meeting. Conclusions: Because of the manageable toxicity profile of LY, the 300 mg/day dose administered as an intermittent dosing has been advanced into phase II investigation, either as a monotherapy or in combination with approved chemotherapies. Clinical trial information: NCT01682187.

Background: The optimal use of bevacizumab (bev) in recurrent glioblastoma (GBM) remains uncertain including the choice between monotherapy or combination therapy as well as the role of continuing bev beyond disease progression. Methods: This was a sequential stratified two part randomized phase II study. Eligibility criteria included: recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, ECOG PS 0-2. The primary objective (Part 1) was to determine the effect of bev plus carboplatin versus bev alone on 6 month progression-free survival (6PFS) using modified RANO criteria. Bev was given 2-weekly 10mg/kg, carboplatin 4-weekly AUC5. On progression, patients (pts) able to continue treatment were randomized to continue or cease bev (Part 2). Secondary endpoints included response rate (RR); cognitive function; quality of life; toxicity and overall survival (OS). Results: 122 pts (median age 55) were enrolled from 18 Australian sites. 87 (71.3%) were PS 0-1. The current median follow up is 14.7 months with median on-treatment time 3.7 months. 6PFS was 26% (combination) versus 24% (monotherapy) (HR 0.96, 95%CI (0.66, 1.39), p ⫽ 0.82). RR (CR⫹PR) was 15% versus 13%. Median OS was 6.9 versus 6.4 months (HR 1.08, 95%CI (0.74, 1.59), p ⫽ 0.68). There were 2 treatment (bev) related deaths in the combination arm (one GI perforation, one CNS hemorrhage). To date, overall incidence of bev-related AEs is similar to prior literature with 10 (8.3%) venous thromboembolic events and 5 (4.2%) hemorrhages (all grades) reported. There were 3 episodes of G3-4 neutropenia, all in the combination arm (5%) and 9 episodes of G3-4 thrombocytopenia. As of January 14, 2013, 47 pts have continued on to Part 2. Data for bev beyond progression is not yet available. Conclusions: In this study of patients with recurrent GBM, the addition of carboplatin to bev did not result in additional clinical benefit compared to bev monotherapy. This large multicentre population-based study demonstrated that clinical outcomes in patients with recurrent GBM treated with bev were inferior to previously reported studies. Ongoing follow-up of patients on bev beyond progression, and novel secondary and exploratory endpoints continues. Clinical trial information: ACTRN12610000915055.

2018

2019^



A first-in-human study of neural stem cells (NSCs) expressing cytosine deaminase (CD) in combination with 5-fluorocytosine (5-FC) in patients with recurrent high-grade glioma. Presenting Author: Jana Portnow, City of Hope, Duarte, CA

BTTC08-01: A phase II study of bevacizumab and erlotinib after radiation therapy and temozolomide in patients with newly diagnosed glioblastoma (GBM) without MGMT promoter methylation. Presenting Author: Jeffrey J. Raizer, Northwestern University, Feinberg School of Medicine, Chicago, IL

Background: Human NSCs are inherently tumor-tropic, making them attractive drug delivery vehicles. This pilot-feasibility study assessed the safety of using genetically-modified NSCs for tumor selective enzyme/ prodrug therapy. An immortalized, clonal NSC line was retrovirallytransduced to stably express CD, which converts the prodrug 5-FC to 5-fluorouracil (5-FU), producing chemotherapy locally at sites of tumor in the brain. Methods: Patients 18 years or older with recurrent high-grade glioma underwent intracranial administration of NSCs during tumor resection or biopsy. Four days later, 5-FC was administered orally every 6 hours for 7 days. Study treatment was given only once. A standard 3⫹3 dose escalation schema was used to increase doses of NSCs from 1 x 107 to 5 x 107 and 5-FC from 75 to 150 mg/kg/day. Intracerebral microdialysis was performed to measure brain levels of 5-FC and 5-FU; serial blood samples were obtained to assess systemic drug concentrations. Three patients received iron-labeled NSCs for MRI tracking. Brain autopsies were done on 2 patients. Results: Fifteen patients received study treatment. Three were inevaluable for toxicity and replaced. All patients tolerated the NSCs well. There was 1 dose-limiting toxicity (grade 3 transaminitis) possibly related to 5-FC. At the highest dose level of NSCs, the average steady-state concentration of 5-FU in the brain was 63.9⫾7.9 nM. The average maximum 5-FU level in brain was 104⫾88 nM compared to 24⫾36 nM in plasma, indicating local production of 5-FU in the brain by the NSCs. MR imaging of iron-labeled NSCs showed preliminary evidence of NSC migration. Autopsy data documented (by IHC, FISH, and PCR) NSCs at distant sites of tumor in the brain and no development of secondary tumors. Conclusions: This first-in-human study has demonstrated safety and proofof-concept regarding NSC-mediated conversion of 5-FC to 5-FU and NSC tumor-tropism. NSCs have the potential to overcome obstacles of drug delivery that limit current gene therapy strategies. Results of this pilot study will serve as the foundation for future NSC studies. (Supported by NCI 1R21 CA137639-01A1, CIRM DR-01421). Clinical trial information: NCT01172964.

Background: Patients (pts) with GBM with unmethylated MGMT have a worse prognosis than those with methylated MGMT. Novel approaches for this poor risk group are warranted. The Brain Tumor Trials Collaborative (BTTC) performed a phase II trial evaluating standard chemoradiation followed by bevacizumab and erlotinib in patients with MGMT unmethylated GBM. EGFR and VEGFR are upregulated during radiation suggesting that this combination could be more effective than post-radiation adjuvant temozolomide (TMZ). Methods: After informed consent, adult patients with supratentorial GBM, KPS ⱖ 70 and ⬎ 1 cm2 tumor block for MGMT promoter analysis were screened. Only tumors with confirmed unmethylated MGMT promoter were enrolled. All patients received RT ⫹ TMZ and then approximately 4 weeks after RT they received bevacizumab 10 mg/kg every 2 weeks and erlotinib 150 mg/day, continuously. One cycle was 4 weeks; evaluation by MRI was every 2 cycles. Treatment continued until disease progression or intolerable adverse events. Results: 115 patients were screened; 48 were enrolled (2 unevaluable: 1 for an infratentoral GBM and 1 withdrew after 7 days of treatment) with 29 men, 17 women. Median age was 56 yrs (29-75); median KPS was 90 (70-90). The median number of cycles was 8 (2-38) with 4 patients remaining on trial at the time of analysis. Objective responses: 4 CR, 12 PR and 30 SD. Median PFS is 7.3 months (95% CI (6.4, 11)) and median OS 14.2 months (95% CI (10.7, not reached)). There were no unexpected toxicities; grade 3/4 rate ⬍ 5%. Conclusions: Adjuvant bevacizumab and erlotinib in GBM with unmethylated MGMT is well tolerated. Preliminary efficacy data is comparable with outcomes in similar unmethylated MGMT patient populations from the EORTC/NCIC and RTOG 0525 studies. Tissue correlation is being performed. Clinical trial information: NCT00720356.




Temozolomide plus bevacizumab in elderly patients with newly diagnosed glioblastoma and poor performance status: An Anocef phase II trial. Presenting Author: German Reyes-Botero, Service de Neurologie 2-Mazarin, Groupe Hospitalier Pitié-Salpêtrière, Paris, France Background: The optimal treatment of glioblastoma multiforme (GBM) in elderly patients (age ⱖ70 years) with impaired functional status (Karnofsky performance status, KPS⬍70) remains to be established. A previous study using temozolomide (TMZ) alone suggested an increase in median overall survival (OS) compared to supportive care (25 weeks vs. 12-16 weeks, respectively). Median progression-free survival (PFS) was 16 weeks and 26% of patients became transiently capable of self-care (IK⬎70) (J Clin Oncol. 2011; 29: 3050-5). The present clinical trial evaluated the efficacy and safety of the combination of TMZ with bevacizumab (BV) as an initial treatment for elderly patients with GBM and KPS⬍70. Methods: Patients aged ⱖ 70 years with KPS ⬍ 70 and a newly supratentorial GBM diagnosed by biopsy were eligible for this multicentric, prospective and nonrandomised phase II trial. The primary endpoint was the OS and secondary endpoints included median PFS, quality of life, safety and cognition. Treatment consisted of TMZ 130-150 mgs/m2/d for 5 days every 4 weeks plus BV 10mgs/kg every 2 weeks, until 12 cycles or tumoral progression. Neither surgical resection nor radiotherapy was performed. Follow-up included clinical assessment every 2 weeks and brain MRI every 8 weeks. Results: Between October 2010 and March 2012, 66 patients (median age, 77 years; median KPS, 60) were enrolled. Median OS was 24 weeks (95% CI, 19-27.6) and median PFS was 16 weeks (95% CI, 13.1–19.3). Twenty-five patients (38%) became transiently capable of self-care (IK⬎70). Grade 3 and 4 haematological toxicity occurred in 13(19.6%) cases, whereas non-haematological toxicities were reported in 21(32%), including high blood pressure in 7(10%), thromboembolic events in 3(4.5%), intracerebral haemorrhage in 2(3%) and intestinal perforation in 2(3%) cases. Conclusions: This study confirms that TMZ-based treatment is of help in elderly GBM patients with poor KPS. However, the addition of bevacizumab does not appear to be of benefit in term of PFS and OS.

2022


2021

119s


A large prospective Italian population study (Project of Emilia-Romagna Region in Neuro-Oncology; PERNO) in newly diagnosed GBM patients (pts): Outcome analysis and correlations with MGMT methylation status in the elderly population. Presenting Author: Enrico Franceschi, Medical Oncology Department, Bellaria-Maggiore Hospital, Azienda USL of Bologna, Bologna, Italy Background: The role of temozolomide concurrent with and adjuvant to radiotherapy (RT/TMZ) in elderly pts with GBM remains unclear. We therefore evaluated the efficacy of this approach in pts ⬎70 years in the context of the Project of Emilia-Romagna Region in Neuro-Oncology (PERNO), the first Italian prospective observational population-based study in neuro-oncology. Methods: The criteria for selecting pts enrolled in the PERNO study were: age ⬎70 years; PS 0-3; histologically confirmed GBM; postoperative radiotherapy after surgery; residence in the Emilia Romagna region. Data were collected prospectively. Results: Pts accrual, started on January 1 2009, was closed, as planned, on December 31 2010. In the pts enrolled (n⫽53), median overall survival (mOS) was 11.1 months (95% CI: 8.8 - 13.5); survival rates at 1-, 2- and 3-years were 41.5% (95% CI: 28.2 – 54.8%), 15.2% (95% CI: 4.8 – 25.6%) and 6.1% (95%CI: 0 – 15.9%), respectively. Twenty-eight pts received RT/TMZ, and 25 pts RT alone. mOS was 11.6 months (95% CI: 8.6 – 14.6) following RT/TMZ and 9.3 months (95% CI: 8.1 – 10.6) following RT alone. mOS for pts with MGMT methylated status (n ⫽ 17) was 13.5 months (95% CI: 7.7 – 19.2), being 17.2 months (95% CI: 11.5 - 22.9) in those treated with RT/TMZ (n ⫽ 6) and 8.8 months (95% CI: 2 – 15.6) in those treated with RT alone (n ⫽ 11, p ⫽ 0.09). Elderly pts with MGMT unmethylated status (n ⫽ 25) had a mOS of 8.5 months (95% CI: 6 – 11, p ⫽ 0.014), being 8.5 months (95% CI: 2.3 – 14.7) in pts treated with RT/TMZ (n ⫽10), and 8 months (95% CI: 3 – 12.9) in those treated with RT (n ⫽ 15, p ⫽ 0.55). Conclusions: RT/TMZ appears to be more effective in prolonging the mOS of elderly pts in those with MGMT methylation status (17.2 vs 8.5 months), and seem to perform better than TMZ alone, for which mOS was 9.7 months in the Nordic phase III trial. These findings underline the value of the ongoing randomized EORTC 26062-22061/NCIC CE.6 phase III comparing RT/TMZ with short course RT alone.

2023^


The Stupp regimen preceded by early post-surgery temozolomide versus the Stupp regimen alone in the treatment of patients with newly diagnosed glioblastoma multiforme (GBM). Presenting Author: LF Zhou, Department of Neurosurgery, Huashan Hospital SMC FDU, Shang Hai, China

Biomarker (BM) evaluations in the phase III AVAglio study of bevacizumab (Bv) plus standard radiotherapy (RT) and temozolomide (T) for newly diagnosed glioblastoma (GBM). Presenting Author: Ryo Nishikawa, Saitama Medical University International Medical Center, Saitama, Japan

Background: In treatment of newly diagnosed GBM with the Stupp chemoradiotherapy regimen, following by adjuvant chemotherapy, patients were treated with temozolomide (TMZ) & combined radiotherapy 4-5 weeks after surgery. In the interval between surgery and chemo-radiotherapy, it is not known whether additional TMZ treatment will improve efficacy or safety. This trial evaluated the safety and efficacy of the Stupp regimen ⫹ early post-surgery TMZ chemotherapy in the treatment of patients with newly diagnosed GBM. Methods: The trial was a multi-center, randomized open-label study. 99 newly diagnosed GBM patients were enrolled and randomly assigned to the Stupp regimen ⫹ early post-surgery TMZ chemotherapy arm (experimental group, n ⫽ 52) or to Stupp regimen alone (control group, n ⫽ 47). Fourteen days after surgery, the patients in experiment group recieved TMZ orally at 75mg/m2/day for 14 days. The primary endpoint of the study was the overall survival (OS). The secondary endpoints included the progression-free survival (PFS), objective tumor assessment and adverse events (AEs). Results: The median OS time was 17.58 months (95% CI: 15.18 – 23.03 months) in the experiment group and 13.17 months (95% CI: 11.14 – 18.76 months) in the control group (log-rank test, p ⫽ 0.021). There is no significantly difference in the median PFS between experiment group and control group (8.74 months, 95% CI: 6.41-14.85 months vs 10.38 months, 95% CI: 8.18-15.44 months, p ⫽ 0.695). No statistically significant difference was detected as regards to the objective tumor assessments. There is no significance in OS or PFS between MGMT positive and MGMT negative groups. TMZ treatment was well tolerated in the study. AE types and rates were generally similar between the two groups. There were 22 SAEs in this study, with only 1 SAE (lung infection) in Stupp regimen group was possibly drug-related. Conclusions: The addition of early post-surgery TMZ chemotherapy to the Stupp regimen for newly diagnosed GBM resulted in a statistically significant survival benefit with minimal additional toxicity. Clinical trial information: NCT00686725.

Background: Bv plus 1st-line standard of care (SoC; T⫹RT) achieved a PFS benefit in the AVAglio phase III, randomized, double-blind, placebo [P]-controlled trial in patients (pts) with newly diagnosed GBM. AVAglio includes BM evaluation to identify pts benefiting most from Bv. Analysis of plasma VEGF-A and VEGFR-2 was prioritized based on encouraging findings in Bv trials in several tumor types. Methods: AVAglio includes an optional, exploratory correlative BM analysis; participating pts provided informed consent for BMs. Baseline (BL) plasma samples were analyzed using the Roche IMPACT platform, based on multiplex ELISA technology. Pts were dichotomized according to BM levels using either Q1, median or Q3 cut-offs. Potential interactions between BL BM levels and PFS were tested using Cox regression analyses. Results: Of 921 patients enrolled, 571 (62%) were evaluable in the BM study. Baseline characteristics and PFS outcome were comparable in the ITT and BM-evaluable populations. Median BL VEGF-A and VEGFR-2 levels were 77.0 pg/mL and 12.6 ng/mL, respectively. No significant interaction for PFS was seen at ␣⫽0.025. Conclusions: The potential predictive (VEGF-A, VEGFR-2) and prognostic (VEGF-A) value seen in breast, pancreatic and gastric cancers was not apparent in BL BM samples from AVAglio using a median, Q1 or Q3 cut-off. Additional plasma and tumor BM analyses are ongoing. Clinical trial information: NCT00943826. VEGF-A P (nⴝ287) N/ events Q1 Low 148/123 High 139/122 Median Low 148/123 High 139/122 Q3 Low 215/184 High 72/61

VEGFR-2

Bv (nⴝ278)

Median PFS (mo)

N/ events

MedianPFS (mo)

6.1 5.9

137/107 141/113

11.8 10.1

6.1 5.9

137/107 141/113

6.0 5.7

209/166 69/54

P (nⴝ283) HR 95% CI

Median PFS (mo)

N/ events

MedianPFS (mo)

0.64 [0.48; 0.84] 0.610 Low 78/69 0.59 [0.45; 0.78] High 205/172

6.4 5.9

63/49 216/172

10.3 11.3

0.49 [0.32; 0.75] 0.831 0.63 [0.51; 0.79]

11.8 10.1

0.64 [0.48; 0.84] 0.610 Low 145/129 0.59 [0.45; 0.78] High 138/112

6.1 5.9

136/108 143/113

10.5 11.5

0.54 [0.41; 0.71] 0.736 0.66 [0.50; 0.87]

10.9 10.8

0.63 [0.50; 0.78] 0.678 Low 216/185 0.58 [0.39; 0.87] High 67/56

6.0 6.1

206/162 73/59

10.6 11.5

0.61 [0.49; 0.75] 0.716 0.61 [0.41; 0.92]

P

N/ events

Bv (nⴝ279) HR 95% CI

P

Q ⫽ quartile.


120s 2024


Association of matrix metalloproteinase 2 (MMP2) baseline plasma level to objective response (OR), progression free survival (PFS), and overall survival (OS) and changes under treatment in patients treated with bevacizumab (Bev) for recurrent high-grade glioma (HGG). Presenting Author: Emeline Tabouret, University Hospital Timone, Marseille, France Background: Predictive marker of Bev activity is an unmet medical need. We evaluated predictive value of selected circulating prebiomarkers involved in neoangiogenesis and invasion on patient outcome in recurrent HGG treated with Bev. Methods: A set of eleven prebiomakers of interest (VEGF, VEGF-R2, bFGF, SDF1, PlGF, uPA, PAI1, MMP2, MMP7, MMP9, and adrenomedulline) were analyzed in plasma, using ELISA, at baseline from Bev initiation in a prospective cohort of 26 patients (Cohort1). Correlations were validated in a separate retrospective Bev treated cohort (Cohort2; n ⫽ 50) and then tested in a cohort of patients treated with cytotoxic agents without Bev (Cohort3; n ⫽ 34). Dosages were correlated to OR, PFS, and OS. MMP2 and MMP9 were then analyzed at multiple time points up to progression. Results: In cohort1, high MMP2 baseline level was associated with an OR rate of 83.3% for high levels versus 15.4% for low MMP2 levels (p ⫽ 0.001). In multivariate analysis, MMP2 baseline level was correlated with PFS (hazard-ratio (HR), 3.92; 95% confidence-interval (CI):1.4610.52; p ⫽ 0.007) and OS (HR, 4.62; 95%CI 1.58-13.53; p ⫽ 0.005), as MMP9 (p ⫽ 0.016 for PFS and p ⫽ 0.025 for OS). Similar results were found in cohort2 for MMP2, (MMP2: p⬍0.001 for OR; p ⫽ 0.009 for PFS; p ⫽ 0.009 for OS) but not for MMP9. In cohort3, no association was found between MMP2, MMP9 and outcome. Significant changes in MMP2 and MMP9 plasma levels were observed during treatment. MMP2 increased after Bev initiation (p ⫽ 0.002), and decreased at progression (p ⫽ 0.002) while MMP9 initially decreased (p ⫽ 0.007) then increased at progression (p ⫽ 0.031). Conclusions: In patients with recurrent HGG treated with bevacizumab, but not with cytotoxic agents, high MMP2 plasma levels are associated with prolonged tumor control and survival while changes over time may reflect tumor control. MMP2 should be tested in randomized clinical trials that evaluate bevacizumab efficacy, and its biological role should be reassessed.

2026


Use of DNA copy number analysis of grade 2-4 gliomas to reveal differences in molecular ontogeny associated with IDH mutation status. Presenting Author: Mariko Sato, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT Background: The genetic alterations of glioma have been studied extensively. IDH1 mutation is associated with younger age and better survival. However, differences in molecular ontogeny within glioma related to IDH1 mutation remain unknown. Here we describe a detailed analysis of copy number alterations (CNA) between IDH1mut vs IDH1wt gliomas of grade 2-3 and 4. Methods: CNA were detected by molecular inversion probes (Affymetrix) and analyzed with Nexus Copy Number Software (BioDiscovery). DNA was extracted from 94 patient FFPE samples including grade 2-3: IDH1wt (n ⫽ 17) and IDH1mut (n ⫽ 28), and grade IV: IDH1wt ( n ⫽ 25) and IDH1mut(n ⫽ 24). Chromothripsis was detected using a stringent criteria of at least ten switches of CNA in individual chromosomes. Results: We validated prior findings that IDH1wt GBM have higher frequency of Chr7 amplification (including EGFR) and loss of Chr10 (including PTEN). Other CNA across all grades were: gain of 19q12 and loss of 14q11 in IDH1wt, and gain of 11q21, 10p11, 8q21 and loss of 11p15, 19q13 in IDH1mut. Within grade 2-3 samples, few CNA were associated with mutation status: 2-3wt demonstrated higher frequencies of gain of 7q and loss of 10q, 14q11, and 22q13, while 2-3mut demonstrated higher frequencies of 11q21 gain and 19q13 loss. Grade 4 tumors demonstrated more CNA that differed by mutation status, with 4wt tumors demonstrating gain of 7 and loss of 10 and 14q11, while 4mut demonstrated gains of 8q, 10p, 12p13, 1q23, and loss of 11p15, 3p, 19q13, among others. Comparison of grade 2-3mut vs grade 4mut tumors demonstrated larger number of CNA in the grade 4mut tumors including gain of 1p, 14q, 13q33, 9p, 8q and loss of 22q, 11p15, 10q, and 3p, among others. A significantly higher incidence of chromothripsis events was observed in grade 4mut compared to grade 4wt (p ⫽ 0.0374). Conclusions: CNA analysis showed significant differences in molecular ontogeny between IDH1wt and IDH1mut, some of which may further elucidate pathogenesis. Significant CNA increases and increased chromthripsis in grade 4mut support malignant transformation of low grade gliomas through accumulation of genomic instability and genomic catastrophe.

2025


Impact of adjuvant temozolomide and IDH mutation status among patients with anaplastic astrocytoma. Presenting Author: Sani Haider Kizilbash, Mayo Clinic, Rochester, MN Background: Although adjuvant radiation has demonstrated a clear survival benefit in anaplastic astrocytomas (AA), the role of concurrent temozolomide (TMZ) remains controversial. Methods: All adult patients diagnosed with AA from 2001 to 2011 and treated with standard doses of adjuvant radiation were identified retrospectively using the neuro-oncology database at the Mayo Clinic (Rochester, MN). Clinical data was extracted from the electronic medical record. IDH mutation status was also determined by obtaining either IDH1R132H immunostain on existing unstained slides or paraffin block sections, or by sequencing. Cumulative survival probabilities were estimated using the Kaplan-Meier method. Univariable and multivariable Cox proportional hazards regression models were fit to compare patients who did/did not receive TMZ. Results: 218 patients were identified that met inclusion criteria. 34 patients were excluded due to missing data on adjuvant chemotherapy. 146 patients had received adjuvant TMZ while 38 had not. Of these, IDH mutation status was determined on 124 patients who received TMZ and 33 of those who had not. The median duration of follow up was 36.4 months. On univariable analysis, adjuvant TMZ demonstrated a trend towards improved median survival from 35.2 to 53.1 months (p⫽0.06). As an independent variable, patients with IDH mutations had longer median survivals (111.7 months) when compared to IDH wild-type patients (23.3 months) (p⬍0.001). On multivariable analysis, five-year-survival was significantly impacted by receipt of adjuvant TMZ (HR ⫽ 0.56, p⫽0.03) and IDH mutation status remained a significant prognostic factor (HR ⫽ 0.19, p ⬍ 0.001) (see Table). Conclusions: IDH mutation strongly predicts a favorable outcome in patients with AA. Secondarily, concurrent TMZ is also associated with improved survival in patients with AA who are receiving adjuvant radiotherapy. Five-year survival Variable Concurrent TMZ Age at diagnosis (years) Male sex Subtotal or gross total resection IDH mutation

2027

Hazard ratio (95% CI) 0.56 (0.33-0.94) 1.06 (1.04-1.08) 0.91 (0.55-1.50) 0.91 (0.55-1.53) 0.19 (0.09-0.42)

P value 0.03 ⬍0.001 0.71 0.73 ⬍0.001


Long-term survival in primary glioblastoma revisited: The contribution of isocitrate dehydrogenase mutations. Presenting Author: Michael Weller, University Hospital, Zurich, Switzerland Background: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in WHO grade 2/3 gliomas, but rare in primary glioblastomas, and associated with longer survival. Methods: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival ⬎ 36 months (LTS-36), including 33 patients surviving ⬎ 60 months (LTS-60), with 259 patients surviving ⬍ 36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations and IDH1/2mutations were determined by standard techniques. Results: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23/67 patients) as opposed to 4.3% in controls (11/257 patients). Long-term survivors with IDH1/2 -mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Among LTS-36 patients, wild-type TP53 status, MGMT promoter methylation, and absence of EGFR amplification, but not IDH1/2 mutation, were associated with prolonged survival. Among 11 patients with IDH1/2mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had been treated initially with radiotherapy alone and had TP53 mutations less frequently. Conclusions: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade 2/3 gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified.




Association of VEGFA SNP rs2010963 with prognosis and prediction of vascular toxicity of bevacizumab in recurrent glioblastomas. Presenting Author: Anna Luisa Di Stefano, Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l’Institut du Cerveau et de la Moelle épinière (CRICM), Neurologie 2, Paris, France Background: VEGFA has become an attractive target in high grade gliomas but there is no predictor of response or toxicity to anti-VEGF therapy. We investigated here the association between functional single nucleotide polymorphism (SNP) ⫹405 G⬎C (rs2010963), located in 5’ untranslated terminal region of VEGFA gene, survival, response to bevacizumab (BVZ), and vascular toxicity. Methods: The rs2010963 was analyzed in blood DNA using a Taqman SNP Genotyping Assay and confronted to Progression Free Survival (PFS), Overall Survival (OS) in the general population of gliomas, and -for the glioblastomas (GBM) treated with BVZ at recurrence- with Response, PFS, and thrombo-hemorragic events. Results: In the general population of 954 gliomas stratified per grade (362 grade 2, 269 grade 3, 323 grade 4) there was no association between rs2010963 and OS or PFS. In the population of 123 recurrent GBM treated with BVZ, we observed a favourable trend in PFS associated with the C allele of rs2010963 (5.4 vs 4.2 months, p ⫽ 0.07). Most importantly the CC genotype was associated with the occurrence of thrombo-hemorragic events (6/16 vs 2/107 in CG⫹GG, p ⬍0.0001). Conclusions: Our data suggest that rs2010963 status has not prognostic significance in gliomas, but is associated with vascular events in recurrent GBM treated with BVZ. The impact of rs2010963 on response to BVZ needs to be further investigated.

2030


Combined whole genome copy number genotyping and multiplex somatic mutation profiling of FFPE brain tumor specimens for clinical diagnosis and trial selection. Presenting Author: Brian Michael Alexander, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, Boston, MA Background: Multi-dimensional cancer genotyping is increasingly needed for clinical diagnostics and trial selection. Whole genome copy number is relevant for glioblastoma and other brain tumors but routine prospective FFPE-based multiplex copy number and somatic mutation genotyping for clinical trials has not been achieved. Methods: Using novel DNA extraction protocols we implemented whole genome copy number (Agilent aCGH stock 1M feature arrays) and somatic mutation profiling (Oncomap v4.4 Sequenom) assays into a CLIA-certified laboratory setting. Twenty-three copy number aberrations (CNAs) relevant to brain tumors were reported from whole genome data and Oncomap results were reported for 471 cancer-related mutations in 41 genes. Results: During the initial eight months of our combined copy number and mutation-testing program, aCGH and Oncomap were performed prospectively on 239 and 157 brain tumor patients respectively. Copy number was reported in 90% of patients (214/239) and failures were due to insufficient DNA from small biopsies. GBMs (n ⫽ 94) harbored gains and losses at expected rates and included amplifications of common drug targets (EGFR, EGFRv3, MET, MDM2, MDM4, PDGFRA, CDK4, CDK6). Emerging candidate drug targets were identified including variant EGFR deletions (e.g. EGFRv2) and FGFR3TACC3 gains for which other clinical tests are not available. Oncomap results for 78 GBMs revealed mutations in TP53, PTEN and IDH1. Less frequent mutations occurred in BRAF, RB1, PIK3CA, PIK3R1 and KRAS. We integrated copy number and mutation data for 27 GBMs, allowing for improved evaluation of tumor suppressor inactivation status (e.g. PTEN mutation with monosomy 10). In combination, our assays reported data on 10 clinically actionable drug targets relevant for 15 clinical trials open at the time of patient testing. Conclusions: We implemented complementary assays for efficiently detecting genome-wide CNAs and mutations on FFPE brain tumor samples in a CLIA-certified environment. Systematic integration of these results broadens the range of diagnostic and actionable data available to identify patients for trials of targeted therapeutics.

2029

121s


Association of PIK3CA-activating mutations with more disseminated disease at presentation and earlier recurrence in glioblastoma. Presenting Author: Shota Tanaka, Massachusetts General Hospital, Boston, MA Background: The PI3K signaling pathway is a potent pro-survival pathway and associated with increased grade of malignancy in glioma. Activating mutations in PIK3CA are observed in 6% to 15% of glioblastomas, although their clinical significance is unknown. Our objective was to examine whether PIK3CA activating mutation is associated with a specific phenotype in newly diagnosed glioblastoma patients. Methods: We molecularly profiled 183 consecutive adult glioblastomas from December 2009 to June 2012. We included in our analysis all newly diagnosed primary glioblastoma patients with a KPS score of 60 or greater who were treated with standard chemoradiation. Molecular profiling consisted of SNaPshot genotyping, FISH for gene amplification (EGFR, MET, PDGFRA), and methylation-specific PCR for MGMT promoter methylation. Results: 158 patients were included in the study (median age: 58 years (range, 23-85), 90 males, median KPS: 90). With a median follow-up of 13.8 months, median progression-free survival (PFS) and overall survival (OS) were 11.6 and 26.2 months, respectively. Established molecular prognostic factors such as IDH1 mutation and MGMT promoter methylation were associated with longer PFS and OS (IDH1: PFS p⫽0.001, OS p⫽0.02; MGMT: PFS p⫽0.0005, OS p⫽0.0002). 12 patients (7.6%) harbored PIK3CA activating mutation by SNaPshot assay (4 at R88, 4 at hotspots 542-546, 4 at H1047). PIK3CA mutation was associated with younger age (p⫽0.02) and shorter PFS (6.8 vs. 11.8 months, p⫽0.0004). Shorter PFS for PIK3CA mutation remained significant after adjusting for age, KPS, gross total resection, IDH1 mutation, and MGMT promoter methylation (p⫽0.01). There was a significant association between PIK3CA mutation and more disseminated disease at diagnosis, as defined by gliomatosis, multicentric lesions, or distant leptomeningeal lesions. Eight of 12 (66.7%) PIK3CA mutant GBMs were disseminated versus 15.1% of PIK3CA wild-type tumors (p⫽0.0002). Conclusions: PIK3CA activating mutations are associated with younger age and early recurrence in primary glioblastoma. The aggressive behavior of these tumors may be related to their propensity to present with widespread disease.

2031


Whole brain radiation therapy (WBRT) with or without oral topotecan (TPT) in patients (pts) with non-small cell lung cancer (NSCLC) with brain metastases: Final analysis of an open-label phase III study. Presenting Author: Rodryg Ramlau, Poznan University of Medical Sciences, Wielkopolskie Centrum Pulmonologii i Torakochirurgii, Poznan, Poland Background: Brain metastases from NSCLC occur in ~ 20% of pts and if untreated are associated with a 1 to 2 month overall survival (OS). Pre-clinical studies show that TPT added to radiation results in a radiotherapy enhancement ratio of 1.4 to 1.6. This trial was designed to test the effect of TPT co-administered with WBRT on OS. Methods: Pts with NSCLC and at least one measurable brain lesion were eligible. 472 pts were randomized to WBRT (3 Gy/day x 10 days) or WBRT and TPT 1.1 mg/m2/day for 10 days. Stratification factors: number of brain metastases and recursive partitioning analysis (RPA) class. Two weeks following WBRT, systemic anti-cancer therapy could be restarted at the treating physician’s discretion. Results: 468 pts were in the modified ITT population; 235 pts (WBRT ⫹ TPT) and 233 pts (WBRT⫹ best supportive care [BSC]). Of the 235 pts administered WBRT ⫹ TPT, 91 also received TPT after WBRT. The treatment arms were balanced for gender, age and smoking history. Median daily TPT dose was 2.25 mg. The median OS in the TPT arm was not better than in the BSC alone arm; 4.0 months (95%CI 3.4,4.8) vs.3.6 months (95%CI 3.0, 4.0), respectively; HR 0.88 (0.73, 1.07), P⫽0.1862. In the ITT population analysis by stratification variables, RPA class (I vs. II/III) was significantly different (HR 0.59) whereas baseline brain lesions (1 vs ⬎1) were not (HR 0.97). Complete response and overall response rates in the WBRT⫹ TPT were 10% and 27%, and with BSC 5% and 26%, respectively. There were no differences in time to response or neurologic signs and symptoms. All adverse events (AEs) were more frequent in the TPT arm (87% vs. 64%) as were AEs related to study treatment (57% vs. 21%), serious AEs (41% vs. 18%) and fatal AEs (5% vs. 0%). The AEs more frequently seen in the TPT arm were typical for TPT (hematologic toxicity, febrile neutropenia and diarrhea). Conclusions: The study did not achieve its primary objective. There was no difference in OS achieved by the addition of TPT to WBRT. AEs were more common in the TPT arm. Clinical trial information: NCT00390806.


122s 2032


Multicenter randomized phase II trial of methotrexate (MTX) and temozolomide (TMZ) versus MTX, procarbazine, vincristine, and cytarabine for primary CNS lymphoma (PCNSL) in the elderly: An Anocef and Goelams Intergroup study. Presenting Author: Antonio Marcilio Padula Omuro, APHP-CHU Pitié-Salpêtrière, Paris, France Background: There is no standard chemotherapy defined in PCNSL. Elderly patients (pts) are not candidates for whole brain radiotherapy and therefore establishing an optimal MTX-based regimen is crucial. This prospective multicenter study conducted in 13 French institutions tested two promising MTX-based chemotherapy regimens in elderly pts with newly diagnosed PCNSL. Methods: Pts with histologically confirmed newly diagnosed PCNSL with age ⱖ60 and KPS ⱖ40 were stratified by institution and KPS, then randomized to receive three 28-day cycles of MTX (3.5 g/m2 D1 and D15) and TMZ (100-150mg/m2 D1-5 and 15-19) [MT arm] or 3 cycles of MTX (3.5 g/m2 D1 and D15), procarbazine 100mg/m2 (D1-7), vincristine (1.4mg/m2 D1 and 15), followed by cytarabine consolidation (3g/m2/d X2d) [MPV-A arm]. Neither arm included radiotherapy; prophylactic G-CSF and standardized corticosteroids (methylprednisolone 60mg/d D1-5) were given to both arms. The primary endpoint was PFS (one-stage Fleming design; ␣⫽ 5%; ␤⫽10%). Evaluations included neuropsychological testing and quality of life. Results: Accrual has been completed (7/2007- 3/2010), with 98 pts randomized and 95 analyzed (MT: 48 pts; MPV-A: 47). Pre-treatment characteristics were well balanced between the two arms (all pts: median age⫽72- range 60-85; median KPS⫽ 70; range 40-100). In the MPV-A arm, the CR rate ⫽ 62% (vs 45% in MT arm [p⫽0.11]), objective response rate⫽ 82% (vs 71%; p⫽0.23), median PFS⫽ 9.5m (vs 6.1m; HR⫽ 1.14- 95% CI [0.72 ; 1.81]; p⫽0.6) and median OS⫽ 31m (vs 13.8m; HR⫽ 1.4 - 95% CI [0.84 ; 2.34]; p⫽0.2). The incidence of grades 3-4 toxicities was 72% in the MPV-A vs 71% in the MT arm. Abnormal liver function test was the most common toxicity (MPV-A: 18 pts; MT: 21). Baseline cognitive impairment (MMSE ⬎24 vs ⱕ24) predicted OS (p⫽0.04). Conclusions: This is the first randomized PCNSL study testing two different MTX-based combination regimens. In this elderly population, toxicities were frequent but similar in both arms, and all efficacy endpoints tended to favor the MPV-A arm. The MPV-A regimen is recommended for further development in PCNSL. Clinical trial information: NCT00503594.

2034


2033


Preirradiation chemotherapy with methotrexate, rituximab, and temozolomide and post-irradiation temozolomide for primary central nervous system lymphoma: RTOG 0227 phase II study results. Presenting Author: Jon Glass, Thomas Jefferson University, Philadelphia, PA Background: This prospective phase II study tested a methotrexate (MTX), temozolomide (TMZ) and rituximab (RTX) pre-irradiation regimen with hyperfractionated whole brain radiation therapy (hWBRT) followed by post-irradiation TMZ for patients with primary CNS lymphoma (PCNSL). The primary phase II endpoint was the 2-year overall survival (OS) rate compared with the 2-year OS from RTOG 93-10 (MTX, procarbazine, vincristine, whole brain radiation therapy, cytarabine). Secondary endpoints were pre-irradiation chemotherapy tumor response rates (compared to RTOG 93-10), progression free survival (PFS), acute and late neurologic toxicities, and quality of life. Methods: 53 patients (28 women, 25 men), median age 57.5 years, median Zubrod 1 were treated with RTX 375 mg/m2 3 days prior to first cycle of MTX; 5 cycles of intravenous MTX 3.5 g/m2 with leucovorin rescue on weeks 1, 3, 5, 7, 9; TMZ 100 mg/m2 daily for 5 days weeks 4 and 8; hWBRT 1.2 Gy twice daily fractions 5 days/week on weeks 11, 12, 13 for a total of 36 Gy and TMZ 200 mg/m2 daily for 5 days on weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, 50. Results: Dosing of pre-irradiation temozolomide at 100 mg/m2 was determined in the phase I portion of the study. With a median follow-up of 3.6 years, 2-year OS and PFS rates were 80.8% and 63.6%, respectively. Compared with historical controls from RTOG 93-10, 2-year OS and PFS were significantly improved (p ⫽ 0.006 and 0.03). The overall response rate to the pre-irradiation chemotherapy was 37.7% (complete response 11.3%, partial response 26.4%). 38% experienced grade 3 and 25% experienced grade 4 toxicities before the start of hWBRT. 33% experienced grade 3 and 21% experienced grade 4 toxicities attributable to post-hWBRT chemotherapy. Conclusions: The combination of MTX, TMZ, RTX followed by hWBRT and TMZ for PCNSL is safe with demonstrated improved 2 year OS and PFS compared with RTOG 93-10. Further investigations regarding the role of hWBRT and post-hWBRT TMZ are indicated. This project was supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from the National Cancer Institute (NCI) and Schering-Plough. Clinical trial information: NCT00068250.

2035


High-dose methotrexate with and without rituximab for the treatment of newly diagnosed primary CNS lymphoma: Johns Hopkins Hospital experience. Presenting Author: Matthias Holdhoff, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD

A prospective phase II study to determine the efficacy of GDC 0449 (vismodegib) in adults with recurrent medulloblastoma (MB): A Pediatric Brain Tumor Consortium study (PBTC 25B). Presenting Author: Amar J. Gajjar, St. Jude Children’s Research Hospital, Memphis, TN

Background: The current institutional standard for treatment of patients with newly-diagnosed primary CNS lymphomas (PCNSL) at Johns Hopkins Hospital (JHH) consists of treatment with high-dose methotrexate plus rituximab (hd-MTX/R) every 2 weeks until complete response (CR), progression or unacceptable toxicities. Once CR is achieved, this is followed by monthly treatments for a total of up to one year for consolidation. Prior to 2008, the institutional standard had been treatment with hd-MTX alone. The benefit of adding rituximab to hd-MTX has not been formally evaluated. Methods: This is a retrospective study of HIV-negative adult patients with newly-diagnosed PCNSL treated at JHH with either hd-MTX or hd-MTX/R as initial therapy. Patients were identified using the cancer center registry (1995-2012) and were included if they had received at least one cycle of therapy (intention-to-treat). Primary objectives were CR rate (patients with sufficient imaging data; centrally reviewed) and overall survival (OS, all patients included). Results: A total of 81 patients were analyzed (median age of 65 yrs; 52% male). 54 patients received hd-MTX alone (median age, 65 yrs) and 27 patients received hd-MTX/R (median age, 66 yrs). 37 and 24 patients in the two groups were evaluable for response, respectively. Among these, the CR rate was 51% in patients treated with hd-MTX alone (overall response rate, ORR, 76%) and 79% in patients treated with hd-MTX/R (ORR 96%). The median number of cycles to CR was 5 and 4.5, respectively. Median OS among all patients (both groups combined) was 26 months (95% CI: 11-44). Conclusions: These data show potential clinical benefit from the addition of rituximab to hd-MTX for newly diagnosed patients with PCNSL based on a higher CR rate. Analysis of OS benefit between patients treated with hd-MTX and hd-MTX/R is pending maturation of further survival data.

Background: Almost 80% of adult medulloblastoma are of the SHH subtype. Second line therapy for adult MB is limited; therefore we tested the efficacy of vismodegib, a small molecule inhibitor of Smoothened (SMO) among patients with this disease. Methods: Adult patients with refractory or recurrent MB and who had measureable disease were enrolled on the study. Immunohistochemistry (IHC) was used to stratify patients to Stratum A (non-SHH group); Stratum B (SHH tumors) and Stratum C (indeterminate). All patients were treated with vismodegib at 150 mg/day PO daily. Tumor response, which had to be maintained for 8 weeks to meet protocol definition of sustained response, was assessed using RECIST criteria and central imaging review. Separate but identical Simon 2-stage MinMax designs (␣ ⫽ 0.10) were used in strata A and B to test for evidence that sustained response rates exceeded 5% with 90% power to detect 25% sustained response rates. Thus, 3/20 sustained responses were needed to declare potential activity of vismodegib. Results: 32 patients with a median age of 30 years (range 22.4-51.9) were enrolled on the study [Stratum A (n ⫽ 8); Stratum B (n ⫽ 20); Stratum C (n ⫽ 4)], including 18 males and 14 females. No responses were observed in Strata A or C and the median duration of treatment was 1.5 months (range 0.66-2.33). Three of 20 patients enrolled on Stratum B had sustained responses. The median duration of therapy for Stratum B patients was 2.76 months (range 0.3313.61). Six patients were on treatment for ⱖ6.44 months and 3 remain on treatment after 5.42, 9.34 and 13.61 months. During course 1, 2 patients experienced grade 3 decrease in lymphocytes; 1 experienced a grade 4 thromboembolic event; and 2 experienced grade 3 toxicities (back pain & syncope). During course 2, 3 patients experienced grade 3 toxicities (decrease in lymphocytes; myalgia & seizure). One other patient experienced grade 3 hypophosphatemia in courses 1 and 2. Conclusions: Vismodegib has activity against recurrent or refractory adult ‘SHH-subtype’ medulloblastoma and should be considered as a therapeutic option for newly diagnosed patients with this disease. Clinical trial information: NCT00939484.




A phase I clinical trial of veliparib and temozolomide in children with recurrent central nervous system tumors: A Pediatric Brain Tumor Consortium report. Presenting Author: Jack M. Su, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX Background: A phase I trial of veliparib (ABT-888), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, and temozolomide (TMZ) was conducted in children with recurrent brain tumors to: 1) estimate the maximum tolerated doses (MTD) or recommended phase II doses (RP2D) of veliparib and TMZ using the Continual Reassessment Method; 2) describe the toxicities of this regimen; and 3) evaluate plasma pharmacokinetics (PK) and peripheral blood mononuclear cell (PBMC) PARP inhibition after veliparib treatment. Methods: TMZ was given once daily and veliparib twice daily for 5 days, every 28 days. Five veliparib/TMZ dose levels were studied: 20/180; 15/180; 15/150; 20/135; and 25/135 mg/m2/dose, respectively. Baseline and serial veliparib PK samples were obtained on days 1 and 4. PBMC poly(ADP-ribose) (PAR) levels were also measured using an ELISA assay. A total of 12 subjects were enrolled at the RP2D. Results: Thirty-one patients (29 evaluable) with a median age of 7.0 years (range 1.3-19.8) were enrolled. Dose-limiting toxicities (DLT) included grade 4 neutropenia and thrombocytopenia at the 20/180 and 15/180 mg/m2/dose levels. Based on the toxicity profile, PKs and PBMC PAR results, the RP2D were veliparib, 25 mg/m2 BID, and TMZ, 135 mg/m2/day, for 5 days every 28 days. No objective responses were observed, although 4 subjects had SD ⬎ 6 months duration, including one patient each with glioblastoma multiforme, anaplastic ependymoma, pilocytic astrocytoma, and optic pathway glioma. At the veliparib RP2D, the PK parameters included: Cmax, 1.2 ⫾ 0.7 ␮M; AUC0-12 hr, 1.53 ⫾ 0.61 ␮g●hr/mL; and Cl/F, 173 ⫾ ml/min/m2. PARP inhibition was observed in PBMC but did not correlate with veliparib dose levels. Conclusions: The combination of veliparib and TMZ was well tolerated in children with recurrent CNS tumors. Veliparib PK parameters at RP2D are similar to those in adults. PBMC PARP inhibition did not correlate with veliparib dose levels, perhaps due to the smaller number of patients at each dose level and the technical limitations of specimen collection/processing and the ELISA assay. A phase II trial of veliparib/TMZ in children with recurrent primary brain tumors is planned. Clinical trial information: NCT00946335.

2038

General Poster Session (Board #1B), Sat, 8:00 AM-11:45 AM

Factor Xa: PAR-1 growth loop is blocked by low-molecular weight heparins—A new perioperative and adjuvant concept in glioblastoma. Presenting Author: Susanne Antje Kuhn, Department of Neurosurgery, Hospital Ernst von Bergmann, Potsdam, Germany Background: Glioblastoma patients suffer from thromboembolism, aggravating the disease. Recently, increased activity was shown for coagulation factors II, VIII, IX, X, XI, and XII in patient peripheral blood. In vitro, the high potential of FXa-PAR1-loop as growth factor system and significant effects of its blockade were proven. Methods: Patient samples (n⫽108) were analyzed for FXa and PAR-1. In immunodeficient mice, glioblastoma xenografts were established and treated with low-molecular weight heparins (LMWH) (30mg/kg SC daily for 3 wks). Phosphate buffered saline served as control. Tumor growth rates, final tumor size, tumor proliferation (Ki67), and tumor vascularization (CD31) were determined. Results: Human glioblastomas overexpressed FXa and PAR-1 in the compact tumor center (FXa: p⬍.001; PAR-1: p⬍.001) and in the invasion zone (FXa: p⫽.006; PAR-1: p⫽.005). Neoangiogenic endothelial cells disproportionately high expressed FXa and PAR-1 with rising intensity in the invasion zone (FXa: p⬍.001; PAR-1: p⬍.001), and the compact tumor mass. (FXa: p⬍.001; PAR-1: p⬍.001). Growth curves of LMWH-treated tumors slowed (p⬍.001). Final tumor size was reduced (s.c.: p⬍.001; i.c.: p⬍.05). Tumor cell proliferation was massively inhibited in situ (tinzaparin: p⬍.001; enoxaparin: p⬍.001) as was the number of CD31 positive endothelial cells ((tinzaparin: p⬍.001; enoxaparin: p⬍.001) and the tumor vascularization (p⬍.001 each). Conclusions: Glioblastoma patients display abnorm activation of coagulation factors in peripheral blood and show high levels of FXa and PAR-1 in the tumor center, invasion zone and angiogenic endothelia. LMWH caused tumor growth retardation and size reduction with blockade of proliferation and vascularization. FXa inhibition should be considered as continuous thrombosis prophylaxis and adjuvant glioblastoma treatment.

2037

123s General Poster Session (Board #1A), Sat, 8:00 AM-11:45 AM

Prognostic utility of neuraxis imaging in leptomeningeal metastasis (LM): A retrospective case series. Presenting Author: Marc C. Chamberlain, Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA Background: Correlate imaging of the central nervous system that includes both brain and spine MRI and radio-isotope cerebrospinal fluid [CSF] flow studies with survival in a retrospective case series of patients with LM. Methods: 240 adult patients with LM (125 non-brain solid tumor patients with positive CSF cytology; 40 non-brain solid tumor patients with negative CSF cytology and MRI consistent with LM; 50 lymphoma and 25 leukemia patients with positive CSF flow cytometry), all considered appropriate for LM-directed treatment, underwent prior to treatment brain and entire spine MRI and radio-isotope CSF flow studies. Results: Median overall survival was significantly shortened in patients with large volume MRI defined disease (defined as measurable tumor ⬎ 5 x 10 mm in orthogonal diameters) and in patients with non-corrected CSF flow obstruction irrespective of primary tumor histology. Additionally, cause of death differed wherein patients with large volume of disease or uncorrected obstructed CSF flow more often died of progressive LM disease whereas patients with normal or small volume disease and patients with normal or re-established CSF flow more often died of progressive systemic disease. Conclusions: Neuraxis imaging utilizing brain and spine MRI as well as radio-isotope CSF flow studies appears to have prognostic significance and may be predictive of median overall survival in this large cohort of patients with LM all of whom were considered for treatment with LM.

2039

General Poster Session (Board #1C), Sat, 8:00 AM-11:45 AM

Phase Ib study evaluating safety and pharmacokinetics (PK) of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor LY2157299 monohydrate (LY) when combined with chemoradiotherapy in newly diagnosed malignant gliomas. Presenting Author: Cristina Suarez, Vall d’Hebron University Hospital, Barcelona, Spain Background: Based on preclinical data suggesting an additive antitumor effect of combining TGF-ß inhibitors with temozolomide based chemoradiation (TMZ/RT), a Phase 1b study was initiated to evaluate the safety and PK of LY combined with TMZ/RT in patients with newly diagnosed glioma. Methods: LY was evaluated sequentially in 2 doses (160 mg/day and 300 mg/day) combined with TMZ/RT. TMZ/RT was administered as approved and LY given as intermittent dosing (14 days on/14 days off⫽1 cycle). Toxicity was assessed using the CTCAE, version 4. The PK profile of LY in combination with TMZ/RT was determined. Results: 19 patients with glioma (16 World Health Organization Grade 4; 3 Grade 3 were treated with LY (160 mg/day, n⫽10; 300 mg/day, n⫽9) and TMZ. The median number of cycles was 5 (range 1-13). Regardless of relatedness to study treatment, the following treatment-emergent adverse events (TEAEs) were observed in ⱖ25% of patients: nausea (n⫽11), fatigue (n⫽11), thrombocytopenia (n⫽11), headache (n⫽9), vomiting (n⫽8), lymphopenia (n⫽6), anorexia (n⫽6), constipation (n⫽5), radiation skin injury (n⫽5), and alopecia (n⫽5). The following TEAEs were related specifically to at least LY: thrombocytopenia (n⫽3, 2 Gr 3 and 1 Gr 4), fatigue (n⫽2), maculopapular rash (n⫽2, Gr 3), dermatitis acne form (n⫽3, 1 Gr 3) and in 1 patient each: nausea, vomiting, hypertension, hypersensitivity and leucopenia (Gr 4). No change in the PK profile of LY was shown when LY was combined with TMZ/RT. In the combination therapy, area under the curve (0-⬁) at steady state was observed geomean (%CV) to be 5.5 (48%) mg*h/L following 300 mg/day (n⫽9). Following monotherapy with LY, these exposures were similar with a median (20th-80thpercentiles) of 4.7 (2.5-8.8) mg*h/L (n⫽37). Conclusions: No dose-limiting toxicities and no clinically meaningful cardiotoxicities were observed; hence, the treatment of LY at 300 mg/day in combination with standard chemoradiation has a manageable toxicity profile. A Phase 2a trial has been initiated to relate the pharmacodynamic effects with overall survival. Clinical trial information: NCT01220271.


124s 2040

Central Nervous System Tumors General Poster Session (Board #1D), Sat, 8:00 AM-11:45 AM

Characterization of candidate tissue and blood biomarkers in a rare cohort of myxopapillary ependymoma patients. Presenting Author: Aysegul IlhanMutlu, Department of Medicine I, Comprehensive Cancer Center CNS Tumours Unit, Medical University of Vienna, Vienna, Austria Background: Myxopapillary ependymoma (MPE) is a very rare tumor of the distal spinal cord. Despite benign histopathology, local recurrences occur in approximately 30% of patients and distant metastases have been described in few cases. We investigated candidate tissue and blood biomarkers in a rare MPE series. Methods: Formalin fixed paraffin embedded (FFPE) tumour tissues from 21 MPE patients were immunohistochemically investigated for expression of isocitrate dehydrogenase 1 R132H (IDH-R132H), Secretagogin, glial fibrillary acidic protein (GFAP), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), progesterone receptor (PR), estrogen receptor (ER), Ki-67, arg, plateled derived growth factor a (PDGFRa) and b (PDGFRb), pc-kit and pc-abl. EGFR gene was evaluated using exon-sequencing. In addition, we analyzed circulating plasma-GFAP using ELISA in 3 patients with completely resected MPE, 1 patient with locally advanced MPE, 2 patients with pleuropulmonary metastases of MPE and 12 control subjects. Results: Secretagogin and GFAP were expressed in all tissue samples. arg, PDGFRa, PDGFRb, pc-kit and pc-abl were positive in 15, 1, 2, 3 and 2 patients, respectively. The Ki-67 index ranged from 1% to 12.8% (median⫽7.1%). We detected no expression of EGFR, IDH-R132H, HER2, PR or ER. One patient showed a silent mutation in exon 21 of the EGFR gene (c.2508C⬎T). We found very high concentrations of plasma-GFAP in two MPE patients with pleuropulmonary metastases, while all other MPE patients were negative. Conclusions: Our data indicate that (i) targeted tyrosine kinase inhibitors may be rational for the therapy of selected MPE patients and that (ii) circulating GFAP could be useful as circulating marker for the early detection or follow-up of distant metastases in MPE patients.

2042

General Poster Session (Board #1F), Sat, 8:00 AM-11:45 AM

Survival outcome of early versus delayed bevacizumab treatment in patients with recurrent glioblastoma. Presenting Author: Mohamed Ali Hamza, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Bevacizumab (BEV) is widely used for treatment of patients with recurrent glioblastoma (GB). Differences in outcome between early versus delayed BEV treatment of recurrent GB are not well defined. We examined the relationship between the time of start of BEV treatment and outcomes in patients with recurrent GB. Methods: In this retrospective chart review derived from our longitudinal database, we identified patients with recurrent GB between 2001 and 2011, who were treated with BEV alone or BEV-containing regimens. Data was analyzed to determine overall survival (OS) from time of diagnosis and progression free survival (PFS) from time of BEV start. Early BEV was defined as start of BEV treatment at first recurrence, while delayed BEV was defined as start of treatment at second recurrence or later. Results: A total of 298 patients with recurrent GB who received BEV were identified, of whom 149 patients received early BEV, 134 patients received delayed BEV, and 15 patients who were excluded because they received BEV upfront. There were no significant differences in the age, sex, performance status and extent of resection between patients treated with early BEV and those treated with delayed BEV. The median time from diagnosis to first recurrence was more than 6 months (mos.) for both groups (6.5 mos. for early BEV and 7.6 mos. for delayed BEV, p ⫽ 0.01). The median time from diagnosis to start of BEV was 7.9 mos. for patients with early BEV and 15.6 mos. for patients with delayed BEV (p⬍0.001). There was no significant difference in PFS between patients that received early BEV and those that received delayed BEV (5.73 mos. vs. 4.33 mos., p ⫽ 0.07). Patients who were treated with delayed BEV had longer OS when compared to those treated with early BEV (25.9 mos. vs. 19.7 mos., p ⫽ 0.0002). Conclusions: In patients with recurrent GB, there was no significant difference in PFS between early and delayed BEV; however, patients treated with delayed BEV have longer OS when compared to those treated with early BEV. These results indicate that delaying treatment with BEV is not detrimental and may be associated with a favorable survival outcome.

2041

General Poster Session (Board #1E), Sat, 8:00 AM-11:45 AM

Biomarker analysis of glioblastoma and potential implications for therapy. Presenting Author: Joanne Xiu, Caris Life Sciences, Phoenix, AZ Background: Glioblastoma multiform (GBM), the most aggressive CNS cancer, has limited effective therapeutic options, with underlying molecular heterogeneity contributing to the differences in treatment response. Our study was designed to interrogate biomarkers from a large cohort of GBM patients to seek therapeutic implications. Methods: Data was analyzed from 570 high grade astrocytoma patients (vast majority GBM) who received tumor profiling at Caris Life Sciences from 2009 to 13. Test methodologies included IHC, FISH, CISH, Sanger SEQ, MGMT promoter methylation and NextGen SEQ (Illumina TruSeq). Results: In our patient cohort, 59% had MGMT methylation and 70% had negative MGMT IHC, predicting potential response to temozolomide. Protein expression for ERCC1, TOPO1, and TS was 53% negative, 49% positive, and 37% negative, indicating potential benefit from cisplatin, irinotecan and fluorouracil, respectively. Drug pumps PGP and MRP1, were positive by IHC in 10% and 67% of patients, suggesting possible resistance to etoposide, vinca alkaloids and methotrexate. For targeted therapies, c-Kit IHC was positive in 7% patients, mutated in 6% and PDGFRA IHC was positive in 27%, indicating potential benefit from imatinib and other TKI’s. RAS/RAF and PIK3CA/mTOR pathway activation was also noted with BRAF, KRAS, PIK3CA mutations and PTEN loss, observed in 8%, 3%, 7% and 10% of cases, respectively. TS negativity was seen in 91% of MGMT methylated patients and in 37% of MGMT unmethylated patients (p ⫽ 0.025, student’s t-test), revealing a possible novel combination therapy of fluoropyrimidines with temozolomide for a select cohort. Similarly, biomarker profiles of molecular subgroups defined by EGFR amplification (44% in our cohort) and IDH1, p53 mutations will be analyzed for therapeutic implications. Conclusions: By profiling tumor biomarkers from a large cohort of GBM patients using validated assays in a single facility, we demonstrate the vast molecular heterogeneity of GBM and highlight the importance of individualized therapy based on a patient’s unique tumor profile. Incorporating a comprehensive biomarker analysis into clinical management of this aggressive cancer allows for an informed selection of more effective therapies.

2043

General Poster Session (Board #1G), Sat, 8:00 AM-11:45 AM

Efficacy and safety of radiotherapy (RT) plus temozolomide (TMZ) in elderly patients (EP) with glioblastoma (GBM). Presenting Author: Giuseppe Lombardi, Medical Oncology 1, Veneto Institute of Oncology-IRCCS, Padova, Italy Background: the optimal management of EP with GBM remains controversial. The role of RT with TMZ for EP is unclear, and EP are often treated with RT alone, TMZ alone or palliative approaches. We describe our experience of combining RT with concurrent TMZ for treatment of EP with GBM Methods: medical records of patients ⱖ65 years old with newly GBM, histologically confirmed at Veneto Institute of Oncology – Padua, and treated with RT plus TMZ, were reviewed. Concomitant TMZ was 75mg/m2/ die. The adjuvant treatment consisted of TMZ 150-200mg/m2/die for six cycles. Median progression-free survival(PFS) and overall survival(OS) were estimated with Kaplan-Meier method. Toxicity was scored according to CTCAE 4.0 Results: we analyzed 60 patients(PTS), 34 males and 26 females; the average age was 70 (range 65-82); ECOG PS was 0-1 in 35 PTS and 2 in 25 PTS; complete surgery was performed in 35 PTS, partial surgery in 25 PTS. 40 and 20 PTS received RT within 6 or more weeks (range 7-9) from surgery. MGMT and IDH1 were analyzed in 43 PTS: MGMT methylated in 20 PTS (46%), all PTS had wild-type IDH1. 34 PTS were treated with RT 40Gy in 15 fractions, 26 PTS with RT 60Gy in 30 fractions with no significant difference in ECOG PS, MGMT and type of surgery between the two subgroups. For all PTS, PFS and OS were 9.5 and 12.7 ms, respectively. OS was 13.7 and 12.4 ms (p⫽0.9) in PTS receiving RT within 6 or more weeks from surgery, respectively. 13% of PTS showed grade 3-4 haematological toxicity, 12% grade 3-4 asthenia, 3% nausea/ vomiting. MGMT methylated and complete surgery was associated with a longer survival. PFS was 9 vs 10 months (p⫽0.4) and OS was 11.7 vs 13.7 ms (p⫽0.1), for PTS treated with 40Gy and 60Gy, respectively. Regarding toxicity: grade 3-4 haematological toxicity was 9% vs 23%, severe asthenia was 9% vs 15%, nausea/vomiting was 3% vs 4% of PTS receiving RT 40Gy and 60Gy, respectively. Conclusions: RT plus TMZ is effective and safe in EP with GBM and good ECOG PS. PFS and OS was not statistically different between PTS receiving RT 40Gy or 60Gy, although we showed a trend for longer OS with RT 60Gy; in contrast, severe toxicity was higher in PTS with RT 60Gy. OS was similar between PTS receiving RT within 6 or more weeks (7-9ws) from surgery.



General Poster Session (Board #1H), Sat, 8:00 AM-11:45 AM

Imaging biomarkers of ramucirumab and olaratumab in patients with recurrent glioblastoma. Presenting Author: Jaishri O’Neill Blakeley, The Johns Hopkins University, School of Medicine, Baltimore, MD Background: VEGF and PDGF receptors are overexpressed in glioblastoma (GBM). Both receptor families may be important therapeutic targets. We explored early biologic markers of VEGFR-2 or PDGFRa inhibition with functional MRI. Methods: A subset of patients (pts) from a multicenter phase II study of monoclonal antibodies to VEGFR-2 (ramucirumab 8mg/kg IV q2wks) or PDGFRa (olaratumab 20mg/kg IV q2wks) in adult patients with recurrent GBM underwent a standardized MRI brain protocol with dynamic contrast enhanced (CE); diffusion tensor; perfusion weighted and routine sequences at -1d, ⫹1d, ⫹28d and every ⫹56d from treatment initiation. ACRIN performed site qualification and imaging QA. Regions of CE and T2w hyperintensity were manually defined; percent change in volumes and change in normalized image intensities was calculated. Results: 28 patients were evaluable. Pts receiving ramucirumab (n⫽11; 7 male) had a median age of 54 (43-67), KPS 90 (70-100) and Dex dose 2mg (0-8). Pts receiving olaratumab (n⫽17; 14male) had a median age of 58 (24-72), KPS 80 (70-100) and Dex dose 2mg (0-4mg). KPS and Dex were stable over time. Conclusions: Preliminary results show that within 1 day of ramucirumab, CE volume, relative CE intensity and blood volume decreased and by 28 days, T2 volume and ADC decreased suggesting a potent antiangiogeneic effect. PDGFRa inhibition had no effect on lesion volume, but reduced relative CE intensity and blood volume at 28 days. Clinical efficacy results are anticipated in mid-2013. Clinical trial information: NCT00895180. Ramucirumab 1d

ⴙ28d

ⴙ56d

2.0 (1.2-2.3) 0.9 (0.5-1.6) 73 (61-89) 1.7 (1.4-1.8)

80 (56-100) 97 (86-110) 1.7 (1.1-2.3) 0.8 (0.3-1.2) 70 (56-80) 1.6 (1.4-1.8)

73 (41-130) 81 (40-108) 1.6 (1.0-2.0) 1.0 (0.3-2.1) 76 (58-82) 1.6 (1.3-1.8)

82 (46-140) 65 (33- 90) 1.5 (1.1-2.2) 1.0 (0.3-1.5) 72 (66-85) 1.6 (1.2-2.0)

% volume change CE T2 Normalization T1wGd intensity Relative Peak Height DSC % Recovery in CE lesion Normalized ADC

2046

Olaratumab

-1d

-1d

ⴙ1d

ⴙ28d

ⴙ56d

1.6 (1.0-2.3) 1.1 (0.3-2.8) 61 (50-83) 1.7 (1.4-2.4)

100 (80-130) 100 (70-130) 1.9 (1.0-2.2) 1.1 (0.3-2.1) 65 (36-84) 1.7 (1.4-2.5)

130 (60-250) 110 (70-170) 1.6 (0.8-2.2) 1.1 (0.4-2.7) 61 (48-81) 1.7 (1.3-2.4)

120 (45-400) 85 (50-848) 1.6 (0.7-2.1) 0.7 (0.4-2.3) 58 (49-73) 1.6 (1.3-1.8)


2045


Prognostic value of 18FET positron emission tomography (18FET-PET) for the clinical course in newly diagnosed glioblastoma. Presenting Author: Joerg Christian Tonn, Department of Neurosurgery, LMU Munich, Munich, Germany Background: Aim of this prospective longitudinal study was to evaluate whether 18FET-PET allow to monitor and quantify the therapeutic effects of surgery, radiotherapy and chemotherapy in newly diagnosed glioblastoma and whether 18FET-PET can provide additional prognostic information on response to therapy and outcome. Methods: 92 patients with newly diagnosed glioblastoma considered eligible for radiochemotherapy (RcX) were included; diagnosis was obtained by biopsy (n⫽46) or resection (n⫽46). Patients were to undergo 18FET-PET and cocomitant MRI scans prior to surgery, following RcX and as well as after three cycles of adjuvant temozolomide (TMZ). At each time point, biological tumor volume (BTV), maximal 18FET uptake as ratio to background (SUVmax/BG), and tumor uptake kinetics (TAC) were obtained. Overall survival (OS) was primary endpoint, progression-free survival (PFS) as defined by MRI using Macdonald criteria was a secondary endpoint. ROC analyses were done to determine optimal cut-off values of 18FET-PET parameters for survival outcome. To identify predictors for OS/PFS, Cox regression analysis was performed. Results: 79 patients were eligible for further evaluation. ROC analysis revealed cut-off values for pre-RCX BTV (9.5 ccm) and SUVmax/BG (2.95) with a sensitivity and specificity of both 70% for BTV and 68/73% for SUVmax/BG. Both pre-therapeutic BTV and SUVmax/BG were associated with PFS and OS (p⬍0.05). In contrast to MRI-based volume, the prognostic value of BTV remained highly significant in the multivariate Cox analysis independently of MGMT status.. Furthermore, 18FET TAC pattern and its changes were related to OS and PFS. Conclusions: Serial 18FET-PET imaging in glioblastoma before and after concomitant radio-/chemotherapy is a highly powerful tool to provide prognostic information for the outcome in newly diagnosed glioblastoma patients. These findings might help to personalize therapy and response evaluation in forthcoming clinical investigations. Clinical trial information: NCT01089868.

2047


Phase I/II trial of vorinostat combined with temozolomide (TMZ) and radiation therapy (RT) for newly diagnosed glioblastoma (GBM) (N0874ABTC0902, Alliance): Final results of the phase I trial. Presenting Author: Evanthia Galanis, Mayo Clinic, Rochester, MN

RTOG 0913: A phase I study of daily everolimus (RAD001) in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma. Presenting Author: Prakash Chinnaiyan, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL

Background: Vorinostat (VOR) is a histone deacetylase inhibitor that represents a rational targeted agent in GBM treatment. Given its singleagent activity in recurrent disease (Galanis,et al, 2009) and radiosensitizing properties, this phase I/II trial was designed to test the addition of VOR to standard chemoradiation in newly diagnosed GBM patients (pts): the phase I portion of the trial is the focus of this report. Methods: A standard cohorts of three design was used to assess the safety of VOR in combination with RT and concomitant TMZ and establish the phase II dose of the combination. VOR was given orally days 1 - 5 every wk beginning with the first dose of RT (total dose 60 Gy) and (75mg/m²/day). Following a 4 - 6 week rest, pts received up to 12 cycles of standard adjuvant TMZ in combination with VOR on days 1-7 and 15 – 21 of each cycle; dose was based on NABTT trial 04-03 (Lee, et al, 2012). Results: The phase I component is complete with 15 pts, 12 pts at dose level 0 (VOR 300 mg/day days 1 - 5, weekly x 6 wks), and 3 pts at dose level 1 (VOR 400 mg/day, days 1 – 5 weekly x 6 wks) in combination with RT/TMZ. Dose limiting toxicity (DLT) in dose level 1 included grade 3 fatigue in 2 pts, grade 3 wound dehiscence in 1 pt, and grade 4 neutropenia and thrombocytopenia in 1 pt. In dose level 0, 1/6 pts had DLT (gr 3 dyspnea). An MTD expansion cohort of 6 additional patients was added to dose level 0; one patient experienced grade 4 thrombocytopenia and grade 3 fatigue, and 1 patient experienced grade 3 febrile neutropenia. In the 12 pts treated in the phase II dose, most common toxicities were hematologic, including lymphopenia (gr 3/4 in 66.7%), thrombocytopenia (gr 3 in 16.7%, gr 4 in 16.7%) and neutropenia (gr 3 in 16.7%, gr 4 in 8.3%). Grade 3 fatigue was observed in 8.3% of the pts. Conclusions: MTD for VOR in combination with TMZ/RT in newly diagnosed GBM patients is 300 mg/d, days 1 - 5 weekly during RT. Toxicity was primarily hematologic. This dose was used in the recently completed phase II trial of the combination (110 pts). RNA expression profiling in patient samples is in process to assess vorinostat responsive signatures observed in preclinical models. Clinical trial information: NCT00731731.

Background: To determine the safety of the mTOR inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients. Methods: Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (TMZ) (75 mg/m2/day). Everolimus was escalated from 2.5 (Dose Level 1), to 5 (Dose Level 2), to 10 mg/day (Dose Level 3). Maintenance TMZ was delivered at 150-200 mg/m2 on days 1 to 5 every 28 days for up to 12 cycles with concurrent everolimus at the previously established daily dose of 10 mg/day. Dose escalation continued if a dose level produced DLTs in ⱕ 2 of the first 6 evaluable patients. Results: Between October 28, 2010 and July 2, 2012, the Radiation Therapy Oncology Group (RTOG) 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria, receiving drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined MTD of 10 mg/day. Two of the first 6 eligible patients experienced a DLT at each dose level. DLTs included: gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were Grade 1/2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was one death reported, which was attributed to tumor progression. Conclusions: Daily oral everolimus (10 mg) combined with both concurrent radiation therapy and TMZ followed by maintenance TMZ, is well tolerated, with an acceptable toxicity profile. A phase II randomized clinical trial with mandatory correlative biomarker analysis is currently underway, designed to both determine the efficacy of this regimen and identify molecular determinants of response. Supported by RTOG U10 CA21661 and CCOP U10 CA37422 grants from NCI and Novartis. Clinical trial information: NCT01062399.


126s 2048

Central Nervous System Tumors General Poster Session (Board #2D), Sat, 8:00 AM-11:45 AM

Final results from a large prospective Italian population study on glioblastoma and correlations with MGMT status: The Project of Emilia-Romagna Region in Neuro-oncology (PERNO). Presenting Author: Alba Ariela Brandes, Medical Oncology Department, Bellaria-Maggiore Hospital, Azienda USL of Bologna, Bologna, Italy Background: The impact on the general population of temozolomide concurrent with and adjuvant to radiotherapy (RT/TMZ) was assessed in the context of the Registry of the Project of the Emilia-Romagna Region in Neuro-Oncology (PERNO), the first Italian prospective observational population-based study in the field of neuro-oncology. Methods: Patients (pts) meeting the following inclusion criteria were evaluated: age ⱖ18 years; PS 0-3; histologically confirmed GBM, no previous or concomitant non-glial tumoral disease, residence in the Emilia Romagna region. The data were collected prospectively. Results: Study accrual, started on January 1 2009, was closed, as planned, on December 31 2010. Two hundred sixty-eight pts (F⫽111, M⫽157; median age, 63.5 [range 29-34] years) were studied. mOS was 10.7 months (95%CI: 9.2 – 12.3). MGMT status, assessed in 186 (89%) of 210 pts who had at least radiotherapy was evaluable in 174 pts (83%), being methylated in 76 (43.7%), and unmethylated in 98 (56.3%) pts. mOS for pts with MGMT methylated status was 18.5 months (95%CI: 14.4-22.6), and 12.4 months for those with MGMT unmethylated status (95%CI: 10.5 - 14.3, p⬍0.0001). 140 pts ⬍70 years were treated with RT/TMZ; mOS in this group was 16.4 months (95% CI: 14.5 – 18.4). mOS was 20 months in the 59 pts (42%) harboring MGMT methylation (95% CI: 12.8 - 27.2), and 13.5 months in the 73 pts (52%) without MGMT methylation (95% CI: 10.8 – 16.2, p⬍0.0001). At multivariate analysis, a significant prognostic role was found for performance status (p⫽0.001), extent of surgery (p⫽0.009), age (p⫽0.004), postsurgical treatment (p⫽0.03), and MGMT status (methylated vs unmethylated, p⫽0.01). Conclusions: The data from the present large prospective population study are in line with those reported in the EORTC/NCIC randomized trial, confirming that this successful approach has been widely incorporated in daily practice.

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zr-GC1008 PET imaging and GC1008 treatment of recurrent glioma patients. Presenting Author: Martha W. den Hollander, Department of Medical Oncology, University Medical Center Groningen, Groningen, Netherlands

Background: Transforming growth factor-␤ (TGF-␤) signaling is involved in glioma development. GC1008 is a monoclonal antibody that has demonstrated significant neutralization of all mammalian isoforms of TGF-␤ in preclinical models (Lonning, Curr Pharm Biotechnol 2011). The aim of this study was to investigate whether GC1008 uptake in brain tumors can be visualized using the 89Zirkonium (Zr)-GC1008 PET scan and to assess treatment outcome in patients with recurrent glioma treated with GC1008 (NCT01472731). Methods: Patients with WHO II-IV glioma who presented with recurrent disease were eligible. After iv administration of 37 MBq (5 mg) 89Zr-GC1008, 89Zr-GC1008 PET scans were performed on day 2 and day 4 post injection. Thereafter, patients were treated with 5 mg/kg GC1008 iv every 3 weeks. MRI scans were made for response evaluation after 3 courses or as clinically indicated. Results: Twelve patients with 1st-8th recurrent disease were included (10 glioblastoma, 1 anaplastic oligodendroglioma, 1 anaplastic astrocytoma), all underwent an 89ZrGC1008 PET scan on day 4, 4 patients also underwent a PET scan on day 2 after tracer injection. Median SUVmax on day 4 was in tumor lesions 4.6 (range 1.5-13.9) and median SUVmean in normal brain tissue 0.3 (range 0.2-0.5). In 3 out of 4 patients who underwent a day 2 and day 4 whole body scan uptake decreased in most normal organs but not in tumor lesions, supporting tumor specific 89Zr-GC1008 uptake. No major toxicity of GC1008 treatment was observed, but all patients showed clinical and/or radiological progressive disease after 1-3 cycles. Median progression free survival was 61 days (range 25-80) and median overall survival 106 days (range 37-287⫹). Conclusions: 89Zr-GC1008 showed excellent uptake by recurrent gliomas. Clinical benefit of GC1008 treatment was not observed in this limited study population. Clinical trial information: 01472731.

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Marrow-ablative chemotherapy followed by tandem autologous hematopoietic cell transplantation (AuHCT) in pediatric patients with malignant brain tumors. Presenting Author: Jhon Guerra, The Neuro-oncology Program, Children’s Center for Cancer and Blood Diseases, Children’s Hospital Los Angeles & Keck School of Medicine, University of Southern California, Los Angeles, CA Background: In an effort to both improve cure rates and quality of survival in young children with malignant brain tumors, irradiation-avoiding or at least minimizing marrow-ablative chemotherapy with AuHCT has been incorporated in both up-front as well as recurrent therapies. To decrease the toxicity of single cycle marrow-ablative chemotherapy regimens, and possibly enhance cure through overall dose intensification, use of fractionated multiple (tandem) cycles of marrow-ablative chemotherapy with AuHCT has been explored. Methods: In this retrospective analysis, we investigated the outcome of children with malignant brain tumors treated with marrow-ablative chemotherapy and tandem AuHCT at Children’s Hospital Los Angeles between June 1999 and July 2012. Results: Fortyfour children (24 males) with a median age of 7.1 years (range 0.6- 19.0 years) with malignant brain tumors were studied. Twenty-one had medulloblastomas/primitive neuro-ectodermal tumors, 8 atypical teratoid/rhabdoid tumors, 5 high-grade gliomas, 4 malignant germ cell tumors, 3 ependymomas and 3 choroid plexus carcinomas. Twenty-nine patients receive 3 and 15 received 2 tandem transplants, respectively. Twenty-seven patients were newly-diagnosed and 17 recurrent disease. Thirty-one patients received irradiation at some time. The 5-year post-transplant progressionfree (PFS) and overall survivals (OS) for all patients were 46.3⫾8.2% and 51.7⫾8.5% respectively. The PFS and OS for newly-diagnosed patients were 68.9 ⫾ 9.9% and 73.5⫾9.3% respectively, compared with those transplanted at relapse 11.8⫾9.8 (p ⬍0.001) and 15.1⫾12.3% (p ⫽ 0.0231) respectively. The 5-year post-transplant PFS and OS in unirradiated patients was 74.0⫾13.0% and 74.0⫾13.0% versus33.2⫾9.8% and 40.2⫹/-10.6% in irradiated patients (p ⫽ 0.11 and p ⫽ 0.239 respectively). One patient (2.3%) died of transplant-related toxicity. Conclusions: Marrow-ablative chemotherapy with tandem AuHCT is feasible and safe in children with malignant brain tumors with encouraging irradiation-free survival in newly-diagnosed children.

2051


Quality of life (QOL) and cognitive status among irradiated brain tumor survivors treated with donepezil or placebo. Presenting Author: Doug Case, Wake Forest University, School of Medicine, Winston Salem, NC Background: Cognitive problems after cancer therapy can decrease QOL. This phase III randomized trial tested the effect of donepezil (5-10 mg daily for 24 weeks) on cognition and QOL in brain cancer patients. Methods: Between 2/2008-12/2011, 198 (99 placebo; 99 donepezil) adult primary and metastatic brain tumor survivors ⬎ 6 months post radiation (⬎ 30 Gy) were recruited at 24 sites affiliated with the Wake Forest CCOP Research Base, 3 CTSU sites, and M.D. Anderson. Outcomes were assessed at baseline, 12 and 24 weeks. Regression analyses examined the association of demographics, fatigue (FACIT-Fatigue), and a cognitive performance composite score (CC) (comprised of the Controlled Oral Word Association Test, Hopkins Verbal Learning Test-Revised, Digit Span Test, Trail Making Test A&B, Rey-Osterreith Complex Figure-modified, Grooved Pegboard) on QOL, measured by the FACT-Brain (FACT-Br) total score. Results: Participants had a median age of 55, were predominantly female (54%) and non-Hispanic White (91%), with a median time from diagnosis of 38 months. Study completion was 74%. At 12 and 24 weeks, treatment had no significant effect on QOL, unadjusted and adjusted for race/ethnicity, age, sex, fatigue, baseline FACT-Br, and baseline CC. However, for those below the median on the baseline FACT-Br subscale (i.e., greater cognitive symptoms), donepezil was associated with higher (better) post-tx FACT-Br total scores (p ⫽0.004), unadjusted for covariates. After adjustment for covariates, donepezil was borderline significantly associated with higher post-tx QOL (p⫽0.052). Improvement in QOL was associated with being female (p⫽0.017) and less baseline fatigue (p⫽0.005). For participants with baseline FACT-Br subscale scores above the median, only lower baseline FACT-Br total scores (p⫽0.015) were significantly related to greater improvements in FACT-Br. Donepezil treatment was not significant (p⫽0.48). Conclusions: The impact of donepezil on QOL was greater in survivors with more cognitive symptoms at baseline, although the results were borderline significant. Fatigue continued to be a major factor in lower QOL. Other interventions to better manage survivors’ symptoms are needed. Clinical trial information: NCT00369785.




Patterns of relapse after concurrent temozolomide and dose-escalated intensity-modulated radiation therapy (IMRT) in newly diagnosed glioblastoma (GBM). Presenting Author: Corey Speers, University of Michigan Health System, Ann Arbor, MI Background: We hypothesized that IMRT would permit us to safely escalate the dose of radiation with concurrent temozolomide substantially above the current standard of 60 Gy and that this increased dose would more adequately control local disease leading to an alteration in the patterns of relapse in patients with GBM. Methods: Between 2003 and 2012 a total of 69 patients were treated with dose-escalated IMRT with concurrent temozolomide. 39 patients were initially treated in a combined phase I/II trial with IMRT doses of 66 to 81 Gy over 6 weeks with concurrent daily temozolomide (75 mg/m2) followed by adjuvant cyclic temozolomide (200 mg/m2 d1-5 q28d for 6 or more cycles). Subsequently, 30 additional patients were treated to 66-72 Gy based on the reported efficacy and safety of the initial phase I/II study. Results: All 69 patients were assessed to evaluate the effect of dose escalation on late toxicity and patterns of progression. Median RT dose was 72 Gy and median overall survival was 19.0 months. Late CNS grade III toxicity was observed at 78 (2 of 7 patients) and 81 Gy (1 of 9 patients). 0 of 53 patients receiving 75 or less Gy developed necrosis. 64% (44/69) of patients had progression of their disease after dose-escalated chemoradiotherapy. The patterns of progression differ, however, from previous studies which identify in-field relapse of 72-80% with standard dose radiation (Brandes AA, Tosoni A, Franceschi E, et al: J Clin Oncol. 27:1275-9, 2009). In this cohort, 41% (18/44) of patients developed marginal or distant relapse compared to 59% (26/44) who developed local, in-field relapse. Conclusions: Patients with GBM can safely receive standard temozolomide with up to 75 Gy in 30 fractions, delivered using IMRT. Dose-escalated chemoradiotherapy improves local control and leads to an increased percentage of patients progressing distally, highlighting the need for improved tumor targeting with newer imaging modalities to identify the initial extent of tumor involvement as well as the need for more effective systemic treatment. I/II study.

2054


A phase I study of cediranib in combination with cilengitide in patients with recurrent glioblastoma. Presenting Author: Elizabeth Robins Gerstner, Massachusetts General Hospital, Boston, MA Background: Despite high vascularity, duration of response of glioblastoma (GBM) to anti-angiogenic therapy is short. One proposed mechanism of resistance is via co-option of native brain blood vessels and tumor infiltration into normal appearing brain. We designed a Phase I study of cediranib, a VEGFR tyrosine kinase inhibitor, in combination with cilengitide, an integrin inhibitor, to block this infiltrative relapse. Methods: A phase I study was conducted through the Adult Brain Tumor Consortium in patients with recurrent GBM. Once the MTD was determined, 40 patients enrolled in a dose expansion cohort. Standard eligibility criteria were included and all patients needed to have at least 1 cm of residual disease to assess tumor response. In the dose expansion cohort, 20 patients had received prior anti-VEGF therapy and 20 had never received anti-VEGF therapy. The primary endpoint was the safety of cediranib with cilengitide. Secondary endpoints were overall survival, the proportion of patients alive and progression free at 6 months (APF6), radiographic response (RR), and exploratory analyses of advanced MRI (perfusion, permeability, diffusion imaging) and blood biomarkers. Results: Forty-five patients were enrolled with a median age of 54 (23-80) and a median KPS 80 (60-100). No DLTs were observed and the MTD was cediranib 30mg daily and cilengitide 2000 mg twice weekly. There were no unexpected Grade 3 or 4 toxicities. Thirty patients experienced disease progression, 8 patients went off study for toxicity, and 5 patients withdrew from the study. Thirty nine patients have died. Partial response was seen in 2 patients, stable disease in 13, progression in 21, and 7 patients were not evaluable for RR. Median OS was 6.4 months, median PFS was 2.4 months, and APF6 was 7.5%. Conclusions: Combination cediranib/cilengitide was well tolerated but the median PFS/OS, APF6, and RR were not very promising. Ongoing analysis of the correlative imaging and blood biomarkers may shed light on a subset of patients who might benefit from this regimen and if anti-VEGF therapy blocked the penetration of cilengitide into the tumor. Clinical trial information: NCT00979862.

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Phase II study of PX-866 in recurrent glioblastoma. Presenting Author: Marshall W. Pitz, University of Manitoba, Winnipeg, MB, Canada Background: Glioblastoma (GBM) is the most aggressive malignancy of the central nervous system. The majority have genetic changes that increase the activity of the phosphatidylinositol-3-OH kinase (PI3K) signal transduction pathway, critical for cell motility, proliferation, and survival. We present the results of PX-866, an oral PI3K inhibitor, in patients (pts) with recurrent GBM. Methods: A multinomial design of response and early progression (⬍ 8 weeks on study) was used. In stage 1 (15 pts), 0 responses and ⱖ 10 early progressions would stop accrual; after full accrual, ⱖ 4 responses OR ⱕ 13 early progressions was prespecified as of interest. Pts with histologically confirmed GBM, at first recurrence after chemoradiation and adjuvant temozolomide were given PX-866 8 mg daily on this single-arm phase II study. MRI and clinical exam were done every cycle (8 weeks). Tumour tissue was collected for analysis of potential markers of PI3K inhibitory activity (PTEN, EGFRviii, PIK3CA mutations). Results: A total of 33 pts were enrolled, eligible and evaluable. Median age was 56 (range 35-78), 12 were female; 29 had performance status (PS) 0-1 and 4 had PS 2. Median time from initial diagnosis to enrolment was 308 days (range 141-1256). Median number of cycles was 1 (range 1-7). Thirty-two pts have discontinued therapy, 26 due to disease/symptomatic progression and 6 due to toxicity (5 LFT elevation and 1 allergic reaction). Other adverse effects (AE): fatigue (16 pts/2 grade 3), diarrhea (11 pts/5 grade 3), nausea (19 pts/1 grade 3), vomiting (11 pts/1 grade 3) and lymphopenia (29 pts/7 grade 3/4). Five pts had related serious AEs (1 LFTs, 1 GI and 3 venous thromboembolism) All pts were evaluable for response; 25 had a best response of progression, 1 had partial response (overall response rate 3%) and seven (21%) had stable disease (SD, median 7.3 months; range 3.1-13.6). Six month PFS was 17%. In preliminary analyses, no statistical association was found between SD and PTEN or EGFRviii status (results pending in 16 pts). Conclusions: PX-866 was relatively well tolerated. Overall response rate was low, and the study did not meet its primary endpoint; however, 21% of pts obtained durable stable disease. Further correlative work is required to identify the predictor of this effect. Clinical trial information: NCT01259869.

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Contrast-enhanced T1-weighted subtraction maps for response assessment in recurrent glioblastoma treated with bevacizumab. Presenting Author: Benjamin M. Ellingson, Department of Radiological Sciences, Biomedical Physics, and Bioengineering; University of California, Los Angeles, Los Angeles, CA Background: Antiangiogenic therapy in glioblastoma (GBM) results in decreased enhancement on post-contrast T1w images, which complicates standard response assessment and is likely the reason no studies have found predictive value in enhancing tumor size or change in size. The current study examined whether contrast-enhanced T1-weighted subtraction maps (CE-⌬T1w) calculated from subtracting pre-contrast (T1) from post-contrast T1w images (T1⫹C) can improve quantification and predict response in GBM patients treated with bevacizumab. Methods: Recurrent GBM patients (n⫽160) from the BRAIN trial (AVF3708g), a multicenter Phase II trial evaluating bevacvizumab, were used in the current study. CE-⌬T1w maps were calculated 2 weeks before and 6 weeks after the first dose of bevacizumab by: 1) performing registration between T1 and T1⫹C images, 2) image intensity normalization of T1 and T1⫹C images, and 3) subtraction of T1 from T1⫹C images. The volume of tumor regions with positive contrast enhancement after subtraction was retained for analysis. Results: CE-⌬T1w maps greatly improved detectability of subtly enhancing lesions, particularly post-treatment. Results for PFS and OS are summarized in the table below. In all scenarios, CE-⌬T1w maps outperformed conventional tumor segmentation. Results show that size and change in size are both predictive of PFS and OS. Conclusions: CE-⌬T1w maps improve visualization and quantification of contrast enhancing tumor regions in recurrent GBM, allowing for more accurate response assessment. Univariate Cox conventional or (CE-⌬T1w) [HR; p value]

Conventional vs. CE-⌬T1w [p value]

Interaction (method and threshold) [p value]

Pre-Tx t1/2 (hour)

15 17.5 15 17.5 15 17.5

1.711⫾1.069 1.738⫾0.889 0.682⫾0.376 0.682⫾0.432 0.773⫾0.438 1.633⫾2.559

0.243⫾0.172 0.236⫾0.132 0.056⫾0.032 0.059⫾0.033 0.074⫾0.045 0.131⫾0.166

7.821⫾1.281 6.080⫾2.478 ND ND ND ND


Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics 2516^

Poster Discussion Session (Board #4), Tue, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

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A phase I study of the first-in-class mitochondrial metabolism inhibitor CPI-613 in patients with advanced hematologic malignancies. Presenting Author: Timothy S. Pardee, Wake Forest University Health Sciences, Winston-Salem, NC

A phase I first-in-human study of REGN910 (SAR307746), a fully human and selective angiopoietin-2 (Ang2) monoclonal antibody (MAb), in patients with advanced solid tumor malignancies. Presenting Author: Kyriakos P. Papadopoulos, START Center for Cancer Care, San Antonio, TX

Background: Altered metabolism is a hallmark of cancer, including hematologic malignancies. This altered metabolism is a possible therapeutic target. The lipoate derivative CPI-613 is a first in class agent that targets pyruvate dehydrogenase complex.This trial was designed to determine the maximally tolerated dose (MTD), safety, and efficacy of CPI-613 given as a single agent by IV infusion. Methods: CPI-613 was given over a 2 hour infusion on days 1 and 4 for 3 weeks every 28 days with a starting dose of 420 mg/m2. The dose was escalated in 6 cohorts to a final dose of 3780 mg/m2. Treatment could be continued if the patient experienced clinical benefit. Results: A total of 26 patients with advanced relapsed or refractory hematologic malignancies were enrolled. Patients were heavily pretreated with a median of 3 previous therapies (range 1-11). CPI-613 was well tolerated when infused over 2 hours, with no worsening of cytopenias at any dose level. After the dose was escalated to 2940 mg/m2 the protocol was amended to a 1 hour infusion. When infused over 1 hour, 2 patients developed grade 3 renal failure. Infusion time was then returned to 2 hours and dose escalation resumed. At a dose of 3780 mg/m2, one patient experienced prolonged grade 3 nausea and one patient grade 3 renal failure, defining this dose as above the MTD. Renal failure resolved in all but one patient who opted for hospice care. A total of 6 patients were treated at a dose of 2940 mg/m2over 2 hours with no DLTs observed, establishing this as the MTD. Of the 21 patients evaluable for a response, eight achieved a response of stable disease or better for a response rate of 38%. Responses included a complete remission maintained over 27 cycles in one AML patient and clearance of marrow blasts in another, sustained partial response in both a Burkitt’s and a cutaneous T cell lymphoma patient maintained over 17 and 8 cycles respectively, and stable disease in 2 multiple myeloma and 2 myelodysplasia patients. Conclusions: To our knowledge this is the first report of an agent with activity in aggressive hematological malignancies that is not myelosuppressive. The therapeutic index appears high suggesting CPI-613 should be further studied in phase II trials. Clinical trial information: NCT01034475.

Background: REGN910 is a selective, fully human Ang2 MAb that potently blocks signaling through the Tie2 receptor regulating tumor angiogenesis and growth. In multiple mouse xenograft models of human solid tumors, REGN910 inhibits tumor growth. Methods: This first-in-human phase I study (3⫹3 design) explored the safety, recommended phase II dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of REGN910 as a single agent. REGN910 was given IV at escalating doses. At RP2D, expansion cohorts were initiated to confirm safety and assess anti-tumor activity in about 20 patients (pts). Results: 37 pts [17M/20F; median age 57 (range 22-82); ECOG PS 0(9)/1(28)] were enrolled. Twenty-three (23) pts were enrolled in the dose escalation cohorts. No DLTs were reported, and a MTD was not reached. Most common G1/2 treatment-related adverse events (TRAEs) were fatigue 7(19%), peripheral edema 6(17%), diarrhea 5(14%), abdominal distension 4(11%), and decreased appetite 4(11%). There were no ⱖ Grade 3 TRAEs. A confirmed sustained PR (16 wks) was observed in 1 pt with adrenocortical cancer treated at 1 mg/kg. SD (range 6.9-46.8 wks) was reported for 17 of 32 (53%) pts evaluable for efficacy. Fourteen pts received treatment ⬎16 wks. One pt with thyroid cancer had SD for 46 wks, and 1 pt with hepatocellular cancer had SD for 16 wks with ⱖ50% decline in alphafetoprotein. Across all dose levels, REGN910 pharmacokinetics appeared linear and dose-proportional. The PK profile was characterized by an initial distribution and a single mono-exponential elimination phase. Total circulating serum Ang2 levels appeared saturated following treatment in all cohorts, indicating systemic target engagement at all doses tested. Conclusions: Administration of REGN910 in patients with advanced cancer is well tolerated, with generally mild and moderate TRAEs. Dose escalation is completed, and enrollment to the expansion cohorts continues. The safety profile supports combination with chemotherapy and/or other antiangiogenic agents. Clinical trial information: NCT01271972.

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A phase I study of carboxyamidotriazole orotate (CTO) in of advanced solid tumors. Presenting Author: Alan Sandler, Knight Cancer Institute, Oregon Health and Science University, Portland, OR Background: CTO is an orotate salt of carboxyamidotriazole (CAI), which is an inhibitor of calcium-dependent intracellular and extracellular signal transduction pathways (presumably affecting VEGF and PI3K) and has tumor anti-proliferative and anti-invasive properties. The activity of CTO alone and in combination with temozolomide or 5Efluorouracil was demonstrated in human glioblastoma, melanoma, and colon tumor xenografts. Methods: This study assessed the maximum tolerated dose (MTD), safety, pharmacokinetics and activity of CTO monotherapy in 34 patients (pts) with advanced solid tumors meeting eligibility criteria with adequate organ function. The CTO study NCT01107522 enrolled pts in 8 cohorts receiving continuous daily oral CTO capsules at doses ranging from 50mg- 555mg/m2/ day. The MTD has not been determined. Pharmacokinetic (PK) sampling was performed during cycle 1 at each dose level. CT scans were performed at baseline and after 8 weeks to assess anti-tumor effect. Patients remained on study if they achieved stable disease (SD) or tumor response and did not experience dose limiting toxicities (DLT). Results: The most frequently recorded adverse events (Grade 1 and 2) were fatigue, nausea, vomiting, and dizziness. DLTs of grade 3 fatigue (219 mg/m2) and grade 3 creatine kinase elevation (555 mg/m2) occurred in one pt each. No cardiac QTc prolongations have been recorded. PK data demonstrated therapeutically relevant CAI levels beginning at the 219mg/m2 dose. Nine pts continued CTO dosing beyond 2 cycles. Tumor assessments demonstrated SD at different doses of CTO: i) 75mg/m2 renal carcinoma (1, 12 cycles); ii) 219 mg/m2-small cell lung cancer (1, 4 cycles), squamous cell lung cancer with PIK3CA mutation (1, 10 cycles and continuing), and lung adenocarcinoma with EGFR mutation (1, 10 cycles and, continuing); iii) 285 mg/m2-1 colon cancer with BRAFV600E mutation (1, 6 cycles), and squamous cell carcinoma (tonsil) with PI3KCA and NRAS mutations (1, 9 cycles, and continuing). Conclusions: CTO given as monotherapy up to 555mg/m2/day is safe and tolerable and without MTD. Six patients with different malignancies and genomic markers achieved SD; combinatorial investigations in malignant gliomas have started. Clinical trial information: NCT01107522.


Phase I, first-in-human, open-label, dose-escalation study of U3-1565, a fully human anti-HB-EGF monoclonal antibody, in patients with advanced solid tumors. Presenting Author: Kathleen N. Moore, University of Oklahoma Health Sciences Center, Oklahoma City, OK Background: Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is an EGF family member and a ligand for EGFR and Her4. U3-1565 is a fully human anti-HB-EGF monoclonal antibody with preclinical anti-tumor and anti-angiogenesis activity. In this study, we evaluated safety, tolerability, immunogenicity, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity of U3-1565 in patients with advanced solid tumors refractory to standard treatment. Methods: The 3⫹3 method of enrollment and dose-escalation was used to test U3-1565 at 2, 8, 16, and 24 mg/kg once every two weeks (with the second dose given three weeks after the first), and at 24 mg/kg weekly. Results: 15 patients (11 females, 4 males; median age 62 (range 47-77) years; 5 CRC, 5 NSCLC, 3 ovarian and 2 other cancer) were enrolled, 3 in each dose level cohort. No dose-limiting toxicity was observed and a maximum tolerated dose was not reached. The highest administered dose of 24 mg/kg weekly generated Cmin above the predetermined target concentration corresponding to Cave resulting in 90% preclinical tumor growth inhibition. U3-1565 was safe and well tolerated with related AE consisting of infrequent and non-dose-related G2 (fatigue, anemia, and appetite loss, seen in 20, 13, and 7% of cases, respectively) and G1 toxicities. No anti-U3-1565 antibody was detected. U3-1565 showed bi-exponential disposition with Cmax and AUC increasing proportional to the dose across all dosing regimens. 13 patients discontinued the study, 12 due to progressive disease and 1 due to non-drug-related AE. After 6 months on study, 2 patients entered study extension phase: A 77 year-old female with NSCLC given 24 mg/kg every two weeks, showed SD (best SLD change -3%) for 26 weeks before progression; and a 76 year-old female with CRC given 24 mg/kg weekly, showed PR (best SLD change -35%) and remains on treatment after 71 weeks. Conclusions: U3-1565 is safe and well tolerated up to 24 mg/kg weekly. Anti-tumor activity was observed and is being further explored in an open-label, dose-expansion study. Clinical trial information: NCT0129041.


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Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics Poster Discussion Session (Board #8), Tue, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

A phase I and biodistribution study of ABT-806i, an 111indium-labeled conjugate of the tumor-specific anti-EGFR antibody ABT-806. Presenting Author: Hui K. Gan, Ludwig Institute for Cancer Research, Melbourne, Australia Background: ABT-806 is a humanized antibody targeting a conformationally exposed epitope only available when tumor Epidermal Growth Factor Receptor (EGFR) is overexpressed or (EGFRvIII) mutated. A prior trial treated 8 patients (pts) with a chimeric homologue (single-dose 5-40 mg/kg), with a minor response in one squamous cell carcinoma of skin pt. A prior phase 1A study of ABT-806 treated 26 pts (2-24 mg/kg IV q2w), with prolonged SD in one head and neck (H&N) cancer pt. No pt had a typical EGFR-inhibitor rash. The current study gathers further ABT-806 clinical data, assesses ABT-806i dosimetry in normal and malignant tissues and examines its relationship to clinical and PK/PD data. Methods: Pts with advanced tumors likely to express EGFR, ECOG 0-2, measurable disease and adequate organ function were enrolled. ABT-806i scans comprised ABT-806i 5-7mCi injection followed by whole body and regional SPECT scans over one week. Cohort (C) 1 pts (n⫽6) had ABT-806i scans alone. C2 pts (n⫽12) had ABT-806i scans at baseline and at week 6 (after 3 fortnightly doses of ABT-806; 6 pts at 18 mg/kg and 6 at 24 mg/kg). Subjects with PR/SD could receive ABT-806 on an extension study until progression. Results: 18 pts (M:F 11:7; median age 57 yrs) with tumors of H&N (6), colon (3), lung (2), brain (2), bladder (1), cervical (1) and other (3) were treated. An H&N pt had a confirmed PR whilst 5 pts had SD (lasting 37 and 24 wks in an adrenal carcinoma and H&N pt respectively). Two potential toxicities were seen at 24mg/kg on the extension study: equivocal rash (G1; three transient lesions on nose) and allergic reaction (Sweet’s syndrome, G2). Dosimetry in C1 pts confirmed safe radiation exposure levels to normal tissues. Many pts showed high, specific tumor uptake of ABT-806i, including 1 pt with an intracranial tumor. ABT-806i uptake was not significantly affected by concurrent ABT-806 treatment. Ongoing analyses of how ABT-806i uptake correlates with tumor EGFR and clinical response may inform the recommended phase 2 dose of ABT-806. Conclusions: The high therapeutic index and specificity of ABT-806 merits further investigation as monotherapy or an antibody-drug conjugate. ABT-806i may have utility as a bioimaging agent. Clinical trial information: NCT01472003.

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A first-in-human trial of RG7116, a glycoengineered monoclonal antibody targeting HER3, in patients with advanced/metastatic tumors of epithelial cell origin expressing HER3 protein. Presenting Author: Didier Meulendijks, Deptartment Clinical Pharmacology, Division of Medical Oncology , The Netherlands Cancer Institute, Amsterdam, Amsterdam, Netherlands Background: The Human Epidermal Growth Factor Receptor 3 (HER3) is a key heterodimerization partner for other HER family members thereby acting as a downstream signal amplifier. This is a first in human study evaluating the safety of RG7116, a humanized anti-HER3 monoclonal antibody with potent HER3 signal inhibition. Due to a glycoengineered Fc-part this antibody displays enhanced antibody-dependent cellular cytotoxicity as compared to conventional antibodies. Methods: Patients (pts) with advanced or metastatic carcinomas with centrally confirmed HER3 protein expression were included. A “3⫹3” dose escalation design was performed starting at 100 mg flat dosing in a q2w regimen. In addition to single agent RG7116 (Part A), RG7116 plus cetuximab (Part B) and RG7116 plus erlotinib (Part C) combinations are evaluated. The results of Part A are presented. Results: Twenty-five pts have been enrolled in 6 cohorts (100 to 2000 mg). No DLTs were observed. Pts had a median (range) of 3 (2 to 6) prior chemotherapy lines. Nine infusion-related reactions (IRRs) Gr 1 to 3 occurred in 7 pts. Three drug-related AEs Gr 3 were reported, 1 IRR, 1 GGT increase, and 1 neutropenia. Only 1 patient was tested positive for human anti human antibodies (HAHA). The PK of RG7116 was non-linear from 100 mg up to 400 mg, possibly as a result of target-mediated drug disposition. Both Cmax and AUC showed a greater than doseEproportional increase over the same dose range, accompanied by a decline in total clearance. Dose proportionality was observed from 800 mg onwards. PD effects were observed from the first dose level onwards with HER3 membranous protein down-regulation in skin and from 200 mg onwards in ontreatment tumor samples. Five pts (1 NSCLC, 2 CRC, 1 SCCHN, 1 BC) had a best response of SD. Confirmed SD (⬎16 weeks) was observed in 2 pts. One BC patient achieved a PR in 18 FDG-PET and significant shrinkage of non-target tumor lesions on CT scan. Conclusions: RG7116 is the first glycoengineered monoclonal anti-HER3 antibody in clinical development. RG7116 monotherapy was well tolerated, and demonstrated preliminary signs of clinical activity. Clinical trial information: NCT01482377.

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Phase I study of volasertib (BI 6727) combined with afatinib (BIBW 2992) in advanced solid tumors. Presenting Author: Marc Peeters, Department of Oncology, Antwerp University Hospital, Edegem, Belgium Background: Volasertib is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases (Plk). Volasertib and afatinib, an irreversible ErbB family blocker, have shown single agent anti-tumor activity and manageable safety profiles in patients (pts) with advanced solid tumors. This dose escalation study was designed to determine the maximum tolerated dose (MTD) of two combination schedules of volasertib and afatinib in pts with advanced solid tumors refractory to or not amenable to standard therapy. Methods: In a 3 ⫹ 3 design, cohorts of 3– 6 pts received volasertib 150 –300 mg IV d1 Q3W ⫹ afatinib 30 –50 mg PO QD d2–21 Q3W (Schedule A) or afatinib 50 –90 mg d2– 6 Q3W (Schedule B). Up to 12 additional pts were enrolled at the MTD. Primary endpoint was the MTD per schedule. Secondary endpoints included pharmacokinetics (PK), safety and efficacy (RECIST). Results: 57 pts (median 58 yr; ECOG PS 0/1/2: 35%/60%/5%) were treated (n⫽29, Schedule A; n⫽28, Schedule B). MTD was volasertib 300 mg/afatinib 30 mg (Schedule A) and volasertib 300 mg/afatinib 70 mg (Schedule B). Cycle 1 dose limiting toxicities (DLTs) were experienced by 5 (Schedule A) and 7 (Schedule B) pts. Most common DLTs were diarrhea (n⫽5), neutropenia (n⫽3), fatigue (n⫽2) and decreased ejection fraction (n⫽2) in Schedule A, and thrombocytopenia (n⫽6), neutropenia (n⫽5), diarrhea (n⫽4) and febrile neutropenia (n⫽3) in Schedule B. Most common grade 3/4 adverse events were neutropenia (n⫽8), thrombocytopenia (n⫽6), diarrhea (n⫽3) and febrile neutropenia (n⫽3). Volasertib exhibited multi-exponential PK behavior with a long half-life (130 hr), moderate clearance (900 mL/min) and large volume of distribution (Vss ⬎6000 L). Co-administration of volasertib and afatinib had no effect on the PK profile of either drug. Two pts in Schedule A (volasertib 300 mg/afatinib 30 mg) achieved partial responses (tumor types: NSCLC, head and neck). Conclusions: MTD of volasertib was 300 mg Q3W combined with afatinib 30 mg d2-21 (Schedule A) or afatinib 70 mg d2-6 (Schedule B). Both agents could be combined at previously shown active single agent doses. At the MTD, treatment was manageable and showed preliminary anti-tumor activity. Clinical trial information: NCT01206816.

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A phase I, dose-escalation trial of continuous and pulsed-dose afatinib (A) combined with pemetrexed (P) in patients (pts) with advanced solid tumors: Final analysis. Presenting Author: Quincy S. Chu, Cross Cancer Centre, Edmonton, AB, Canada Background: A is an irreversible ErbB Family Blocker that has shown additive effects when combined with P in EGFR-mutant NSCLC cell lines. This Ph I trial assessed the MTD, safety and PK of continuous and pulsed-dose A ⫹ P in pts with advanced solid tumors. Methods: In a3⫹3 dose-escalation design, IV P (500 mg/m2) was administered on day (d) 1 of each 21-d cycle combined with either continuous oral A qd (Schedule A; SA) on d1–21 (d2–21 in Cycle 1) or pulsed-dose oral A qd (Schedule B; SB) on d1– 6 of each 21-d cycle. In SA, A starting dose was 30 mg, escalated to maximum of 50 mg. Once the MTD was reached in SA, A was administered at a starting dose of 50 mg in SB. Pts received up to 6 cycles of P with the option for A monotherapy thereafter. P and steady state A PK were analyzed by intra-individual comparison in SA only for possible drug– drug interaction. Results: 53 pts were treated (SA: n⫽23, median age 58 yrs; ECOG 0/1/2 [30%/65%/4%]; SB: n⫽30, median age 62 yrs, ECOG 0/1/2 [27%/70%/3%]). MTD of A in SA was 30 mg; 8 pts had dose-limiting toxicities (DLTs) in Cycle 1 (40 mg: 2/3 pts; 30 mg; 6/19 pts). 30-mg cohort included 19 evaluable pts; 1 pt was replaced during expansion (incomplete PK collection) and had a DLT. MTD of A in SB was 50 mg; 11 pts had DLTs in Cycle 1 (70 mg: 4/5 pts; 60 mg: 6/17 pts; 50 mg: 1/6 pts). Most frequent drug-related AEs in SA were diarrhea (91%), stomatitis (65%) and rash (61%) and in SB were diarrhea (83%), rash (83%) and fatigue (80%); most were Grade 1/2. 6 pts in SA and 8 pts in SB completed 6 treatment cycles; 1 pt in each schedule remain on treatment. Best response in SA was 1 confirmed partial response (CPR; NSCLC, prior sequential chemotherapies and erlotinib) and 6 pts with stable disease (SD). In SB, best response was 1 CPR (bladder cancer, prior sequential chemotherapies) and 10 pts with SD. No clinically relevant PK interactions between A and P were observed. Conclusions: Continuous or pulsed-dose A combined with P exhibited a manageable safety profile. No clinically relevant PK interactions were seen in SA. Continuous dose A 30 mg/d with P 500 mg/m2 (d1 of each 21d cycle) is the recommended dose for further Ph II studies. No apparent safety or dose advantage was observed in SB. Clinical trial information: NCT01169675.


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First-in-human evaluation of CO-1686, an irreversible, selective, and potent tyrosine kinase inhibitor of EGFR T790M. Presenting Author: Lecia V. Sequist, Massachusetts General Hospital, Boston, MA

A phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of the selective aurora kinase inhibitor GSK1070916A. Presenting Author: Iain McNeish, Barts Cancer Research UK Centre, London, United Kingdom

Background: Efficacy of existing EGFR tyrosine kinase inhibitors (TKIs) in NSCLC is limited by emergence of the T790M mutation in approximately 50% of patients, and significant skin rash and diarrhea, caused by wild-type (WT)-EGFR inhibition, compromises tolerability. CO-1686 is an orally active TKI that targets common activating EGFR mutations and T790M, while sparing WT-EGFR. Animal models suggest maximal efficacy when trough plasma concentrations exceed 200ng/ml. Methods: This is a first in human phase 1 (3⫹3) dose-finding study of oral CO-1686, administered continuously in 21-day cycles. To be eligible, patients must have EGFR-mutant NSCLC and prior therapy with an EGFR TKI. Endpoints include safety, pharmacokinetics (PK), and efficacy. All patients undergo a biopsy for genotyping before starting study drug. Results: As of 18 Jan 2013, 35 patients (18/28 (64%) T790M⫹; 7 pending) have been treated with CO-1686. Dosing started at 150mg QD and escalated in steps to 900mg QD, 600mg BID and 400mg TID, with a maximum tolerated dose not yet reached. A recommended phase 2 dose is expected to be reached soon. Related AEs of grade 3 or higher were hypoglycaemia (n⫽1) and hyperglycaemia (n⫽1). AEs typical of WT-EGFR inhibition (rash, diarrhea) have not been observed. Dose-proportional PK was observed; plasma half-life was 4-5 hrs and at 900mg QD Cmax⫽3000ng/ml but trough concentrations were ⬍ 200ng/ml. At ⱖ300mg BID and TID dosing, trough concentrations can exceed 200ng/ml. At 900mg QD, 2 of 3 patients showed clinical benefit after 2 cycles of CO-1686 including one with clinically-relevant tumor shrinkage (18%) and a second with stabilization of a pleural effusion that had previously required repeat thoracenteses at ~10 day intervals. At 300mg BID, one patient (Del(19)/T790M⫹) with PK trough concentration ⬎200ng/ml exhibited significant tumor shrinkage (29%) after 2 cycles. Further efficacy data from BID/TID cohorts and centrally-confirmed genotypes will be presented at the meeting. Conclusions: CO-1686 offers potential for improved activity and better tolerability over current EGFR TKIs, particularly in the treatment of T790M⫹ disease, an area of high unmet clinical need. Clinical trial information: NCT01526928.

Background: GSK1070916A is a potent and selective inhibitor of Aurora B and C. This phase I study in collaboration with GlaxoSmithKline was part of the Cancer Research UK Clinical Development Programme. Methods: Patients (pts) with advanced/metastatic solid cancers for whom there was no standard therapy, with adequate performance status and organ function were eligible for GSK1070916A (1 hour i.v. infusion days 1 – 5, every 21 days). The primary objectives were to determine the safety profile, dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of GSK1070916A. The starting dose was 5mg/m2/day, with initial single pt cohorts, followed by “3 ⫹ 3” cohorts and expansion at the MTD. DLTs included prolonged (⬎ 5 days) or complicated grade 4 neutropenia; the MTD was the highest dose at which ⬍ 1 of 3 - 6 pts experienced DLT. Cycle 1 blood and healthy skin biopsies were obtained for PK and PD assays. The expanded cohort included 6 pts having pre- and post-treatment functional imaging studies (FDG PET-CT and MRI), and a further 6 having paired tumour biopsies for PD studies. Results: Nine single pt cohorts received up to 73mg/m2/day of GSK1070916A with no grade 3 or 4 related adverse events. At 102.2mg/m2/day, 1 pt had a DLT (febrile neutropenia) and 2 pts non-DLT grade 4 neutropenia; this dose was considered unacceptably toxic and 23 pts received a lower dose of 85mg/m2/day; 7/23 pts had prolonged/ complicated grade 4 neutropenia, 5 of whom continued GSK1070916A with dose reduction ⫹/- delay. There were no treatment related deaths. A pt with ovarian cancer (102.2mg/m2/day) had a RECIST PR; 19 pts had stable disease for ⬍ 223 days. GSK1070916A PK were linear with a strong correlation between exposure (AUC) and reduction in neutrophils (r2 0.91). At the 85 mg/m2 dose, mean day 1 t1/2 was 8.98 hours and Cl 9.2 l/h; AUCinf was 10% higher on day 5 than day 1. PD results in healthy skin (phosphoHistone-H3, Ki 67 and cleaved caspase-3) were inconsistent. Conclusions: The MTD of GSK1070916A as a 1 hour i.v. infusion on days 1 – 5, every 21 days is 85mg/m2/day, with predictable and manageable neutropenia as the DLT and evidence of clinical activity. Serum levels of cytokeratin-18, tumour PD and functional imaging data will be presented. Clinical trial information: NCT01118611.

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Phi-53: (NCI#7251): Phase I trial of belinostat (PXD101) in combination with 13-cis-retinoic acid (13c-RA) in advanced solid tumor malignancies—A California Cancer Consortium NCI/CTEP sponsored trial. Presenting Author: Thehang H. Luu, City of Hope, Duarte, CA Background: Belinostat has a reported maximum tolerated dose (MTD) of 1,000 mg/m2 given days 1 to 5 every 21 days as a single agent, although in one study in hepatocellular carcinoma belinostat was given at 1,400 mg/m2on the same schedule. Pre-clinical evidence suggests HDAC inhibitors enhance retinoic acid signaling with a synergistic impact in a variety of solid tumors. We conducted a phase I study of belinostat and 13c-RA in advanced solid tumors. Methods: Dose limiting toxicity (DLT) was defined as cycle 1 hematologic toxicity: ⱖgrade 3 that not resolved to ⬍grade 1 within 1 week or non-hematologic toxicity: ⱖgrade 3. We sought the MTD of belinostat days 1-5 with 13-cRA days 1-14, every 21 days, in patients (pt) with advanced solid tumors. Eligibility criteria included normal organ function and QT/QTc interval; 4 weeks from previous therapy. Results: 51 pt were treated: median age 61 (range 40-80); 29 men; 57% ECOG 0, 41% ECOG 1, 2% ECOG 2; 13 lung, 11 breast, 8 colorectal, 3 pancreatic. 11 dose levels (DL) were tested starting from belinostat 600 mg/m2/day and 13c-RA 50 mg/m2/day to belinostat 2000 mg/m2/day and 13c-RA 100 mg/m2/day. Only two DLTs were observed: a grade 3 hypersensitivity reaction with dizziness and hypoxia at DL 8 (belinostat 1700 mg/m2/day, 13c-RA 100 mg/m2/day); and a grade 3 allergic reaction in a patient with an ECOG PS 2 at DL 11 (belinostat 2000 mg/m2/day, 13c-RA 100 mg/m2/day). The MTD was not reached. Pharmacokinetics of belinostat suggests dose proportionality. Median number of cycles: 2 (range 1–56). 10 patients had SD including: 1 neuroendocrine pancreatic stable for 56 cycles; 1 breast pt for 12 cycles; 1 lung pt 8 cycles. 2 pt had PRs: a keratinizing squamous cell carcinoma (tonsil) and a lung cancer pt. Conclusions: Belinostat 2000 mg/m2 days 1-5and 13-cis-Retinoic acid 100 mg/m2days 1-14, every 21 days, was well-tolerated and an MTD was not reached despite doubling the established single agent MTD. Future studies building on this combination to belinostat are warranted. Support: U01CA062505 and P30CA033572 (City of Hope); U01CA099168 and P30CA047904 (University of Pittsburgh).


Phase I trial of belinostat in combination with cisplatin (Cis) and etoposide (Etop). Presenting Author: Sanjeeve Balasubramaniam, National Cancer Institute, National Institutes of Health, Bethesda, MD Background: Histone deacetylase inhibitors (HDIs) are epigenetic therapies in development. To exploit the unique activity in impairing DNA repair, HDIs have been combined with chemotherapy. Belinostat is a potent HDI combined with Cis and Etop based on enhanced DNA damage and apoptosis in small cell lung cancer (SCLC) cells. Methods: Patients with relapsed/refractory cancer or previously untreated advanced stage SCLC were eligible. Belinostat was administered by continuous infusion (CIV) over 48h, from 400 mg/m2/24h, in cohorts of 3. Cis was administered on day 1 and Etop daily X3. Belinostat pharmacokinetics (PK) and several pharmacodynamic (PD) measures were assessed, including lysine acetylation in peripheral blood mononuclear cells (PBMCs) and ␥H2Ax staining in PBMCs and in hair follicles. Results: Five dose levels were explored in 20 patients with solid tumors, including 5 patients with SCLC, two who had no prior therapy. At the first dose level, dose-limiting toxicities (DLT) of gr 4 ANC in 1, and gr 3 HTN in 1 were observed. Cis and Etop were reduced to 60 mg/m2 and 80 mg/m2, respectively, and the dose level repeated without DLT. At the next dose level, 800 mg/m2/24h belinostat, grade 3 HTN and grade 4 pneumonitis were observed. At the MTD of 600 mg/m2/24h belinostat, DLT was seen in 1 of 6 pts; however, all 6 pts required later dose reductions. We thus considered 500 mg/m2/24h in combination with Cis and Etop to be the recommended Phase II dose; confirmation ongoing. PKs show belinostat levels at 1 uM over the 48h infusion, decreasing rapidly to the 60h timepoint. In total 11 pts, 3 with SCLC, completed 6 cycles. PR was seen in 6 pts (3 with SCLC). PD studies confirmed ␥H2AX staining in PBMCs and hair follicles, peaking at 36h and 60h, respectively. Tubulin and lysine acetylation (Ac-K) in PBMCs peaked at 36h; Ac-K recovered more rapidly than tubulin, mirroring ␥H2AX. Conclusions: The MTD of belinostat over 48h by CIV was 600 mg/m2/24h, in combination with Cis 60 mg/m2 on day 1 and Etop 80 mg/m2 on days 1 - 3. PD endpoints indicate that belinostat is active in promoting both acetylation and DNA damage. The HDI combined with chemotherapy requires dose reduction and likely represents an on-target increase in DNA damage. Clinical trial information: NCT00926640.


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Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics Poster Discussion Session (Board #16), Tue, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

Phase I, dose-escalation study of the investigational drug TAK-733, an oral MEK inhibitor, in patients (pts) with advanced solid tumors. Presenting Author: Alex A. Adjei, Roswell Park Cancer Institute, Buffalo, NY Background: This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), MTD, and efficacy of TAK-733 – an oral, selective, allosteric inhibitor of MEK1/2 – in pts with advanced solid tumors (NCT00948467; completed study). Methods: Eligibility: age ⱖ18 y; ECOG PS 0 –2; evaluable tumors. Pts received escalating doses of TAK-733 QD in a modified 3⫹3 design for 21 d in a 28-d cycle to determine the MTD based on DLTs in cycle 1. Plasma (PK) and peripheral blood samples (PD: pERK reduction in PBMCs) were obtained pre-dose (d 1, 8, 15, 21) and post-dose (d 1, 21) in cycle1. Results: 51 pts (median age 58 y; 51% M) received escalating doses of TAK-733 (0.2–22 mg; median 2 cycles, range 1–11 [5 pts ⱖ6 cycles]). 4 pts had DLTs: grade 3 acneiform dermatitis, 1 each at 11.8 and 16mg; grade 3 pustular rash and grade 2 rash/stomatitis (qualifying as a DLT) at 22mg, leading to the 16 mg dose being selected as MTD. 45 pts (88%) had a drug-related AE; most frequent was acneiform dermatitis (47%). 10 pts (20%) had a grade ⱖ3 drug-related AE; most frequent were creatine phosphokinase increase and acneiform dermatitis (each n⫽3, 6%). 7 pts discontinued due to AEs. TAK-733 exhibited a moderately fast absorption with a median Tmax of 3 hr. Steady-state exposure of TAK-733 (0.2–22mg) did not increase in a dose proportional manner based on the power model analysis. The mean terminal t1/2 (11.8, 16, and 22 mg) was 43 hr. Overall mean accumulation ratio was 3.5 following QD dosing for 21 d. On d 21, Emax of blood pERK modulation was 56 –99%, and time-averaged modulation over the dosing interval at steady-state was 76 –98% at MTD. This range correlates well to the 76 – 89% for pERK modulation associated with maximal efficacy in xenograft models. 1 pt (16 mg) with melanoma (BRAF L597R) had a confirmed partial response after 4 cycles (treated for 9 cycles). 15 pts had a best response of stable disease (4 –11.7 months in 6 pts). Conclusions: From preliminary data, TAK-733 appears generally well tolerated, pharmacodynamically active and shows signs of anti-tumor activity in pts with advanced solid tumors. MTD was associated with significant pERK inhibition in peripheral blood. Clinical trial information: NCT00948467.

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Phase I study of everolimus (E, RAD001) and ganitumab (G, AMG 479) in patients (pts) with advanced solid tumors. Presenting Author: Shadia Ibrahim Jalal, Indiana University, Indianapolis, IN Background: Synergism between IGF and mTOR inhibitors has been documented preclinically. We conducted a phase I study to determine the safety, recommended phase II dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor efficacy of E with G. Methods: Eligible pts had good organ function, ECOG PS 0-1. The study had a standard “3⫹3” design, using E 5 or 10 mg orally daily (QD), and G 12 mg/kg IV every 2 wks (Q2W) in 28 day cycles (C); an expansion cohort was added at MTD for further efficacy analysis. E was given as single agent during C1D1-7 with PKs on C1D1 and D7, and continuously after C1D16. G was started on C1D15 with single agent PK. PKs for both drugs at steady state were performed on C3D1. PDs (blood and serial tumor biopsies) for IGF and PI3K/Akt/mTOR pathways were performed at baseline, C1D7, C3D1 and time of progression. Results: 20 ptswere enrolled to date, M/F: 8/12, median age 55 yrs (24-70); PS: 0/1⫽ 13/7. The table summarizes dose levels and DLTs. The most common toxicities were fatigue (5), diarrhea, mucositis, dysgeusia, anemia and thrombocytopenia (4 each), and rigors (3). Grade (Gr) 3 toxicities were: mucositis (3), anemia (2), thrombocytopenia (2), and diarrhea (1). Pts received a median of 3 cycles (0-9). One pt discontinued study on C1D9 due to intracerebral bleed and 1 pt withdrew consent on C1D15. Among 18 evaluable pts, none responded and 9 pts (50%) had SD with a median duration of 20 wks (range 11-35). Prolonged clinical benefit (SD ⱖ 20 wks) was noted in refractory fibrolamellar HCC, neuroendocrine, GIST and urachal cancers. PKs showed no significant interaction between E and G. Baseline IGF-1R and PTEN expression, and IGF1 levels did not affect clinical benefit. pS6 downregulation and pAkt upregulation in paired tumor biopsies occurred in all (7/7) or most (6/7) samples evaluated, and did not correlate with efficacy. IGF1 and IGFBP3 levels increased on-treatment in 80-90% of pts. Conclusions: E⫹G is safe and the RP2D is E 10 mg QD ⫹ G 12 mg/kg Q2W. While on target pS6 reduction occured, the IGF1-R inhibition did not affect pAkt upregulation from mTOR blockade. Clinical trial information: NCT01122199. Cohort (# pts) E (mg) G (mg/kg) # DLT DLT 1* (8) 2 (3) 2 expansion (9)

5 10 10

12 12 12

1 0 1

Gr 3 mucositis Gr 3 mucositis

* Two pts not evaluable for DLT.

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Combination of a MEK inhibitor, pimasertib (MSC1936369B), and a PI3K/mTOR inhibitor, SAR245409, in patients with advanced solid tumors: Results of a phase Ib dose-escalation trial. Presenting Author: Rebecca Suk Heist, Massachusetts General Hospital, Boston, MA

Safety, pharmacokinetics, and preliminary activity of the ␣-specific PI3K inhibitor BYL719: Results from the first-in-human study. Presenting Author: Ana M. Gonzalez-Angulo, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: PI3K/mTOR and MAPK signaling pathways are often deregulated in tumors. Simultaneous inhibition of these pathways with the MEK1/2 inhibitor, pimasertib, plus the dual PI3K/mTOR inhibitor, SAR245409, (ClinicalTrials.gov NCT01390818) was investigated. Methods: This was a phase Ib, modified 3⫹3, dose-escalation trial in patients (pts) with advanced solid tumors. Pts received pimasertib and SAR245409 at the following dose levels (DLs): DL1, 15/30; DL2a, 30/30; DL2b, 15/50; DL3, 30/50; DL4a, 60/50; DL4b, 30/70; DL5, 60/70; DL6a, 90/70; DL6b 60/90 and DL7, 90/90 mg (once-daily, qd). After the qd maximum tolerated dose (MTD) was established, twice-daily (bid) dosing was tested: DL1a, 60/30; DL1b, 45/50 and DL2 60/50 mg bid. A recommended phase II dose (RP2D) was determined. Enrollment continued at the RP2D in four expansion cohorts (18 pts each): dual KRAS/PIK3CA mutated (mt) colorectal cancer (CRC), triple-negative breast cancer, KRAS mt non-small cell lung cancer (NSCLC) and BRAFmt melanoma. Results: 53 pts were treated qd and 7 pts bid. The most common tumors were CRC (n⫽16), NSCLC (n⫽8), ovarian and pancreatic (n⫽7, each). At DL6b 2/3 pts had dose-limiting toxicities (DLTs; both grade [Gr] 3 nausea/vomiting). DL6a was confirmed as the MTD for the qd schedule. At bid DL1a 2/4 pts (both Gr 3 skin rash) and at DL1b 2/3 pts (Gr 3 skin rash and Gr 3 asthenia) had DLTs. DL5 was the RP2D based on tolerability after prolonged exposure. The most common adverse events in qd schedule were: rash (62%, 13% Gr 3), diarrhea (56%, 4% Gr 3), fatigue (51%, 2% Gr 3), nausea (49%, 2% Gr 3), vomiting (45%, 2% Gr 3), peripheral edema and pyrexia (34%, each) and visual impairment with underlying serous retinal detachment (21%). Preliminary pharmacokinetic results suggest no drug-drug interaction. There were 4 partial responses: KRAS mt CRC (n⫽1) and low-grade ovarian cancer (n⫽3, 1 KRAS mt/PIK3CA mt and 2 wild-type). Enrollment in expansion cohorts at DL5 is ongoing. Conclusions: Continuousqd dosing of pimasertib and SAR245409 is tolerated and has shown signs of activity. Phase II trials are being planned. Clinical trial information: NCT01390818.

Background: BYL719 is an oral small-molecule inhibitor of the p110␣ catalytic subunit of phosphatidylinositol 3-kinase (PI3K), which is encoded by the PIK3CA gene, one of the most commonly mutated genes in human cancers. BYL719 inhibits proliferation of PI3K␣-driven cancer cell lines in vitro and causes regression of PIK3CA-mutant tumor models in vivo. Methods: This Ph I study was performed in patients (pts) with advanced solid tumors carrying a somatic mutation of PIK3CA. Dose escalation used an adaptive Bayesian logistic regression model with overdose control. Following determination of the maximum tolerated dose (MTD), an expansion cohort was opened at the MTD to evaluate safety, pharmacokinetics (PK), and clinical activity in pts with PIK3CA-mutant advanced solid tumors, including estrogen receptor-positive (ER⫹) metastatic breast cancer (mBC). Results: During dose escalation 36 pts received doses up to 450 mg/d, where 4/9 pts had dose-limiting toxicities (DLTs). The MTD for once-daily dosing was declared as 400 mg/d. As of Nov 20 2012, DLTs were hyperglycemia, nausea, vomiting, and diarrhea. The most common BYL719-related adverse events (all grades, all cohorts, ⬎25%) were hyperglycemia (49%), nausea (45%), diarrhea (40%), decreased appetite (38%), vomiting (30%), and fatigue (27%). 39 pts are enrolled in the MTD dose-expansion cohort. Investigation of a twice-daily regimen is also ongoing. BYL719 has a favorable, approximately dose-proportional PK profile with a Tmax of 2h and a T½ of 11h at the MTD. Partial responses were seen in 7 pts (in ER⫹ breast [2], cervical, trichilemmal, endometrial, ovarian, and head &neck cancer [1 each]); 17 pts stayed on study for ⬎24 weeks. For 67 pts (76%) treated at doses of ⱖ270 mg/d, the median progression-free survival (mPFS) was 3.6 months (mo; 95% CI: 3.5–5.5 mo). mPFS in 15 ER⫹ HER2– mBC pts treated at ⱖ270 mg/d was 5.5 mo (95% CI: 3–7 mo). Conclusions: BYL719 displays dose-proportional and predictable PK. The safety profile is favorable, with mostly manageable on-target toxicities. At doses of ⱖ270 mg/d, tumor regression and prolonged disease control were observed in heavily pretreated pts with various tumor types carrying a PIK3CA mutation. Clinical trial information: NCT01219699.




A pilot study of sirolimus (S) in subjects with Cowden syndrome (CS) with germ-line mutations in PTEN. Presenting Author: Takefumi Komiya, National Cancer Institute, Bethesda, MD

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General Poster Session (Board #1A), Mon, 8:00 AM-11:45 AM

Phase Ib safety trial of CVX-060, an intravenous humanized monoclonal CovX body inhibiting angiopoietin 2 (Ang-2), with axitinib in patients with previously treated metastatic renal cell cancer (RCC). Presenting Author: Ashwin Gollerkeri, Pfizer BioTherapeutics, Cambridge, MA

Background: CS is characterized by germline PTEN mutations. Because tumors from CS patients show increased activation of the PI3K/Akt/mTOR pathway, mTOR inhibitor such as S might have activity in such patients. Methods: Eligibility: subjects with germline PTEN mutation who meet international diagnostic criteria for CS, age 18, ECOG PS 0-2, and adequate organ function. Subjects were treated with a 56-day course of daily oral S (2 mg). Objective: Inhibition of the mTOR pathway in benign skin/GI lesion, as assessed by IHC (P-AKT, Total S6, P-S6, P-4E-BP1, score 0-4), changes in benign or malignant tumor by CT/MRI/PET, digital dermoscopy/endoscopy, and changes in cerebellar testing by modified SARA (Neurology 2006). Protocol was amended to allow up to 20 subjects. Results: A total of 18 pts/16 families were enrolled. Median age 42 (range 19-69). Male/Female: 9/9. Involvement in skin, thyroid, GI polyps, breast, CNS, and all of the five organs was observed in 18, 15, 13, 8, 18, 5 subjects, respectively. 7 had h/o malignancies: 3 renal cell, 4 breast, 3 thyroid, 4 others. 3 cerebellar gangliocytomas and 2 others were measurable by CT or MRI. PTEN mutations: 6 families in Exon 1-2, 1 in Exon 4, 9 in Exon 5-8. All but one (D24H) were truncating mutations. 11 of 16 pts who completed a 56-day course reported subjective improvement in energy, mood, focus or skin lesion. Pts with Ex6-8 mutation (n⫽4) had a median SUV decrease of 29.4%. Regression of skin and GI lesions was observed by dermoscopy or endoscopy. Cerebellar evaluation showed a significant improvement in a total SARA score at 1 month (n⫽9, p⫽0.034). 3 pts were treated for only 28 days due to voluntary withdrawal. IHC analysis in skin and GI benign lesions showed a decrease in average P-S6K, P-S6, Total S6, P-S6/Total S6 in response to S. P-S6K/Total S6 ratios at d14 and d56 were significantly lower than at baseline (p⫽0.0026, 0.0391, respectively). The most common AEs (all grades ⬎25%) were LFTs/Hb (39%), fatigue/hypercholesterolemia (28%). Grade 3 AEs: 1 pt hypophosphatemia/lymphopenia. Conclusions: A 56-day course of S was well tolerated in subjects with CS and was associated with improvement in symptoms, skin/GI lesions, cerebellar function and decreased mTOR signaling. Clinical trial information: NCT00971789.

Background: PF-04856884 is a recombinant humanized monoclonal antibody fused to two Ang-2 binding peptides. Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factors (VEGFs) that is approved for patients (pts) with advanced renal cell cancer who failed 1 prior therapy. Metastatic RCC (mRCC) is an angiogenic tumor sensitive to VEGF tyrosine kinase inhibitors. Resistance to VEGF targeted therapy may be mediated by Ang-2. Methods: In Part I (safety lead in) of the study, the primary endpoint was treatment related dose limiting toxicities (DLT) in pts with mRCC who had received 1-3 prior treatments. Pts received PF-04856884 (15 mg/kg/week) plus axitinib (5 mg BID) for 4 week cycles (the recommended Phase II dose of each) and were assessed for DLT, PK, and potential predictive biomarkers (Ang-2 and VEGF-A). For Part II (Phase II portion), pts with mRCC who had received 1 prior anti-VEGF agent were to be randomized to PF-04856884 ⫹ axitinib or axitinib alone to assess median progression free survival. Results: Part I enrolled 18 pts with median age of 62.5 years (39-82), and ECOG performance status of 0-1. One pt had a DLT of Grade 4 pulmonary embolism (PE). Most common related AEs: anorexia in 10 pts (56%), diarrhea 8 (44%), fatigue 8 (44%), nausea 7 (39%), hypertension 6 (33%) and vomiting 6 (33%). Treatment-related thromboembolic events (TEEs) were observed: PE in 2 pts (11%), and cerebrovascular accident (CVA), presumed bowel ischemia, and possible cardiac chest pain in 1 pt (6%) each. One pt had Grade 2 venous thrombosis unrelated to either treatment. Due to the reported TEE, PF-04856884 was reduced to 10 mg/kg in pts remaining on study and enrollment to Part II was not initiated. No significant PK interaction was observed. Two pts had partial response (PR) and 1 pt had unconfirmed PR. Twelve pts (66%) remained on study ⱖ91 days with a median duration of 120 days (8-279). Anti-PF-04856884 antibody results are not available. Conclusions: Due to the higher than expected TEEs, alternate doses of PF-04856884 and/or disease settings are being considered. Clinical trial information: NCT01441414.

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General Poster Session (Board #1B), Mon, 8:00 AM-11:45 AM

General Poster Session (Board #1C), Mon, 8:00 AM-11:45 AM

Phase I trial of trebananib (AMG 386) plus temsirolimus (Tr ⴙ T) in patients (pts) with advanced solid tumors (PJC-008/NCI#9041). Presenting Author: David Shao Peng Tan, Princess Margaret Cancer Center, Toronto, ON, Canada

A phase I study of ombrabulin (O) combined with bevacizumab (B) in patients with advanced solid tumors. Presenting Author: Michael Ong, The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom

Background: Preclinical data suggest that combined Ang1/2 and mTOR blockade has synergistic anti-cancer activity. The combination of Tr (inhibits angiogenesis by preventing interaction of Ang1/2 with Tie2) with the mTOR inhibitor T was evaluated in pts with advanced solid tumors to determine safety, tolerability, maximum tolerated dose (MTD), pharmacodynamics and preliminary antitumor activity. Methods: Pts were enrolled using 3⫹3 design. Tr and T were dosed on Day 1 (D1), 8, 15 and 22 of a 28-day cycle. Peripheral blood was collected for evaluation of Tie2expressing monocytes (TEMs) and thymidine phosphorylase (TP) (an angiogenic enzyme increased in TEMs upon Tie2 stimulation) by flow cytometry. Tumor response was assessed every 2 cycles. Results: 13 pts have been enrolled, 6 at dose level (DL) 1 (15mg/kg Tr ⫹ 25mg T) and 7 (1 died from disease before DLT assessment) at DL -1 (15mg/kg Tr ⫹ 20mg T). Median age was 57yrs, ECOG 0-1, median previous chemotherapy lines 3 (range 1-8). In DL 1, 1/6 pts experienced DLT (Grade (Gr) 2 pneumonitis). In view of frequent Gr2 adverse events (AEs) in DL 1, DL -1 was evaluated with DLTs in 2/6 evaluable pts (Gr3 mucositis and intolerable Gr2 limb edema preventing start of cycle 2 within 14 days). The most common related AEs (all Gr across both DL) were: fatigue (77%), edema (69%), anorexia (62%), and nausea (54%). Common Grⱖ3 AEs included lymphopenia (23%) and fatigue (23%). Of 10 evaluable pts, best RECIST responses were: 1 breast cancer pt (ER⫹/ HER2-/ PIK3CA mutant) with PR (now in cycle 9), 7 pts with SD, and 2 pts with PD. Four pts with ovarian cancer (1 PIK3CAmutant) had SD ⱖ11weeks with 2/3 pts (1 not evaluable) demonstrating GCIG response (⬎50% decrease in CA125). In preliminary analyses, TP expression in TEMs was decreased (mean -18%) in 4pts with tumor shrinkage, but increased (⫹6%) in 1pt with tumor growth, suggesting a trend between reduced TP and tumor response. Conclusions: The MTD was exceeded at 15mg/kg Tr and 20mg T weekly. The safety of 10mg/kg Tr and 20mg T weekly is currently being evaluated. The combination of Tr and T shows early signs of antitumor activity. TP expression in TEMs by flow cytometry as an early marker of treatment benefit warrants further evaluation. Clinical trial information: NCT01548482.

Background: O, a vascular-disrupting agent derived from combretastatin A4-phosphate, induces rapid tumor vascular shutdown via endothelial cell damage. Resistance to O may occur by surges in circulating endothelial progenitors (CEP) that repopulate the tumor vasculature. Experimental models suggest prolonged and synergistic antitumor activity when O is combined with VEGF-blockade, with reduction in CEP surge. This phase I study was performed to determine the maximum tolerated dose, safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary antitumor activity of O combined with B. Methods: Patients (pts) with advanced treatment-refractory solid tumors, ECOG PS ⱕ1, and adequate organ function were eligible. O (mg/m²) was administered intravenously (IV) on day (d)1 with B (mg/kg) IV on d2 in 21d cycles (C). A Bayesian model informed dose escalation steps. PK sampling, dynamic contrast-enhanced ultrasound (DCE-US) for tumor perfusion, and CEP samples were collected. Results: 39 pts (M:F 10:29; median age 51 years [range 25-75]) were treated at 12 dose levels combining O [8 to 50mg/m2] with B [5, 10, or 15mg/kg]. Ovary (16/39, 41%) and colon (4/39, 10%) were the most common primary sites. No C1 dose-limiting toxicities occurred in 37 evaluable pts. Drug-related grade 3-4 treatment emergent adverse events (AE) were hypertension (6/39, 15%), intestinal perforation (2/39, 5%), headache (1/39, 3%), myocardial infarction (1/39, 3%), and pulmonary embolism (1/39, 3%). 36 pts (14 ovarian) were evaluable for response by RECIST 1.1. Antitumor activity was observed at O 20mg/m2⫹ B 10mg/kg and above, with confirmed partial responses in 2/14 pts with ovarian primary (14%), CA125 responses in 2 further ovary/endometrial cancers lasting ⱖ 6 months, and stable disease in 15/36 pts (42%) lasting ⱖ 6 months in 3 pts. PK indicated no interactions of O⫹B. Analyses of CEP levels post O and paired DCE-US data are ongoing. Conclusions: The maximum administered dose (MAD) was O 50mg/m2 with B 15mg/kg, with no dose-limiting toxicities and vascular toxicity that was manageable. Promising antitumor activity was observed at doses below the MAD and warrants further evaluation. Clinical trial information: NCT01193595.


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Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics General Poster Session (Board #1D), Mon, 8:00 AM-11:45 AM

Phase I study of safety, tolerability, and pharmacokinetics of pazopanib in combination with oral topotecan in patients with advanced solid tumors. Presenting Author: Bojana Milojkovic Kerklaan, The Netherlands Cancer Institute-Antoni Van Leeuwenhoek Hospital, Amsterdam, Netherlands Background: To determine the maximum-tolerated dose (MTD), safety, tolerability and pharmacokinetics of the oral anti-angiogenic drug pazopanib in combination with oral topotecan, an inhibitor of topoisomerase-I. Methods: Two-stage, two-arm, dose escalation and pharmacokinetic phase I study of pazopanib and oral topotecan in patients with advanced solid tumors, (NCT00732420, www.clinicaltrials.gov). This interim report describes the bioavailability and safety results for daily pazopanib combined with oral topotecan (days 1, 8, 15) in a 28-day cycle. Results: Twenty-eight of 32 patients completed at least one cycle and were evaluable for analysis. Three dose-limiting toxicities (DLTs) occurred: grade 3 hand-footsyndrome, diarrhea and neutropenia. Pazopanib 800 mg/topotecan 10 mg exceeded the MTD with two DLTs in six patients. The most frequent treatment-related toxicities were grade 3 anemia (3/28), leukocytopenia, neutropenia and fatigue (2/28 each). One death due to hepatic failure occurred at pazopanib 800mg/toptecan 2mg in a heavily pre-treated patient with sarcoma that may have been related to paracetamol ingestion but attribution to the pazopanib can not be excluded. Topotecan AUC0-⬁ increased 1.58-fold (90%CI: 1.09 –1.29) and Cmax increased 1.78-fold (90%CI: 1.08-2.92) when given with pazopanib compared to single administration (n⫽7). Pazopanib AUC0-24 and Cmax ratios were not increased when co-administered with topotecan: 0.98 (90%CI: 0.95-1.02) and 0.96 (90%CI: 0.92-1.01). Twenty-three patients were evaluable for response (RECIST): PR (2/23; 9%, both ovarian cancer); SD (13/23; 57%) and PD (8/23; 35%). Pazopanib 800 mg/topotecan 8 mg is currently being explored in an expansion cohort. A second treatment arm of pazopanib 800 mg with topotecan daily x5 is ongoing and will be reported separately. Conclusions: Daily pazopanib and weekly oral topotecan is tolerable with handfoot syndrome, neutropenia and fatigue as dose limited side effects. Pazopanib increased topotecan exposure 1.58-fold (AUC0-⬁) and 1.78-fold (Cmax). Clinical trial information: NCT00732420.

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General Poster Session (Board #1F), Mon, 8:00 AM-11:45 AM

A phase I trial and pharmacokinetic study of trebananib (AMG386) in children with recurrent or refractory solid tumors: A Children’s Oncology Group Phase 1 Consortium report. Presenting Author: Sarah Leary, Seattle Children’s, Seattle, WA Background: Trebananib is a first-in-class peptibody (peptide-Fc fusion protein) that selectively inhibits Angiopoietin 1 and Angiopoietin 2 to inhibit interaction with the Tie2 receptor tyrosine kinase and prevent angiogenesis by a VEGF independent mechanism. A pediatric phase 1 trial was performed to define the dose limiting toxicities (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of trebananib. Methods: Trebananib was administered as a weekly 30 - 60 minute IV infusion. Three dose levels (10, 15 or 30 mg/kg/dose) were evaluated using a rolling-six design. PK sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks of therapy. Results: Fifteen eligible patients (14 evaluable for toxicity) with a median age of 14 yrs (range, 3 to 20) and diagnoses of neuroblastoma (n⫽4), rhabdomyosarcoma (n⫽3), Ewing sarcoma (n⫽3), osteosarcoma (n⫽2), other soft tissue sarcoma (n⫽2), or nasopharyngeal carcinoma (n⫽1) have been enrolled. There were no DLTs observed at either the 10 mg/kg (n⫽6 pts) or 15 mg/kg (n⫽3 pts) dose. 1/6 pts receiving 30 mg/kg/dose developed DLT (venous thrombosis at a central line site). Non-dose limiting grade 3 or 4 toxicities included lymphopenia (n⫽2) hypertension (n⫽1), and neutropenia (n⫽1). Response in evaluable patients after eight weeks of therapy included stable disease (n⫽6 pts) and progressive disease (n⫽7 pts). PK were linear over the 3 dose levels, with t1/2 and Clpvalues of 69⫾18 h and 1.6⫾0.5 ml/h/kg, respectively. Conclusions: Trebananib is well tolerated in pediatric patients with recurrent or refractory solid tumors with recommended Phase 2 dose of 30 mg/kg. Correlative biology studies will be presented. Further study is planned to evaluate tolerability and changes in vascular permeability in patients with primary CNS tumors. Clinical trial information: NCT01538095.

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General Poster Session (Board #1E), Mon, 8:00 AM-11:45 AM

Pharmacodynamic study using FLT PET/CT in patients treated with axitinib. Presenting Author: Glenn Liu, University of Wisconsin Carbone Cancer Center, Madison, WI Background: Axitinib (AX) is a potent VEGFR2 TKI. The objective of this study was to characterize tumor vascular and proliferative changes in patients treated with AX. Methods: Thirty pts with solid malignancies with at least one target lesion appropriate for FLT PET/CT imaging were enrolled. Pts were treated in Cycle #1 (C1) with AX at 5 mg BID x 2 wks, followed by a 1 wk drug holiday. Subsequent cycles continued the AX BID on a continuous basis until progression or unacceptable toxicity. In cohort A, FLT PET/CT was obtained at baseline, C1D14 (during AX) and C1D21 (AX withdrawal). Cohort B used the same treatment schedule, but FLT PET/CT was obtained on C1D14, C1D16 and C1D21. At each imaging time, peak FLT Standardized Uptake Values (SUVpeak), AX pharmacokinetics and plasma VEGF levels were obtained. Results: Of the 30 total pts, 28 had at least 1 PET/CT scan with 24 completing all planned PET/CT scans (13 in Cohort A; 11 in Cohort B). Strong proliferative flare (36% increase in SUVpeak from C1D14 to C1D21) was observed in majority of pts with most of the flare occurred within two days after AX withdrawal (25% increase in SUVpeak from C1D14 by C1D16). A robust vascular flare paralleled proliferative flare (R⫽0.57). A trend linking short progression free survival with high withdrawal flare was seen (44% increase in SUVpeak for PFS ⱕ 6mo vs 11% increase in SUVpeak for PFS ⬎ 6 mo; p⫽0.14). VEGF levels and AX PK levels increased during treatment, followed by decrease during withdrawal. Conclusions: The observed AX pharmacodynamics is consistent with our prior observation with another VEGFR TKI and suggests that acute AX withdrawal results in a robust withdrawal flare. This information suggests that the timing of cytotoxic chemotherapy during the flare may increase the therapeutic index, as opposed to concurrent administration which may be antagonistic. This study also shows the power of quantitative molecular imaging, which can simultaneous evaluate treatment response heterogeneity, as well as compensatory effects that may lead to early treatment failure. Clinical trial information: NCT00859118.

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General Poster Session (Board #1G), Mon, 8:00 AM-11:45 AM

Treatment of cancer and cancer stem cells by blocking the Notch pathway. Presenting Author: Agamemnon A. Epenetos, St. Bartholomew’s Hospital, London, United Kingdom Background: Current treatments often fail to cure cancer. It has been shown (JCO, 26, June 10, 2008) that Cancer Stem Cells, (CSCs), are responsible for the initiation, metastasis and recurrence of many cancers and may be a key reason for the failure of current therapies.The NOTCH pathway is an important pathway in the development of many tumors ,and cancer stem cells in particular. Methods: We have generated genetically and synthetically a hybrid protein (Antp-DNMAML) .consisting of the truncated version of MastermindElike (MAML) that behaves in a dominant negative (DN) fashion inhibiting Notch activation, and the cell penetrating peptide Antennapedia (Antp). Results: It is demonstrated that Antp-DNMAML translocates into the nucleus and suppresses Notch activation. Attenuation of Notch signaling with AntpEDNMAML reverts the transformed phenotype, inhibits the anchorageEdependent growth, induces self contact inhibition and apoptosis in highly tumorigenic epithelial human breast cancer cells. More significantly, we provide direct evidence that inhibiting Notch signaling at the transcriptional level with the Antp-MAML protein ,suppresses the expression of downstream Notch targets, induces tumor cell apoptosis, and inhibits or eliminates human tumor growth in nude mice, without organ or systemic toxicity. Conclusions: Intracellular delivery of dominant-negative transcription complex proteins using the Antp platform is a new and specific approach for cancer therapy.



General Poster Session (Board #1H), Mon, 8:00 AM-11:45 AM

First-in-human evaluation of the human monoclonal antibody vantictumab (OMP-18R5; anti-Frizzled) targeting the WNT pathway in a phase I study for patients with advanced solid tumors. Presenting Author: David C. Smith, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI Background: The WNT pathway is a key oncologic pathway in numerous tumor types. Vantictumab is a first-in-class anti-Cancer Stem Cell (CSC) antibody that interacts with the extracellular domain of 5 Frizzled receptors (1, 2, 5, 7, 8) and blocks canonical Wnt signaling (PNAS 109, 11717). In patient-derived xenograft models, vantictumab inhibits growth of many tumor types, reduces CSC frequency, promotes differentiation of tumor cells, and synergizes with many chemotherapeutic agents. Methods: Using a 3⫹3 design, vantictumab was given intravenously, first every 1 week (q1w) or q2w, and, ultimately, q3w. Objectives were determination of maximum tolerated dose, safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Results: 18 patients have been treated in 5 dose-escalation cohorts (0.5 & 1 mg/kg q1w; 0.5 mg/kg q2w; 1 & 2.5 mg/kg q3w). Most common related adverse events (AEs) included Grade 1 and 2 fatigue, vomiting, abdominal pain, constipation, diarrhea and nausea. Only related Grade ⱖ3 AEs were dose-limiting toxicities of Grade 3 diarrhea and vomiting in 1 patient at 1 mg/kg q1w. Vantictumab clearance was dose-dependent, consistent with target-mediated drug disposition, with the half-life ranging from 1.5 (0.5 mg/kg) to 3 days (2.5 mg/kg). Exposure at highest dosed cohorts correlates with efficacy in preclinical tumor models. PD biomarkers indicate manipulation of WNT pathway in patient tumors and surrogate tissue. 1 patient at 0.5 mg/kg q1w had a bone fracture on Day 110 with an ~4-fold increase by Day 28 of ␤-C-terminal telopeptide (␤-CTX), a marker for bone degradation. A revised safety plan and less frequent dosing enabled further dose escalation. Upon ␤-CTX doubling, 2 patients received zoledronic acid, and ␤-CTX returned to baseline. 3 patients with neuroendocrine tumors (NETs) had stable disease (SD) for 7⫹, 3.5, and 9⫹ months; ~2-, 4- and 7-fold longer, respectively, than on prior therapy. Conclusions: Vantictumab is well tolerated up to 2.5 mg/kg q3w. Bone toxicity appears manageable and reversible. Prolonged SD in 3 patients with NETs may represent single-agent activity. Dose escalation continues. Clinical trial information: NCT01345201.

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Effects of a soluble activin type 2B receptor Fc fusion protein (STM 217) in TOV-21G, a mouse xenograft model of clear cell ovarian cancer. Presenting Author: John Lu, Amgen, Inc., Thousand Oaks, CA Background: Response rate and survival with the clear cell subtype of ovarian cancer is has not been improved by the introduction of platinum and taxane chemotherapy. Elevated serum activin is associated with inferior ovarian cancer survival, suggesting that activin inhibition may provide a new treatment strategy. STM 217 (recombinant hu-sActR2B-Fc) is a potent (IC50 ⬍ 1nM) inhibitor of activin and myostatin signaling that was tested for anti-ovarian tumor activity. Methods: Athymic nude mice received TOV-21g (clear cell ovarian cancer model) xenografts in the abdominal flank region and after 14 days, weekly subcutaneous STM 217 was administered alone or in combination with 5-fluorouracil (5-FU). Mice were monitored for body weight and tumor volume. Results: After 52 days from tumor cell injection, STM 217 treatment resulted in a statistically significant 43% (p⬍0.0001) tumor growth reduction, versus the vehicletreated tumor bearing group tested using ANOVA. In the combination efficacy experiment, 5-FU monotherapy resulted in a 47% (p⬍0.0001) tumor growth reduction, and the combination of STM217 and 5-FU together resulted in a 73% (p⬍0.0001) tumor growth reduction. During the course of the study, body weight of the mice receiving STM 217 increased by 26%, mice receiving STM 217 and 5-FU increased by 22%, while control tumor bearing mice receiving vehicle exhibited a 10% body weight loss. Conclusions: Our study demonstrates that inhibition of activin signaling by use of a ligand trap results in antitumor activity, both as a monotherapy, and that additive activity was observed in combination with chemotherapy. Increases in body weight were not impaired by concomitant administration of 5-FU chemotherapy. This study suggests that a phase 1 clinical trial of activin inhibition in metastatic ovarian cancer is warranted.

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A dose-escalation phase I study of a first-in-class cancer stemness inhibitor in patients with advanced malignancies. Presenting Author: Adrian Langleben, Oncology Department, McGill University, Montreal, QC, Canada

Therapeutic p53 gene agent in the treatment of refractory cancer cases: A phase I study. Presenting Author: Xia He, Jiangsu Cancer Hospital, Nanjing, China

Background: Cancer Stem Cells (CSC) are considered to be fundamentally responsible for malignant growth, relapse, metastasis, and resistance to conventional therapies. BBI608 is an orally-administered first-in-class cancer stemness inhibitor which blocks CSC self-renewal and induces cell death in CSC as well as non-stem cancer cells by inhibition of the Stat3, Nanog and b-catenin pathways, and has shown potent anti-tumor and anti-metastatic activities pre-clinically. Methods: A phase 1 dose escalation studyin adult patients with advanced cancer who had failed standard therapies was conducted to determine the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics and preliminary antitumor activity of BBI608. A modified Simon accelerated titration scheme was used for dose escalation, with a cycle consisting of twice-daily oral administration of BBI608 for 4 weeks. Cycles were repeated every 4 weeks (28 days) until progression of disease, unacceptable toxicity, or other discontinuation criteria were met. Results: Fourteen cohorts (N⫽41) were dosed from 20 mg to 2000 mg/day with adverse events being generally mild; the most common being grade 1-2 diarrhea, nausea, anorexia and fatigue. Four grade 3 events included diarrhea (n⫽3) and fatigue (n⫽1). MTD was not reached and further dose escalation was limited by pill burden. By the 400 mg/day dose level the plasma concentration of BBI608 was sustained for over 8 hours at a concentration above 1.5 uM (several fold above the IC50). 17/26 patients evaluable for tumor response achieved SD, for a DCR of 65%. Prolonged TTP was observed in 12/26 evaluable patients (46%), including patients with colorectal (CRC), head and neck, gastric, ovarian, melanoma, and breast cancer. In the subset of patients with CRC (N⫽18), SD was seen in 8/12 evaluable (67%). A median PFS of 14 weeks and median OS of 47 weeks were observed in evaluable CRC patients. Conclusions: Dose escalation of BBI608, a first-in-class cancer stem cell pathway inhibitor, has been achieved without dose limiting toxicity. BBI608 has shown an excellent safety profile, favorable pharmacokinetics, and encouraging signs of clinical activity particularly in CRC Clinical trial information: NCT01775423.

Background: To evaluate the benefit of adding therapeutic p53 gene agent into the standard treatment regimens for refractory cancer cases. Methods: Recombinant adenoviral human p53 gene (rAd-p53), was given intravenously at a dose of 2⫻1012 viral particles /day on 5 consecutive days one week before routine anti-cancer treatment start, and was repeated after an interval of 16 days. The inclusion criteria include: 1.Pathologically confirmed recurrent cancers; 2. Disseminated cases; 3. Patients with key organ metastasis; 4.Unresectable lesions; 5.Chemo- or radio-therapy resistant cases. The exclusion criteria include: 1.With severe liver, kidney, heart or hemotologic disorders; 2.Pregnancy; 3.Without informed consent. Efficacy was evaluated according to the results of contrasted MRI or CT. Results: A total of 16 patients entered the study with a median age of 59 years old (range 30-76 years), 13 were male and 3 were female. 5 were recurrent cases(4 HNSCC and 1 esophageal cancer), 5 were widely infiltrated unresectable HNSCC, esophageal carcinoma(2 cases) and undifferentiated thyroid carcinoma(1 case). 3 were disseminated cases(2 NPC and 1 Lung cancer). Two cases were breast cancer with multiple brain metastasis. One was refractory central nervous lymphoma. One patient did not finish the planned chemoradiation due to radiation-induced pneumotitis. Another one patient experienced chemotherapy delay due to A grade 4 hemotologic toxicity. 93.8% patients had shivering and fever after injection of rAd-p53. Other acute toxicities during the treatment included: leukopenia(Grade 3/4) 43.8%, thrombocytopenia (Grade 3/4) 25.0%, oral mucositis(Grade 3/4) 18.8%, vomiting(Grade 2 and above) 31.3%, ALT elevation (Grade 2 and above) 6.3%. No Cr elevation was observed. The acute toxicities were controllable and reversible. At the 3 months after treatment, PR, SD and PD rate were 56.3%, 25.0% and 18.7%, respectively. Conclusions: The therapeutic p53 gene agent can be intravenously safely added to routine anti-cancer regimens with controllable and reversible acute toxicities. A randomized controlled phase II is needed to make clear the role of the therapeutic p53 gene agent.


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Phase I study of c-Met inhibitor ARQ197 in combination with FOLFOX for the treatment of patients with advanced solid tumors. Presenting Author: Suzanne Fields Jones, Sarah Cannon Research Institute, Nashville, TN

Characteristics and survival of patients with advanced cancer and TP53 mutations in phase I clinical trials. Presenting Author: Rabih Said, The University of Texas Health Science Center at Houston, Houston, TX

Background: C-Met protein is a receptor tyrosine kinase which is overexpressed or mutated in a variety of tumor types, causing cell proliferation, metastasis, and angiogenesis. Tivantinib is an orally bioavailable small molecule which binds to the c-Met protein. This phase I study was designed to determine the maximum tolerated dose (MTD) of tivantinib in combination with standard dose FOLFOX for the treatment of patients with advanced solid tumors. Methods: Patients with advanced solid tumors for which FOLFOX (5-FU IV 400 mg/m2 day 1; 5-FU CIV 2400 mg/m2 day 1; Leucovorin IV 400 mg/m2 day 1; Oxaliplatin IV 85 mg/m2 day 1) would be appropriate chemotherapy received escalating doses of tivantinib BID (days 1-14) in a standard 3 ⫹ 3 design. Dose-limiting toxicities (DLTs), non-dose-limiting toxicities (NDLTs), safety, and preliminary efficacy were evaluated. Results: Fourteen patients (50% colorectal) were treated across 3 dose levels: 120 mg (n⫽3); 240 mg (n⫽5); 360 mg (n⫽6). No DLTs were observed until the 3rd dose level (treatment delay ⱖ3 days, secondary to grade 3 neutropenia). Common related adverse events (% grade 1/2; % grade 3/4) included: diarrhea (36%; 0%), neutropenia (0%; 29%), nausea (14%; 14%), vomiting (14%; 14%), dehydration (14%; 7%), and thrombocytopenia (14%; 0%). To date, 7 patients have been evaluated for response including 4 (57%) with stable disease evident at the 8-week evaluation (CRC, 2 patients; unknown primary favoring CRC, 1 patient; esophageal, 1 patient) and 3 (21%) with disease progression. The 4 patients with stable disease are continuing on treatment; three (CRC and unknown primary) had received prior FOLFOX. Conclusions: The addition of tivantinib to standard therapy FOLFOX appears tolerated up to its recommended phase II monotherapy dose of 360 mg. Preliminary efficacy is encouraging, and a phase II study is proceeding with this regimen for the first line treatment of advanced gastroesophageal patients. Clinical trial information: NCT01611857.

Background: The classical hot spot mutations within the central sequencespecific DNA-binding region of p53 protein (R175H in exon 5 and G245S, R248Q, R249S, R273H and R282W in exon 8) disrupt its ability to bind to DNA. These inactivating point mutations of p53 may result in loss of its function and/or acquisition of a gain of function, which has been associated with the development of invasive and metastatic tumors in mouse models. We assessed the frequency and survival of p53 mutations in patients with advanced cancer. Methods: P53 mutation in patients’ tumor was identified in a CLIA-certified laboratory using PCR, sequenom analysis or next generation sequencing. Results: P53 mutations were identified in 212 patients. Median survival by tumor type and distribution of p53 mutations by exon are shown in the Table. The median survival (from time of referral to Phase I clinic) by mutations in “hot spot” amino acids was as follows: R175H, 9.1 months (n⫽18); R248Q, not reached/5 deaths (n⫽22); R273H, 12.6 months (n⫽11); other mutations, 11.9 months (n⫽160). The median survival of patients with a tumor mutation in exons 5 or 8 appeared to be shorter than that of patients with mutations in other exons (9.4 vs. 14.6 months) although the difference was not statistically significant (p⫽.12) owing to the small number of patients. Conclusions: Our results demonstrate that the distribution and clinical significance of various p53 mutations differs by tumor type and suggest that mutations in R248Q may be associated with longer survival.

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Effects of gefitinib and vandetanib on human equilibrative nucleoside transporter 1 and on gemcitabine cytotoxicity. Presenting Author: Vijaya L. Damaraju, University of Alberta, Edmonton, AB, Canada Background: Combination chemotherapy with tyrosine kinase inhibitors (TKIs) and gemcitabine has been attempted with little added benefit to patients. We hypothesized that TKIs that were designed to bind to ATP pockets of growth factor tyrosine kinases also bind to proteins that recognize nucleosides, thereby potentially interfering with gemcitabine pharmacology. Methods: Interaction of TKIs with human nucleoside transporters (NTs) was studied using recombinant NTs produced in yeast. Effects of TKIs on uridine transport, gemcitabine transport and accumulation, regulation of NT activity and cytotoxicity with and without gemcitabine were evaluated in human A549 lung cancer cells. Results: In yeast, vandetanib inhibited two equilibrative NTs (hENT1, hENT2) and three concentrative NTs (hCNT1, hCNT2, hCNT3) with the greatest inhibition seen with hENT1 whereas gefitinib strongly inhibited hENT1 and hCNT1 only. In A549 cells, which possess major hENT1 and minor hENT2 activities, [3H]uridine uptake was inhibited by vandetanib and gefitinib with IC50 values of 16 ⫾ 4 and 5 ⫾ 0.3␮M, respectively. Both TKIs also inhibited [3H]gemcitabine transport and accumulation in A549 cells. hENT1 protein levels were decreased during exposures to vandetanib or gefitinib for 24 hours, and cytotoxicity was greatest when gemcitabine was given prior to vandetanib or gefitinib. Conclusions: Vandetanib and gefitinib inhibited human NTs, especially hENT1, resulting in reduced intracellular gemcitabine accumulation. Gefitinib or vandetanib levels achieved in plasma and tumor tissues are sufficient to inhibit hENT1 activity. Because TKIs can block uptake of nucleoside chemotherapy drugs in cultured cancer cells, attention must be paid to TKIs and nucleoside pharmacokinetic properties when scheduling TKIs and nucleoside chemotherapy.

Cancer type Colorectal Ovarian Gastrointestinal, other Lung Genitourinary Gynecologic other Head and neck Breast Sarcoma Endometrial Melanoma Pancreatic Thyroid Other

No. of pts.

Median survival, months

Exon 5 (%)

Exon 6 (%)

Exon 7 (%)

Exon 8 (%)

Other exon (%)

46 23 17 16 12 12 12 11 8 7 7 3 3 35

13.0 9.5 9.4 4.4 6.7 9.9 10.2 11.1 11.4 9.7 33.2 19.2 9.6 12.6

15 (33) 9 (39) 5 (29) 5 (30) 2 (17) 2 (17) 3 (25) 2 (18) 3 (38) 2 (29) 1 (14) 0 0 7 (20)

5 (11) 3 (13) 1 (6) 5 (30) 2 (17) 4 (34) 2 (17) 2 (18) 1 (12) 1 (14) 4 (58) 0 0 5 (14)

10 (21) 4 (18) 4 (24) 2 (13 3 (25) 2 (17) 3 (25) 2 (18) 0 4 (57) 1 (14) 2 (67) 1 (33) 7 (20)

9 (19) 6 (26) 4 (24) 2 (13) 3 (25) 3 (24) 1 (8) 1 (9) 2 (25) 0 0 1 (33) 1 (33) 7 (20)

7 (14) 1 (4) 3 (17) 2 (13) 2 (16) 1 (8) 3 (25) 4 (37) 2 (25) 0 1 (14) 0 1 (33) 9 (26)


MLN2480, an investigational oral pan-RAF kinase inhibitor, in patients (pts) with relapsed or refractory solid tumors: Phase I study. Presenting Author: Drew Warren Rasco, South Texas Accelerated Research Therapeutics (START), San Antonio, TX Background: MLN2480 is an investigational pan-RAF kinase inhibitor. In vivo, MLN2480 showed antitumor activity in melanoma, colon, lung, and pancreatic cancer xenograft models. This first-in-human study aimed to evaluate the safety of MLN2480, determine the MTD/recommended phase 2 dose (RP2D), and evaluate pharmacokinetics (PK) and preliminary efficacy. Methods: Pts aged ⱖ18 yrs with advanced solid tumors who had failed/were not candidates for standard therapy received oral MLN2480 every other day (Q2D) in 22-d cycles, with dose escalation (3⫹3 design) based on DLTs in cycle 1. AEs were graded per NCI-CTCAE v4.03. Blood samples for plasma PK assessment were taken pre-dose and at multiple times post-dose, d 1 and 21, cycle 1. Results: 24 pts (10 male, median age 64.5 yrs [range 37– 83]) have been treated at 20, 40, 80, 135, 200, and 280 mg (n⫽4, 3, 3, 3, 4, and 7), respectively. The most common tumors included colorectal cancer in 11 pts and non-small-cell lung cancer in 2 pts. Pts received a median of 2 (range 1– 6) cycles. 2 pts treated at 280 mg had DLTs: grade 3 macular rash and grade 3 periorbital edema. 20 pts had drug-related AEs, including fatigue 46%, arthralgia 25%, maculopapular rash 21%, and myalgia 17%. 4 pts had drug-related grade ⱖ3 AEs, which included the 2 DLTs listed above, anemia, dyspnea, and fatigue. No keratocanthomas/ squamous cutaneous carcinomas have been seen to date. 4 pts discontinued due to AEs. There were 3 on-study deaths (1 treatment-related per investigator; dyspnea and respiratory failure). At 20 –200 mg MLN2480 PK data (13 pts) exhibited rapid absorption (median Tmax 2 hr), low fluctuation at steady state (mean peak to trough ratio 2.1), and mean accumulation half-life of 67 hr. Overall mean accumulation was 2.6-fold following repeated Q2D dosing for 21 d. Steady-state (d 21) exposures increased in an approximately doseproportional manner over 20 –200 mg range. No pts had an objective response to date; no pts with BRAF mutation enrolled to date. Conclusions: In this first-in-human study (n⫽24), the safety profile of MLN2480 up to 200 mg Q2D was acceptable. Accrual continues at 200 mg to confirm the MTD. Melanoma expansion cohorts are planned at the RP2D using a Q2D 28-d cycle. Clinical trial information: NCT01425008.




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Efficacy of the Royal Marsden Score (RMS) to improve the selection patients (pts) considered for participation to dose-seeking phase I trial. Presenting Author: Veronique Favre, Centre Georges François Leclerc, Dijon, France

Survival of patients considered for participation to contemporary doseseeking phase trial: Matter of tumour burden, nature of treatment or of dose-levels? Presenting Author: Juliette Bouchet, Institut Claudius Regaud, Toulouse, France

Background: Selection of pts entering in phase trials remains difficult. An international network of expert centers had validated the efficacy of the RMS as selection tool in such context. Nevertheless, RMS have been developed (Arkenau EJC 2008) and validated (Olmos et al. JCO 2012) in cohorts of already enrolled pts, whereas that the question of eligibility is crucial at the time of screening. We have then implemented and measured the efficacy of the RMS in 453 pts entering in the screening process in 4 expert centers. Methods: We have analyzed pts having signed the PIS/IC. RMS (0 to 3) is sum of the following prognostic factors: LDH⬎ULN, met. sites⬎2 and albumin ⬍35 g/L. We have established the rates of enrolled pts, of pts dying within 90 days, of pts having completed PK/PD analysis, with accurate tumor assessment, having to be replaced according to RMS value. Results: Score was as follows: 0 (122/453, 27.0%), 1 (147/453, 32.4%), 2 (79/453, 17.4%), 3 (20/354, 4.4%) & not assessable (84/453, 19.2%). OS according to RMS value were 615, 299, 239 & 136 days (p⫽0.0001). The rates of 90-day mortality were 5.3%, 12.6%, 26.6% & 41.1% (p⫽0.0001). The rates of enrolled pts were 79.5%, 77.5%, 60.7% & 50.0% (p⫽0.001). Among enrolled pts, the rates of pts having completed the PK/PD analysis were 87.6%, 79.8%, 70.8% & 50.0% (p⫽0.007). Among enrolled pts, the rates of tumor assessment available were 95.8%, 88.6%, 89.5% & 70.0% (p⫽0.006). The rates of pts having to being replaced 4.1%, 5.2%, 2.0% & 50.0% (p⫽0.04). The time under study was 118, 81, 56 and 62 days (p⫽0.005). Conclusions: We confirm that the RMS is a reliable, easily obtained tool for selecting pts in such context. The enrollment of pts with RMS⫽3 is associated with a high risk of attribution rate & risk to be replaced. The time under study was significantly lower in cases of RMS ⫽[2-3].

Background: We have analyzed the survival of pts considered for participation to contemporary phase 1 trial. Methods: All consecutive pts having signed the PIS/IC have been analyzed. OS have been measured using Kalan-Meier method. RMS had been calculated, RMS (0 to 3) is sum of the following prognostic factors: LDH⬎ULN, met. sites⬎2 and albumin ⬍35 g/L. Comparisons have been done with Log-rank tests and Cox model. Results: OS of the entire cohort was 448 days. 73.4% of pts having been enrolled. Among not enrolled pts, 74.1% of pts received another treatment. The OS was 497, 247 and 110 days, in pts enrolled in phase I trial, in pts not enrolled but receiving another treatment and in non-treated pts (p⫽0.001). After adjustment to RMS and with pts not enrolled but receiving other treatment as reference, the HR was 0.47 (95-CI:0.340.66; p⫽0.0001) in pts enrolled in phase 1 compared and 3.54 (1.926.52; p⫽0.0001) in non-treated pts. We have then more specifically analyzed the pts enrolled in single-agent dose-escalating phase I. The OS was 894, 272 and 395 days in pts receiving the 2 first dose-levels, in those receiving intermediate dose-levels and those receiving the phase 2-recommended dose, respectively (p⫽0.001). The OS was 328 in pts receiving molecular targeted agent and 539 in those receiving cytotoxic agents (p⫽0.004). In a multivariate analysis, the nature of investigational agent and the dose-level were not associated with better outcome. The sole prognostic factor for OS in multivariate analysis was the RMS (0⫹1 vs 2⫹3: HR⫽3.80 [1.76-8.20], p⫽0.01). Conclusions: Inclusion in phase 1 trial was associated with better outcome in both crude analysis and after adjustment to RMS. Among enrolled pts, in multivariate analysis RMS reflecting the tumor burden was the sole prognostic factor, the nature of the drug and the dose-level were not associated with the outcome.

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Phase Ib trial of combining aldoxorubicin plus doxorubicin. Presenting Author: Kamalesh Sankhala, University of Texas Health Science Center at San Antonio, San Antonio, TX Background: Aldoxorubicin is a novel drug that covalently binds to albumin in the circulation with release in low pH environments. Preclinical studies in pancreatic and ovarian tumor xenograft models demonstrated that aldoxorubicin plus doxorubicin administered at 50% of their MTD provided complete and prolonged tumor remission in these models with less toxicity than each drug administered at their MTD. We evaluated the toxicity profile of a fixed dose of doxorubicin and escalating doses of aldoxorubicin in subjects with advanced solid tumors. Methods: Phase 1b open label, dose-escalation study of aldoxorubicin administered at either 175, 240 or 320 mg/m2 (130, 180, or 240 mg/m2 doxorubicin equivalents) iv ⫹ 35 mg/m2doxorubicin iv, both on Day 1 of 21 day cycles, for up to 8 cycles. The MTD is the dose level immediately below where 2/6 subjects experience a dose limiting toxicity (DLT) , or the maximum dose of 320 mg/m2aldoxorubicin. Additional subjects may be enrolled at the MTD to provide more safety data. Results: 10 subjects have been treated as of January 21, 2013. No DLT was observed and the MTD was defined as 320 2 mg/m aldoxorubicin and 35 mg/m2 doxorubicin iv administered on Day 1 of 21 day cycles. A median of 4.5 cycles have been received. 3/10 subjects were terminated due to either progressive disease (2) or death (1). No subject was terminated due to an adverse event. Grade 3 or 4 neutropenia was seen at all dose levels (8/10 subjects). 4/10 subjects exhibited grade 3 or 4 thrombocytopenia and 3/10 subjects had grade 3 or 4 anemia. Neutropenic fever occurred in 3/10 subjects. Other grade 3/4 adverse events seen in 2 or fewer subjects included fatigue, increased liver enzymes and dehydration. No significant mucositis or cardiotoxicity was observed. At this time the best response has been stable disease in 6/10 subjects and a partial response in 1 subject (malignant fibrous histiocytoma). Conclusions: The combination of aldoxorubicin (320 mg/m2)) ⫹ doxorubicin (35 mg/m2) can be safely administered to subjects with solid tumors. Hematologic toxicity is common and can be controlled with growth factors. The dose of aldoxorubicin is 90% of the MTD of aldoxorubicin administered as a single agent. Thus, doxorubicin does not appear to add to the toxicity of this combination. Clinical trial information: NCT01673438.


Phase I dose escalation study of the protein kinase C iota inhibitor aurothiomalate for advanced non-small cell lung cancer, ovarian cancer, and pancreatic cancer. Presenting Author: Aaron Scott Mansfield, Mayo Clinic, Rochester, MN Background: Protein kinase C iota (PKCi) is overexpressed in non-small cell lung (NSCLC), ovarian and pancreatic cancers and promotes tumorigenesis. The gold compound aurothiomalate (ATM) inhibits downstream activation of Rac1 by PKCi. We sought to determine the maximum tolerated dose (MTD) of ATM. Methods: We conducted a phase I dose escalation trial of ATM in patients with NSCLC, ovarian or pancreatic cancer. In the dose escalation cohort patients received ATM IM weekly for three cycles (cycle duration 4 weeks) at 25 mg, 50 mg or 75 mg in a 3⫹3 design. The dose was not escalated for individual patients. Up to 9 subjects were allowed to enroll in the expansion cohort at the MTD. Blood samples were analyzed for elemental gold levels. Patients were evaluated for response every eight weeks with computed tomography using modified response evaluation criteria in solid tumors. Results: Fifteen patients, all pretreated, enrolled in this study. There were ten patients with NSCLC, four with ovarian cancer and one with pancreatic cancer. Six patients were treated at the 25 mg dose, 6 patients at 50 mg, and 2 at 75 mg. There was 1 dose limiting toxicity (DLT) at 25 mg (hypokalemia), 1 DLT at 50 mg (urinary tract infection), and none at 75 mg. There were 3 grade 3 hematologic toxicities in the dose escalation cohort. The recommended MTD of ATM is 50 mg, and 1 subject was treated in the expansion cohort at 50 mg. Patients received treatment for a median of 2 cycles (range 1-3). The best response observed was stable disease in 2 subjects. There appeared to be a dose-related accumulation of steady-state plasma concentrations of gold with concentrations exceeding 20 ␮M after one month of therapy with 75 mg of ATM and after 2 months of therapy with 50 mg of ATM, consistent with linear pharmacokinetics. Conclusions: In summary, this phase I study was successful in identifying ATM 50 mg IM weekly as the MTD. In this heavily pre-treated group of patients in who we observed at best stable disease, it remains unclear whether future investigations that target PKCi should focus on single agent ATM, combination therapy with ATM, or other PKCi inhibitors that are currently in development. Clinical trial information: NCT00575393.


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Heat shock protein 90 (HSP90) inhibition in squamous cell carcinoma of the head and neck (SCCHN): An in vitro analysis with a focus on p16 status. Presenting Author: Kirtesh R Patel, Department of Radiation Oncology and Winship Cancer Institute, Atlanta, GA

CTEP #8342 autophagy modulation with antiangiogenic therapy: A phase I trial of sunitinib (Su) and hydroxychloroquine (HCQ). Presenting Author: Nataliya Melnyk, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ

Background: Despite advances in therapy, the overall 5 year survival for SCCHN is close to 50%. Cisplatin and radiation therapy remain the current standard for treating locally advanced SCCHN. Novel treatment approaches are urgently needed, especially in HPV negative disease. We examined the expression of HSP90 in HPV positive and negative SCCHN and investigated if the HSP90 inhibitor ganetespib can sensitize mutant p53 SCCHN to cisplatin and radiation therapy in vitro. Methods: Phase 1 trials of ganetespib at 150 mg/m2 have shown the maximum clinically achievable concentration (CAC) in patients to be ~166 nM. We treated p53 deficient or mutant p53 SCCHN cells (SCC25 and Detroit 568, CAL27and FADU, respectively) with ganetespib at 10-50 nM alone and in combination with cisplatin or radiation therapy and assessed survival. We measured HSP90, HSP70 and p53 protein expression levels in SCCHN cell lines by immunoblotting and analyzed HSP90 protein levels in p16 positive and p16 negative SCCHN tumor samples by immunohistochemistry. Results: Ganetespib at CAC was significantly more cytotoxic in mutant p53 compared to p53 deficient SCCHN cells (p ⬍ 0.05). When combined with CAC doses of cisplatin or radiation therapy, ganetespib displayed strong sensitizing activity (p ⬍ 0.05 and p ⬍ 0.01 respectively). Ganetespib treatment upregulated HSP70 and HSP90 expression while decreasing p53 expression in the mutant cell lines. HSP90 expression was significantly higher in p16 negative than p16 positive SCCHN tumor samples (79.5% vs. 51%, ANOVA p ⫽ 0.016). Conclusions: Our results demonstrate a potential efficacy of ganetespib as a single agent and in combination with cisplatin and radiation therapy in SCCHN. HSP90 expression is upregulated in p16 negative SCCHN. Further exploration of the role of HSP90 in SCCHN, and utility of HSP90 inhibitors, is warranted.

Background: Angiogenesis inhibitors promote autophagy, a response to nutrient deprivation in which autophagosomes (AP) and lysosomes fuse to recycle intracellular constituents, leading to sustained tumor viability. We hypothesized that the VEGF-R2, c-kit, PDGFR inhibitor Su induces autophagy. The autophagy inhibitor HCQ may then interfere with autophagy dependent tumor survival, possibly improving patient (pt) outcomes. Methods: This trial determined the MTD of Su⫹HCQ in pts with advanced malignancies using a 3⫹3 design. Su 50 mg qd was given in 4 week on/2 week off cycles (C) with daily HCQ in escalating dose cohorts. A MTD expansion cohort of 12 pts was also enrolled. Modulation of autophagy was measured by changes in the AP marker light chain-3 (LC3)II/I ratio in paired PBMC samples from C1 and C2. Results: 21 pts, median age 59, PS 0 (7), 1 (13) or 2 (1) enrolled, including 5 colon, 2 renal and 5 sarcomatous tumors. 4 DLTs were observed: 3 DLTs (gr 3 confusion, gr 3 colon fistula, gr 3 thrombocytopenia) in DL2 (50 mg Su, 200 mg bid HCQ), and 1 DLT (gr 3 dehydration) in DL1 (50 mg Su, 200 mg HCQ). DL1 was thus declared the MTD. Gr 3/ 4 toxicities included: related to Su, thrombocytopenia (14%), fatigue (19%), neutropenia (14%), hypertension (14%), intestinal perforation (10%); related to HCQ, fatigue (14%). PK data of Su alone, its active metabolite SU012662 and the total were evaluated using noncompartmental analysis. Cmax and AUCs of the active metabolite SU012662 significantly increased (p⬍0.005) during C2 relative to C1, indicating drug-drug interactions between HCQ and Su. 9 of 21 (43%) had stable disease for ⬎ 3 cycles (median 73 days). Inconsistent autophagy modulation was seen in PBMCs. LC3 immunohistochemistry on baseline tumor blocks to assess individual tumor autophagy levels is in progress. Conclusions: pK interaction between Su and HCQ resulting in accumulation of Su metabolites may be responsible for the predominantly Su-associated toxicities observed which prohibited further HCQ dose escalation. Lack of evidence for autophagy modulation is likely due to the inability to escalate HCQ to doses necessary to induce autophagy inhibition. Further study of this combination seems unwarranted. Clinical trial information: NCT00813423.

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Phase I trial and pharmacokinetic (PK) study of satraplatin in children and young adults with refractory solid tumors including brain tumors. Presenting Author: Srivandana Akshintala, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD Background: Satraplatin is an orally bioavailable platinum analog. Based on pre-clinical activity (IC500.02-8 ␮g/ml) including activity in cisplatin resistant cell lines, and clinical activity without neuro-, nephro-, or ototoxicity in adults with refractory tumors, we developed a phase 1 trial to determine the toxicities, maximum tolerated dose (MTD), and PKs of satraplatin in children with refractory solid tumors. Methods: Satraplatin (10 and 50 mg capsules) was administered orally once daily on days 1 - 5 of a 28 day cycle to cohorts of 3-6 patients (pts) at 60 mg/m2/dose (DL 1) and 80 mg/m2/dose (DL 2). Plasma ultrafiltrate (PUF) platinum was measured using atomic absorption spectroscopy during cycle 1 for PK analysis. Results: 9 pts [5 male, 4 female, median age 17 years (range 8-19)] with malignant glioma (n⫽4), ependymoma (n⫽2), medulloblastoma (n⫽1), osteosarcoma (n⫽1), or hepatoblastoma (n⫽1) received 1-10⫹ cycles (median 2). The MTD was exceeded at DL 2 as 2/4 pts had dose limiting toxicities (DLT) of delayed and prolonged myelosuppression (grade 3 thrombocytopenia, n⫽1; grade 3-4 neutropenia, n⫽2). 0/5 pts at DL 1 had DLTs. Grade 1 ototoxicity was seen in 1 pt at cycle 10. Non-DLTs included myelosuppression, gastrointestinal toxicities, fatigue, headache, liver enzyme elevation, and electrolyte abnormalities. No objective responses were observed, but 1 pt with gliomatosis cerebri has had radiographic stable disease through cycle 10⫹. Satraplatin mean exposure (AUC) and peak concentration (Cmax) were similar at both dose levels [day 1 PUF AUC0-24h 1.22 ⫾ 0.55 ␮g/ml*h at DL1 (n⫽3), 1.02 ⫾ 0.45 ␮g/ml*h at DL2 (n⫽3); Cmax0.17 ⫾ 0.08 ␮g/ml at DL 1 (n⫽3), 0.16 ⫾ 0.05 ␮g/ml at DL 2 (n⫽3)]. Terminal half-life was 14 ⫾ 6 h and apparent clearance was 76 ⫾ 29 L/h (n⫽6). Conclusions: The MTD of oral satraplatin in children with solid tumors is 60 mg/m2/dose daily x 5 q28 days. The toxicity profile was similar to adults, and delayed myelosuppression was DLT. Satraplatin exposure appears higher in pediatric pts compared to adults (PUF AUC0-24h 0.25-0.47 ␮g/ml*h at 60-80 mg/m2/dose). DL 1 will be expanded to gain additional experience regarding toxicities and PKs in a broader age range. Clinical trial information: NCT01259479.


A drug-drug interaction study between the strong CYP3A4 inhibitor ketoconazole (keto) and ixazomib citrate (MLN9708), an investigational, orally active proteasome inhibitor, in patients with advanced solid tumors or lymphoma. Presenting Author: Neeraj Gupta, Millennium Pharmaceuticals, Inc., Cambridge, MA Background: MLN9708 is an oral proteasome inhibitor currently being investigated in multiple myeloma and amyloidosis in phase 3 studies. MLN9708 immediately hydrolyzes to its biologically active form, MLN2238, in aqueous solutions or plasma. Metabolism by multiple cytochrome p450s (CYPs) including 3A4 and 1A2 (⬎25% contribution by each) was expected to be the primary clearance mechanism for MLN2238 based on human liver microsomal metabolism studies. This open-label, multicenter study (NCT01454076) characterizes the effect of CYP3A4 inhibition with keto on single-dose pharmacokinetics (PK) of MLN9708 in a fixed sequence design. Methods: Patients received MLN9708 2.5 mg on d 1 and 15, and keto 400 mg (PO) daily on d 12–25. On d 15, MLN9708 and keto were administered concomitantly. Serial blood samples were collected over 0 –264 hr after MLN9708 doses on d 1 and 15 for PK characterization. Plasma PK parameters were estimated by non-compartmental methods. The effect of keto co-administration on MLN9708 AUC0 –264hr and Cmaxwas evaluated by Analysis of Variance of log-transformed values. Results: 16 PK-evaluable patients (11 Caucasian, 3 African American, 2 Hispanic; 6M, 10F) with mean (range) age of 61 years (48 –79) and body surface area of 1.8 m2 (1.5–2.3) were enrolled. Co-administration of MLN9708 and keto resulted in a 2-fold increase in MLN9708 AUC0 –264hr but no change in Cmax(Table). No differences in adverse events were observed ⫹/- the addition of keto, to a single dose of 2.5 mg MLN9708. Conclusions: The observed 2-fold increase in MLN9708 AUC0 –264hrwith a strong CYP3A4 inhibitor suggests the contribution of CYP3A4 clearance to the total clearance of MLN9708 is significant. These results support the continued exclusion of strong CYP3A4 inhibitors in ongoing and planned clinical trials of MLN9708. Clinical trial information: NCT01454076.

Cmax, ng/mLa AUC0–264, ng*hr/mLa Tmax, hrb

D1 MLN9708 alone (Reference)

D 15 MLN9708ⴙketo (Test)

Test vs Reference, least square geometric mean ratio (90% CI)

41.3 (46) 608 (30) 1.1 (0.5–2.1)

41.6 (63) 1249 (40) 1.5 (0.5–3.1)

1.0 (0.8–1.3) 2.1 (1.9–2.3) -

aGeometric mean (%CV) bMedian (range).




A phase I dose-escalation study of volasertib (BI 6727) combined with nintedanib (BIBF 1120) in advanced solid tumors. Presenting Author: Filippo G. De Braud, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Background: Volasertib (V) is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases. Nintedanib (N) is a triple angiokinase inhibitor of VEGF, PDGF, and FGF receptors. Both have shown clinical activity with a manageable safety profile in patients (pts) with advanced solid tumors. This study was designed to determine the maximum tolerated dose (MTD) of V combined with N in these pts. Methods: Cohorts of 3– 6 pts received V (100 – 450 mg IV Q3W) ⫹ oral standard dose N (200 mg BID continuously, except V infusion day). Treatment continued until clinical progression. Up to 12 pts were treated at the MTD for additional safety data. Primary endpoint was the MTD; secondary endpoints were pharmacokinetics (PK), overall safety, and preliminary efficacy. Results: 30 pts were treated (median age, 56.5 yr; ECOG PS 0/1/2, 33%/60%/7%; ⱖ3 prior therapies, 87%). At V doses ⬎200 mg, 7 pts experienced 13 dose-limiting toxicities (DLTs) during cycle 1: increased alanine aminotransferase [ALT] or aspartate aminotransferase [AST], neutropenia and thrombocytopenia. The MTD was V 300 mg (Table). At the MTD, the most common all grade (Gr) adverse events (AEs) were neutropenia (69%), asthenia and thrombocytopenia (62% each), increased ALT, increased AST and diarrhea (54% each). Median (range) duration on treatment was 4 (1–18) cycles. Treatment was discontinued due to progressive disease (80%), DLT (3%) and other non-AE related reasons (17%). 2 objective responses were observed (1 complete [breast cancer] and 1 partial [NSCLC]), both with the 300 mg dose. 6 pts had SD for ⱖ 6 mo. PK data will be presented at the meeting. Conclusions: MTD of V ⫹ standard dose N (200 mg BID) was determined to be 300 mg Q3W (the same as the recommended phase II single agent dose of V in solid tumors). This combination had a manageable safety profile without unexpected or overlapping toxicities and showed preliminary antitumor activity. Clinical trial information: NCT01022853. Cycle 1 DLTs. V (mg)

Pts

Pts with DLTs

DLTs (n of pts)

100 200 300

3 4 13

0 0 3

350

8

2

400

2

2

– – Gr 4 neutropenia (1); Gr 3 ALT increase (3); Gr 3 AST increase (2) Gr 4 neutropenia (2); Gr 4 thrombocytopenia (1); Gr 3 ALT increase (1) Gr 4 thrombocytopenia (2); Gr 4 neutropenia (1)

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Phase I clinical trial of the intraperitoneal (IP) administration of a novel nanoparticle formulation of paclitaxel (NTX). Presenting Author: Stephen K. Williamson, University of Kansas Cancer Center, Westwood, KS Background: IP therapy is an attractive option for patients with IP carcinomatosis as many of these malignancies remain confined IP. Agents whose plasma clearance rates substantially exceed their rates of uptake from the peritoneal cavity are especially suited for IP administration. Pre-clinical studies of a novel formulation of nanoparticulate paclitaxel in animal tumor models demonstrated superior activity and substantially reduced systemic toxicity. This allowed for significant IP doses and concentrations, yet yielded very low systemic concentrations of paclitaxel. We report here the results of a Phase I trial of IP administered NTX. Methods: Patients (ECOGⱕ2) had relapsed, treatment refractory solid IP tumors and adequate organ function. NTX was administered IP as a bolus injection after 500 ml saline followed by IP administration of up to 2 L of saline. We utilized an accelerated dose escalation scheme until one DLT occurred during cycle 1, followed by a standard dose escalation (3⫹3 design) based on CTCAE V3 toxicities. The pharmacokinetics of IP administered NTX were characterized in plasma and ascites fluid. Secondary objectives were to define the recommended phase 2 dose of NTX, and characterize preliminary activity and toxicity. Results: 20 patients were treated at dose levels from 50 – 275 mg/M2 q 28 days. Primary malignancy was ovarian cancer (74%). Treatment was well tolerated at all dose levels. Common toxicities potentially related to NTX were: gastrointestinal (68%), constitutional (42%), and pain (42%). Average number of cycles received was 2 (range 1 to 6). Best response was stable disease (4 patients, 21%). Median length of disease stability was 99 days (range 85 to 151 days); median time on study patients with stable disease was 313 days (range 142 to 740 days). All Cmax in plasma were less than 35 ng/mL, with ascites fluid Cmax generally greater than 1000 ng/mL. Conclusions: IP NTX is well tolerated. MTD has not yet been reached. Pharmacokinetic data demonstrate significant, persistent IP exposure to paclitaxel with minimal systemic exposure. Accrual at the 275 mg/M2 dose level continues; updated results will be presented. Further clinical development of NTX is indicated. Clinical trial information: NCT00666991.

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A pharmacokinetic and dose-escalating study of paclitaxel injection concentrate for nano-dispersion (PICN) alone and with carboplatin in patients with advanced solid tumors. Presenting Author: Wen Wee Ma, Roswell Park Cancer Institute, Buffalo, NY Background: PICN is a novel Cremaphor-free composite of paclitaxel nano-particles stabilized with polymer and lipid using Nanotecton Technology. The MTD of PICN alone was previously determined to be 295 mg/m2 iv every 3 weeks in a South Asian population. This study aimed to determine the pharmacokinetic (PK) profile of PICN alone and with carboplatin (C), and the MTD of PICN plus C. Methods: Patients (pt) with advanced solid malignancies and ECOG PS 0-1 were eligible. Part A was a PK study designed to examine cohorts of 3 pts, receiving PICN over 30 min at dose levels of 175, 260, and 295 mg/m2 every 3 weeks; PK were performed at pre-determined time-points. Part B used a ‘3⫹3’ dose escalation scheme, designed to determine the MTD of PICN (220, 260, and 295 mg/m2) when combined with C at AUC 6. Only standard anti-emetic pre-medications were used. Adverse events (AEs) were graded using CTCAE 4.0 and tumor response by RECIST 1.1. Results: A total of 18 evaluable pts (9 in Part A, 9 in Part B) were enrolled from 2 US academic centers. No infusion reactions were observed with PICN. No dose limiting toxicity (DLT) was observed in Part A. In Part B, the DLTs were G3 febrile neutropenia and G4 thrombocytopenia requiring platelet transfusion at PICN 260/C AUC 6. A total of 6 pts were treated at PICN 220/C AUC 6 with no DLT. G3 or worse AEs for all cycles were as follow: Part A, bilateral lower extremity weakness, neuropathy, anorexia and neutropenia; Part B, anemia, thrombocytopenia, neutropenia and empyema. Partial responses were observed in biliary(Part A; PICN 260 mg/m2), breast (Part B 220/6) and anal cancers (Part B 260/6). PK analysis showed dose-proportional increase in total plasma paclitaxel level. Conclusions: PICN alone was tolerable in the dose range evaluated. When administered with C AUC 6, the MTD of PICN was 220 mg/m2 administered every 3 weeks. Anti-cancer activity was observed in biliary, breast, and anal cancers. Final PK, toxicity and efficacy data of PICN alone and with C will be presented at the conference. Clinical trial information: NCT01304303.

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A phase I trial of GBS-01 for advanced pancreatic cancer refractory to gemcitabine. Presenting Author: Masafumi Ikeda, Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan Background: Arctigenin, which is abundant in the seeds of Arctium lappa Linné, was found by a novel strategy to attenuate cancer cells’ tolerance to glucose deprivation (antiausterity) and showed antitumor activity in mouse xenograft models. GBS-01 is an orally administered drug and contains rich arctigenin extracted from Arctium lappa Linné, which is one of the traditional herbal medicine. This study investigated the maximumtolerated dose of GBS-01 based on the frequency of dose-limiting toxicities (DLT) in patients with refractory advanced pancreatic cancer, which is considered as one of the hypoxic cancer. Methods: Histologically or cytologically proven advanced pancreatic adenocarcinoma patients refractory to gemcitabine were enrolled. GBS-01 was administered orally at escalating doses from 3g to 12g qd. DLT was defined as grade 4 hematological toxicities and grade 3 or 4 non-hematological toxicities during first 28 days of the treatment. Response evaluation based on RECIST criteria and progression-free survival were set as secondary endpoint for efficacy evaluation. Results: Fifteen patients (GBS-01 3g: 3 patients, 7.5g: 3 patients, 12g: 9 patients) were enrolled in this trial. All patients were refractory to S-1 as well as gemcitabine. All patients at the three dose levels did not demonstrate any sign of DLT. The main adverse events of this agent were increased ␥GTP, hyperglycemia, and increased total bilirubin, but all toxicities were extremely mild. Of all 15 enrolled patients, 1 patient showed a partial response and 4 patients had a stable disease. The median progression-free and overall survival time for all patients were 1.05 months and 5.68 months, respectively. Conclusions: The recommended dose of GBS-01 was 12 g qd (4 g as a extract of Arctium lappa Linné), and favorable clinical responses were obtained. A multicenter phase II trial is being planned to evaluate the efficacy and safety of this agent. Clinical trial information: 000005787.


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Phase I study of cabazitaxel (Cbz) plus cisplatin (Cis) in patients (pts) with advanced solid tumors: Substudy to evaluate the impact of a strong CYP3A inhibitor (ketoconazole; K) or inducer (rifampicin; R) on the pharmacokinetics (PK) of Cbz. Presenting Author: Alain C. Mita, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA

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Phase I dose-escalation, open-label study of HSP990 administered orally in adult patients with advanced solid malignancies. Presenting Author: Leticia De Mattos-Arruda, Vall d’Hebron University Hospital, Barcelona, Spain

Background: Cbz is approved for treatment of pts with hormone-refractory metastatic prostate cancer after progression on a docetaxel-containing regimen. The dose-escalation part of this Phase I study (NCT00925743) found the maximum tolerated dose (MTD) of Cbz/Cis to be 15/75 mg/m2. No Cbz–Cis PK interactions were seen. As Cbz is mainly metabolized by CYP3A, the study also evaluated the impact of a strong CYP3A inhibitor (K; study part 3) or strong CYP3A inducer (R; study part 4) on the PK of Cbz in combination with Cis. Methods: The study included pts with metastatic or unresectable solid tumors for which Cis-based therapy was considered appropriate. Pts received Cbz/Cis every 3 weeks at MTD, with K 400 mg (part 3) or R 600 mg (part 4) administered orally once daily prior to, on, and after Cycle 2 Day 1 for a total of 10 (K) or 14 (R) days. In part 3, the Cbz/Cis dose was 5/75 mg/m2 in Cycles 1 and 2 to provide a safety margin to the MTD. Effects on Cbz PK were assessed with a linear mixed-effects model. The primary endpoint was Cbz clearance (CL). Safety assessments included adverse events (AEs) and laboratory abnormalities. Results: The PK population included 23 pts (part 3) and 21 pts (part 4). Repeated administration of K resulted in a 20% decrease in Cbz CL (L/h/m2) (geometric mean ratio [GMR]: 0.80; 90% confidence interval [CI]: 0.55, 1.15; n ⫽ 18), corresponding to a 25% increase in AUC (ng*h/mL/mg/m2) (GMR: 1.25; 90% CI: 0.86, 1.81; n ⫽ 18). Repeated administration of R resulted in a 21% increase in Cbz CL (L/h/m2) (GMR: 1.21; 90% CI: 0.95, 1.53; n ⫽ 20), corresponding to a 17% decrease in AUC (ng*h/mL/mg/m2) (GMR: 0.83; 90% CI: 0.65, 1.05; n ⫽ 20). The GMR of AUC0 –24was 1.09 (90% CI: 0.9, 1.33; n ⫽ 21), suggesting a low impact of R during the initial phases of Cbz elimination. The most frequent AEs included nausea (part 3: 68%; part 4: 74%), vomiting (part 3: 68%; part 4: 74%) and fatigue (part 3: 52%; part 4: 70%). Conclusions: The CL of Cbz was decreased by 20% by co-administration with K and increased by 21% by co-administration with R. Safety results were consistent with prior findings for this Cbz/Cis combination. Clinical trial information: NCT00925743.

Background: NVP-HSP990 is a synthetic small molecule that potently and selectively inhibits heat-shock protein 90. HSP990 leads to degradation of client proteins, offering potential simultaneous blockade of multiple oncogenic signaling pathways. The primary objective of this Phase l first-in-man study (NCT00879905) was to determine the single-agent MTD of HSP990 administered once (qw) or twice (biw) weekly to patients (pts) with advanced solid malignancies (preselected CYP2C9 genotypes only). Secondary objectives included safety, efficacy, PK, and biomarkers. Methods: HSP990 was administered orally qw or biw in 28-day cycles. Dose escalation was guided by a Bayesian logistic regression model. The MTD was determined by assessing DLTs in Cycle 1. Eligible pts included those with histologically confirmed advanced solid tumors that had progressed on standard therapy or for whom no standard therapy exists. Results: 64 pts (median age 57 yr: 44% male; 37.5% Stage IV; WHO PS 0/1) received HSP990. 53 pts received HSP990 qw at 2.5, 5, 10, 20, 30, 50 or 60 mg; and 11 pts received HSP990 biw at 25 mg. Median duration of exposure was 8 wks; 12 pts remained on treatment for ⬎16 wks. DLTs occurred in 7 pts: 4/22 at 50 mg qw (including G3 diarrhea, G3 QTc prolongation, G4 ALT/AST elevations); 2/5 at 60 mg qw (including G3 tremors); and 1/11 at 25 mg biw (including G2 ataxia, G2 confusion, G2 visual hallucination). The 50-mg qw dose was declared as the MTD. Further dose escalation was not possible due to neurologic toxicity. Most common reported CTCAE G3/4 AEs were diarrhea (12.5%), increased ALT/AST (11% each), anemia, or cholestasis (6% each). HSP990 had Tmax of 3 h and T½ of ~20 h. Large inter-patient variability in PK exposures was observed. For qw dosing, approximate dose-dependent HSP70 induction was observed from 5⫺30 mg qw, which plateaued after 20 mg qw. There were no objective responses; however, 25 pts (39%) had SD. (RECIST v1.0). No pt showed a complete metabolic response (MR; by FDG-PET) and 11 pts (17%) showed a partial MR. All pts discontinued treatment, primarily due to disease progression (84%). Conclusions: The single-agent MTD of HSP990 in pts with advanced solid tumors was 50 mg qw. SD was observed in 39% of pts. Clinical trial information: NCT00879905.

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Use of gene expression profiling to identify responsive patients treated with carboplatin (Carb), paclitaxel (Pac), and everolimus as first-line treatment for cancer of unknown primary (CUP): NCCTG N0871 (Alliance). Presenting Author: Matthew P. Goetz, Mayo Clinic, Rochester, MN Background: Empiric chemotherapy (taxane/platinum) is standard for CUP. Because prognosis is poor, novel approaches are needed. The PI3K/mTOR pathway is frequently dysregulated in cancer. Everolimus (E), an mTOR inhibitor, is approved for multiple malignancies. We performed a phase II study of Pac ⫹ Carb ⫹ E as first-line therapy in metastatic CUP patients (pts). We additionally determined if a gene expression profiling (GEP) test that identifies tissue of origin (Pathwork Tissue of Origin) could identify responsive pts. (NCT00936702) Methods: Newly diagnosed, untreated CUP pts were eligible. Central pathology review confirmed CUP prior to registration; GEP was performed on formalin fixed tumor tissue. Pac (200 mg/m2), Carb (AUC⫽6) and E (30 mg once weekly) were delivered every 3 wks until progression or intolerable adverse events (AEs). The primary endpoint was confirmed response, with ⱖ11 of 50 responses (22%) needed for trial success. Secondary endpoints were OS, progression-free survival (PFS) and AEs. Results: 46 pts (median age 61) received a median 4 cycles (range: 1-33). 39 (85%), 21 (46%) and 1 (2%) experienced ⱖ1 grade (gr) 3⫹, 4⫹, or 5 (sepsis) AE, with gr 3⫹ hematologic AE most common (74%). Of 44 evaluable pts, 15 had a confirmed response (RR 34%, 95% CI: 21-50%), with a median PFS and OS of 4.1 and 10.1 mos, respectively. Adequate tissue for GEP was available in 36 pts and predicted 10 different sites of origin. In pts with a predicted tissue of origin in which taxane/platinum is standardly used, higher RR and significantly longer PFS and OS were observed compared with pts whose GEP identified a malignancy where taxane/platinum is not standard (Table). Conclusions: In pts with untreated CUP, Carb ⫹Pac ⫹E demonstrated promising antitumor activity. The GEP test identified patients clinically responsive to Carb/Pac/E therapy, and may be useful to select CUP pts for specific antitumor regimens. Clinical trial information: NCT00936702. Predicted tissue of origin Pancreas, colon, Lung, breast, kidney, sarcoma, ovary, bladder hepatocellular, gastric RR Median PFS (mo) Median OS (mo)

N⫽18 50% (9/18) 5.8 15.5

N⫽18 28% (5/18) 3.7 10.0

P 0.17 0.039 0.026


Phase Ib study evaluating safety and pharmacokinetics (PK) of the oral transforming growth factor-beta (TGF-ß) receptor I kinase inhibitor LY2157299 monohydrate (LY) when combined with gemcitabine in patients with advanced cancer. Presenting Author: Mark Kozloff, Ingalls Hospital and University of Chicago, Harvey, IL Background: Based on animal studies, the combination of a TGF-␤ inhibitor and gemcitabine is expected to enhance antitumor activity of gemcitabine. Hence, we started a combination study of LY with gemcitabine to assess the safety of this combination therapy. Methods: Gemcitabine was administered as approved and LY was given daily as intermittent dosing (14 days on/14 days off⫽1 cycle). A dose escalation consisting of 3 cohorts (80 mg/day, 160 mg/day, and 300 mg/day) evaluated the safety of LY in combination with gemcitabine. Toxicity was assessed using the CTCAE, version 4. Pharmacokinetic (PK) profile of LY in combination with gemcitabine was determined. Results: A total of 14 patients were evaluated (cohort 1 [n⫽5, 4 adenocarcinoma of colon, 1 non-small cell lung cancer, cohort 2 [n⫽4, adenocarcinoma, 1 each of esophageal, well differentiated, pancreas, lung], cohort 3 [n⫽5, 3 pancreatic, 2 rectal cancer]) in this study. The median number of cycles was 2 (range (1-6). Regardless of causality, the following treatment-emergent adverse events (TEAEs) were observed in ⱖ25% of patients: anemia (n⫽10), nausea (n⫽8), thrombocytopenia (n⫽6), neutropenia (n⫽6), vomiting (n⫽6), anorexia (n⫽5), fatigue (n⫽5), diarrhea (n⫽5) asthenia (n⫽5), pyrexia (n⫽4), AST increased (n⫽4), and constipation (n⫽4). Possibly related to LY, (Grade, Gr, 3/4 as mentioned) TEAEs observed were: nausea (n⫽5), asthenia (n⫽4), fatigue (n⫽3, 1 Gr 3), neutropenia (n⫽3, 1 Gr 3), anemia (n⫽3, 2 Gr 3 ), and in 2 patients each, thrombocytopenia (both Gr 3), headache, edema peripheral, rash, anorexia, diarrhea (1 Gr 3), mucosal inflammation, vomiting and reversible rhabdomyolysis (n⫽1, Gr 4). No change in the PK profile of LY was shown when LY was combined with gemcitabine. Conclusions: There were no dose limiting toxicities observed and no clinically meaningful cardiotoxicities were detected. Because of the observed manageable safety profile, LY at 300 mg/day has been advanced into a randomized Phase 2 trial in pancreatic cancer in 1st line setting to assess the antitumor activity of the combination. Clinical trial information: NCT01373164.




PHI-55: (NCI#7427): A phase I study of halichondrin B analog (E7389) in combination with cisplatin (CDDP) in advanced solid tumors: A CCC, NCI/CTEP-sponsored trial (grant U01 CA 062505). Presenting Author: Marianna Koczywas, City of Hope, Duarte, CA

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Phase I study to evaluate the safety and to assess the food effect of HM781-36B, a novel pan-HER inhibitor continuously given in patients with advanced solid tumors. Presenting Author: YuJung Kim, Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Soengnam-SI, South Korea

Background: E7389 is a structurally simplified synthetic macrocyclic ketone analog of the marine sponge natural product Halichondrin B, which inhibits microtubule dynamics via a novel mechanism characterized by suppression of microtubule growth, lack of effect on microtubule depolymerization, and sequestration of tubulin into nonfunctional aggregates. Methods: The goals of this trial were to determine the DLT, the MTD, and PK of E7389 (administered on days 1, 8 and 15 every 28 days) in combination with CDDP (administered on day 1 every 28 days) in patients (pts) with advanced solid tumors. The protocol was amended after dose level 4 (E7389 1.4 mg/m2, CDDP 60 mg/m2) when it was not feasible to administer E7389 on day 15 due to neutropenia; the treatment schedule was changed to E7389 days 1 and 8 and CDDP day 1 every 21 days. Eligibility criteria included normal organ function and ⬍ 2 prior chemotherapy regimens. Results: To date, 36 pts have been treated (E7389 0.7-1.4 mg/m2 and CDDP 60-75 mg/m2). Median age 61 years; 19 males; the most common tumor types were lung (8), pancreatic (5), head and neck (6). 36% ECOG 0, 56% ECOG 1, 8% ECOG 2; Median number of cycles was 3 (1 – 8). There were 3 pts with DLT’s on the 28-day cycle: gr 4 febrile neutropenia (1.0/60); gr 3 anorexia/fatigue/hypokalemia (1.2/60); and gr 3 stomatitis/fatigue (1.4/60). There were 3 pts with DLTs treated on the 21-day schedule: gr 3 hypokalemia/hyponatremia (1.4/60); gr 4 mucositis (1.4/60); and gr 3 hypokalemia (1.2/75). With 2 DLTs out of 6 pts at E7389 1.4 mg/m2 and CDDP 60 mg/m2, E7389 was reduced, CDDP was escalated, and the MTD was determined to be E7389 1.2 mg/m2 and CDDP 75 mg/m2(1 patient out of 6 with a DLT). At the MTD, protocol defined dose modifications or delays were required in 2 of the 6 patients by cycle 2. Notably, all DLTs were observed in patients exposed to at least 2 prior lines of chemotherapy. Two pts had an unconfirmed PR (pancreatic, breast) and 2 had a PR (esophagus, transitional bladder). Conclusions: On a 21 day schedule,E7389 in combination with CDDP appears well tolerated and showed preliminary activity. The MTD was determined to be E7389 1.2 mg/m2 and CDDP 75 mg/m2. Clinical trial information: 00400829.

Background: HM781-36B, a novel pan-HER tyrosine kinase inhibitor, showed potent in vitro and in vivo antitumor activities for EGFR mutant models including T790M mutation. In the previous 2-weeks on, 1-week off phase I study, the maximum tolerated dose (MTD) was determined as 24 mg/day. Phase I study with a continuous daily dosing schedule was conducted to determine the recommended dose (RD), and to assess the effect of food on pharmacokinetics (PK) in patients (pts) with advanced solid tumors. Methods: Eligible pts had advanced malignancies refractory to standard therapies. Standard 3⫹3 scheme was used in the dose escalation study, and additional 8 patients were enrolled to test food effects. Results: 20 pts (median age: 55 years [range32-77], M:F⫽13:7, ECOG PS 0/1/2/3 8/12/0/0) were enrolled (5 NSCLC, 4 colon cancer, 3 stomach cancer, 2 breast cancer, 2 rectal cancer, 2 common bile duct cancer, 1 pancreatic cancer and 1 esophageal cancer); 12 in the dose escalation and 8 in the food effect study cohort. Twelve pts were heavily pretreated(ⱖ4 regimens). Dose limiting toxicities (DLTs) were G3 anorexia in 1 pt at 18mg/day, G3 diarrhea and anorexia in 1 pt, and drug compliance ⬍80% due to G2 adverse events in 1 pt at 24mg/day. The MTD was determined as 18 mg/day, and RD was determined as 16 mg/day. The most common drug-related adverse events were diarrhea, stomatitis, skin rash, paronychia, pruritus and anorexia. Among 16 evaluable pts, 4 achieved partial responses (PR)[1 NSCLC, 2 breast cancer, 1 common bile duct cancer], and the duration of response were 32, 40⫹, 21, and 8 weeks, respectively. Five pts had stable disease (SD). The median duration of treatment in pts with PR or SD was 33.5 weeks (range, 15-82). Under both fasted and fed condition, there were no significant differences of AUClast values, whereas Cmax values were lower in fed condition than in fasted condition. Conclusions: Continuous daily dosing schedule of HM781-36B is safe and well tolerated in advanced solid tumors. It exerts anticancer activity, without being influenced by food. Updated data will be presented at the meeting. Clinical trial information: NCT01455584.

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A first-in-human (FIH) dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of intravenous BAL101553, a novel microtubule inhibitor, in adult patients with advanced solid tumors. Presenting Author: Alan Hilary Calvert, University College London, London, United Kingdom

Clinical pharmacokinetics (PK) and translational PK-pharmacodynamic (PD) modeling and simulation to predict antitumor response of various dosing schedules to guide the selection of a recommended phase II dose (RP2D) and schedule for the investigational agent MLN0128. Presenting Author: Chirag G. Patel, Millennium Pharmaceuticals, Inc., Cambridge, MA

Background: BAL101553, a pro-drug of the small molecule BAL27862, is a novel microtubule targeting agent (MTA) with cytotoxic and vascular disrupting properties. Pre-clinical data showed anti-proliferative activity in several in vitro and xenograft tumour models, including tumours refractory to conventional MTAs through diverse resistance mechanisms. Primary objectives of this FIH study were determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). Secondary objectives included the evaluation of PK, PD and anti-tumour activity. Methods: An accelerated titration dose-escalation design was used. Eligible patients (pts) with advanced solid tumours, who had failed standard therapy, received BAL101553 as a 2-h intravenous infusion on days 1, 8 and 15 of a 28-day cycle. Adverse events (AEs) were assessed according to CTCAEv4. Disease response was assessed by RECIST 1.1 every 2 cycles. Results: 16 pts (7 male; median age 52 years; range 29-80) with solid tumours were treated at 4 dose levels (15, 30, 45 and 60 mg/m2). DLTs were observed at 60 mg/m2 and included rapidly reversible grade (G) 3 hypertension (HTN) and G3 reduced mobility/ dizziness. DLT criteria for HTN were subsequently modified. Frequent drug-related AEs were injection site reactions, nausea, vomiting (all G1-2), and G2-3 HTN (transient during the infusion; responding to nifedipine). One pt experienced G2 peripheral neuropathy at 60 mg/m2. PK analyses indicated conversion of BAL101553 to the active BAL27862, dose proportional exposure for both compounds and a half-life of BAL27862 in a range of 11 to 27 h. Preliminary tumour PD data comparing pre/post biopsies showed loss of CD34⫹ capillaries and focally decreased proliferation. A confirmed partial response was demonstrated in 1 pt with ampullary (pancreaticobiliary) cancer maintained on treatment for ⬎16 cycles with intra-pt dose escalation. 2 pts (laryngeal and rectal cancer) demonstrated stable disease ⬎16 weeks. Conclusions: BAL101553 is well tolerated up to 60 mg/m2 with evidence of anti-tumour activity. Dose escalation continues to determine the MTD. Clinical trial information: NCT01397929.

Background: MLN0128 (INK128) is an investigational oral, potent, and highly selective inhibitor of mammalian target of rapamycin complex 1 and 2 (mTORC1/2) currently in clinical investigation. In the phase1 study INK128-001, MLN0128 was administered once daily (QD), once weekly (QW), QDx3D/week, and QDx5D/week, with respective MTDs of 6, 40, 16, and 10 mg. To guide selection of dose/schedule for further investigation, PD modulation in skin (pS6, p4EBP1, pNDRG1, pPRAS40) was put into context of clinical PK in INK128-001. A preclinical translational dynamic-PK efficacy model was used to describe the relationship and determine PK drivers of efficacy in tumor xenograft models. This model was implemented using human PK parameters to predict tumor volume-time curves, which was utilized to help determine the optimal MLN0128 dose/schedule. Methods: Phoenix NLME v1.1 was used for compartmental modeling of clinical and preclinical PK data, and modeling the preclinical PK-efficacy relationship of MLN0128. PD activity in skin was measured by immunohistochemistry, reported as H scores. Tumor growth curves were simulated using NONMEM v7.2; predicted tumor growth curves were plotted in S-Plus v8.1. Results: Clinical skin PD data suggests exposure dependent inhibition of pS6, and p4EBP1. A two compartment PK model adequately described the PK characteristics of MLN0128 [mean (%CV) ka: ~5.305 h-1 (114), k12: ~0.490 h-1(85), k21: ~0.67 h-1(69), V/F: ~180 L (44), Tlag: 0.317 h (73)]. Simulation of human tumor volume-time curves suggest efficacy is dependent on schedule and that MLN0128 administered in more frequent schedules (QD, QDx5D) provides stronger antitumor effect vs less frequent schedules (QW, QDx3D). Conclusions: The results indicate that per unit MLN0128 plasma exposure, QD and QDx5D may be optimal in comparison with QDx3D and QW dosing. However, these results will also need to be put into context with the overall safety profile and respective MTDs and RP2Ds for each schedule with their resultant achievable total cycle dose by schedule. Clinical trial information: NCT01058707.


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Influence of mild and moderate hepatic impairment on the pharmacokinetics (PK) of the pan-HER inhibitor dacomitinib. Presenting Author: Nagdeep Giri, Pfizer Oncology, La Jolla, CA

Phase I trial of ADI-peg 20 plus docetaxel (DOC) in patients (pts) with advanced solid tumors. Presenting Author: Ben Kent Tomlinson, UC Davis Comprehensive Cancer Center, Sacramento, CA

Background: Dacomitinib (D) is a highly selective irreversible small molecule inhibitor of the HER family of tyrosine kinases in clinical development for NSCLC.Prior clinical studies of D, which has minimal renal excretion (~3%), enrolled pts with protocol-defined adequate liver function. Liver metastases, leading to abnormal liver function tests, are common in pts with advanced cancer. This study evaluated the effect of hepatic impairment on PK and safety of D following a single oral dose in subjects with mild or moderate hepatic impairment. Methods: In this phase I, open-label, parallel group study, 25 subjects with either normal hepatic function (n⫽8) or mild (Child-Pugh A; n⫽8) or moderate (Child-Pugh B; n⫽9) hepatic impairment were administered a single, oral dose of D (30 mg). PK samples were collected at intervals up to 264 h post-dose and safety was assessed by laboratory abnormalities, physical examination, vital signs, ECGs, and AE monitoring. Analysis of variance was performed on natural logtransformed AUC and Cmaxto estimate adjusted mean differences between groups and 90% CIs, which were exponentiated to produce the adjusted GMR and 90% CI of the ratios. Results: GMR and 90% CI for AUCinf and Cmax (preliminary analyses) are listed.Mean D exposure (AUCinf and Cmax) was similar in subjects with normal hepatic function and those with mild impairment. Moderate hepatic impairment decreased D exposure by 15% and 20% for AUCinf and Cmax, respectively, vs normal hepatic function, but the 90% CI was relatively wide, and included 1. Plasma protein binding of D was similar in the 3 groups. No clinically significant treatment-related AEs were reported. Conclusions: Mean D exposure (AUCinf and Cmax) was similar in subjects with normal hepatic function and those with mild impairment. Mean D exposure appeared slightly lower in subjects with moderate impairment. Dose reduction of D in subjects with mild or moderate hepatic impairment may not be necessary. A single 30 mg dose of D was well tolerated in subjects with mild or moderate hepatic impairment. Clinical trial information: NCT01571388.

Background: ADI-PEG20 is an enzyme that degrades arginine (Arg), an amino acid relevant to biosynthetic pathways of normal and malignant cells. It has shown tolerability and activity in several solid tumors. Preclinical studies have shown that Arg deprivation by ADI-PEG 20 in cancer cells induces autophagy, caspase-independent apoptosis, and potentiates DOC-induced cytotoxicity in prostate cancer (PC) models. A phase I trial (standard 3⫹3 design) of ADI-PEG20 (IM weekly) plus DOC (IV on day 1 q 3 weeks) was conducted to assess feasibility and safety of the combination. Methods: Eligible pts were ⬎18 years of age, had advanced malignant solid tumors, adequate end organ function, and performance status (PS) 0-2. ADI-PEG 20 was escalated over 4 dose levels (4.5, 9, 18, 36 mg/m2). DOC dose was 75 mg/m2. Dose limiting toxicity (DLT) was defined as any of the following in cycle 1: thrombocytopenia [grade (Gr) 3 with bleeding/transfusion, or Gr 4]; neutropenia with fever or documented infection attributable to ADI PEG20; or any ⱖ Gr 3 non-heme toxicity related to study drug except alopecia. Allergic reaction associated with DOC was not considered a DLT. Serum levels of Arg were serially measured. Results: 18 pts were accrued: median age, 64.5 yrs; male, 83%; PS 0, 72%. Most common tumors were NSCLC (8), PC (3), and tongue cancer (TC) (2). Median number of prior systemic therapies was 3. One DLT was seen in dose level 1 (urticarial rash) requiring expansion of that dose level to 6 pts. No additional DLTs attributable to ADI PEG20 were seen. Serious adverse events (all expected and attributed to DOC) were recorded in 11/18 pts, including Gr IV neutropenia (6, 33%) and Gr IV anemia (2, 11%). There were 2 on-study deaths unrelated to protocol therapy. In 11 pts with evaluable disease, 1 with TC had a partial response (PR), 6 had stable disease (SD) (3 NSCLC, 2 PC, 1 TC). Arg levels decreased in the 1st cycle for 6/11 pts with available data, including 2 with SD, and 1 with PR. Conclusions: The combination of ADI PEG20 and DOC is feasible with reasonable tolerability in this heavily pre-treated cohort. Full doses of both agents were achievable: ADI-PEG 20 at 36mg/m2 with DOC 75 mg/m2. An expansion cohort of castration resistant PC pts is now accruing at this recommended dose. Clinical trial information: NCT01497925.

Hepatic impairment Mild Moderate

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GMR (90% CI) vs normal hepatic function Cmax AUCinf 1.00 (0.73–1.38) 0.85 (0.62–1.15)

1.03 (0.69–1.53) 0.80 (0.55–1.17)


A genotype-directed study to optimize dosing of irinotecan according to the UGT1A1 genotype. Presenting Author: Federico Innocenti, The University of Chicago, Chicago, IL Background: The risk of severe neutropenia from irinotecan (I) is in part related to UGT1A1*28, a polymorphism that reduces the elimination of SN-38, the active metabolite of I. We aimed to identify the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of I in advanced solid tumor patients (pts) stratified by*1/*1, *1/*28, and *28/*28 genotypes. We hypothesized that *1/*1 pts would tolerate a higher MTD than the standard 350 mg/m2 dose and that *28/*28 pts would require dose reduction. Methods: 68 pts (30 lung, 30 gastrointestinal, 8 other cancers) received q3w, flat-dose I. Genotype frequencies were 46% (*1/*1), 41% (*1/*28), and 13% (*28/*28). Pts (66% males, median age 68 years) had 0-1 PS (only one pt had PS 2). 82% were Caucasians, 13% African Americans, and 4% Hispanics. The I starting dose was 700 mg in *1/*1 and *1/*28 pts, and 500 mg in *28/*28 pts. Pharmacokinetics was obtained at cycle 1. DLT at cycle 1 was defined as grade (G) 4 neutropenia (N) for ⱖ4 days, Gⱖ3N on a treatment day, Gⱖ3 febrile N, G4 anemia or thrombocytopenia, or Gⱖ3 non-hematological toxicity. Results: In *1/*1 pts, the MTD was 850 mg (4 DLTs/16 pts), and 1000 mg was not tolerated (2 DLTs/6). In *1/*28 pts, the MTD was 700 mg (5 DLTs/22) and 850 mg was not tolerated (4 DLTs/6). In *28/*28 pts, the MTD was 400 mg (1 DLT/6) and 500 mg was not tolerated (3 DLTs/3). DLTs were mainly G4N, Gⱖ3 febrile N, and G3 diarrhea. I clearance followed linear kinetics. I and SN-38 AUCs were associated with decreased log10ANC nadir (r2 0.27 and 0.30, respectively, p⬍0.0001). At the MTD, I AUC in *28/*28 pts was 50% and 62% lower than that of *1/*28 and *1/*1 pts (16.8⫾4.4, 33.4⫾11.9, 44.2⫾11.3 h*ug/ml [mean⫾SD], respectively). At the MTD, SN-38 AUC in *28/*28 pts was 30% and 26% lower than that of *1/*28 and *1/*1 pts (620⫾407, 881⫾715, 841⫾888 h*ng/ml). 3 PRs were observed (NSCLC-700 mg-*1/*28, gastric-850 mg-*1/*1, small bowel850 mg-*1/*28). Conclusions: In a heavily pretreated population, UGT1A1*28 information can be used to individualize dosing of I. Additional studies should evaluate the effect of genotype-guided dosing on efficacy in pts receiving I. Clinical trial information: NCT00708773.

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Dose-ranging randomized pharmacokinetic (PK) and pharmacodynamic (PD) study of vorinostat in patients with advanced solid tumors. Presenting Author: Tara C. Gangadhar, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA Background: Continuous 400 mg daily vorinostat (V) is effective treatment for cutaneous T-cell lymphoma, but has displayed erratic activity in combination therapy for solid tumors. Short-course high-dose vorinostat may have a better therapeutic index for solid tumors, but dose/exposure/PD relationships have not been tested in sufficiently powered studies. Methods: Patients (pts) were randomized to either V 1600 mg daily, days (d) 1-3 then 400 mg d8-10 or 400 mg d1-3 then 1600 mg d8-10 with complete PK sampling on d3 and d10 to determine the increase in Cmax upon increasing V from 400 to1600 mg. To assess safety and tolerability of high dose V added to carboplatin, pts then received high dose V d15-17 with carboplatin AUC 5 on d17; this combination was repeated every 21d thereafter. Platelet counts were determined weekly. To detect with 80% power a difference in vorinostat Cmax between 400 and 1600 mg required at least 10 pts in each sequence. In vitro studies of gene expression in solid tumors suggested as a secondary endpoint the frequency of pts achieving Cmax ⬎ 1000 ng/mL. Results: 24 pts (11 men/13 women) enrolled between April 2011 and March 2012 and were evaluable for study endpoints. No sequence dependence of change in Cmax was detected. Cmax for V 1600 mg was nearly double that for 400 mg (1184⫹/-631 vs. 616⫹/-442 ng/mL, p ⬍ 0.001). The PD effect on platelets (d10) was greater for the higher dose (median -76 vs. -14 K/␮L, p⫽ 0.02). There were no dose limiting toxicities. Of 24 pts, 11 achieved Cmax ⬎ 1000 ng/mL. Conclusions: The 1600 mg dose of vorinostat results in a higher Cmax than 400 mg and greater PD effect than 400 mg and is tolerable in combination with carboplatin. The carboplatin/vorinostat doublet serves as a DNAdamaging/epigenetic modifier module to be combined in more complex regimens. Clinical trial information: NCT01281176.




A phase I, first-in-human study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of IMGN853 in patients (Pts) with epithelial ovarian cancer (EOC) and other FOLR1-positive solid tumors. Presenting Author: Carla Kurkjian, University of Oklahoma, Oklahoma City, OK Background: IMGN853 is an antibody-drug conjugate (ADC) comprising a folate receptor 1 (FOLR1)-binding antibody and the potent maytansinoid, DM4. FOLR1 is over-expressed on many solid tumors, particularly EOC, endometrial cancer, non-small cell lung cancer (NSCLC), and clear-cell renal cell cancer. Methods: The primary study objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives include evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy. In dose escalation, patients with any type of FOLR1-expressing, refractory solid tumor may be enrolled. Once the MTD is defined, 3 expansion cohorts will evaluate patients with (1) primary platinum refractory or resistant EOC; (2) relapsed/refractory EOC, amenable to biopsy, and (3) relapsed/refractory NSCLC. Cohorts 2 and 3 will have IMGN853 PD assessment by pre-and post-dose tumor biopsy and by FLT-PET imaging, respectively. IMGN853 is given intravenously (IV) on Day 1 of each 21-day cycle. During dose escalation, an accelerated titration design was used. Responses are assessed using RECIST and GCIG criteria (as appropriate). Results: Eleven patients have been enrolled across 6 dose levels ranging from 0.15 to 5.0 mg/kg: 7 patients with EOC and 4 patients with endometrial cancer. No study drug-related serious adverse events (SAEs) or dose-limiting toxicity (DLT) have been reported. Among these 11 patients, 3 patients reported adverse events (AEs) considered study drug related; these were mild or moderate. At the 3.3 mg/kg dose level, one patient with serous EOC had an 82% reduction in CA125 (confirmation pending). The other 2 patients at this dose level, one with EOC and one with endometrial cancer, have stable disease. Drug exposure has been measured in 8 patients and has been found to generally increase linearly, with a half life at 3.3 mg/kg (3 patients) of approximately 4 days. Conclusions: IMGN853 is well tolerated at doses up to 3.3 mg/kg. Safety evaluation continues at 5 mg/kg and dose escalation is ongoing. Clinical trial information: NCT01609556.

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Phase I dose-escalation clinical trial with 5-imino-13-deoxydoxorubicin in cancer patients. Presenting Author: Raymond J. Hohl, University of Iowa, Iowa City, IA Background: 5-imino-13-deoxydoxorubicin (DIDOX; GPX-150) is a doxorubicin (dox) analog modified in two locations to prevent formation of a) cardiotoxic metabolites and b) reactive oxygen species. In a rabbit model comparing the cardiotoxicity of dox vs. DIDOX, chronic doses of each caused similar myelosuppression, but only dox caused cardiotoxicity as assessed by echocardiography and histopathology scoring. In view of the non-cardiotoxic nature of DIDOX along with its anticancer efficacy in preclinical studies, DIDOX was entered into a Phase I, open-label, non-randomized dose-finding study in up to 30 patients with solid tumors. Methods: Inclusion criteria included progressing solid tumors and cardiac ejection fraction (CEF) 110% of lower limit of institutional normal (assessed by MUGA). There are 8 dose cohorts and up to 8 cycles/cohort, dosing (iv) once every 3 weeks with an accelerated titration dosing design at the three lowest cohorts. Cohort A ⫽14, B⫽28, C⫽56, D⫽84, E⫽112, F⫽150, G⫽200, and H⫽265 mg/m2/cycle. Dose was escalated to next dose level if ⬍ 1 dose limiting toxicity (DLT) is reported. Maximum tolerated dose (MTD) will be exceeded when 2 or more patients in a cohort elicit DLT; the next lower dose is defined as the MTD. DLT occurs when a decrease in CEF is grade 2 or higher, or grade 4 neutropenia lasts ⬎ 5 days. Results: Cohorts A-G have been completed. Number of patients for the cohorts are: A⫽1, B⫽1, C⫽1, D⫽4 E⫽3 F⫽3 G⫽4, and H ⫽ 2 (with 4 more to be enrolled in H). No decrease in CEF occurred in any cohorts. There were no DLTs in cohorts A-G. One patient in H had neutropenia grade 4 for 11 days (a DLT). Another patient in H had neutropenia grade 4 for 4 days. There was no disease progression at the completion of dosing for 6 of the 12 patients in cohorts E-H. In contrast, all 7 patients had disease progression in cohorts A-D. Conclusions: No cardiotoxicity was observed in any patient. No DLT was observed in cohorts A-G. With one DLT in cohort H, one more DLT will define MTD for DIDOX at 200 mg/m2. At higher DIDOX doses (E-H), 6 of 12 patients showed no disease progression. (IND No. 77,051). Clinical trial information: NCT00710125.

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Phase I study of inotuzumab ozogamicin (INO) combined with R-GDP for relapsed CD22ⴙ B-cell non-Hodgkin lymphoma (B-NHL). Presenting Author: Randeep Sangha, University of Alberta, Edmonton, AB, Canada Background: CD22 is expressed on most B-NHL. INO, an anti-CD22 antibody linked to calicheamicin, has activity in refractory B-NHL. This study hypothesized that INO plus rituximab, gemcitabine, dexamethasone, and cisplatin (R-GDP) for relapsed CD22⫹ B-NHL was safe and tolerable. Methods: Patients (pts) with relapsed CD22⫹ B-NHL treated with ⱖ1 prior R-chemo regimen were enrolled using an up-and-down independent dose-escalation schema for G and P. INO (0.8 mg/m2 day 2) was combined with R-GDP (R 375 mg/m2, G, and P day 1; oral D 40 mg days 1-4) on a 21-d cycle for up to 6 cycles. Dose-limiting toxicity (DLT) included febrile neutropenia, grade (Gr) 4 ANC lasting ⱖ7 d, Gr 4 platelets ⱖ7 d, Gr ⱖ3 platelets with bleeding and transfusion support, Gr ⱖ3 QTc prolongation, Gr 4 AST/ALT, Gr 2 bilirubin ⱖ7 d, G-CSF during cycle 1, Gr ⱖ3 clinically significant or drug-related nonhematologic toxicity ⱖ7 d, and Gr ⱖ2 drug-related nonhematologic toxicity causing dose delay of ⱖ7 d. Results: Thirty-seven pts were treated: 15 DLBCL, 11 FL, 7 MCL, 1 MZL, 1 SLL, and 2 indolent B-NHL. Characteristics: aged 33 to 81 y (median 65 y); 34 with ECOG PS £1; median of 2 prior chemo regimens (range 1-6); 5 refractory to prior therapy. No DLTs were observed at the starting dose of G 500 mg/m2, P 37.5 mg/m2 (n ⫽ 6); 2 DLTs (febrile neutropenia, Gr 2 platelets) at G 1000 mg/m2, P 37.5 mg/m2 (n ⫽ 3); no DLTs at G 1000 mg/m2, P 0 mg/m2 (n ⫽ 6); 2 DLTs (febrile neutropenia; Gr 4 ANC ⱖ7 d) at G 500 mg/m2, P 50 mg/m2 (n ⫽ 8); and 2 DLTs (Gr 3 hypokalemia, Gr 4 neutropenic sepsis) at G 500 mg/m2, P 75 mg/m2 (n ⫽ 4). In a maximum tolerated dose (MTD) confirmation cohort of 10 additional pts, 3 pts had DLTs (2 with Gr 4 platelets, 1 with febrile neutropenia); thus MTD was determined to be INO 0.8 mg/m2, R 375mg/m2, G 500 mg/m2, D 40 mg, P 50 mg/m2. Gr ⱖ3 adverse events included thrombocytopenia (68%), neutropenia (54%), lymphopenia (32%), anemia (27%), leukopenia (24%), hypokalemia (22%), fatigue (11%), and febrile neutropenia (11%). Median treatment cycle was 4 (range 1-6). There were 8 complete and 9 partial responses. Conclusions: INO 0.8 mg/m2 with R-GDP is tolerable at reduced doses of G (500 mg/m2) and P (50 mg/m2). Preliminary efficacy is being explored in the ongoing MTD expansion cohort. Clinical trial information: NCT01055496.

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General Poster Session (Board #6D), Mon, 8:00 AM-11:45 AM

ProGem1: Phase I first-in-human study of the novel nucleotide NUC-1031 in adult patients with advanced solid tumors. Presenting Author: Essam Ahmed Ghazaly, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom Background: NUC-1031 is a novel nucleotide (ProTide) that evades all three key cellular resistance mechanisms associated with gemcitabine (dFdC). NUC-1031 bypasses nucleoside transporters, is activated independent of deoxycytidine kinase and is resistant to cytidine deaminase-mediated degradation. NUC-1031 has demonstrated broad antiproliferative activity in vitro and in vivo. Methods: Patients with relapsed/refractory advanced solid tumors entered in sequential cohorts of up to 6 patients, with escalating doses of NUC-1031 administered as a 5-10 minute IV injection weekly or twice-weekly. Ongoing objectives are to determine recommended phase II dose, safety profile, pharmacokinetics (PK) and preliminary anti-tumor activity. Results: 8 patients (5 female, 3 male) with pancreatic (2), colorectal (2), breast (1), and ovarian (1) cancers; cholangiocarcinoma (1) 2 and unknown primary (1) have been enrolled. Two dose levels 500mg/m (4) and 1000mg/m2 (1) weekly and one dose level - 375 mg/m2(3) twice-weekly. No DLTs have been observed. Mean AUC (0 - 24 h) for NUC-1031 was 150.3 ⫾ 84.8 ␮M/h (n⫽5). dFdC and dFdU were detected in plasma up to 24 h (range of 0 - 5.8 ␮M for dFdC and 0 - 14.9 ␮M for dFdU). NUC-1031 excreted in urine mainly as dFdU. The Table shows rapid elimination of NUC-1031 from plasma and high intracellular levels of the active gemcitabine triphosphate at 2 and 24 h. Stable disease achieved in 1 patient with rapidly progressing breast cancer. Two further patients had symptomatic relief and improved QOL, including a dramatic reduction in ascites and pain. Conclusions: PK data show NUC-1031 has ⱖ 10x higher intracellular levels of the active compound, dFdCTP, and significantly lower plasma Cmax levels of the toxic metabolite, dFdU, compared to equivalent levels of gemcitabine. NUC-1031 has shown better intracellular delivery and toxicity profile than gemcitabine with some promising early indicators of clinical efficacy. Clinical trial information: NCT01621854. Time (h) 2 24 Plasma NUC-1031 Intracellular NUC-1031 Intracellular dFdC Intracellular dFdCMP Intracellular dFdCTP

1.8 ⫾ 2.1 ␮M 0.67 ⫾ 0.71 ␮M/mg ⬍ 0.01 ␮M/mg 0.04 ⫾ 0.04 ␮M/mg 3.36 ⫾ 1.64 ␮M/mg

0.18 ⫾ 0.20 ␮M 0.20 ⫾ 0.47 ␮M/mg ⬍ 0.01 ␮M/mg 0.70 ⫾ 1.53 ␮M/mg 0.43 ⫾ 0.23 ␮M/mg


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Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics General Poster Session (Board #6E), Mon, 8:00 AM-11:45 AM

Novel toxicity endpoint for dose-finding designs evaluating molecularly targeted agents (MTA). Presenting Author: Monia Ezzalfani, Institut Gustave Roussy, Biostatistics and Epidemiology Department, Villejuif, France Background: The emergence of MTA in oncology has revolutionized the phase I design paradigm. The usual dose-limiting toxicity (DLT) endpoint is an oversimplification of the complex toxicity profile resulting in loss of information. Moreover, MTAs can induce less DLTs but more multiple moderate toxicities that may lead to dose reduction in long lasting treatment. We thus sought to develop a new toxicity endpoint, the Total Toxicity Profile (TTP), to incorporate multiple toxicities. Methods: We reanalysed the phase I trial that evaluated erlotinib (75, 100, 125, 150 mg/m2) in children with brain stem glioma (NCT00418327). Only 2/21 patients experienced protocol defined DLTs, but multiple moderate toxicities were observed. The TTP endpoint is a weighted combination of all toxicities experienced by the patient (Euclidean norm of the weights), where the weights (ranging from 0 to 10) reflect the clinical importance of each grade and type of toxicity. The weights and the acceptable toxicity target (target TTP) were elicited from 3 clinicians using hypothetical patient cohorts with various toxicity outcomes. They were asked to make a decision of where the next cohort of patients would be treated: higher, lower or same dose level. The target TTP was defined as the mean of TTPs of the cohorts associated with a decision to repeat the dose. We used the TTP-driven Quasi-Likelihood Continual Reassessment Method (QL-CRM) to re-estimate the recommended dose. Results: Clinicians identified 5 main dermatological toxicity types possibly attributable to erlotinib. The consensus weights (table below) as well as the target TTP (set at 4.66) were easily obtained, confirming the feasibility of the process. The weights differed from the CTCAE grades, confirming the interest of the approach. The recommended dose based on the retrospective analysis of all grades toxicity was lower than that identified by the DLT-driven CRM (100 instead of 125mg/m2). Conclusions: By neglecting multiple moderate toxicities, DLT-driven designs may over-estimate the recommended dose when investigating MTA. Our proposal is an appealing alternative design for MTA. Toxicity

1

CTCAE grade 2

3

Folliculitis Erythema Pruritis Xerosis Long eyelashes

2 1 2 1 1

4.5 3 4 3 3

8 6 7 6 6

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Phase I study of olaparib in combination with carboplatin and/or paclitaxel in patients with advanced solid tumors. Presenting Author: Ruud van der Noll, The Netherlands Cancer Institute-Antoni Van Leeuwenhoek Hospital, Amsterdam, Netherlands Background: This three-center phase I study evaluated the PARP1/2 inhibitor olaparib (O) in combination with carboplatin (C), paclitaxel (Pa) or both (CPa) in patients (pts) with advanced solid tumors refractory to standard therapies (NCT00516724). Methods: This ongoing study consists of multiple parts (P) in which escalating doses of O capsule and tablet formulations were studied. Capsule formulation data are presented; continuous O with C (P1; 21 day cycle), CPa (P2a; 21 day cycle) and weekly Pa (P2b; 28 day cycle) or intermittent O with CPa (P3; 21 day cycle). Primary and secondary objectives were safety/tolerability and antitumor activity (RECIST), respectively. Results: This analysis (non validated data) included 87 enrolled pts (P1 [n⫽25] P2a [n⫽20] P2b [n⫽12] and P3 [n⫽30]). Most common tumor types were breast (26%), melanoma (10%) and ovarian (7%). 12 pts had known gBRCA1/2 mutations. A tolerable continuous dosing schedule of O with CPa was not determined. Most common AEs (all grades) were myelosuppression (71%) notably neutropenia (54%) and thrombocytopenia (26%), and fatigue (77%). Excessive treatment cycle delays due to hematologic toxicity occurred with continuous O combined with standard doses of C or CPa. Two doses were identified as tolerable: continuous O 100 mg bd with weekly Pa 80 mg/m2 and intermittent O 200 mg bd (d1–10) with CPa AUC4/175 mg/m2 q 3 weeks. 14/87 pts (16%) had an objective response (complete response [CR] 5%; partial response [PR] 11%); 28% had stable disease for ⱖ4 months. Activity appeared greater in pts with BRCA1/2 mutations (CR 17%; PR 33%). Conclusions: Continuous O in combination with CPa exacerbated hematologic toxicities leading to schedule delays. Tolerability improved with intermittent O. Antitumor activity was highest in pts with a BRCA1/2 mutation. This study identified two tolerable O capsule treatment schedules for further development. Clinical trial information: NCT00516724. Treatment schedule Part

Olaparib (mg, bd)

Carboplatin (AUC; q 3 wks)

50 100 50 200 50 50 50 100 100 200 Intermittent 200 (d1–10) 200 (d1–10) 400 (d1–10) 200 (d1–5) 400 (d1–5)

4 4 5 4 4 4 4 4

Paclitaxel (mg/m2; q 3 wks)

Continuous P1 P1 P1 P1 P2a P2a P2a P2a P2b P2b P3 P3 P3 P3 P3

4 5 4 5 5

90 135 175 175 80* 80* 175 175 175 175 175

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A first-in-human phase I study of CZ48, a lactone ring protected oral camptothecin, in patients with advanced solid tumors. Presenting Author: Devalingam Mahalingam, Institute for Drug Development, Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, San Antonio, TX Background: CZ48, the 20-O-propionate ester of camptothecin (CPT), is a prodrug of CPT first described by Cao et al. in 1998. The side-chain is enzymatically cleaved in tissues. This gives rise to CPT, a potent inhibitor of topoisomerase I. Methods: An open-label, single-arm, dose-escalation Phase I study was performed to determine the maximum tolerated dose (MTD) of CZ48 in patients with advanced solid tumors. Initial dosing started qd po 80mg/m2, advancing to 2560mg/m2 for 21 consecutive days, followed by 7 days rest. Dosing was restarted in cohorts of 3 patients tid po at 18mg/m2 and escalated to 1g/m2on a 5 days on, 2 days off schedule for 28 days. Patients were prescreened by measuring CPT levels in plasma following a single pilot dose of CZ48. Dose was doubled until occurrence of at least Grade 2 adverse event, at which time 3⫹3 patient cohorts with a dose escalation of 33%-100% were implemented. DLT in 2/6 patients defined the MTD as the preceding DLT dose. PK parameters were measured prior to dosing, days 1-5, and day 28 of Cycle 1. Results: Poor absorption led to initial qd dosing reaching 2560mg/m2 with no signs of DLT. Subsequent tid dosing showed improved plasma levels and arrival at DLT. 34 patients were treated across 8 dose levels from 18 to 1000 mg/m2. The most frequent study-related adverse effects were cystitis, vomiting, diarrhea and fatigue. Grade IV toxicities observed were febrile neutropenia, anemia, and thrombocytopenia. Preliminary PK data in the qd dosing showed poor correlation between dose and Cmax or AUC, while PK in tid patients showed slightly improved correlation between dose and both CZ48 AUC (Pearson’s correlation coefficient |⫽0.476, p⬍0.01) and CZ48 Cmax(| ⫽0.51, p⬍0.01). Evidence of clinical activity with stable disease ⱖ 6 months was observed in 2 heavily pre-treated colon and one breast cancer patient. Conclusions: The MTD of tid po CZ48 administered 5 days on, 2 days off of 28-day cycle is between 750 mg/m2 and 576 mg/m2. Overall toxicity is relatively mild, with DLT being cystitis and myelosuppression. Even with tid dosing, PK values correlate poorly to dose. A new formulation with 3-5 fold higher preclinical absorption values is being considered for introduction into the trial. Clinical trial information: NCT00947739.

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First-in-human trial of novel oral PARP inhibitor BMN 673 in patients with solid tumors. Presenting Author: Johann Sebastian De Bono, The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom Background: BMN 673 is the most potent and specific inhibitor of PARP1/2 in clinical development (IC50⬍1nM). In tumors genetically dependent on DNA repair by homologous recombination PARP inhibition induces synthetic lethality. Methods: Pharmacokinetics (PK), pharmacodynamics (PD), safety and anti-tumor activity of BMN 673 were evaluated in a 2-stage dose-escalation study with 3-6 patients (pts)/dose level. In dose escalation (Stage 1) cycle 1 was 6 wks, with drug taken on days 1 and 8-35, for PK and PD assays, followed by daily continuous dosing in 4-wk cycles. Stage 2 (expansion at MTD) recruits pts with tumors defective in DNA repair: Ewing sarcoma, small cell lung cancer or tumors associated with BRCA mutation (mut). Results: 39 pts (33F/6M) were enrolled in 9 cohorts from 25 to 1100 ␮g/d that defined a MTD of 1000 ␮g/d. Median (range) age was 58 (19-81), PS 0 (0-1) and # of prior therapies 4 (1-13). Tumors (# with deleterious BRCA 1/2 mut) included 23 ovarian/primary peritoneal (17); 8 breast (6); 3 pancreas; 2 colon; 1 prostate (1), and 1 mullerian carcinosarcoma. 17 and 8 pts had BRCA 1 and 2 mut, respectively. Dose-limiting thrombocytopenia occurred in 1/6 and 2/5 pts at 900 and 1100 ␮g/d, respectively. Potentially-related adverse events in ⬎10% of pts (# grade 1 and 2/grade 3 and 4) included fatigue (10/0); nausea (10/0); flatulence (4/0); anemia (5/2); neutropenia (4/3); thrombocytopenia (1/3); and grade 1 alopecia (10). Inhibition of PARP activity in PBMCs was observed at doses ⱖ 100 ␮g/d. BMN 673 plasma concentrations peaked 1-2 hrs post-dose; exposure increased dose proportionally. Steady state plasma concentrations were reached by the end of the 2nd week of daily dosing; mean Cmax: 0.30 - 25.4 ng/mL and AUC0-24: 3.96 - 203 ng-hr/mL across the 25 to 1100 ␮g/d dose range after 28d of daily dosing. RECIST and/or CA-125 responses occurred at doses ⱖ 100 ␮g/d in 11/17 BRCA carrier ovarian/peritoneal cancer pts. Objective responses occurred in 2/6 BRCAcarrier breast cancer pts. Conclusions: BMN 673 is well tolerated with impressive anti-tumor activity in pts with BRCA mut with a single agent recommended Phase II trial dose of 1000 ␮g/d due to dose-limiting thrombocytopenia. Clinical trial information: NCT01286987.

* Weekly; wks, weeks; d, days.




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Phase IB study of olaparib (AZD2281) plus gefitinib in EGFR-mutant patients (p) with advanced non-small-cell lung cancer (NSCLC) (NCT01513174/GECP-GOAL). Presenting Author: Rosario García Campelo, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain

Assessment of ␥H2AX levels in circulating tumor cells in patients treated with veliparib in combination with doxorubicin and cyclophosphamide in metastatic breast cancer. Presenting Author: Antoinette R. Tan, The Cancer Institute of New Jersey, New Brunswick, NJ

Background: Progression-free survival (PFS) and response to EGFR tyrosine kinase inhibitors (TKIs) vary in p with NSCLC driven by EGFR mutations. In our experience, high BRCA1 mRNA expression was associated with shorter PFS in EGFR-mutant p treated with erlotinib. We hypothesized that since olaparib downregulates BRCA1 expression, the addition of olaparib to gefitinib could improve PFS in these p. Methods: This is a Phase IB dose escalation study to identify the maximum tolerated dose (MTD), dose limiting toxicity (DLT), pharmacokinetics, and clinical activity of orally administered olaparib in combination with gefitinib in EGFR-mutant advanced NSCLC p. In a standard 3⫹3 design, p were treated with gefitinib 250mg once daily plus olaparib tablets at escalating doses ranging from 100mg BID to 250mg TDS during a 28-day cycle. Results: 18 p have been included across four dose levels of olaparib: 100mg BID (3), 200mg BID (6), 200mg TDS (3) and 250mg TDS (6). Median age, 69; male, 4; PS 0, 17; EGFR TKI treatment-naïve, 10. Toxicities: anemia (66.6%), leucopenia (33.3%), nausea (33.3%), diarrhea (33.3%), asthenia (27.7%), rash (22.2%) vomiting (11%), decreased appetite (16%), and hyperlipasemia (5.5%). Most toxicities were G1-2; G3 drug-related events included leucopenia (1) and anemia (3). No DLT at dose levels 1, 2, and 3; 1 DLT at dose level 4 (G3 anemia and repeated blood transfusion within 4-6 weeks). Few dose reductions or interruptions were needed. 1 p died due to pulmonary embolism unrelated to treatment. Partial responses (PR) were observed in 7 p (41.1%), all EGFR TKI-naïve; stable disease (SD) in 7 (41.1%), most previously treated; progressive disease (PD) in 3 (17.6%), all previously treated. Durable PR and SD were observed in EGFR TKI-naïve and previously treated p. 8 patients are still on treatment. Enrollment to dose level 4 will be completed in February 2013. Conclusions: This phase IB trial of gefitinib plus olaparib, has confirmed the activity and tolerability of the combination. The final recommended dose of olaparib is expected to be between 200 and 250 mg TDS. A phase II randomized trial in treatment-naïve EGFR-mutant advanced NSCLC will be opened in 2013. Clinical trial information: NCT0151317.

Background: Veliparib (V) is a potent PARP inhibitor that delays repair of DNA damage induced by chemotherapeutic agents. In metastatic breast cancer pts, we evaluated V with doxorubicin (A) and cyclophosphamide (C) given both on day 1 with V at 100 mg po BID for 7 days post-chemotherapy every 21 days, to increase DNA damage. We report use of ␥H2AX, (phosphorylated histone protein), a marker of DNA double-strand breaks, in circulating tumor cells (CTCs) to assess DNA damage. We evaluated number of CTCs and percentage of ␥H2AX-positive CTCs pre- and posttreatment. Methods: Eligibility included prior A ⱕ 300 mg/m2 and EF ⱖ 50%. Further A was omitted after a cumulative dose of 420 mg/m2. Primary objective was to assess DNA damage response to treatment by measuring ␥H2AX-positive CTCs during cycle 1 on days 1 (pre-treatment), 2, 7, and 14. Cell Search System was used to enumerate CTCs. ␥H2AX was quantitated using a validated assay. Results: Eleven pts enrolled. Median age was 53 (34 – 73); median ECOG PS 1 (0 – 2); there were 1 ER-negative/HER2⫹, 4 triple-negative (BRCA2⫹, n ⫽1), and 6 ER⫹/PR⫹/ HER2-negative (BRCA2⫹, n ⫽2) tumors. Most common drug-related toxicities were grade (gr) 4 neutropenia, gr 2 anemia and thrombocytopenia, and gr 1 nausea and vomiting. In BRCA2⫹ pts, there were 2 PRs and 1 SD. In BRCA wt or unknown status, 5 pts had SD ⱖ 3 mo and there were 3 PDs. CTCs (ⱖ 8) were detected in 10/11 pts on days 1 and 2. Day 7 samples were not obtainable in 2 pts. On day 7, 1/8 pts had 0 CTCs and rest had ⱖ 3 CTCs. A decrease in CTCs (p ⬍ 0.0001) occurred from day 1 (median: 22, range, 8-1216) to day 7 (median: 5, range 3-37). At baseline, 7 pts had ⱖ 10% ␥H2AX-positive CTCs. Fraction of CTCs positive for ␥H2AX increased to ⱖ 50% by day 7 in 6/7 pts and persisted to day 14 in 5 pts. Conclusions: The toxicity profile of V 100 mg BID days 1-7 with AC (60/600 mg/m2) on day 1 on a 21-day cycle was expected. Objective antitumor activity was seen in BRCA mutation carriers. CTCs decreased and percentage of ␥H2AX-positive CTCs increased after combination treatment with a PARP inhibitor and chemotherapy. This observation is notable and we plan to extend dosing of V to 14 days. This work is supported by NCI U01-CA132194. Clinical trial information: NCT00740805.

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A phase I imaging and pharmacodynamic trial of CS-1008 in patients (pts) with metastatic colorectal cancer (mCRC). Presenting Author: Marika Ciprotti, Ludwig Institute for Cancer Research, Melbourne, Australia

Phase I study of ABT-888 in combination with carboplatin and gemcitabine in subjects with advanced solid tumors. Presenting Author: Katherine M. Bell-McGuinn, Memorial Sloan-Kettering Cancer Center, New York, NY

Background: Death receptor 5 (DR5) is a member of the TNFR superfamily that initiates the extrinsic apoptotic pathway. CS-1008 is a humanised, monoclonal IgG1 agonistic antibody (Ab) to human DR5 created by CDR grafting of the murine Ab TRA-8. The aim of this study was to investigate the impact of CS-1008 dose on biodistribution, quantitative tumor uptake and anti-tumor response in pts with mCRC. Methods: Pts with mCRC were treated with weekly IV CS-1008 in 5 non-sequential cohorts (Co). Different loading doses were used on days 1 and 8 (0.2 to 6 mg/kg), followed by a weekly dose of 2 mg/kg. D1 and D36 doses were trace-labeled with 111In, followed by whole-body planar and regional SPECT imaging over 10 days. Primary endpoints: initial biodistribution, pharmacokinetic (PK) and tumor uptake following single infusion; changes in biodistribution, PK and tumor uptake following sequential doses. Secondary endpoints: tumor response; changes in tumor metabolism by FDG-PET; serum apoptosis biomarkers and tumor response markers. Results: 19 pts (median age 64 yrs; M:F 11:8; 2-6 prior chemotherapy regimens) were enrolled as follows: Co 1, n⫽2; Co 2, n⫽4; Co 3, n⫽5; Co 4, n⫽3; and Co 5, n⫽5. Tumor uptake was variable: 7 pts had no uptake, 11 pts had uptake in all sites of disease but liver, 1 pt showed liver uptake. Tumor uptake and PK were not affected by dose or repeated drug administration. No anti-CS-1008 Ab responses were detected. DR5 expression in archived samples did not correlate with uptake or response. 111In᎑CS᎑1008 biodistribution showed gradual blood pool clearance and no abnormal uptake in normal tissue. Mean % change in SUVmax from baseline in lesions with uptake was higher than in those with no uptake. There were 8 SD, 1 PR and 10 PD. Duration of PR was 3.7 months (mo). Mean duration of SD was 4 mo. Disease control rate (SD ⫹ PR) in pts with uptake was 58% vs 28% of pts with no uptake. Lesions with no uptake were more likely to progress, with a PD risk of 3.4 times higher than those lesions with uptake. Conclusions: Tumor DR5 expression, assessed by 111 In-CS-1008 imaging, revealed real-time heterogeneous DR5 expression and appeared to be a promising predictive imaging biomarker of clinical benefit in pts with mCRC receiving CS-1008. Clinical trial information: NCT01220999.

Background: Veliparib (V) is an oral inhibitor of poly(ADP-ribose) polymerases (PARP)-1 and -2, which are essential for base excision repair of ssDNA breaks. BRCA deficient tumors are more sensitive to PARP inhibitors when used as monotherapy or in combination with DNA-damaging agents. The objectives of this study were to determine the maximum tolerated dose (MTD), pharmacokinetic interactions, and safety/tolerability profile of V in combination with carboplatin (C) and gemcitabine (G). Methods: Eligibility criteria included patients (pts) with metastatic or unresectable solid tumors for which C/G was a treatment option. During the study, eligibility was amended to limit prior chemotherapy regimens to ⱕ 2. C AUC 4 /G 800 mg/m2was given intravenously on Day 1 and G given on Day 8 of 21 day cycles. To assess tolerability of C/G prior to V, V was started in Cycle 2. When C/G was stopped, pts could stay on monotherapy V until progression. Dose-escalation used a Bayesian continual reassessment method. Results: 59 pts (51 female, median age 52) were enrolled. The most common tumor types were ovarian (n⫽39) and breast (n⫽10). Germline BRCA mutations were known in 24 ovarian pts. 58 pts had prior chemotherapy (1-6 regimens, median 2), and 51 had prior platinum. Grade 3/4 AEs in ⬎10% of pts were neutropenia, thrombocytopenia, anemia, and leukopenia. Dose limiting toxicities were thrombocytopenia (n⫽3) and neutropenia at V 310 mg twice daily (BID) and thrombocytopenia at 250 mg BID. Other frequent AEs were nausea, constipation, and fatigue. Preliminary results showed co-administration of V did not affect C or G pharmacokinetics. Treatment cycles (range, median) were 1-28, 5 for V; 2-10, 5 for C; and 2-10, 4 for G. Day 8 G was stopped in some pts to improve tolerability. 28 pts stayed on monotherapy V (1-23 cycles). Partial and complete responses were seen in 11 and 2 pts. Response rates were 47% (8/17) in known BCRA deficient ovarian, 25% (3/12) in other ovarian, and 13% (2/15) in other evaluable pts. Conclusions: V combined with C and G was tolerated with a safety profile similar to C and G alone. The MTD was V 250 mg BID, C AUC 4.0, G 800 mg/m2. Promising anti-tumor activity was observed in BRCA deficient ovarian pts. Clinical trial information: NCT01063816.


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A phase I dose-escalation and PK study of continuous oral rucaparib in patients with advanced solid tumors. Presenting Author: Rebecca Sophie Kristeleit, University College London, London, United Kingdom

A phase I study of oral rucaparib in combination with carboplatin. Presenting Author: L Rhoda Molife, The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom

Background: Rucaparib, a potent, oral small molecule inhibitor of poly (ADP-ribose) polymerase (PARP) 1 and -2, is being developed for treatment of homologous recombination repair deficient (HRD) ovarian cancer. This study evaluated oral rucaparib as monotherapy. Primary objectives were to define maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and PK of continuous oral rucaparib. Methods: A standard 3⫹3 dose escalation design was used. Intra-patient dose escalation was allowed. Patients (pts) aged ⱖ18 with advanced solid tumor that progressed on standard treatments were recruited. Rucaparib was taken orally qd or bid until disease progression. Plasma PK assessments included full profile, trough levels, and food effect. Results: 29 pts (median age 52 yrs [range 21-71]; 26 female; 15 ECOG PS⫽0; 17 breast cancer (BC), 7 ovarian/ peritoneal cancer (OC), 5 other tumor) were enrolled in 6 dose cohorts to date (40, 80, 160, 300 and 500 mg qd, 240 mg bid). Evaluation of 360 mg bid rucaparib is nearly complete. No DLTs have occurred and no pts have discontinued treatment due to toxicity. Treatment-related adverse events (primarily CTCAE grade 1-2) reported in ⱖ2 of 29 pts include fatigue (n⫽5), anorexia (n⫽3), nausea (n⫽3), vomiting (n⫽3), and diarrhea (n⫽2). To date, two pts (1 OC, 1 BC; both BRCA1mut) treated with 300 mg qd rucaparib achieved PR at wk 6; both are ongoing in wk 17. An additional 10 pts (5 OC, 4 BC, 1 CRC; 7 BRCAmut, 2 BRCAunk, 1 BRCAwt) achieved best response of stable disease (SD) ⬎12 wks thus far; 4 pts (3 OC, 1 BC) are ongoing at 17 (n⫽2) and 30 (n⫽2) wks. Overall disease control rate (CR⫹PR⫹SD⬎12 wks) in OC pts across all dose levels was 86% (6/7). Dose proportional PK was observed up to 500 mg qd with mean t1/2 of 15 h (range 4.3 - 29 h). Following qd dosing, steady state was achieved by Day 8. As expected, bid dosing increased trough levels above 2 ␮M target with low interpatient variability. Conclusions: Continuous oral rucaparib is very well tolerated, with encouraging clinical activity, including objective responses and durable SD, observed during dose-escalation. Once confirmed, the RP2D will be evaluated in platinum-sensitive OC pts with a gBRCA mutation. Clinical trial information: NCT01482715.

Background: Targeting poly (ADP-ribose) polymerase (PARP), an enzyme involved in DNA damage repair, may increase efficacy of DNA-damaging agents. This study evaluated the tolerability of oral rucaparib, a potent and selective PARP1/2 inhibitor, in combination with carboplatin (CP). Methods: Patients (pts) aged ⱖ18 with advanced solid tumors were included. Pts received lead-in doses of IV and oral rucaparib on Days -10 and -5, respectively, followed by CP on Day 1 and oral rucaparib on Days 1-14 q21 days. Treatment continued until disease progression. Pts with benefit could continue on rucaparib monotherapy once CP dosing was completed. Dose escalation was based on toxicities observed in Cycle 1 in cohorts of n⫽3-6. PK was assessed during Cycle 1. Results: 23 pts (median age 62 yrs [range 20 – 76]; 16 female; 9 ECOG PS⫽0; 6 ovarian/peritoneal cancer (OC), 5 breast cancer (BC), 2 NSCLC, 10 other tumor) were enrolled. Rucaparib doses of 80, 120, 180, 240, and 360 mg were administered with AUC3 CP, followed by 360 mg rucaparib with AUC4 CP, and currently with AUC5 CP. No DLTs have been reported. Median treatment cycles is 3 (range 1 – 15⫹). Treatment-related adverse events in ⱖ4 pts, all grades, include anemia (n⫽10), fatigue (n⫽9), nausea (n⫽7), thrombocytopenia (n⫽6), constipation (n⫽5), lethargy (n⫽5), neutropenia (n⫽5), and anorexia (n⫽4). One pt (OC, BRCAwt, AUC3 CP/180 mg rucaparib) had a PR of 5.1 mo duration. Two patients (both with OC; 1 BRCAunk, 1BRCAwt) discontinued CP (after 4 & 8 cycles) and continued on rucaparib monotherapy (additional 5 and 7⫹ cycles, respectively). An additional 4 pts (all BRCAunk) had stable disease (SD) ⬎12 wks. Overall disease control rate (CR⫹PR⫹SD⬎12 wks) in OC pts across all dose levels was 50% (3/6). Dose-proportional increase in rucaparib exposure was observed with steady state achieved by Day 14 and mean t1/2of 15 h. Oral bioavailability was 38% and dose-independent. Rucaparib exposure was not changed by CP co-administration. Conclusions: The combination of oral rucaparib and CP is well tolerated and exhibits activity at clinically relevant doses of each agent. Further studies in platinum-sensitive and homologous recombination repair deficient populations are warranted. Clinical trial information: NCT01009190.

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Phase I study of the HDAC inhibitor vorinostat in combination with capecitabine in a biweekly schedule in advanced breast cancer. Presenting Author: Edward Samuel James, Yale School of Medicine, New Haven, CT Background: Synergy between histone deacetylase inhibitors and 5-fluorouracil is thought to be due to down regulation of thymidylate synthase. Study objectives are to assess maximum tolerated dose (MTD), dose limiting toxicities (DLT) and objective response rate of vorinostat (V) in combination with capecitabine (C). Secondary aims are pharmacodynamics of V. Methods: Cohorts of 3-6 patients (pts) were enrolled on a 3⫹3 dose-escalation phase to assess MTD of escalating doses of oral C (1500/1800/2000mg) with V 200 mg BID on days 1-7 and 15-21 of a 28 d cycle. 10 pts enrolled on dose expansion phase and treated at MTD. Pts received a “run in” treatment of V for 5 d and pre/post V biopsy (bx) collected when feasible. DLT was defined as ⱖ grade 3 non hematological toxicity, grade 4 thrombocytopenia, grade 4 neutropenia ⬎ 5 d, grade 4 febrile neutropenia requiring hospitalization, QTc ⬎500ms,or treatment delay ⬎ 2 weeks from toxicity. Microarray analysis was performed using Illumina HT-12 gene arrays on pre/post bx from 4 pts. Results: 23 ptswith median age 51 (range 33-69) were treated: 8 pts at 1500/200mg, 5 pts at 1800/200mg, and 10 pts treated on dose expansion phase at 1500/200mg. Median # of prior lines of chemotherapy was 2 (range 0-7). 3 pts are still on study. Median # of cycles on study were 2 (range 1-42). Cycle 1 DLT was grade 3 fatigue in 2 pts treated on 1800/200mg, and in 1 pt treated on 1500/200mg. Other grade 3/4 toxicities are summarized in the Table. 14 pts are evaluable for response (12 pts at 1500/200mg and 2 pts at 1800/200mg). No objective responses were seen, 3 pts had stable disease ⬎ 6 months (1 pt completed 42 cycles). Changes in pathways involved in extracellular matrix and TGFb pathway were noted. Conclusions: DLT of C concomitant with V was fatigue. MTD was 1500 mg C combined with 200 mg V BID. Combination has modest clinical activity. Consistent modulation of pathways involved in extracellular matrix and TGFb pathway, suggesting biomarkers of response to V. Clinical trial information: NCT00719875. Adverse events Thrombocytopenia Leukopenia Anemia Mucositis Hand-foot syndrome Nausea/vomiting Hypokalemia Hyponatremia Hypoalbuminemia Syncope Ataxia Dyspnea Bone pain Infection

Grade 3 # pts

Grade 4 # pts

2 3 3 1 2 2 1 1 1 1 1 0 1 1

1 0 1 0 0 0 1 0 0 0 0 1 0 0


Impact of UGT1A4, UGT2B7, and UGT2B15 pharmacogenetics on tamoxifen (TAM) metabolism. Presenting Author: Joanne Siok-Liu Lim, National Cancer Centre, Singapore, Division of Medical Sciences, Laboratory of Clinical Pharmacology, Singapore, Singapore Background: The aims were to characterize the genetic profiles of UGT1A4, UGT2B7 and UGT2B15in Asian healthy populations (Chinese, Malay, Indians, N⫽80 each) and investigate the effects of these SNPs on the disposition of TAM in Asian breast cancer patients (N⫽202). Methods: Healthy Asian subjects and Asian breast cancer patients were genotyped for UGT1A4, UGT2B7 and UGT2B15 SNPs. Plasma levels of tamoxifen and its metabolites in Asian patients were determined via LC-MS/MS analysis. Genotypic-phenotypic differences were examined using non-parametric tests. Haplotypic effects were examined using haplotype-specific generalized linear model. Results: Screening of the 5= upstream, exonic, exonicintronic junctions and 3= downstream regions identified 61, 77 and 47 SNPs in UGT1A4, UGT2B7 and UGT2B15respectively. A total of 16, 14 and 20 tag-SNPs were identified in these genes respectively and genotyped in patients. Haplotypic analysis revealed associations between LD block 1 (-1548A⬎G, -1531C⬎T, -419G⬎A, -219C⬎T, -163G⬎A, 142T⬎G, 448T⬎C, 804G⬎A, IVS1⫹196T⬎C, IVS1⫹346T⬎G, IVS1⫹414A⬎G, IVS2⫹307A⬎G) and higher plasma Tam-N-Gluc level and MRTAM-N-Gluc/ TAM after adjustment for significant covariates. The median (range) MRTAMN-Gluc/TAM was 2.1- and 1.9-fold higher among patients carrying one and two copies of H2 (GCATAGCACTGG), respectively, compared to patients who carried two copies of H1 haplotype (ACGCGTTGTTAA) [H1/H1 vs H1/H2 vs H2/H2: 0.35 (0.11 - 2.09) vs 0.74 (0.19 - 3.60) vs 0.66 (0.52 - 1.66), P ⬍ 0.0001]. Similar association was observed between H2 and Tam-N-Gluc level [H1/H1 vs H1/H2 vs H2/H2: 0.75 (0.15 - 4.45) vs 1.29 (0.19 - 9.20) vs 1.66 (0.62 - 2.83) ng/ml, P⫽ 0.004]. UGT2B15 LD block 3 (1568A⬎C, *168C⬎T, *186A⬎T, *⫹630C⬎G and *⫹888A⬎G) was associated with modest decrease and increase in (E)-END and MRZ-NDM-4-O-GLUC/E-END, respectively. UGT2B7haplotypes were not associated with O-glucuronidations of 4-OHT and END. Conclusions: This study highlights the involvement of UGT1A4 haplotypes in the variability in TAM N-glucuronidation while UGT2B7 and UGT2B15 variants played limited role in the variabilities of O-glucuronidations of 4-OHT and END in Asian breast cancer patients. Clinical trial information: 0822570P.




Can estimated glomerular filtration rate (eGFR) replace isotopic measurement of GFR for carboplatin dosing in stage 1 seminoma? Presenting Author: Scott T.C. Shepherd, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom Background: Accurate determination of GFR is essential for correct dosing of carboplatin, the standard adjuvant therapy for stage 1 seminoma. Isotopic methods (e.g. 51Cr-EDTA) remain the gold standard for determination of GFR. However, the use of eGFR could reduce the need for such isotope studies. As novel formulae to estimate GFR such as CKD-EPI and MDRD4 have improved the assessment of renal function in non-oncological settings, we investigated their utility for carboplatin dosing. Methods: 115 patients (pts) (mean age 40.3, std dev. 10.1) who received adjuvant carboplatin for stage 1 seminoma at our institution between 2007-2012 were identified. All pts underwent 51Cr-EDTA measurement of GFR with carboplatin dose calculated using the Calvert formula, based on GFR uncorrected for body surface area (BSA). Theoretical carboplatin doses were then calculated using eGFR values obtained using the CKD-EPI and MDRD4 formulae with additional calculation to uncorrect for BSA. Creatinine clearance was calculated by Cockcroft-Gault (CG) formula. For each pt the carboplatin doses calculated by eGFR were compared with the actual dose calculated by the gold-standard method; a difference of less than 10% was considered acceptable. Results: The Table shows the percentage of pts who would have received an equivalent carboplatin dose using each eGFR formula compared to the dose calculated using 51Cr-EDTA. The CKD-EPI formula performed best with 58.9% of pts receiving within 10% of the correct dose. Pts predicted to be underdosed by CKD-EPI eGFR were more likely to be obese (BMI ⬎30) (p⫽0.01); there were no predictors of the 18.8% who would have received an excess dose. Conclusions: Our data support further evaluation of the CKD-EPI formula but highlight the clinically significant variances in carboplatin dosing when using nonisotopic methods of GFR estimation. Comparison of carboplatin dose calculated using eGFR formulae versus 51Cr-EDTA. eGFR formula MDRD4 CKD-EPI CKD-EPI unadjusted CG

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Same dose n (%)

Overdosed n (%)

Underdosed n (%)

27 (24.1) 66 (58.9) 51 (45.9) 45 (40.5)

10 (8.9) 21 (18.8) 41 (36.9) 61 (55.0)

75 (67.0) 25 (22.3) 19 (17.1) 5 (4.5)


Dose-dependent pharmacokinetic (PK) interaction of pegylated liposomal doxorubicin (PLD) with escalating doses of veliparib in a phase I study. Presenting Author: Bhavana Pothuri, New York University School of Medicine, New York, NY Background: PARP1 inhibition enhances the effects of DNA-damaging agents such as doxorubicin. We sought to investigate PK of PLD in a phase I study of veliparib (ABT-888, V) and PLD in patients (pts) with recurrent ovarian, fallopian tube, and primary peritoneal, and triple negative breast cancers. No prior PK interactions have been described in V clinical trials. Methods: Complete blood samples on day (D) 1 (pre-PLD and 1 hr post PLD), D 8, D 22 on cycle 1 and 2 of treatment in pts receiving PLD 40 mg/m2, day (D) 1 and V D1-14 at varying dose levels of 50,100,150, 200, 300, 350 mg twice daily, were collected in 25 of 31 pts enrolled to a previously reported dose finding phase I study of V and PLD (SGO2012). Plasma PLD levels were measured by HPLC methodology detailed by Gabizon et al Cancer Chemo Pharmacol 2008, 61:695. PK parameter estimates were obtained using non-linear modeling programs available in Winnonlin Ver 5.3. Affect of V dose on PK parameters was estimated with linear regression analysis. Due to a higher degree of GI toxicity with V dosages ⬎ 200 mg, we utilized a cut-off of 200 mg for V. PK parameters in the group with dosages greater than or equal to 200 mg (high V, n⫽18) and those less than 200 mg (low V, n⫽7) were compared, utilizing an unpaired, 2 sided t-test. Results: PLD clearance (CL) was reduced, half-life (hL) was increased, and AUC/mg was increased with higher dosages of V when compared to historical published data. We noted a positive correlation of the auc/mg dose, p⫽0.001 and a negative correlation with the CL, p⫽0.001 and increasing V dose. When analyzed as low and high V groups, the mean ⫾ SEM hL (hrs) was significantly lower in the low V when compared to the high V group, 83.2 ⫾ 11.7 vs 108.6 ⫾ 6.0(p ⫽0.042) , and the mean PLD clearance (ml/h)was greater in the low V versus the high V group 35.9 ⫾ 5.6 vs 14.2 ⫹ 1.0, P⬍.0001. Similarly the AUC/mg dose (mg x h/L) was significantly lower in the low vs high V groups, 35.0 ⫾5.2 vs 74.9 ⫾ 4.4, P⬍0.0001. Conclusions: Higher exposure of PLD is noted with V at doses greater than or equal to 200 mg twice daily. An expansion cohort with patients receiving PLD alone in cycle 1, and PLD ⫹ V 200 mg twice daily in subsequent cycles, will validate the presence of a PK interaction. Clinical trial information: NCT01145430.

2590

163s


Involvement of compensatory CD44ⴙ stem cells following BCL-2 suppression by antisense oligonucleotides. Presenting Author: Marvin Rubenstein, Hektoen Institute for Medical Research, Chicago, IL Background: Gene therapy is in theory specific but encounters difficulties in practice. Suitable targets are found in many pathways and tumors do express altered patterns of expression. However the actual activity of most regulatory genes are similar to normal. Resistance develops because biochemical pathways are complex, regulated by stimulatory and inhibitory factors, each possibly affected by therapy. It’s suggested that tumors alter dependence on targeted gene products for growth by relying upon others, through compensation. Antisense oligos have targeted regulatory proteins in both in vivo and in vitro prostate cancer models. Cells treated with antisense directed against bcl-2 compensated by suppressing caspase-3 (an apoptosis promoter) and enhancing androgen receptor (AR), (coactivating) p300 and IL-6 expression. This suggests that in LNCaP a progression to increased androgen sensitivity accompanies bcl-2 suppression with a pattern of co-activation associated with more advanced prostate tumors. Methods: We evaluated mono- and bispecific oligos which targeted and equally suppressed bcl-2 expression in LNCaP cells. To further evaluate compensatory mechanisms related to tumor resistance we evaluated the level of CD44 expression employing RT-PCR and agarose gel quantification. Bands representing pcr product were photographed, converted to black and white and assessed by MIPAV software. Results: Comparable amounts of RNA from LNCaP cells treated with either mono- or bispecific oligos directed against bcl-2 (and EGFR in the bispecifics) were evaluated by RT-PCR using primers directed against CD44. When background intensity was subtracted, the relative intensity of the bands corresponding to CD44, and representing cells treated with MR4, MR24 and MR42 (compared to controls) were respectively increased 3.0% ⫾ 33.6 (NS), suppressed 16.4% ⫾ 49.1 (NS) and suppressed 9.2% ⫾ 26.5 (NS). These results were pooled from both duplicate PCR runs and gels, and indicate no significant changes in CD44 expression was produced by any oligo type. Conclusions: Stem cells expressing this marker were unaffected by treatment, suggesting this population is not altered by suppressive bcl-2 therapy.

2592


CYP3A4 phenotyping with midazolam to predict sunitinib exposure. Presenting Author: Nielka P van Erp, Department of Clinical Pharmacy, University Medical Centre Radboud, Nijmegen, Netherlands Background: Patients treated with sunitinib show high inter-patient variability in drug exposure (40-60%), which is largely unexplained. Since sunitinib is metabolized by CYP3A4, variability in the activity of this enzyme may explain a considerable proportion of the observed variability. We therefore prospectively studied the relationship between CYP3A4 activity and systemic exposure to sunitinib. Methods: In fifteen patients treated with sunitinib in a four weeks “on” – two weeks “off” regimen the pharmacokinetics of sunitinib and its active metabolite SU12662 were assessed. To determine sunitinib⫹SU12662 steady-state exposure, samples were collected over 24hrs after at least 14 days of sunitinib therapy. To assess CYP3A4 activity, midazolam 7.5mg orally was administered on the final day of the two weeks “off”. Plasma concentrations were measured over a period of 7hrs to determine midazolam exposure. Exposures (AUC) were calculated using a trapezoidal approach (Phoenix WinNonlin v6.3). The relationship between CYP3A4 activity (midazolam exposure) and sunitinib⫹SU12662 exposure was determined by linear regression analysis. The percentage of variability in sunitinib⫹SU12662 exposure that could be explained by CYP3A4 activity was calculated by Pearson’s correlation. In addition, the correlation between sunitinib⫹SU12662 Ctrough levels and sunitinib⫹SU12662 exposure was assessed. Results: A strong correlation between midazolam exposure (AUC0-7hr) and steady-state sunitinib⫹SU12662 exposure (AUC0-24hr) was found (p⫽ 0.002); CYP3A4 activity explained 55% of the observed inter-patient PK variability of sunitinib⫹SU12662. Furthermore sunitinib⫹SU12662 Ctrough levels were highly predictive (96%) for overall sunitinib⫹SU12662 exposure (AUC0-24hr). Conclusions: Midazolam as a phenotyping probe could be useful before start of sunitinib therapy to identify patients at risk for under- respectively overtreatment at a standard dosage regimen. Therefore, CYP3A4 phenotyping could be useful to individualize sunitinib therapy. Additionally, sunitinib⫹SU12662 trough levels are highly predictive for sunitinib⫹SU12662 exposure and thus can be used for monitoring and guiding sunitinib therapy in clinical practice. Clinical trial information: NCT01743300.


164s 2593


A randomized, crossover phase I study to assess the effects of formulation and meal consumption on the bioavailability of dovitinib (TKI258). Presenting Author: Sunil Sharma, Huntsman Cancer Institute, Salt Lake City, UT Background: Dovitinib (TKI258), an oral multitargeted receptor tyrosine kinase inhibitor, is being studied in a phase 3 trial for renal cell carcinoma. A previous study compared the bioavailability of 2 capsule formulations of dovitinib. Arm 1 of the current study compared relative bioavailability of the final market image (FMI) form (monohydrate tablets) with the clinical service form (CSF; anhydrate capsules) of dovitinib. Arm 2 assessed the effect of food on bioavailability of the FMI tablet in adult patients (pts) with advanced solid tumors. Both arms employed crossover designs. Methods: In arm 1, pts were randomized to receive a single 500-mg dose of dovitinib either as a CSF capsule or FMI tablet, followed by a single 500-mg dose of the other formulation after 7 days of rest. Plasma pharmacokinetic (PK) profiles were determined from blood samples. A linear mixed-effects model fitted to log-transformed PK parameters maximal concentration (Cmax) and area under the curve (AUC0-tlast) was used to determine the relative bioavailability of FMI vs CSF. In Arm 2, pts received 300 mg of the FMI formulation once daily for 22 days after being randomized to 1 of 6 meal sequences with 3 fed or nonfed states (no meal [NM], low-fat [LF] meal, or high-fat [HF] meal) on days 8, 15, and 22. The relative bioavailability of dovitinib under LF and HF vs NM state was determined using the same model as arm 1 for the PK parameters Cmax and AUC0-tlast. Results: The study accrued 21 pts to arm 1 and 42 pts to arm 2. Based on the interim analysis, PK was assessed in 17 evaluable pts in arm 1. The geometric mean ratios (GMRs; 90% CI) for Cmax and AUC0-tlast comparing FMI vs CSF were 0.99 (0.91-1.08) and 0.96 (0.89-1.04), respectively. The FMI formulation was used in arm 2; PK was assessed in 19 pts. Cmax GMR (90% CI) was 0.82 (0.71-0.94) and 0.90 (0.78-1.03) for HF/NM and LF/NM, respectively. AUC0-tlastGMR (90% CI) was 0.91 (0.81-1.02) and 0.99 (0.88-1.10) for HF/NM and LF/NM, respectively. Conclusions: The oral bioavailability of the FMI tablet and CSF capsule were comparable, and there was no clinically relevant effect of food (HF or LF meals) on the bioavailability of the FMI tablet form of dovitinib. Clinical trial information: NCT01155713.

2595


Application of pharmacokinetic (PK)-guided 5-fluorouracil (FU) in clinical practice. Presenting Author: Jai Narendra Patel, University of North Carolina Institute for Pharmacogenomics and Individualized Therapy, Chapel Hill, NC Background: Body surface area (BSA)-based dosing of FU results in up to 100-fold inter-individual PK variability. PK-guided FU compared to BSAbased dosing resulted in higher response rates and decreased rate of toxicities in two randomized clinical trials. A paucity of data exists on PK-guided FU dosing in the clinical setting. Methods: A total of 70 colorectal cancer (CRC) patients (pts) from 6 academic and community sites received mFOLFOX6 (FU 2,400 mg/m2over 46 h every 2 wks) ⫹/bevacizumab. Peripheral blood was obtained 2-44 h after start of FU infusion and AUCs were estimated using an immunoassay at Myriad Genetics. FU doses for cycles 2-4 (C2-4) were adjusted algorithmically to target an area under the concentration-time curve (AUC) of 20-25 mg*h/L. The primary outcome was the % of pts within target AUC by C4, with a secondary outcome of toxicity rates compared to historical data. Comparisons between cycles were made using generalized linear models, accounting for repeated observations within pt. Results: The % of pts within target AUC post C1 and C4 was 30% (17/57, 95%CI: 18-43%) and 46% (24/52, 95%CI: 32-61%), respectively (OR⫽2.16, p⫽0.05). For each subsequent cycle, the odds of a pt being within range increases by 28% (p⫽0.04) (Table). The median dose needed to achieve target AUC at C4 was 2,580 (range 1,920-3,484) mg/m2. The median AUC post C1 and C4 was 19 and 21 mg*h/L, respectively. Less grade 3/4 mucositis and diarrhea were seen compared to historical data (3 v 15% and 6 v 12%, respectively); however, no difference in grade 3/4 neutropenia was noted (27 v 33%). Nine pts were non-evaluable by protocol for PK analysis, largely due to sampling/ processing errors. Conclusions: PK-guided FU resulted in a greater number of pts achieving the targeted AUC and fewer pts under-dosed at C4 compared to C1. Individualization of FU dosing in the front-line, community and academic, setting is achievable for the treatment of CRC; however, larger clinical trials are needed to define the clinical utility of PK-guided FU. Clinical trial information: NCT01164215. Patients below, within, and above the target AUC at each cycle. AUC mg*hr/L

C1(N ⴝ 57)

C2 (N ⴝ 57)

C3 (N ⴝ 53)

C4 (N ⴝ 52)

25

30 (53%) 17 (30%) 10 (17%)

24 (42%) 21 (37%) 12 (21%)

25 (47%) 21 (40%) 7 (13%)

17 (33%) 24 (46%) 11 (21%)

2594


Investigation of the pharmacogenetic influences of carbonyl reductase on doxorubicin and doxorubicinol in breast cancer patients. Presenting Author: Allison Gaudy, Roswell Park Cancer Institute, Buffalo, NY Background: The anthracycline doxorubicin (DOX) is widely used to treat breast cancer. Doxorubicin is associated with pharmacokinetic and pharmacodynamic variability and despite its use for several years there is limited understanding behind it. Hepatic carbonyl reductases (CBR1 and CBR3) catalyze the reduction of DOX into its main circulating C-13 metabolite doxorubicinol (DOXOL). Polymorphisms in CBR1 and CBR3 influence synthesis of DOXOL, and could potentially play a role in the pharmacokinetic (PK) variability seen with doxorubicin treatment. In this study, we examined the influence of genetic polymorphisms in CBR1 and CBR3 on DOX and DOXOL PK. Methods: DOX was administered IV to 79 breast cancer patients at 60 mg/m2. Population PK modeling was performed on the parent concentration-time profiles with the following patient factors: [BSA (1.4-2.6 m2), weight (40-140 kg), age (25-75), race (78% white), CBR1 rs9024 (78% wild-type), CBR3 V244M (47% wild-type), CBR3 C4Y (20.5% wild-type); followed by model validation. Noncompartmental analysis (NCA) was performed for both DOX and DOXOL and the metabolic ratio was calculated as AUCDOXOL0-24:AUCDOX0-24. Results: A twocompartment model was used to describe DOX PK. Mean predicted (%SEM) clearance (CL), plasma volume (Vp), tissue volume and distribution clearance were 28.1 L/hr (7.72), 22.5 L (3.80), 257 L (13.8) and 13.6L (21.8), respectively. Interpatient variability on CL and Vp were 22.1% and 12.6%, respectively. BSA was found to be a significant predictor of the interpatient variability on CL. No other patient factors were found to be significant on parent drug PK. The metabolic ratio, assessing the conversion of DOX to DOXOL, was stratified by different polymorphisms of CBR1 and CBR3. There were no significant differences in metabolic ratio due to CBR1 and CBR3 genotypes. Conclusions: A PK model was developed that was able to characterize DOX pharmacokinetics. CBR1 and CBR3 polymorphisms were tested as covariates but were not found to be significant contributors to the variable pharmacokinetic profiles of DOX and DOXOL.

2596


CYP3A inhibitors and adverse outcomes in patients treated with docetaxel chemotherapy. Presenting Author: Paul L. Swiecicki, Mayo Clinic, Rochester, MN Background: Docetaxel (D) is an anti-mitotic drug metabolized by the cytochrome P450 (CYP) 3A4 enzyme. While case reports have demonstrated a potential association of CYP3A inhibitor use with severe toxicity in D treated patients (pts), there are no data whether co-administration of CYP3A inhibitors with D increases the rate of hospitalization and/or death. Methods: A retrospective cohort of pts treated with D at the Mayo Clinic Rochester from 1/1/09-10/1/11 was identified. Information regarding D and concomitant chemotherapy (starting dose and dose reductions), type of CYP3A inhibitor, growth factor use, hospitalizations and deaths was abstracted. Time to event analyses (either hospitalization or death) were conducted using Kaplan-Meier estimates and proportional hazards modeling. Results: 384 pts (median age 63, range 20-93) received D as monotherapy (48%) or as multi-agent chemotherapy (52%) for a median of 4 cycles. 56 pts were co-administered CYP3A inhibitors (45 moderate, 11 strong). 90 pts were hospitalized during D chemotherapy and 15 died. The mean time to hospitalization was significantly shorter in pts treated with a mod/strong CYP3A inhibitor (186 days) vs not treated (408 days) (p⫽0.02) . While time to death was not significantly different based on inhibitor use (111 vs. 177 days, p⫽0.49), time to first event (hospitalization or death) varied significantly according to those on inhibitors (187 days) versus not (397 days) (HR: 1.78, p⫽0.02). Time dependent analyses indicated that use of multiage chemotherapy (combination vs D monotherapy; HR 1.96, p⫽ 0.002) and chemotherapy dose reduction of either D (HR 0.54, p⬍0.01) or other chemotherapy (HR 0.61, p⫽0.02) were significantly associated with the risk of an event. In a multivariate analysis, moderate/ strong CYP3A inhibitor use was associated with a higher risk of any event (HR 1.79, p⬍0.02), independent of the use or dose of either multi-agent chemotherapy or D dose. Conclusions: These are the first data to demonstrate that co-administration of CYP3A inhibitors with D increases the risk of hospitalization and/or death. Oncologists should reconcile medications prior to D administration and mod/strong CYP3A inhibitors should be avoided or used with caution.




A pharmacogenetic model predicting low paclitaxel clearance based on the DMET platform. Presenting Author: Annemieke J.M. Nieuweboer, Erasmus MC-Daniel den Hoed Cancer Center, Rotterdam, Netherlands Background: Paclitaxel (PTX) is a commonly used cytotoxic agent. It is metabolized by P450 cytochrome iso-enzymes CYP3A4 and CYP2C8 and has high interindividual variability in pharmacokinetics (PK) and toxicity. Here, we present a genetic prediction model to identify patients with low PTX clearance (CL) using the new Drug-Metabolizing Enzyme and Transporter (DMET; Affymetrix) platform, capable of detecting 1,936 genetic variants (SNPs) in 225 genes. Methods: In a PK study, 270 Caucasian cancer patients were treated with PTX. PK parameters were determined using a limited sampling strategy. HPLC or LC-MS/MS were used to determine PTX plasma concentrations and non-linear mixed effects modelling (NONMEM) was used to estimate individual unbound CL from previously developed PK population models. Subsequently, the cohort of patients was randomly split into a training and validation set. In all patients, the presence of SNPs in metabolic enzymes and transporters was determined using the DMET platform. Selected SNPs were subsequently validated in the validation set. Results: Baseline characteristics were comparable in both sets. The mean CL of the total cohort was 488 ⫾ 149 L/h and the threshold for low CL was set at 339 L/h (1 SD ⬍ total mean CL). 14 SNPs were selected to be included in the prediction model and validated in the validation set. For none of these 14 SNPs, evidence for a biological plausible link to taxane metabolism exists. The developed prediction model had a sensitivity of 95% to identify low PTX CL, a positive predictive value of 22% and remained significantly associated with low CL after multivariate analysis correcting for age, gender and Hb levels at start of therapy (P⫽0.024). Conclusions: This is the first considerably-sized application of the DMET platform to explain PK variability of a widely used anti-cancer drug. Although this validated prediction model for PTX CL had a high sensitivity, its positive predictive value is too low to be of direct clinical use. Likely, genetic variability in DMET genes alone does not sufficiently explain PTX CL, as for example environmental factors may also influence PTX metabolism.

2599


Trastuzumab (T) and everolimus (E) pharmacokinetics (PK) in HER2 positive (ⴙ) primary breast cancer (BC) patients (pts): Unicancer RADHER trial results. Presenting Author: Guillemette Bernadou, Centre Hospitalier Régional Universitaire de Tours, Tours, France Background: T has greatly modified the prognosis of HER2⫹ BC, but few studies have analyzed its PK. The RADHER study evaluated the interest of adding E to T as preoperative therapy for primary HER2⫹ BC. It also aimed at describing the PK of T and studying the impact of E with T in primary BC. Methods: Eligible pts with HER2⫹ operable primary BC were randomized to receive T alone (loading dose 4 mg/kg, then 2 mg/kg/week (W)) or T ⫹ E (10 mg/day (D)) for a 6-W pre-operative treatment. Blood samples were collected to measure T and E concentrations. For T, plasma samples were collected in all pts before each infusion, and at Hour (H) 1, D1, D3, W1, W2, W4, W8 and W12 after the last infusion. E concentrations were determined on whole blood collected at H0, H0.5, H1, H2, H4, H6, H12 and H24 after the first T infusion, and again after the last E intake. T and E PK were described using population compartment analyses. Results: From 82 pts randomized, 79 were evaluable for T and 22 for E PK. Mean estimated PK parameters of T were (interindividual coefficient of variation %): central (Vc) and peripheral (Vp) volumes of distribution ⫽ 2 L (24%) and 1.3 L (39%), systemic (CL) and intercompartment (Q) clearances ⫽ 0.22 L/day (19%) and 0.36 L/day, respectively. Vc increased with body weight and decreased with age, while CL increased with body weight and with tumor volume. Elimination half-life was 11 days, a value lower than that previously reported in metastatic BC (28 days). E PK was best described by a two-compartment model. Mean estimated PK parameters (RSE%) of E were: CL ⫽ 3.96 L/h (22%), Q ⫽ 29.1 L/h (7%), Vc ⫽ 119 L (11%), Vp ⫽ 1530 L (24%). E did not influence T PK. E PK was similar to that previously reported in other indications. Conclusions: This is the first study describing the PK of T and E in primary BC. Notably, T CL increases with tumor volume and the elimination half-life is only 11 days, lower than expected from previous results in metastatic BC. The differences in PK between primary and metastatic BC might lead to take a second look at trastuzumab dose regimen in primary BC. Clinical trial information: NCT00674414.

2598

165s


Recommended phase (Ph) II dose (RP2D) selection for investigational Aurora A kinase (AAK) inhibitor MLN8237 (Alisertib; A) combined with paclitaxel (P): Clinical pharmacokinetics (PK), drug-drug interaction (DDI) assessment, and translational exposure-efficacy modeling. Presenting Author: Karthik Venkatakrishnan, Millennium Pharmaceuticals, Inc., Cambridge, MA Background: Two maximum tolerated doses (MTDs) were reported for P/A combination in Ph 1 of NCT01091428 (Falchook, ASCO 2012). Here we report clinical PK/DDI results in the context of preclinical exposure-efficacy relationship for P/A to select RP2D. Methods: Pts with advanced ovarian/ breast2 cancer received A (oral BID D1–3, 8 –10, 15–17) with 60 or 80 mg/m P on D1, 8, 15 in 28-D cycles, with 3⫹3 dose escalation of A. PK of P was assessed on cycle 1 D1 (P⫹A); during cycle 2, A doses were withheld on D1–3 allowing for PK of P to be determined in the absence of A on D1. Isobolographic analysis of the response surface relating area under the plasma concentration-time curve (AUC) of A and P to tumor growth inhibition in mice bearing MDA-MB-231 xenografts incorporated mousehuman ratios of plasma free fraction and maximum tolerated exposures, allowing rank ordering of predicted antitumor activity for combined P and A. Results: MTDs were 80 mg/m2 P ⫹ 10 mg BID A (80P/10A) and 60 mg/m2 P ⫹ 40 mg BID A (60P/40A), as grade 3/4 toxicities (diarrhea, stomatitis, neutropenia, febrile neutropenia) precluded further escalation. Co-administration with A resulted in a small increase in AUC of P (20 –25% at 80P/10A; 10 –19% at 60P/40A; Table). AUC of P at 60P/40A was below 80P alone. GeoMean D3 concentrations of A at 80P/10A (340 nM) and 60P/40A (1490 nM) were respectively below and within the reported range (590 – 6580 nM) for tumor AAK inhibition by A (Cervantes, CCR 2012) for 60P/40A. Exposures of A dosed with P were as expected from previous single agent population PK (Venkatakrishnan, ASCO 2012). Exposureefficacy modeling and isobolographic analysis predicted a rank-order of efficacy at clinical exposures of P/A: 60P/40A ⬎ 80P/10A⬎80P⫽60P. Conclusions: Safety, PK, and modeling results support 60P/40A as RP2D, currently employed in Ph 2 of NCT01091428, which is enrolling pts with advanced ovarian cancer. Clinical trial information: NCT01091428. GeoMean (%CV) AUC (ng.hr/mL) of P by treatment. 80P/10A 80P 60P/40A 60P

2600

N

AUClast

AUCinf

15 14 14 13

4,551 (29%) 3,683 (34%)

5,282 (27%) 4,377 (30%)

2,628 (24%) 2,184 (28%)

3,072 (23%) 2,789 (21%)


Phase I clinical trials attrition related to central molecular prescreening. Presenting Author: Valentina Boni, START Madrid, Centro Integral Oncológico Clara Campal, Madrid, Spain Background: The increasing trend to incorporate molecular assays as part of selection assessment in Ph1 trials is based on the potential to observe early antitumor activity. Nonetheless, its impact has been almost negligible to date and might affect time to achieve a recommended dose. We assessed the impact on recruitment of pursuing central mandatory molecular assessment of tumor samples on a state-of-the-art Ph1 unit. Methods: Two first-in-human Ph1 studies, requiring central laboratory biomarker assessment as inclusion criterion (DS6 IHC and FGFR mut/ampl, respectively), and a consecutive series of pts in our program for central tumor mutation screening (OncoCarta Panel v1.0) to participate in molecularly-driven Ph1 studies, were reviewed. Results: 13 (4.8%) out of 267 pre-screened pts were able to receive treatment within a targeted Ph1 trial. Conclusions: A vast majority of pts trying to participate in molecularly-driven trial central biomarker screening are not included due to negative results. Still 71.1% pts who were initially eligible and were positive in the central review fail to participate due to clinical and/or analytical deterioration during the time of central molecular assessment. New strategies including local sample pre-screening allowance, as well as anticipated massive molecular profiling in the conventional setting, are needed to reduce this time and improve feasibility of these trials. The derived current “impoverishment” of studies with non-targeted drugs (that lack patients with tumors with “hot” mutations) and of those with targeted drugs (that miss patients with nonmutated tumors) within the same Ph1 Programs, and the need of a joint approach to co-finance for wide-spectrum molecular profiling for different studies, would be discussed as well. Informed consent Withdrew consent Insufficient sample (# in another study lab) Positive test Not included in trial (Screening failure, worse ECOG, no slots) Treated Time to inclusion, median days (range)

DS6 study

FGFR study

OncoCarta panel

133 2 11 (3)

105 2 8 (3)

29 0 11 (0)

24 (18%)

11 (10.5%)

10* (34.5%)

18 (5, 4, 9)

5 (2, 2, 1)

9 (1, 2, 6)

6 (4.5%) 69,5 (22-266)

6 (5.7%) 36 (29-173)

1 (3.4%)(NRAS) 330

* BRAF (melan), FGFR (bladder), NRAS (melan), EGFR (NSCLC), KRAS x 6 (GI).


166s 2601


2602


Copper transporter CTR1 expression and tissue platinum concentration in NSCLC. Presenting Author: Deepak Kilari, University of Rochester Medical Center, Rochester, NY

Pharmacokinetics and safety of an oral ALK inhibitor, ASP3026, observed in a phase I dose escalation trial. Presenting Author: Amita Patnaik, START Center for Cancer Care, San Antonio, TX

Background: Platinum (Pt) resistance is a major limitation in the treatment of advanced non-small cell lung cancer (NSCLC). We previously demonstrated that low tissue Pt concentration in NSCLC tumor specimens was significantly associated with reduced tumor response and worse survival. Furthermore, low expression of the copper transporter CTR1, a transporter of Pt uptake is reported to be associated with poor clinical outcome following Pt-based therapy in NSCLC patients. However, a defect in CTR1expression as a causative factor in reduced Pt accumulation in NSCLC tissues is not well-established. We investigated the relationship between tissue Pt concentrations and CTR1 expression in NSCLC specimens. Methods: We identified paraffin-embedded NSCLC tissue blocks from 30 patients who underwent neoadjuvant Pt-based chemotherapy with known tissue Pt concentrations at MD Anderson Cancer Center. Expression of CTR1 was determined by immunohistochemistry with adequate controls; 0 ⫽ undetectable; 1⫹ ⫽ barely detectable staining; 2⫹ ⫽ readily appreciable staining; and 3⫹ ⫽ dark brown staining. Pt concentration was compared between different CTR1 expression groups. Results: Tissue Pt concentration significantly correlated with tumor response in 30 patients who received neoadjuvant Pt-based chemotherapy (P⬍0.001). There was an uneven distribution of CTR1 expression scores with a majority of specimens demonstrating scores of 2⫹ (N⫽15, 50%). There were 2 specimens with no detectable CTR1 expression (score of 0) and 6 patients with a score of 3⫹. Patients with undetectable CTR1 expression in their tumors had significantly lower Pt concentrations compared to those with scores of 3⫹ (P⫽0.014). Furthermore, those with undetectable CTR1 expression had reduced tumor response compared to those with scores of 3⫹ following Pt-based chemotherapy (P⫽0.039). Conclusions: To the best of our knowledge, this is the first study to correlate CTR1 expression in clinical specimens to both tumor Pt uptake and response. Patients with undetectable CTR1 expression in their tumors had significantly lower Pt concentration and reduced tumor response. Further evaluation with a larger sample size is required. (Supported by 2012 ASCO Young Investigator Award)

Background: ASP3026 (3026) is a selective, potent, ATP-competitive, small molecule oral inhibitor of ALK receptor tyrosine kinase that has not previously been tested in humans. A Phase 1 dose-escalation trial, using a 3⫹3 design, evaluating 3026 as an oral single agent was conducted to investigate PK (Day 1 and Day 28), safety and clinical activity in patients (pts) with advanced malignancies (excluding leukemias) of ECOG PS 2 or less. Methods: 3026 was administered under fasting conditions on a continuous schedule to pts in successive dose-escalating cohorts at doses ranging from 25 mg QD to 800 mg QD. Results: Thirty pts were enrolled into the dose escalation part of the study. The MTD was determined based on DLT data from cycle 1. Three DLTs were observed: grade 2 nausea and vomiting leading to dose reduction at 525 mg QD; grade 3 rash leading to dose reduction, and grade 3 ALT/AST increase leading to study withdrawal at 800 mg QD. The most common AEs were constipation, vomiting, diarrhea, nausea and abdominal pain, and all AEs were manageable and reversible. Median AUC and Cmax increased proportionally with dose from 25 mg QD to 800 mg QD. There was no evidence of non-linear PK at ASP3026 doses ⬎25 mg QD. The median terminal half-life was approximately 10 - 41 hours. Overall, A3026 appears well absorbed with median Tmax around 3 hours for both Day 1 and Day 28. Terminal T1/2 appears adequate for one daily dosing with median values ranging from approximately 18 to 34 hours. Based on visual inspection of pre-dose (trough) values from Days 8, 15, 22, and 28 it appears that steady-state conditions are achieved by day 28. Conclusions: The MTD of 3026 is 525 mg QD. Treatment with 3026 resulted in a promising safety and PK profile in pts with advanced malignancies. Further evaluation of 3026 in pts with tumors harboring gene mutation or ALK fusion genes in the cohort expansion phase at the MTD is ongoing. Clinical trial information: NCT01401504.

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Exposure and clearance of bevacizumab in patients with first-line advanced gastric cancer. Presenting Author: Martina A. Sersch, Genentech, Inc., South San Francisco, CA Background: Bevacizumab (BEV), rhuMAB VEGF, in combination with chemotherapy (CT) is currently approved in various types of cancer. Recently, BEV⫹CT was evaluated in 1st line advanced gastric cancer (AGC) in a double-blind randomized phase 3 trial (AVAGAST), but failed to meet the primary OS endpoint (HR⫽0.87; p⫽0.1002). BEV pharmacokinetics (PK) is well established by a reference population PK (PPK) model, and BEV PK is consistent across multiple cancer indications. However, BEV PK in AGC was never evaluated. We aimed to assess BEV exposure (EXP) and PK in AGC and to explore the influence of demographic, prognostic and biochemical (DPB) factors. Methods: BEV concentrations (Cp) were measured from plasma samples collected following disease progression from 182 patients (7.5mg/kg Q2W) in AVAGAST. Expected BEV Cp [median and 90% prediction interval (PI)] were simulated using the PPK model and compared to the observed BEV EXP. BEV clearance (CL) in AGC was estimated using NONMEM and compared between subgroups stratified by DPB factors. Results: All DPB factors of AGC are similar to those in other cancers except for lower body weight. No cachexia was observed. BEV Cp was detectable in 162 patients. 85% of observed BEV Cp was below the median BEV Cp simulated using PPK model and 38% below the lower limit of the 90% PI. Median BEV CL in AGC was 4.5 L/day/kg vs. 3 L/day/kg in other cancers. BEV CL was significantly higher (p⫽0.0012) in patients without prior gastrectomy (4.9 L/day/kg, n⫽120) than those with gastrectomy (4.1 L/day/kg, n⫽42). CL appeared to be higher in AGC patients with higher ECOG scores, lower albumin, more metastatic sites, poorer response and later stage AGC. Tumor location (GE Jct vs. Stomach), VEGF-A and ethnicity (Asian vs. Non-Asian) did not correlate with BEV CL. Conclusions: Overall, AGC patients exhibited significantly lower BEV EXP due to a 50% increase in BEV CL vs. other cancers. In addition, BEV is cleared significantly faster in patients without prior gastrectomy. The low BEV EXP in AGC could potentially reduce the effect of BEV in AGC. The underlying mechanism for faster BEV CL in AGC is unknown and warrants further research and potential BEV dose modifications.


Phase I clinical trial of lenalidomide with temsirolimus in patients with advanced cancer. Presenting Author: Prasanth Ganesan, Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX Background: Lenalidomide (immunomodulatory and antiangiogenic drug) and temsirolimus (mTOR inhibitor) are potentially synergistic (Raje N, Blood 2004;104(13):4188). We conducted a phase I study of the combination in patients with advanced cancers. Methods: During the escalation phase, lenalidomide (PO days 1-21) and temsirolimus (IV, Q weekly) were given at the following respective doses: level 1 (10 mg, 15mg); level 2 (10 mg, 20 mg); level 3 (20 mg, 20 mg); and level 4 (20 mg, 25 mg) (1 cycle ⫽ 28 days). A “3⫹3” study design was used. The maximum tolerated dose, dose-limiting toxicity, and response were assessed. Results: Forty- three patients were treated (median age: 58 (21-80) years; male/female: 26:17). The most common diagnoses were colorectal cancer (N⫽5), sarcoma (N⫽5) and adenoid cystic carcinoma (N⫽4). Overall, 121 cycles (median: 2) were administered. No dose limiting toxicities were observed. The maximum tested dose (level 4) was used for expansion. Grade 3-4 toxicity (all reversible) occurred in 19 (44%) patients: neutropenia (N⫽12), thrombocytopenia (N⫽6), and infection (N⫽1). Of 43 patients, 31 (72%) received anticoagulation prophylaxis. There were no thrombotic events. Of 36 patients who were evaluable for response, PR was noted in 1 (2.7%), and stable disease (SD) was noted in 17 (47%) patients (SD ⱖ6 months: 17%). Tumors with SDⱖ6 months were soft tissue sarcoma, 2/5 (40%), adenoid cystic carcinoma, 1/4 (25%), parotid ca, 1/2 (50%), adrenocortical ca 1/3 (33%), and neuroendocrine ca, 1/4 (25%) (Table). The median progression-free survival was 2.2 months (95% CI, 1.5-2.9) and overall survival was 7.8 months (95% CI, 5.1-10.6). Conclusions: Lenalidomide and temsirolimus combination was well tolerated and had antitumor activity in selected participants with advanced cancer. Clinical trial information: NCT01183663. Dose level

Age/Sex/ ECOG PS

Diagnosis

4 4 4 4

63/M/1 30/M/1 72/F/1 60/F/0

Parotid Sarcoma Adrenal Adenoid cystic

2/2 4/1 4/3 1/1

-10 -8 -2 0

6 11 5 9⫹

7.6 10.9 6 12.4⫹

Yes/No Yes/Yes No/No No/No

13.8⫹ 13.5 14.5⫹ 12.4⫹

4 4

62/M/1 71/F/1

Sarcoma Neuro-endocrine

3/3 2/2

-21 -51

8 8

8.5 8.2

Yes/No Yes/Yes

11.6⫹ 13.1

Disease sites (N)/ Best RECIST Cycles PFS Progression/ Survival Prior Rx (N) response (%) (N) (months) Death (months)




Phase Ib dose-escalation trial of the AKT inhibitor (AKTi) MK2206 in combination with paclitaxel (P) and trastuzumab (H) in patients (pts) with HER2-overexpressing (HER2ⴙ) cancer. Presenting Author: Amy Jo Chien, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA Background: AKT plays a key role in the survival, resistance, and overall aggressive pathogenesis of HER2⫹ malignancies, suggesting that AKTis may be of therapeutic value. MK2206 is a selective allosteric AKTi that has demonstrated synergy in combination with both H and P in preclinical studies. Methods: We conducted a phase 1b study of MK2206 in combination with weekly P 80 mg/m2 and H 2 mg/kg in pts with HER2⫹ solid tumors. MK2206 was given orally at a starting dose of 135 mg once a week (QW). Dose escalation was performed using a modified Ji method. The maximum tolerated dose (MTD) was defined as the dose level resulting in 3 or fewer dose limiting toxicities (DLTs) in 11 pts, then confirmed in 4 additional pts. Circulating tumor cells and PK samples were collected for all pts. Results: A total of 17 pts were enrolled, and 15 pts were evaluable for toxicity. All pts had HER2⫹ tumors (11 breast, 3 gastric, 1 esophageal). Based on interim toxicity data from other studies, the dose of MK2206 was not escalated beyond 135 mg QW. All 15 pts were treated at this dose level which was determined to be tolerable. Two DLTs were observed including grade 3 rash and grade 3 neutropenia resulting in a ⬎7 day treatment delay. There were no severe adverse events (AEs) related to study treatment. Other grade 3/4 AEs were neutropenia (6 pts), febrile neutropenia (1 pt), peripheral neuropathy (1 pt), and depression (1 pt). The most common all-grade AEs include rash (13 pts), hyperglycemia (13 pts), neutropenia (13 pts), peripheral neuropathy (10 pts), diarrhea (9 pts), fatigue (9 pts), anorexia (9 pts), stomatitis (7 pts). Of the 14 pts evaluable for response, 9 pts (64%) had tumor response (2 CR, 7 PR), and 4 pts had SD. The median duration of response was 5.5 months. Pts were heavily pretreated (median lines of prior therapy 3, 11 prior taxane, 12 prior H). Conclusions: MK2206 at a dose of135 mg QW in combination with weekly P and H is safe and well-tolerated. 135 mg QW is the recommended phase 2 dose for this combination. Preliminary data indicate significant clinical activity in pts with HER2⫹ tumors despite extensive prior therapy. MK2206 is now being tested in the neoadjuvant ISPY2 trial. Clinical trial information: NCT01235897.

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A phase I study of MK-2206 in combination with lapatinib in patients (pts) with advanced solid tumors. Presenting Author: Kari Braun Wisinski, University of Wisconsin Carbone Cancer Center, Madison, WI Background: The AKT protein kinase is a key mediator of signaling in the human epidermal growth factor receptor-2 (HER2) pathway. HER2 inhibition can result in feedback regulation of signaling, leading to high AKT activity. Preclinical studies demonstrate activity of combined HER2 and AKT inhibition. Lapatinib is an oral tyrosine kinase inhibitor of HER2. MK-2206 is an oral selective inhibitor of AKT with a maximum tolerated dose (MTD) of 60mg qod. Both agents cause rash and diarrhea. This study was designed to determine the MTD, dose limiting toxicities (DLTs), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination. Methods: This phase I study evaluated the safety of MK-2206 (30-60 mg qod) and lapatinib (1000-1500 mg qd) continuously. Cycles were 28 days, except cycle 1 (35 days), due to a 1 week MK-2206 lead-in to evaluate for PK interactions. Because of the continuous nature of therapy, protocol-specified intolerable grade 2 AEs were considered DLTs during cycle 1. Results: 23 pts (median age 59 [range 22-72];15 female:8 male) were enrolled. The most common malignancies were colorectal (8 pts), lung (4 pts), and breast (3 pts). 4 pts were unevaluable per protocol; 19 evaluable pts were on study a median of 8 weeks (range 3-35). 3 pts experienced DLTs. At dose level one, 1 pt had grade (gr) 3 hyponatremia and fatigue. At dose level four, 1 pt had gr 4 hyponatremia, gr 3 rash and hypocalcemia and 1 pt had intolerable gr 2 mucositis with delivery of ⬍75% of drug. The most common AEs at least possibly related to therapy included diarrhea (gr 3-4 in 3 pts; gr 1-2 in 16 pts), nausea (gr 3 in 2 pts; gr 1-2 in 14 pts) and rash (gr 3 in 2 pts; gr 1-2 in 12 pts). The MTD was 45mg po qod of MK-2206 with 1500 mg po qd of lapatinib, exceeding biologically active doses for each agent. One pt with adrenal cortical carcinoma was on study for 6 months with stable disease (SD) and 1 pt with colorectal cancer was on study for 5 months with significant tumor marker decline and SD. PK analyses are ongoing. Conclusions: MK-2206 in combination with lapatinib is well-tolerated at biologically active single agent doses. Anti-tumor activity will be evaluated further in a dose expansion cohort in pts with advanced HER2-positive breast cancer. Clinical trial information: NCT01245205.

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Phase I expansion trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid tumors. Presenting Author: Andrea Varga, Institut Gustave Roussy, Villejuif, France Background: CC-223 is an ATP-competitive inhibitor of the mTOR kinase, including both TORC1 and TORC2. CC-223 was selected to address resistance of rapamycin analogues mediated by TORC2 activation. Methods: Following establishment of the MTD (reported at ASCO 2012), subjects with select advanced, refractory solid tumors, including NSCLC, HCC, NET, GBM and breast were enrolled in expansion cohorts of up to 20 evaluable subjects. CC-223 was dosed at 45 mg once daily in 28 day cycles until disease progression. Results: As of 09 January, 2013, 101 solid tumor subjects have been treated, including NSCLC (26), HCC (25), NET (23), breast (14), and GBM (13). Results from the NSCLC, HCC, and GBM cohorts are reported here; NET results are reported separately. The most common (⬎ 20%) related adverse events (all grades) were fatigue, rash, stomatitis, hyperglycemia, anorexia, nausea, vomiting and diarrhea. In addition, related serious adverse events included infection (1), pneumonitis (4), renal insufficiency (2) and pancreatitis (2). CC-223 dose reduction was required in ⬎ 50% of subjects with NSCLC and HCC, usually during cycle 1 or 2. Exposure-dependent TORC1 (p4EBP1) and TORC2 (pAKT) inhibition was observed across cohorts. mTOR pathway inhibition and/or decreased proliferation was demonstrated in paired tumor biopsies, but results were inconsistent. Reduction in glucose uptake (⬎ 25% decrease in SUV) on PET imaging at day 15 was observed in 78% (14/18) of NSCLC and 69% (11/16) of HCC subjects. Partial tumor responses were observed in evaluable subjects with NSCLC (1/17; confirmed, treatment duration 36 weeks) and HCC (3/15; 1 confirmed, treatment duration 15 – 26 weeks). Disease control rate in the overall NSCLC cohort was 42% (11/26) and in the HCC cohort, 40% (10/25). GBM subjects underwent salvage resections on study and none were progression-free at 6 months. CC-223 was present in all (11/11) resected GBM tumors with plasma:tumor ratios of 16 - 77%, confirming transit across the blood-brain barrier. Conclusions: Encouraging signals of biomarker and clinical activity were observed in HCC and NSCLC. Due to the frequency of dose reductions, select additional cohorts will be enrolled at a starting dose of 30 mg QD. Clinical trial information: NCT01177397.

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A first-in-human phase I trial of AR-12, a PDK-1 inhibitor, in patients with advanced solid tumors. Presenting Author: Joaquin Mateo, The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom Background: AR-12 (OSU-03012) is an oral celecoxib analogue lacking COX-2 inhibitory activity that inhibits pyruvate dehydrogenase kinase isoenzyme 1 (PDK-1), AKT and impacts the endoplastic reticulum stress pathway. Preclinical studies indicate antitumor activity of AR-12 in various models and enhanced activity in combination. We completed a first in human clinical trial to determine its safety and tolerability, maximum tolerated dose (MTD) and recommended phase II dose (RD). Secondary objectives included assessment of tumor response, pharmacokinetics (PK) and pharmacodynamics (PD) including food effect. Methods: Patients (pts) with advanced solid tumors, ECOG PS 0-1, and adequate organ function were recruited in a modified 3⫹3 dose-escalation study. Pts received a run-in dose of AR-12 to analyze PK-PD and food effect, followed by continuous daily (QD) dosing in 28-day cycles. A twice daily (BID) cohort was initiated based on safety data. PD analysis was performed in plateletrich plasma (PRP) and paired tumor biopsies when feasible. Results: 35 pts received at least one dose of study drug; 30 were evaluable for dose limiting toxicities (DLT) at dose ranges 100-3200mg QD and 800-1600mg BID. No DLT were observed in the QD cohort; DLT in the BID cohort are listed in table 1. Drug-related events (NCI-CTCAE v3) included rash (G2-2pts; G3-1pt), fatigue (G2-2pts; G3-4pts), nausea (G2-7pts; G3-1pt) and bloating (G2-1pt). Cmax after single dose was dose-proportional but high PK variability was observed, likely due to inadequate disintegration and dissolution of the formulation in the stomach. At RD, partial GSK3ß inhibition in PRP after 4 hours suggests AKT-pathway modulation. Best response (RECIST v1.0) was stable disease ⬎6 cycles for 2 pts. Conclusions: The RD based on safety data is 800mg BID. Signs of pathway modulation were observed in concordance with the expected mechanism of action but were short-lasting. Considering limited drug absorption and PK variability, a new formulation of the drug will be developed to overcome these limitations. Clinical trial information: NCT00978523. Dose-limiting toxicities (BID cohort). Dose (mg; BID)

Patients with DLT

1600

4/7

1200 800

2/4 0/7

DLT G3 fatigue, G3 rash, G3 dizziness, G2 nausea (dose delay ⬎3d) G3 fatigue -


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A phase I study of MM-121 in combination with multiple anticancer therapies in patients with advanced solid tumors. Presenting Author: Monica Arnedos, Institut Gustave Roussy, Villejuif, France

Phase I trial of sorafenib, bevacizumab, and temsirolimus in advanced solid tumors. Presenting Author: Shannon Neville Westin, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: MM-121 is a fully human monoclonal antibody targeting the epidermal growth factor receptor family member ErbB3. ErbB3 has been implicated in driving cancer growth and in the development of resistance to conventional chemotherapies across multiple malignancies. Here we present results of an open-label, Phase 1, multicenter, non-randomized, dose-escalation trial which recently completed enrollment evaluating MM-121 in combination with one of the following chemotherapies: Gemcitabine (Arm A, n⫽11), carboplatin (Arm B, n⫽11), pemetrexed (Arm C, n⫽10), or cabazitaxel (Arm D, n⫽11). Methods: Patients were treated in a dose escalation “3⫹3” design to assess the safety, tolerability and pharmacokinetics (PK) of MM-121 administered weekly in combination with anticancer therapies in subjects with advanced cancer. Doses were escalated until the maximum tolerated dose (MTD) was identified or the combination was shown to be tolerable at the highest planned doses. Secondary objectives included: Determining the objective response rate, clinical benefit rate, PK and immunogenicity of MM-121. Data summarized are as of 1/17/2013 from a live database. Results: Overall, 43 patients, [22 (51%) female and 21 (49%) male] have been treated with a median treatment duration of 57 days (range 1-302). The median age was 59 years (range 42-84) and patients had received a median of four prior lines of therapy (range 0-13). Common (⬎20%) adverse events of any grade and causality across all arms included diarrhea (74%), nausea (54%), fatigue (51%), anemia (44%), vomiting (33%), hypokalemia (30%), decreased appetite (26%), thrombocytopenia (26%), peripheral edema (23%), neutropenia (21%), and constipation (21%). Four DLTs were observed: Two in combination with carboplatin (G4 thrombocytopenia and G3 rash), one with gemcitabine (G4 thrombocytopenia), and one with pemetrexed (G4 hyperuricemia). Overall 38 (88%) patients were evaluable for response and the overall clinical benefit rate (PR or SD ⬎18 weeks), is 32% (12/38). Conclusions: MM-121 can be combined at its recommended single agent dose with standard doses of gemcitabine, pemetrexed, and cabazitaxel and adapted doses of carboplatin. Clinical trial information: NCT01447225.

Background: Pathway crosstalk and emergence of drug resistance have limited the activity of targeted therapies, including anti-angiogenic agents and mTORC1 inhibitors. However, this vulnerability may be addressed by rationally combining targeted therapies to improve outcomes. We sought to determine the MTD/recommended phase II dose and define the pharmacokinetics (PK) of the combination of sorafenib (S), bevacizumab (B), and temsirolimus (T) in patients with advanced solid tumors. Methods: S was given once or twice daily, B was given intravenously every three weeks, and T was given intravenously weekly. Doses were escalated in a stair-step dose escalation with 6 planned dose levels (DL) in a standard 3⫹3 design. Responses were defined using RECIST 1.1. Results: To date, 51 patients have been enrolled. Three patients withdrew consent after only one dose. One dose-limiting toxicity (DLT) occurred at DL 5 (grade 4 fatigue, pain) and one DLT occurred at DL 6 (G3 headache). However, 5/6 patients required dose reduction on DL6 (G2 nausea, fatigue, hand/foot syndrome, rash). Thus, DL5 (B 10mg/kg, T 20mg, S 200mg twice daily) is being explored in dose expansion (N⫽10) and tumor expansion cohorts as the recommended phase II dose. The most common adverse events (⬎10%) were fatigue (69%; G3/4 6%), nausea (38%, G3/4 2%), pain (35%, G3/4 10%), thrombocytopenia (33%, G3/4 8%), mucositis (33%, 0%), constipation (29%, G3/4 0%), hand/foot syndrome (23%, G3/4 0%), rash (19%, G3/4 0%), hypertension (17%, 0%), neuropathy (17%, G3/4 0%), diarrhea (15%, G3/4 6%), vomiting (15%, G3/4 2%), headache (12%, G3/4 2%), and hypertriglyceridemia (10%, G3/4 2%). Of 34 patients evaluable for response, 4 had PR including ovarian (-57%, ⫹6m), gastric (-46%, ⫹5m), colorectal (-32%, ⫹5 m), and thyroid (-31%, ⫹6m) cancer. Eight patients had SD for greater than 4 months including ovarian (0%, ⫹7m), colorectal (-5%, ⫹8m), endometrial (-26%, ⫹5m; -16%, ⫹4m; -15%, ⫹6m), leiomyosarcoma (-5%, ⫹6m), squamous lung cancer (-6%, ⫹6m), and triple negative breast (-15%, ⫹4m) cancer. Conclusions: The combination of S, B, and T is well tolerated and demonstrates preliminary evidence of tumor activity in a variety of solid tumors. PK studies at the recommended phase II dose are ongoing. Clinical trial information: NCT01187199.

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Protein pathway activation mapping guided biomarker development to identify optimal combinations of MEK inhibitor with PI3K/mTOR pathway inhibitors for the treatment of triple-negative breast cancer. Presenting Author: Sarah J. Schweber, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY Background: Activated MAPK and PI3K pathway signaling are associated with poor prognosis in triple negative breast cancer (TNBC). Although some TNBC cell models are sensitive to MEK inhibition, feedback activation of the PI3K pathway mediates resistance. Thus, suppression of both arms of the MAPK/PI3K/mTOR network is a rational approach to targeting TNBC. Here we explore the anti-tumor efficacy of combinations of MEK inhibitor with PI3K, AKT, or mTOR inhibitors with a focus on biomarker development. Methods: Combinations of the MEK inhibitor PD-0325901 with the PI3K inhibitor GDC-0941, AKT inhibitor MK-2206, dual mTORC 1/2 inhibitor Torin 1, or the rapalog temsirolimus were evaluated in TNBC cell lines. Synergy was assessed using the combination index method of Chou and Talalay. We utilized reverse-phase protein array to map the signaling architecture of the treated lines to verify target suppression and identify pharmacodynamic biomarkers. Results: All combinations demonstrated synergy that was mediated by both suppression of proliferation and cell death in a dose-dependent manner. Cell death was delayed, peaking at least 96 hours post-dosing, and was associated with sustained suppression of target proteins in both pathways, including pERKT202/Y204, pS6rpS235/ S65 , and pPRAS40T246. However, suppression of pAKT (at 236, p4EBP-1 T308 or S473) was variable and not consistently required for cell death. Pathway mapping identified a protein network ‘signature’ specific to all combination therapies that emerged at 72 hours and was associated with cell death. Thus, all combinations appear to share common downstream effectors. All combinations showed promising efficacy and will be evaluated in a human-in-mouse model of TNBC. Conclusions: These data support therapeutic strategies for TNBC that simultaneously inhibit both arms of the MAPK/PI3K/mTOR signaling network. For continued biomarker development, we stress the importance of studying the delayed effects of combination therapy. This strategy coupled with a protein network based approach uncovered a unique functional signaling ‘signature’.


A combination of dual PI3K-mTOR inhibitor, GDC-0980, with PARP inhibitor plus carboplatin blocked tumor growth of BRCA-competent triple-negative breast cancer cells. Presenting Author: Nandini Dey, Edith Sanford Breast Cancer Research, Sanford Research/USD, Sioux Falls, SD Background: PARP is a promising target in the TNBC. The PI3K pathway, in addition to its pro-proliferative effects on tumor cells, also controls the repair of DSB (Kumar, 2010; Friedman, 2009; Juvekar, 2012; Ibrahim, 2012). We hypothesize that the growth of TNBC tumor will be blocked due to the inhibition of (1) HR / NHEJ, and (2) PI3K-mTOR pathway mediated survival signals following GDC-0980 (G), when combined with PARP inhibitor (impaired DNA-SSB-repair), and carboplatin (C) (increased DNADSB). Methods: We tested the in vivo efficacy of a combination of G with ABT888 (A) plus C in BRCA-competent TNBC cells, and compared the triple combination arm (A⫹C⫹G) with a combination arm of A⫹C⫹ pan PI3K inhibitor GDC-0941 in mice xenograft (MDA-MB231) model. Mechanistically, we tested, (1) cell survival/ proliferation (5-7 BRCA-wt and mutant cell lines) using MTT assay, CelltiterGLO, and cell cycle analyses, (2) anchorage independent and dependent clonogenic growth (3D ON-TOP and soft-agar assay), (3) apoptosis, and (4) cell signaling marker(s). Results: (1) G alone decreased the tumor growth by 40-50%. (2) The G ⫹ A ⫹ C combination blocked the growth of established tumors by 90% as compared to control(s). (3) Interestingly, G ⫹ A ⫹ C combination had markedly higher percentage of inhibition of tumor growth than the inhibition observed in the A⫹C⫹GDC-0941 arm (36%). (4) G treatment time-dependently increased cl-caspase 3, 9, and cl-PARP and increased AnnexinV positivity both time (24 and 48 hrs) and dose dependently (50 and 200 nM) in cells. (5) G when combined with A⫹C was most effective in inducing apoptosis in PIK3CA-mutated BT20 cells. (6) The triple combination (50 nM G⫹10 ␮M A ⫹ 10 ␮M C) inhibited clonogenic growth of MDA-MB231, MDA-MB468 and BT20 cells. (7)Treatment of G decreased downstream effectors of PI3K-mTOR pathway, pAKTS473, pP70S6K and pS6RP. Conclusions: Tumor growth of BRCA-competent TNBC cells is blocked by a combination treatment of G with A⫹C. The profound anti-tumor effect of this triple combination can be explained by the anti-proliferative and pro-apoptotic actions of the drugs. The combination of G with A⫹C merits further investigation in TNBC.




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A first-in-human phase I study of ER-␣36 modifier icaritin in patients with advanced solid tumors. Presenting Author: Ying Fan, Department of Medical Oncology,Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Final results of a phase I study of lapatinib (LAP) and cetuximab (CET) in patients with CET-sensitive solid tumors. Presenting Author: John F. Deeken, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC

Background: ER-␣36 was recently identified to be expressed in varieties of cancers and may play important roles in carcinogenesis and tumor progression. Icaritin, a natural prenylflavonoid derived from the Chinese herb Epimedium, is a first of its kind ER-␣36 modifier, which demonstrated potent anti-tumor effect in multiple cancer cell lines and their xenograft models. This study aims to determine its safety, tolerability, pharmacokinetics (PK), and potential antitumor activity. Methods: This phase I study comprises phase Ia and Ib. In phase Ia part, patients with advanced breast cancer (ABC) were treated with escalating doses of Icaritin orally once daily on a continuous 28-day dosing schedule. In phase Ib part, dosing was fixed to 600 or 800mg twice daily and expansion was made to other selected malignancies including hepatocellular cancer (HCC), colorectal cancer (CRC) and intrahepatic cholangiocarcinoma (ICC) to further explore PK parameters and efficacy. Results: 24 patients were enrolled to receive Icaritin at six dose levels ranging from 50mg to 1600mg per day in phase Ia. No dose limited toxicity (DLT) was found even in the highest dose defined in the protocol, thus the maximum tolerated dose (MTD) was not reached. Only grade 1 drug-related adverse events were observed including neutropenia, ALT elevation, hypercholesteremia, fatigue, anorexia, hypertriglyceridemia, proteinuria, myalgia, hot flash and rash. PK data from the fed dosing showed 3-fold increase of Cmax and AUC compared with the fast dosing. Half life was around 2-7 hours. Among 22 evaluable subjects, no complete or partial response (CR or PR) was detected, 5 patients had stable disease(SD)for 3 months or longer. For phase Ib study, 24 patients had been enrolled. One ABC, 2 CRC and 3 ICC patients progressed after 2 months of medication. Among 7 HCC patients already evaluated, 1 obtained PR and progressed after one year of treatment and 2 remained in the study, stable for 5 months. Similar drug related toxicity profile was noted in phase Ib. Conclusions: Icaritin was generally well-tolerated without DLT across tested dose levels. Evidence of promising antitumor activity was observed in ABC and HCC. Final results will be presented at the meeting. Clinical trial information: NCT01278810.

Background: Acquired resistance to anti-EGFR MoAb therapy may be via EGFR-ErbB2 heterodimerization and pathway reactivation. Dual anti-EGFR treatment was recently found to be active in colon cancer. We performed a phase I trial of CET and LAP to determine the DLTs, MTD, and clinical activity of the combination. Methods: Pts received CET at 400mg/m2 then 250 mg/m2 weekly, combined with daily LAP in a 3⫹3 dose escalation trial. LAP dose levels (DL) were (1) 750mg, (2) 1000mg, and (3) 1250mg. Cycles lasted 3 weeks, toxicity was assessed through C2, and pts were restaged every 2 cycles. Baseline and post-C1 tumor biopsies were analyzed for phosphoprotein activation in 36 EGFR/ErbB2 pathway proteins. Germ-line pharmacogenetic (PGx) variations were correlated with efficacy and toxicity. Results: Between 10/2010 and 10/2012, 22 pts were enrolled - colon (8), lung (8), head and neck (4), and anal cancers (2) - and 59% had prior anti-EGFR therapy. 18 pts were evaluable for toxicity, and 18 for response. Mean treatment was 3.8 cycles (range 1 - 12); 3 patients are still on trial. One DLT occurred at DL1 (gr 3 rash) and DL2 (gr 3 diarrhea). No pt on DL3 experienced a DLT. No pt experienced a gr 4 toxicity; gr 3 toxicities anytime on therapy included rash (17%), diarrhea (6%), fatigue (6%), lymphopenia (6%), and hypomagnesemia (6%). Rash was experienced by 94% of pts (gr 1⫽50%, gr 2⫽28%, and gr 3⫽17%). Partial responses (PR) occurred in 4 pts (22%), stable disease (SD) in 8 (44%), and disease progression in 6 (33%), for a clinical benefit rate of 67%. Seven of 13 (54%) pts on prior EGFR therapy had SD or PR. Down-regulation of phosphorylated EGFR/ErbB2 pathway components correlated with response; distinct pathway components were up-regulated in non-responders, including PI3K, Jak/Stat, MAPK, and IGF. PGx variants in FcRII correlated with response (p⫽0.045); no variants correlated with toxicity. Conclusions: The RP2D is CET 250 mg/m2 weekly and LAP 1250mg daily. Treatment was well tolerated with few grade 3 toxicities and a significant 67% clinical benefit rate. Non-responders showed upregulation of EGFR pathway components – components which are druggable, warranting further study. A trial in colorectal cancer is ongoing. Clinical trial information: NCT01184482.

2617

TPS2618


Results of two phase I dose escalation studies of the oral heat shock protein 90 (Hsp90) inhibitor SNX-5422. Presenting Author: Todd Michael Bauer, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN Background: SNX-5422 is a prodrug of SNX-2112, a highly potent, non-geldanamycin analog, HSP90 inhibitor with preclinical anti-tumor activity in multiple tumor models. These phase 1 studies were designed to evaluate safety and tolerability, determine dose limiting toxicities, maximum tolerated doses (MTDs), and describe pharmacokinetics of SNX2112 and SNX-5422. Methods: Two phase 1, open-label, 3 ⫹ 3 doseescalation studies evaluated SNX-5422 when given daily (QD) or every-otherday (QOD) during the first 30 days of treatment in patients (pts) with advanced solid tumors or lymphoma. Plasma concentrations of SNX-2112 and SNX-5422 were measured after the first and 11th (steady state) doses. Tumor assessments were performed every 8 weeks. Results: In both studies, pts received SNX-5422 QOD, 3 wks on/1 wk off, with doses ranging from 4 to 133 mg/m2 QOD. In one study, pts also received QD doses from 50 to 89 mg/m2, 3 wks on/1 wk off, and 50 mg/m2 QD continuously. Fifty-six pts (34M/22F; mean age 62 years) were enrolled. Treatment-related adverse events were mainly low grade (G), including diarrhea (64%), nausea (39%), vomiting (29%), fatigue (27%), abdominal pain (14%), and anorexia (14%). Reversible G 1 blurry vision, and G 1-2 blurry vision/vision darkening were reported by 1 pt on 100 mg/m2 QOD, and 4 pts treated with 50 to 89 mg/m2 QD. G 3 diarrhea was dose limiting in 2 of 3 pts (89 mg/m2 QD; 133 mg/m2 QOD). MTDs for the QOD and QD schedules were declared at100 mg/m2 and 67 mg/m2, respectively. The QD schedule was associated with higher incidences of treatment related adverse events. 38 pts were evaluable for response including 1 confirmed durable complete response, 1 unconfirmed partial response, and 17 with stable disease. Activity was seen in adrenal, lung, liver, neuroendocrine, GIST, and prostate. All but 2 were seen with the QOD schedule. Conclusions: SNX-5422 mono-therapy was generally well tolerated and showed promising signs of efficacy in pts with advanced solid tumors. Given the superior benefit-risk profile of QOD dosing over QD dosing based on these preliminary clinical findings, 100 mg/m2 QOD has been selected for further clinical testing. Clinical trial information: NCT00506805 and NCT01611623.


A phase Ib study of combined angiogenesis blockade with REGN910 (SAR307746), a selective monoclonal antibody (MAb) against angiopoietin-2 (Ang2) and ziv-aflibercept in patients with advanced solid tumor malignancies. Presenting Author: Lieve Adriaens, Regeneron Pharmaceuticals, Inc., Tarrytown, NY Background: REGN910 is a selective, fully human Angiopoietin-2 (ANG-2) MAb, which potently blocks signaling through the Tie2 receptor. Zivaflibercept (ZAFL) is a recombinant human fusion protein that acts as a decoy receptor for vascular endothelial growth factor (VEGF)-A, VEGF-B, and placental growth factor (PlGF), thereby preventing the interaction of these ligands with their receptors. In several mouse xenograft models, combination of the 2 anti-angiogenic compounds, REGN910 and ZAFL, demonstrated significantly enhanced tumor growth inhibition relative to either agent alone, suggesting that dual angiogenic blockade is worth exploring in cancer patients. Methods: This phase 1b study employs a standard 3⫹3 dose escalation design exploring 5 different combination treatment dose levels of REGN910 and ZAFL. Once the recommended phase 2 dose (RD) of the combination treatment is determined, additional patients will be enrolled in a safety expansion cohort, for a planned total enrollment of up to 40 patients. The primary study objectives are to evaluate the safety and determine the RD of the 2 drugs in combination when both are administered IV every 2 weeks in patients with advanced solid tumors. Secondary endpoints include characterization of the PK and potential immunogenicity of REGN910 and ZAFL when given in combination, evaluation of correlative PD biomarkers related to REGN910 and ZAFL, and identification of antitumor activity. Enrollment to cohorts 1 and 2 has been completed without DLT. Enrollment to cohort 3 opened in December 2012. Updated enrollment status will be presented. Reference: ClinicalTrials.gov Identifier: NCT01688960. Clinical trial information: NCT01688960.


170s TPS2619

Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics General Poster Session (Board #11G), Mon, 8:00 AM-11:45 AM

Phase I study of VGX-100, an anti-VEGF-C monoclonal antibody, with or without bevacizumab, in patients (pts) with advanced solid tumors. Presenting Author: Gerald Steven Falchook, Department of Investigational Cancer Therapeutics (Phase I Program), University of Texas MD Anderson Cancer Center, Houston, TX

TPS2620


A phase I/IB study of paclitaxel in combination with VS-6063, a focal adhesion kinase (FAK) inhibitor, in patients (pts) with advanced ovarian cancer. Presenting Author: Suzanne Fields Jones, Sarah Cannon Research Institute, Nashville, TN

Background: The vascular endothelial growth factor C (VEGFEC) induces angiogenesis via activation of both VEGFRE2 and VEGFRE3, as well as lymphangiogenesis via activation of VEGFRE3. VGX-100 is a novel fully human IgG1␭ neutralizing monoclonal antibody directed against human VEGFEC. Synergism between the VEGF-A inhibitor, bevacizumab and VGX-100 has been documented pre-clinically. It is thought that tumoral escape and relapse following VEGF-A inhibition, may in part be due to increased VEGF-C that signals through VEGFR-2 and VEGFR-3. Therefore the premise of this study is that administration of VGX-100 in conjunction with bevacizumab would block the two key ligands for VEGFRE2 along with blocking VEGFR-3-mediated tumor angiogenesis and lymphangiogenesis, and thus this drug combination will be clinically synergistic. This study (NCT01514123) is enrolling at MD Anderson and UCLA. Methods: Objectives:establish the safety and toxicity, MTD, pharmacokinetic and pharmacodynamic / biomarker profiles, as well as preliminary anti-tumor activity in refractory pts. Eligibility: pts with advanced solid tumors, good organ function, ECOG PS 0-1, any number of prior therapies, no CNS or cerebrovascular haemorrhage, no MI or reversible posterior leukoencephalopathy syndrome associated with prior anti-VEGF/anti-VEGFR therapy. Design: This is an open-label phase I dose escalation study with a standard “3⫹3” design. The study has two arms: safety data from the 28 day DLT period from Arm A (VGXE100 monotherapy at 6 cohort dose levels: 1, 2.5, 5, 10, 20 and 30 mg/kg, QW) will be available prior to starting the equivalent dose level in Arm B (VGXE100 at 5 cohort dose levels: 2.5, 5, 10, 20 and 30 mg/kg QW with bevacizumab at doses of either 5 or 10 mg/kg, Q2W). Accrual has completed in Cohorts A1 to A5 and B1 to B2. Accrual is underway for Cohort A6 and B3. Clinical trial information: NCT01514123.

Background: Blockade of FAK reduces tumor growth and metastasis through inhibition of tumor cell survival, proliferation and invasion as well as tumor angiogenesis. Furthermore, treatment with FAK inhibitors reduces the proportion of cancer stem cells (CSCs) in a dose dependent manner while paclitaxel treatment enriches for CSCs. (Kolev VN San Antonio Breast Cancer Symposia 2012 abstr P6-11-09). The ability of CSCs to survive exposure to chemotherapy but remain susceptible to novel drugs suggests a unique therapeutic approach whereby standard of care chemotherapy may be sequentially combined with targeted drugs to kill surviving CSCs and thus prevent tumor recurrence and metastasis. VS-6063 (previously PF-04554878) is a potent oral inhibitor of FAK and proline-rich tyrosinekinase -2. The phase I first-in-man trial explored doses ranging from 12.5 -750 mg twice daily (BID). (Jones SF J Clin Oncol 2011 29:1 suppl; abstr 3002) Dose-limiting toxicities consisted of headache, fatigue, and unconjugated hyperbilirubinemia at various dose levels. A maximum tolerated dose was not defined, but doses ⬎ 100 mg BID consistently yielded concentrations above the preclinically predicted minimal efficacious concentration. Seven pts demonstrated stable disease lasting approximately 6 months or greater, including 3 heavily-pretreated ovarian cancer pts (2 platinum resistant). Methods: Pts with advanced or refractory ovarian cancer (ⱕ 4 prior regimens) will be enrolled. In the phase I portion, VS-6063 is administered continuously at a starting dose of 200mg BID with paclitaxel 80 mg/m2 on days 1, 8, and 15 every 28 days, and will be escalated to 400mg BID if tolerated. Pharmacokinetics will be analyzed. An additional 15 pts with biopsiable disease will be enrolled at the recommended dose. A 10-day run-in with VS-6063 alone will be used to obtain paired tumor biopsies in order to examine the effects on pFAK expression, CSCs, and other biomarkers. Patients will continue treatment until disease progression. Clinical trial information: NCT01778803.

TPS2621

TPS2622


A phase I dose-escalation study of TKM-080301, a RNAi therapeutic directed against polo-like kinase 1 (PLK1), in patients with advanced solid tumors: Expansion cohort evaluation of biopsy samples for evidence of pharmacodynamic effects of PLK1 inhibition. Presenting Author: Donald W. Northfelt, Mayo Clinic, Scottsdale, AZ Background: TKM-080301 is a lipid nanoparticle formulation of a small interfering RNA (siRNA) directed against PLK1, a serine/threonine kinase that regulates multiple critical aspects of cell cycle progression and mitosis. Anti-tumor activity, RNA interference and pharmacodynamic effects of PLK1 inhibition have been conclusively demonstrated in preclinical models. Demonstration of pharmacodynamic effects of PLK1 inhibition in patient biopsy samples is an exploratory objective of this first-in-human study. Methods: TKME080301 is being evaluated in an open-label, non-randomized, dose-escalation study in patients with advanced solid tumors or lymphoma. Sequential cohorts of 3 to 6 patients receive TKME080301 as a 30-minute intravenous infusion on Days 1, 8 and 15 of a 28-day cycle. Treatment can continue until disease progression, based on overall clinical benefit. Tumor response is determined according to RECIST criteria. Primary study objectives include determination of safety, maximum tolerated dose and dose limiting toxicities. Secondary objectives include characterization of pharmacokinetics and the preliminary assessment of anti-tumor activity. Five cohorts have been enrolled and a tentative Phase 2 dose has been identified. An expansion cohort of 10 patients began enrolling in February, 2013. The focus of the expansion cohort will be to collect additional safety and pharmacokinetic data at the tentative Phase 2 dose, as well as pharmacodynamic data from mandatory biopsy samples. Pre- and post-dose biopsy samples will be evaluated for potential evidence of PLK1 inhibition using 5’ RACE (rapid amplification of cDNA ends) polymerase chain reaction (to identify the predicted PLK1 mRNA cleavage product), histology (to assess for the presence of aberrant mitotic figures) and immunohistochemistry. An update on enrollment and pharmacodynamic evaluations will be presented. Clinical trial information: NCT01262235.


Phase II, multicenter, open-label, proof of concept study of tasquinimod in patients with advanced/metastatic hepatocellular (HCC), ovarian (OC), renal cell (RCC) and gastric (GC) carcinomas. Presenting Author: Bernard J. Escudier, Institut Gustave Roussy, Villejuif, France Background: Treatment resistance and disease progression are common in HCC, OC, RCC and GC. Tasquinimod is an oral, quinoline-3-carboxamide derivative that binds to S100A9, resulting in immunomodulatory, antiangiogenic and anti-metastatic effects involving downregulation of chemokine receptor type 4 and hypoxia-inducible factor. Tasquinimod significantly improves PFS (7.6 v 3.3 mo) in patients with metastatic hormone-resistant prostate cancer (Pili, R. et al. 2011. JCO 29:4022-8) and is in an ongoing phase III program. Its unique mode of action (MOA) makes tasquinimod attractive for other indications. The primary study objective is to determine the clinical activity of tasquinimod in advanced/metastatic HCC, OC, RCC and GC. Tasquinimod has been shown to delay disease progression with limited tumor shrinkage, therefore an innovative design was proposed, with PFS rate as the main endpoint. Methods: Design: Phase II, multinational, exploratory proof of concept study to evaluate tasquinimod activity in 4 independent cohorts of patients (HCC, OC, RCC and GC) with progressive disease after standard therapy. An innovative design (Litwin S. 2007. Stat Med 26:4400-15) based on the proportion of patients who have not progressed nor died at predefined timepoints (PFS rate) will be used in each cohort independently. Patients: 110 –200 patients (dependent on outcome of futility analyses) aged ⱖ18 yr, ECOG performance status 0 or 1 will be enrolled. Patients must have histologically confirmed and documented HCC, OC, RCC or GC and demonstrable disease progression on standard therapy. Recruitment is ongoing. Dosage: Tasquinimod will be administered as a starting dose of 0.5 mg/day, in each cohort. After 2 wks, the dose will be increased to 1 mg/day based on individual safety and tolerability. Primary endpoint: PFS rate, defined as the proportion of patients who have neither progressed nor died at 12 wks (GC), 16 wks (HCC, RCC) or 24 wks (OC). Secondary endpoints: Include OS, response rate, safety, pharmacokinetics, inflammatory and specific target biomarkers to explore comprehensively the MOA according to each disease type. Clinical trial information: NCT01743469.


Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics TPS2623


Phase I study of pazopanib (PAZ) in combination with PCI-24781 (PCI) in patients (pts) with metastatic solid tumors with new tumor proliferation imaging correlates in renal cell carcinoma (RCC) and sarcoma. Presenting Author: Thach-Giao Truong, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA Background: PAZ is a multi-targeted tyrosine kinase inhibitor of VEGFR, PDGFR, and C-KIT, approved for metastatic RCC and refractory sarcoma based on phase III data showing prolonged PFS (JCO 2010;28:1061-8 and Lancet 2012;379:1879-86). PCI is a potent pan-HDAC inhibitor (panHDACi), observed in cell lines to change regulation of genes involved in cell signaling, apoptosis, proliferation, differentiation, and angiogenesis (Anticancer Res 2011;31:1115-23). Pre-clinical models suggest epigenetic modification with an HDACi potentiates PAZ’s efficacy by causing chromatin instability and gene expression changes involved in drug resistance (Can Res 2005;65:3815-22 and BJC 2009;100:758-63). We therefore designed a Phase Ia/b clinical trial combining PCI with PAZ in pts with advanced solid tumors, with an expansion cohort for preliminary efficacy in RCC and sarcoma. Methods: Primary objective of this phase Ia/b study is to evaluate the safety and tolerability of the combination of PAZ and PCI to determine the MTD and RP2D. In phase Ia, we utilized an accelerated phase I design. The phase Ib portion will include up to 20 pts per expansion cohort, for up to 32-70 pts enrolled. In phase 1a, pts receive run-in PCI alone on C1D-7 to D-4. Starting with C1D1, pts receive oral PCI on D1-5, 8-12, 15-19 BID 4 hrs apart and PAZ daily (D1-28) q28D cycle. CORRELATIVES: Pre- and post-treatment (Tx) H3 & H4 acetylation and HDAC activity in PBMCs. In phase Ib, these will also be studied in tumor biopsies. We will measure expression of VEGF, VEGFR, RAD51, HIF, Ki67; and analyze SNPs through genomic profiling. We will correlate response with pre- and post-Tx tumor thymidine uptake using 18F-fluorothymidine (FLT-PET) PET. Current Status: This is the 1st trial exploring the combination of an HDACi with PAZ in RCC and sarcoma, where there is an unmet need for new tolerable therapies. It will study FLT-PET, an imaging correlate that captures tumor proliferation and may have a role as a predictive biomarker. We are currently in phase Ia. Enrollment in the 3rd cohort exploring higher doses of PAZ will begin in Feb 2013. Clinical trial information: NCT01543763.

TPS2625


Evesor: The first phase I trial combining multiple dose/dosing schedules— Pharmacodynamic assessments and mathematical modeling to optimize the benefit/toxicity ratio of everolimus and sorafenib association. Presenting Author: Benoit You, Centre Hospitalier Lyon Sud; Hospices Civils de Lyon, Lyon, France Background: In 2004, FDA declared the abandon rate of new oncology drugs was too high and new trial designs should be developed. The combination of everolimus (EVE) and sorafenib (SOR) is rational, and has been studied in 11 phase I studies, where approved monotherapy regimens have been used (EVE qd and SOR bid). Although promising efficacy outcomes were found, the combination may be abandoned due to metabolical and skin toxicity. The best doses and dosing schedules of EVE and SOR associated with the optimal benefit/toxicity ratio may be identified using mathematical modeling of data from an adequately designed multiparameter trial. Methods: This academic study is composed of 4 arms with different dosing schedules of EVE and SOR (qd; 1 week/2; 3 days-on . . .), and dose escalations. Patients with different tumor types potentially sensitive to the combination are enrolled. Multiparameter assessments include: pharmacokinetics (PK); pharmacodynamics (PD) with control of signaling pathway inhibition (ERK, AKT, S6K) in 2 tumor biopsies & repetitive PBMC assays; kinetics of circulating tumor DNA kinetics & angiogenesis markers; tumor angiogenesis changes using repeated DCEultrasounds; and radiological/clinical effects. These data enrich a translational multiscale model meant to quantify the relationships between drug dosing modalities, PK, PD, radiological and clinical effects, developed in parallel. The doses and dosing schedules of EVE and SOR which enable maximization of benefit/toxicity ratio (utility function) will be searched using simulations, and then tested. The protocol was approved by ethic committee in 2012. Two patients a month have been enrolled in 2 centers since January 2013. Expected results: Mathematical modeling of the relationships between dosing modalities; PK; PD; radiological and clinical effects based on the data from an adequately designed trial may help determine the optimal doses and dosing schedules of EVE and SOR (with the best benefit/toxicity ratio), and avoid the combination abandon. EVESOR study may embody the proof of concept of this new model-based trial design. Clinical trial information: 2012-002818-39.

TPS2624

171s


A phase I study of the BCR-ABL tyrosine kinase inhibitor nilotinib and cetuximab in patients with solid tumors that can be treated with cetuximab. Presenting Author: Brandon George Smaglo, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC Background: Therapeutic blockade of Epidermal Growth Factor Receptor (EGFR) signaling with the monoclonal antibody cetuximab is clinically effective in the treatment of patients with metastatic squamous cell carcinoma of the head and neck or KRAS wildtype colorectal cancer. However, these patients eventually become resistant to this therapy. An exploration of the EGFR signaling network using an EGFR network-focused small interfering RNA library identified potential regulators of resistance to EGFR-targeted therapies. The ABL1 gene was identified as a central node to target in this complex genomic pathway. In a preclinical EGFRexpressing cancer cell line model, targeting c-abl, the gene product of ABL1, using nilotinib was found to be highly synergistic in decreasing cell survival when combined with anti-EGFR targeted therapy. Methods: We have initiated an open-label Phase I study for patients who progressed after standard therapies for metastatic KRAS wildtype colorectal cancer or metastatic head and neck squamous cell carcinoma. Enrolled patients must have adequate performance status and organ function. Treatment consists of cetuximab 400 mg/m2 on day 1, then 250 mg/m2 once weekly, and nilotinib twice daily, starting on day 1, according to a traditional 3⫹3 dose escalation, from 200mg to 300mg BID. Patients are restaged every 2 cycles (every 8 weeks). The primary endpoint is the maximum tolerated dose (MTD) of nilotinib when used in conjunction with cetuximab. Secondary endpoints are clinical benefit rate (defined as rates of stable disease, partial response, and complete response) and response rate. Additionally, biopsies of metastases obtained prior to and after initiation of therapy will be used to establish primary tumor cell cultures using conditional cellular reprogramming to permit the dynamic study of signaling and drug sensitivity through an evaluation of evidence of a drug effect on EGFR signaling and on Antibody-Dependent Cell-Mediated Cytotoxicity. An additional 10 colorectal cancer patients will be treated as an expansion cohort at the MTD. This expansion cohort data may be used to plan a Phase II trial in the future.

TPS2626


FGFR: Proof-of-concept study of AZD4547 in patients with FGFR1 or FGFR2 amplified tumours. Presenting Author: Elizabeth C. Smyth, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom Background: Genetic modifications of the FGFR family of transmembrane tyrosine kinase growth factor receptors are described in a range of cancers. Amplification of FGFR2 is detected in up to 10% of oesophagogastric cancers where it is associated with poor prognosis. FGFR1 amplification has also been demonstrated in 10% of breast cancers, is more common in luminal B ER positive tumors, and is also associated with inferior survival outcomes. Finally, FGFR1 amplification has been described in up to 22% of squamous cell lung cancers. AZD4547 is a potent and selective inhibitor of FGFR-1, 2 and 3 receptor tyrosine kinases. Preclinically, AZD4547 potently inhibits growth in FGFR amplified gastric and lung cancer cell lines and induces dose dependent tumor growth inhibition and regression in FGFR amplified tumour xenograft and patient derived explant models. Methods: This is an open label, phase II non-randomised multi-centre study to assess the efficacy of AZD4547 monotherapy and resulting molecular changes in serial biopsies in pts with previously treated FGFR1 amplified advanced breast cancer, FGFR2 amplified advanced oesophagogastric cancer, or FGFR1 amplified advanced squamous lung cancer. Eligibility include centrally verified FGFR amplified tumour (ratio ⬎2.2), PS⫽0-2, ability to comply with the collection of tumor biopsies (mandatory at baseline and on days 10-14), calcium and phosphate within normal limits, measurable disease (RECIST 1.1), and no history of significant eye disease. Pts may be prescreened for FGFR amplification on archival tissue while undergoing first line or adjuvant chemotherapy. Sixteen pts will be enrolled per cohort. All pts will receive AZD4547 80mg bd on a two week on, one week off schedule. The primary endpoint is correlation between change in pERK in pretreatment and day 10-14 biopsy and change in tumour diameter on week 8 CT. Secondary endpoints include ORR, DCR and PFS. Multiple exploratory translational endpoints are also planned. The study is currently open at the Royal Marsden Hospital and will open at 15 selected UK cancer centres. This study is sponsored by the Royal Marsden Hospital, funded by AstraZeneca and has been adopted to the UK National Cancer Research Network (NCRN) portfolio. Clinical trial information: 2011003718-18.


172s TPS2627

Developmental Therapeutics—Clinical Pharmacology and Experimental Therapeutics General Poster Session (Board #12G), Mon, 8:00 AM-11:45 AM

A phase I, dose-escalation, safety, pharmacokinetic, pharmacodynamic study of thioureidobutyronitrile, a novel p53 targeted therapy, in patients with advanced solid tumors. Presenting Author: Geoffrey Shapiro, DanaFarber Cancer Institute, Boston, MA Background: Thioureidobutyronitrile, kevetrin, has demonstrated antitumor activity in several wild type and mutant p53 human tumor xenografts without evidence of genotoxicity. In wild type p53 models, kevetrin induces cell cycle arrest and apoptosis through activation and stabilization of wild type p53, resulting in increased expression of p53 target genes p21 and PUMA. Kevetrin also alters processivity of MDM2, and induces monoubiquitination of wild type p53, enhancing its stability (AACR 2011 abstract 4470). Mutant p53 is a complex target since it is an array of mutant proteins with oncogenic properties. Kevetrin induces degradation of oncogenic mutant p53 and induces apoptosis (AACR 2012 abstract 2874). Kevetrin therefore has the unique ability to target both wild type and mutant p53 tumors thereby controlling tumor growth in a wide range of preclinical tumor models. Methods: Adults with refractory locally advanced or metastatic solid tumors, acceptable liver and kidney function, and hematological status were eligible. Objectives include determination of DLT, MTD, recommended phase 2 dose, pharmacokinetics (PK), pharmacodynamics (PD), and evaluating preliminary evidence of antitumor activity. Kevetrin is given as a 1-hour intravenous infusion once weekly for 3 weeks in 28-day cycles. The starting dose was 10 mg/m2. In a 3⫹3 design, groups of 3-6 patients are evaluated for toxicity at each dose level. Dose escalation is based upon the number and intensity of adverse events in cycle 1. Kevetrin PK is characterized for the first and last doses given in cycle 1. Kevetrin induced expression of p21 in lymphocytes in preclinical studies; therefore p21 expression in peripheral blood mononuclear cells will be measured as a PD biomarker. Antitumor activity by RECIST 1.1 criteria and serum tumor markers will be assessed. The p53 status of tumors of selected patients will be determined. The second cohort is currently under evaluation. Conclusion: In preclinical models, Kevetrin has activity against tumors harboring both wild type and mutant p53 by diverse mechanisms. A first-in-human dose escalation trial is underway. Clinical trial information: NCT01664000.


Developmental Therapeutics—Immunotherapy 3000

Oral Abstract Session, Mon, 3:00 PM-6:00 PM

3001

173s Oral Abstract Session, Mon, 3:00 PM-6:00 PM

A study of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic tumors. Presenting Author: Roy S. Herbst, Yale University, New Haven, CT

Biomarkers and associations with the clinical activity of PD-L1 blockade in a MPDL3280A study. Presenting Author: John D. Powderly, Carolina BioOncology Institute, Huntersville, NC

Background: Tumor PD-L1 mediates cancer immune evasion. Therefore, inhibition of PD-L1 binding represents an attractive strategy to restore tumor-specific T-cell immunity.MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Methods: A study was conducted with MPDL3280A administered IV q3w in pts with locally advanced or metastatic solid tumors, including 3⫹3 dose-escalation and expansion cohorts. ORR was assessed by RECIST v1.1 and includes u/cCR and u/cPR. Results: As of Jan 10, 2013, 171 pts were evaluable for safety. Administered doses include ⱕ1 (n⫽9), 3 (n⫽3), 10 (n⫽35), 15 (n⫽57) and 20 mg/kg (n⫽67). Pts in the dose-escalation cohorts did not experience DLTs. No MTD was identified. Pts had received MPDL3280A for a median duration of 127 days (range 1-330). 39% of pts reported G3/4 AEs, regardless of attribution. AEs of special interest included hepatitis, rash and colitis. No G3-5 pneumonitis was observed. MPDL3280A PK was linear at doses >1 mg/kg. 122 pts enrolled prior to Jul 1, 2012 were evaluable for efficacy. RECIST responses were observed in multiple tumor types including NSCLC, RCC, melanoma, CRC and gastric cancer. An ORR of 21% (25/122) was observed in nonselected solid tumors, including several pts who demonstrated tumor shrinkage within days of initiating treatment. Additional pts had delayed responses after apparent radiographic progression (not included in the ORR). Some responders demonstrated prolonged SD prior to RECIST responses. The 24-week PFS was 44%. Pts with PD-L1–positive tumors (from archival samples) showed an ORR of 39% (13/33) and a PD rate of 12% (4/33). In contrast, patients with PD-L1–negative tumors showed an ORR of 13% (8/61) and a PD rate of 59% (36/61). As of the cutoff date, all responses are ongoing or improving. Updated data will be presented. Conclusions: MPDL3280A was well tolerated, with no pneumonitis-related deaths. Durable responses were observed in a variety of tumors. PD-L1 tumor status appears to correlate with responses to MPDL3280A. PK supports q3w dosing at 15 mg/kg or fixed-dose equivalent. Clinical trial information: NCT01375842.

Background: PD-L1, which is highly expressed on tumors, is a ligand of PD-1, an inhibitory receptor present on activated T cells. PD-L1 expression is regulated by intrinsic (mutations) and adaptive (tumor infiltrating T cells) mechanisms. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Methods: A Ph I study was conducted with MPDL3280A administered IV q3w in pts with locally advanced or metastatic solid tumors. The expansion cohort required available tumor tissue. In addition, the study included a serial biopsy cohort with tumor sampling prior to and during treatment. Tumor samples were analyzed by IHC and a Genentech immunochip measuring ⬇90 immune-related genes to characterize the tumor immune microenvironment at baseline (BL) and/or during MPDL3280A treatment. Further, blood-based biomarkers and circulating immune cell subsets were serially measured. Results: Pretreatment tumor samples were available for IHC from 112 pts and for immunochip from 96 pts.In addition, 23 pts had paired BL and on-treatment samples. Bloodbased biomarkers were evaluated in 76 pts. Elevated BL PD-L1 expression by IHC was associated with response to MPDL3280A, and coordinated expression of PD-L1 and CD8⫹ T-cells was observed. Furthermore, a T-cell gene signature (including CD8, IFNg and Granzyme-A) was associated with treatment response. On treatment, responding tumors showed increasing PD-L1 expression and a Th1-dominant immune infiltrate, providing evidence for adaptive PD-L1 upregulation. Nonresponders showed minimal tumor CD8⫹ T-cell infiltration and an absence of T-cell activation (measured by Granzyme-A and Perforin expression). Additionally, a subpopulation of pts exhibited changes in circulating cytokines (IFNg) and activated T-cell subsets (HLADR⫹Ki67⫹). Conclusions: PD-L1 tumor expression and T-cell gene signature correlate with response to MPDL3280A. MPDL3280A therapy led to T-cell reactivation and restored antitumor immunity. These data provide mechanistic insights into immunotherapy and support pt selection for treatment with MPDL3280A monotherapy. Clinical trial information: NCT01375842.

3002^

3003^


Nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients with advanced solid tumors: Survival and long-term safety in a phase I trial. Presenting Author: Suzanne Louise Topalian, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD Background: Blockade of programmed death-1 (PD-1), a co-inhibitory receptor expressed by activated T cells, can overcome immune resistance and mediate tumor regression (Topalian et al., NEJM 2012). Here we present long-term safety and efficacy outcomes from a phase I study of nivolumab, a PD-1 blocking mAb, in patients (pts) with advanced solid tumors. Methods: Pts enrolled between 2008-2012 received nivolumab (0.1⫺10 mg/kg IV Q2W) during dose escalation and/or cohort expansion. Tumors were assessed by RECIST 1.0 after each 4-dose cycle. Pts received ⱕ12 cycles until unacceptable toxicity, confirmed progression, or CR. Results: 304 pts with non-small cell lung cancer (NSCLC, n⫽127, squamous and nonsquamous), melanoma (MEL, n⫽107), renal cell (RCC, n⫽34), colorectal (n⫽19) or prostate cancer (n⫽17) were treated. Durable ORs (CR/PR) were observed in MEL, NSCLC and RCC (Table); in 54 responders with ⱖ1 yr follow-up, 28 lasted ⱖ1 yr. Median OS in these heavily pretreated pts (47% with 3-5 prior systemic therapies) compared favorably with expected outcomes as of July 2012. Drug-related AEs (any grade) occurred in 72% (220/304) and G3/G4 AEs in 15% (45/304) of pts. Drug-related pneumonitis occurred in 3% (10/304), including G3/G4 in 1% (3/304), resulting in 3 deaths early in the trial, which led to increased clinical monitoring and an emphasis on management algorithms. Nivolumab-related pneumonitis characteristics and management will be summarized. Updated survival and safety data from Feb 2013 (ⱖ1 yr follow-up all pts) will be presented, including OS at 3 yr. Conclusions: Nivolumab produced sustained survival with a manageable long-term safety profile in advanced MEL, NSCLC and RCC, supporting its ongoing clinical development in controlled phase III trials with survival endpoints. Clinical trial information: NCT00730639. Tumor type

Dose, mg/kg

ORR, No. pts (%)

MEL

0.1⫺10

33/106 (31)

NSCLC

1⫺10

20/122 (16)

RCC

1 or 10

10/34 (29)

OS median, months (95% CI) 16.8 (12.5 – NR) 9.6 (7.4-13.7) ⬎22

OS rate, %a (95% CI); pts at risk, n 1 Yr 2 Yr 61 (52-71); 50 43 (33-53); 24 70 (55-86); 22

44 (33-56); 24 32 (18-47); 4 52 (32-72); 7


Peripheral and tumor immune correlates in patients with advanced melanoma treated with combination nivolumab (anti-PD-1, BMS-936558, ONO-4538) and ipilimumab. Presenting Author: Margaret K. Callahan, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Nivolumab and ipilimumab are fully human monoclonal antibodies that block the immune checkpoint receptors PD-1 and CTLA-4, respectively. In a multi-cohort, phase I study of nivolumab/ipilimumab combination therapy in melanoma patients (pts), objective response rates up to 47% were observed (NCT01024231). Putative predictive biomarkers from peripheral blood (PB) or tumor, including tumor PD-L1 expression, absolute lymphocyte count (ALC) and PB myeloid derived suppressor cells (MDSC) were evaluated. Pharmacodynamic changes in activated and effector T cells were also assessed. Methods: Tumor PD-L1 membrane expression was assessed in archival FFPE specimens by immunohistochemistry (28-8 PD-L1 antibody). ALC was measured in serial PB samples; changes in the percentage, number and phenotype of activated CD4⫹ and CD8⫹T cells and MDSC were characterized by flow cytometry. Results: PD-L1 expression was seen in 37% (10/27) of pts, using a cut-off of 5% tumor cell membrane staining. Objective responses (OR) were seen in pts with both PD-L1 negative (8/17) and PD-L1 positive (4/10) tumors. Relative to baseline, a rise in ALC was not detected, but phenotypic changes in PB T-cell subsets, including increases in the percentage of CD4 and CD8 expressing HLA-DR, ICOS and/or Ki67 were seen with combination therapy. Low ALC (⬍1.0 at wk 6-7) did not preclude OR as 3 of 12 pts with low ALC responded. Of pts evaluated, OR with ⱖ80% reduction in tumor burden at 12 wk were seen in pts with a low frequency of pretreatment PB MDSC (3/7) but no OR were seen in pts with high MDSC (0/6). Conclusions: In this small subset of pts,OR were seen independent of PD-L1 or ALC status in contrast to prior observations with nivolumab or ipilimumab, respectively. Thus, the immune response generated by combination therapy may have unique features compared to either monotherapy. The relationship between frequency of PB MDSC and reduction in tumor burden will be further explored. Further efforts in this study and in future phase III randomized studies will investigate these and other phenotypic changes in immune cell populations and their relationship to patterns of clinical activity. Clinical trial information: NCT01024231.

a OS estimates after 1 yr reflect censoring and shorter follow-up for pts enrolling later in the study. NR ⫽ Not reached.


174s 3004

Developmental Therapeutics—Immunotherapy Oral Abstract Session, Mon, 3:00 PM-6:00 PM

Phase I study of margetuximab (MGAH22), an FC-modified chimeric monoclonal antibody (MAb), in patients (pts) with advanced solid tumors expressing the HER2 oncoprotein. Presenting Author: Howard A. Burris, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN Background: The anti-HER2 MAb, trastuzumab (H), has proven effective for HER2⫹ breast cancer (BC) and gastroesophageal cancer (GEC). H’s mechanism of action is incompletely understood, but evidence indicates ADCC is important. MGAH22 is an Fc-modified chimeric MAb which preserves the antigen binding properties of H, and exhibits enhanced binding to the activating low affinity Fcg receptor, CD16A, and diminished binding to the inhibitory low affinity Fcg receptor, CD32B. Preclinical data indicate MGAH22 is more potent than H. Methods: 34 pts with HER2 positive (2⫹ or 3⫹ by IHC) tumors have been treated: 19 in 5 dose-escalation cohorts (0.1 - 6.0 mg/kg qw x 4); 15 in 6.0 mg/kg expansion. Tumor types include: BC (10), GEC (13), colon (5), lung (2), salivary (1), ampulla of Vater (1), endometrium (1), bladder (1). Results: MGAH22 was well tolerated. Most common adverse events (AEs) were Grade 1-2 constitutional symptoms and infusion-related reactions. Related AEs ⱖ Grade 3 were limited to a single infusion reaction, 2 episodes of brief lymphopenia confounded by steroids, and transient worsening anemia. No cardiac toxicities were observed. Dose escalation was halted at 6 mg/kg, well above the preclinically predicted minimally effective dose (0.1 mg/kg). Antitumor activity has been observed at all dose levels, including partial responses (PRs) and long times to progression (ⱖ 5 mo). Two PRs lasting 3.5 and 5.5 mo were observed among the 10 BC pts (both had failed prior H and lapatinib). 4/13 GEC pts experienced stable disease lasting a median of 3.6 mo (range 1.5–5.3), all but one previously failing anti-HER2 treatment. Conclusions: Margetuximab is well tolerated with promising activity in pts with BC and GEC who have failed prior HER-2 therapies and in pts with HER2⫹ tumors for which H is considered ineffective. A phase II trial in relapsed or refractory HER2 2⫹, nonamplified BC is underway. Clinical trial information: NCT01195935. Prior MGAH22 dose Benefit Tumor type IHC/FISH Prior H lapatinib >mg/kg cPR

BC BC uPR Salivary gland SD > 5 mos. BC GEC SD with tumor GEC marker decline GEC GEC GEC BC

3006

3⫹/non-A 3⫹/A 3⫹/A 3⫹/A neg/non-A neg/non-A 2⫹/non-A 3⫹/A 3⫹/A 3⫹/A

X X

X X

X

X X X

X X X

X X

3.0 6.0 1.0 0.1 3.0 3.0 6.0 6.0 6.0 0.1


Novel cancer vaccines in combination with oxaliplatin-based chemotherapy as first-line therapy in advanced colorectal cancer: A randomized phase II study. Presenting Author: Hiroaki Tanaka, Osaka City University, Osaka, Japan Background: A phase I cancer vaccination trial using five novel HLA-A24binding peptides derived from not only three oncoantigens, RNF43 (ring finger protein 43), TOMM34 (34 kDa translocase of the outer mitochondrial membrane), and KOC1 (IMP-3; IGF-II mRNA binding protein 3) but also antiangiogenic cancer vaccine targeting VEGFR1 (vascular endothelial growth factor receptor 1) and VEGFR2 had revealed safety and immunogenicity in advanced colorectal cancer (CRC) as presented at 2011 ASCO Oral Abstract Session (No. 2510). We further performed a phase II trial to evaluate the benefit of the cancer vaccination in combination with oxaliplatin-based chemotherapy as first-line therapy. Methods: Ninety-six chemotherapy naïve CRC pts were enrolled to evaluate primarily response rates (RR), and secondarily OS and PFS. Each of the five peptides (3 mg each) was mixed with 1.5 ml of IFA and subcutaneously administered weekly for 12 weeks and after then biweekly. Chemotherapy was performed simultaneously as mFOLFOX6 or XELOX with/without bevacizumab. All enrolled pts had received the therapy without knowing HLA-A status double-blindly, and the HLA genotype were key-opened at analysis point and then, the endpoints are evaluated between HLA-A*2402 positive and HLA-A*2402 negative group. Results: Between February 2009 and November 2012, a total of 96 pts were enrolled in this study. The cutoff date for the main analysis was January 31, 2013 (median duration of follow-up of 26.5months). mFOLFOX6 and XELOX were administered to 93 and 3 pts, respectively. Bevacizumab was used for 5 pts. RR, the primary study end point, was 61.5% (CR 1, PR 58, SD 33, PD 4). It seemed superior as compared to other reports. The median duration to reach the best responses (14 weeks; range 8-69) was surprisingly long and indicated the delayed effect of vaccination. PFS and OS were 8.2 m and 20.7 m, respectively. The HLA genotype will be key-opened at March 2013 and the endpoints will be presented between HLA-A*2402 positive and negative group at the meeting. Conclusions: The phase II cancer vaccine therapy demonstrated the promising response, and warrants further clinical studies. Clinical trial information: UMIN000001791.

3005


Randomized phase II clinical trial of the anti-HER2 (GP2) vaccine to prevent recurrence in high-risk breast cancer patients: A planned interim analysis. Presenting Author: Francois Trappey, Brooke Army Medical Center, San Antonio, TX Background: A prospective, randomized, multi-center, placebo-controlled, single-blinded, phase II trial was designed to evaluate the safety and clinical efficacy of GP2, a HER2-derived peptide vaccine, in breast cancer patients. Methods: Clinically disease-free, node-positive or high-risk nodenegative patients (pts) with any level of HER2 expression were enrolled after standard of care therapy. HLA-A2⫹ pts were randomized to receive GP2 ⫹ GM-CSF (VG) or GM-CSF alone (CG). HLA A2- controls from a parallel arm of the study were also eligible for evaluation, the extended CG (ECG). Pts receive 6 monthly intradermal inoculations (R0-R6) during the primary vaccine series followed by four boosters every 6 mos. Immune responses (IR) were measured by delayed type hypersensitivity (DTH) at R0 and R6. This planned interim analysis was performed at 24 months median follow-up. Results: We have currently enrolled 172 pts (46, VG; 43, CG; 83 extended CG). There are no differences between groups with respect to age, rate of node positivity, tumor grade, tumor size, ER/PR status, and HER2 over-expression (all p ⬎ 0.05). Maximum local toxicity (tox) was similar between the two groups (grade (Gr) 1 and 2: VG 93%, CG 98%; Gr 3: VG 2%, CG 1%). Maximum systemic tox was also similar between the groups (Gr 1 and 2: VG 91%, CG 85%). No Gr 3 systemic tox has been reported. The most frequent systemic reactions are fatigue, headache, and myalgias. IR to GP2 has been robust. DTH is increased from R0 to R6 in the VG (3.0⫾0.98 to 21.5⫾4.04 mm, p ⬍ 0.01) vs. the smaller increase in CG (2.6⫾0.89 to 6.0⫾1.6 mm, p ⫽ 0.01). VG DTH at R6 is significantly higher than the CG (21.5 vs 6.0 mm, p ⬍ 0.01). The recurrence rate (RR) is decreased in the VG vs CG (4.3% vs. 11.6%, p ⫽ 0.41) and VG vs ECG (4.3% vs 9.5%, p ⫽ 0.41). In pts with HER2-overexpressing (IHC3⫹ or FISH⫹) tumors, the RR is decreased in the VG (0% vs 5% CG, p ⫽ 0.28). For TNBC (HER2 low, ER/PR-) pts, the RR is reduced in the VG vs ECG (0% vs 10.6%, p ⫽ 0.251). Conclusions: The GP2 vaccine is safe and the minimal toxicity is comparable between the VG and CG, suggesting that it is due to GM-CSF. Robust in vivo immune response has correlated with a ⬎50% reduction in breast cancer recurrences in the VG. Clinical trial information: NCT00524277.

3007


Effect of algenpantucel-L immunotherapy for pancreatic cancer on antimesothelin antibody (Ab) titers and correlation with improved overall survival. Presenting Author: Gabriela R. Rossi, NewLink Genetics, Ames, IA Background: Hyperacute rejection of tissues expressing the carbohydrate ␣(1,3)Gal xenoantigen is a potent innate immune defense mechanism that was leveraged to treat resected pancreatic cancer patients by immunization with genetically modified allogeneic tumor cells expressing ␣Gal moieties (algenpantucel-L). We propose that adding algenpantucel-L to SOC adjuvant therapy may improve survival and induce immunological biomarkers that positively correlate with improved median overall survival (OS). Methods: Open-label, multicenter phase II study evaluating algenpantucelL⫹SOC (RTOG-9704: gemcitabine ⫹ 5-FU-XRT) for resected pancreatic cancer patients. Endpoints: 1°) disease-free survival (DFS) at 1 year; 2°) OS, toxicity and immunologic analysis. Biomarkers were evaluated including total IgG, complement, CA19-9 levels, anti-␣Gal Ab, anti-CEA Ab, and anti-membrane-bound recombinant mesothelin (MSLN) Ab. Results: Patients received gemcitabine with 5-FU modulated radiation therapy plus algenpantucel-L. The primary endpoint, 12-month DFS, was 62% and 12-month OS was 86%. All evaluable patients have been in follow-up for ⱖ 3 years. We now report OS rates at 3 years of 39% and DFS of 26% at 3 years. Evaluable patients (n⫽64) were tested for the induction of antiMSLN Ab where ⱖ 25% increase in the anti-MSLN Ab compared to baseline was considered significant (p⬍0.001). Twenty of 64 patients (31%) had increased anti-MSLN Ab. Patients responding with anti-MSLN Ab had a median OS of 42 months compared to 20 months for patients without sero-conversion. The positive correlation between increased antiMSLN Ab and improved median OS was statistically significant (p⫽0.027). Conclusions: The addition of algenpantucel-L to SOC for resected pancreatic cancer may improve survival. In 20/64 patients, algenpantucel-Linduced anti-MSLN Ab responses that correlates with improved survival (median OS 42 vs 20 months). Immunological monitoring of algenpantucel-L immunotherapy with this biomarker is feasible and might predict patient response to therapy. A multi-institutional, phase III study is currently underway (ClinicalTrials.gov NCT01072981). Clinical trial information: NCT00569387.




First-in-human phase I study of CetuGEX, a novel anti-EGFR monoclonal antibody (mAb) with optimized glycosylation and antibody dependent cellular cytotoxicity. Presenting Author: Walter Fiedler, Hubertus-Wald University Cancer Center, Hamburg, Germany Background: Epidermal growth factor receptor (EGFR) is a validated target in cancer. EGFR antagonists in clinical use do not exploit the full potential of this target. CetuGEX is an IgG1 mAb against EGFR. Fully human and optimized glycosylation lead to a 10- to 250-fold improvement of ADCCmediated tumor cell killing in all Fc␥RIIIa allotypes and lack of immunogenic carbohydrate-chains, compared to cetuximab. Methods: Eligible patients with advanced solid tumors, progressing after standard treatment, were enrolled into this phase I, first-in-human, multicenter, single agent dose escalation trial. PK, PD and immunological parameters were assessed. Endpoints were safety and tolerability and secondarily pharmacokinetics, immunogenicity and anti-tumor activity. Results: 41 patients were treated on a q1w (8 dose levels from 12 to 1,370 mg flat dose), or q2w (990 mg flat) schedule. 25 pts had received at least 8 weekly doses (per protocol population [PP]).The most frequently observed drug-related AE were nausea (20%), vomiting (20%), hypertension (20%), almost all low grade and acneiform dermatitis (25%), only grade 1 or 2. Infusion-related reactions (IRR), virtually restricted to the first infusion, were associated with cytokine secretion: IL-6, IL-8, TNF␣, IFN␥ and IP-10 as marker of macrophage activation. Optimization of infusion scheme and premedication reduced IRRs in severity and frequency from 76% to 57% mainly of low grade. Blood NK cells were reduced as sign of redistribution. Activity was seen over all dose levels. One patient with NSCLC achieved a complete response. One patient with metastatic colorectal cancer had a partial response, another 2 patients with esophageal and gastric cancer without measurable disease at study entry had marked improvement of symptoms and normalization of tumor markers. Additional 15 pts had stable disease lasting from 8 weeks to over a year, including several minor responses, leading to a clinical benefit rate of 46% (19/41) in the overall and 76% (19/25) in the PP population. PK supports q1w and q2w dosing. Conclusions: CetuGEX shows clear signs of activity and acceptable toxicity. Phase II will soon be initiated. Clinical trial information: NCT01222637.

3009

175s

Poster Discussion Session (Board #1), Sat, 1:15 PM-5:15 PM and 4:45 PM-5:45 PM

Highlighting the challenge of delayed overall survival (OS) curve separation in immunotherapy clinical trials. Presenting Author: Savanna D. Steele, PPD Inc., Wilmington, NC Background: Cancer immunotherapy holds great potential but can elicit delayed responses, unlike chemotherapy. A delay in the separation of OS curves (between the control and treatment arms) has led to difficulty in achieving adequate power for OS analysis (Hoos A, Ann Oncol. 2012). Since combining immunotherapies, such as an anti-CTLA4 and an anti-PD-1, may increase the percentage of subjects achieving durable responses (Curran MA, PNAS. 2010), we sought to determine how adding a complementary immunologic agent to the currently-approved ipilimumab would impact delay in OS curve separation. Arbitrarily assuming that treatment effect on OS was doubled, we determined how various delays in OS curve separation might impact sample sizes. Methods: We evaluated three dual-immunotherapy clinical trial scenarios in which the separation of OS curves either remained the same, decreased, or increased. Baseline OS estimates were from pivotal trial data for ipilimumab in melanoma (Robert C et al, NEJM. 2011). SAS PROC POWER with piecewise linear survival curve was then used to determine approximate corresponding sample sizes. Results: See Table. Conclusions: Demonstrating significance in order to gain regulatory approval is important for providing potentially life-saving medications. For trials evaluating dual-immunotherapies, despite doubling treatment effects, delays in OS curve separation of up to 6 months would require over 2700 subjects to reach statistical power. In an era where treatments are increasingly personalized, these numbers will be difficult to achieve, underscoring the importance of novel trial designs incorporating Bayesian hierarchical modeling, precompetitive collaborations, and/or the use of state-of-the-art predictive biomarkers. Ipilimumab ⴙ dacarbazine ⴙ anti-PD-1 MAb Ipilimumab ⴙ Dacarbazine dacarbazine 2-mo delay 4-mo delay 6-mo delay Median OS (mos) Hazard

9.1 0.076

Hazard ratio after delay* Median OS after delay (mos) Sample size

9.1

11.2

15

13.3

11.7

0.076 0.076 0.076 0.076 (first 4 mos), (first 2 mos), (first 4 mos), (first 6 mos), then 0.054 then 0.042 then 0.042 then 0.042 0.71 0.55 0.55 0.55 12.9

16.6

16.6

16.6

505

1061

2731

* Delay ⫽ delay in separation of OS curves.

3010


Use of tumor growth rate (TGR) to provide useful clinical information in phase I trials and reveal clear drug-specific profiles. Presenting Author: Charles Ferte, Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France Background: The evaluation of treatment response by RECIST does not take into account the tumor growth kinetics along the treatment sequence and may induce misleading information regarding the evaluation of the drug activity. TGR incorporates the time between the tumor evaluations and allows for a dynamic and quantitative evaluation of the tumor kinetics. How TGR is modified along the introduction of experimental therapeutics and is associated with outcome in phase I patients remains unknown. Methods: Medical records from all patients (n⫽304) prospectively treated at Institut Gustave Roussy in 19 phase I trials between 2009 and 2011 were analyzed. TGR was computed both during the pre-treatment period (REFERENCE) and between baseline and first evaluation (EXPERIMENTAL). TGR is defined as: log 10 (Vt/V0)/dt and is represented as a percentage increase of tumor volume per month for clinical relevance. The associations between TGR, RECIST, the most commonly used prognostic scores (ECOG, RMH score, PFS ratio) and the outcome (OS, PFS) were computed (multivariate analysis). The effect of treatment, prognostic scores, histology, and the number of previous treatment lines on TGR were assessed. Results: Overall, we observed a reduction of TGR between the REFERENCE vs. EXPERIMENTAL periods (11.5 vs. 1.5, P⬍.0001). Although most of the patients were classified as stable disease (57%) or progressive disease (28%) by RECIST at the first evaluation, 88% and 69% of them exhibited a decrease in TGR, respectively. TGR reveals clear drug specific profiles along the 19 experimental regimens tested, allowing for an early evaluation of the drug activity. The TGR decrease was associated with both PFS (P⫽.004) and OS (P⫽.001) and remained significant even after adjustment to the other prognostic scores for phase I patients. Conclusions: Adding TGR assessment in phase I patients is simple and provides clinically relevant information: (i) It allows for an early and precise assessment of the tumor growth, (ii) It reveals drug-specific profiles, suggesting its potential use for the early assessment of drug activity, (iii) TGR is independently associated with prognosis in phase I patients.

3011


Mucin 1 (MUC1) expression in patients (pts) with early stage non-small cell lung cancer (NSCLC): Relationship between immunohistochemistry (IHC), tumor characteristics, and survival. Presenting Author: Paul Leslie Mitchell, Ludwig Medical Oncology Unit, Olivia Newton-John Cancer and Wellness Centre, Austin Health, Melbourne, Australia Background: MUC1, a glycoprotein highly expressed in many malignancies, is being explored as an antigen for immunotherapy. How best to measure MUC1 expression as well as its prognostic value in NSCLC are still under discussion. Methods: TMAs were constructed using triplicate 1mm cores of FFPE tumour and stained with 214D4 (recognises protein core) and MA695 (recognises carbohydrate epitope) anti-MUC1 antibodies (abs). TMAs were assessed for polarisation, both cyto and mem staining intensity (scored 0-3) and proportion cells ⫹ve (0-100%; scored 0 –5), averaged for multiple cores. A composite score (intensity x cells ⫹ve) was derived, ranging from 0 –15 (3⫹ in ⬎75% cells). Results: TMAs from 521 pts were analysed: male 362 (69.5%); never smoking 35 (7%); adeno 259 (49.7%), squamous 180 (34.5%), large cell 39 (7.5%); nodal N0 340 (65.3%), N1 71 (13.6%), N2 107 (20.5%). Results of IHC staining intensity, proportion positive cells and depolarisation were very similar for the two abs. There was high concordance in the composite score for the abs (R2⫽0.71, p⬍0.0001). Polarisation was discordant in 7.9% of cases. For 77 cases with paired primary/ N2 nodal tissue, mean 214D4 scores were 8.3 and 8.9 and MA695 10.6 and 9.9 respectively. Discordant staining in primary but not in node was seen in 5.2% and 10.4% with 214D4 and MA695 respectively. Increased expression as assessed by 214D4 (HR⫽1.26; 95% CI 1.014-1.565, p⫽0.04 log rank test) and MA695 (HR⫽1.20, 95% CI 1.042-1.605; p⫽0.02) was associated with improved survival. The prognostic value of depolarisation has yet to be analyzed. Conclusions: Over 93% of cases were MUC1 IHC positive. Composite scores for the 2 abs were highly correlated and depolarisation largely concordant. MUC1 expression was generally maintained in paired primary/nodal tumour. Increased expression of MUC1 was associated with improved survival however further investigation is needed to determine which abs best predict outcomes. 214D4 MA695 No staining Mean intensity Cyto Mem Mean cells ⴙve Mean composite score Adeno Squamous Large cell Depolarization

3.5%

6.4%

1.8 2.1 3.9 10.1 13.0 7.1 7.1 66.3%

1.7 2.2 3.6 9.6 12.0 6.9 7.8 62.0%


176s 3012

Developmental Therapeutics—Immunotherapy Poster Discussion Session (Board #4), Sat, 1:15 PM-5:15 PM and 4:45 PM-5:45 PM

Effective incorporation of biospecimen collection for translational studies into a phase III trial: The NeoALTTO experience (BIG 01-06). Presenting Author: Paolo Nuciforo, Molecular Pathology Laboratory, Vall d’Hebron Institute of Oncology, Barcelona, Spain Background: Translational research studies in the context of clinical trials using targeted therapies are essential for the identification of biomarkers of response or resistance. However, many challenges (e.g. logistic, technical) can impede proper biological sample collection. The NEOALTTO study provided an excellent opportunity to address these issues. Methods: In this large neoadjuvant phase III multicenter, multinational clinical trial, serial samples (plasma, serum, frozen and FFPE specimens) from patients with breast cancer were collected in 86 sites (23 countries) at several time points (baseline, week 2 and surgery). Standardized operating procedures were made available to sites together with pre-assembled kits for sample collection, processing, storage, and shipment to reduce the variability and increase compliance with the study protocol. All biospecimens were centralized for long term storage. Baseline fresh/frozen samples were processed for downstream analyses according to a pre-defined workflow. Evaluable sample population (ESP) was determined based on the following criteria: tumor cellularity, RNA integrity (RIN), and yield. Results: A total of 12,193 serial samples from 449 of 455 randomized patients was collected. The overall sample missing rate was 9.5% (includes samples not collected by site, withdrawn patients and pCR). Missing rates were 9%, 8%, 13%, and 9% for plasma, serum, frozen and FFPE specimens, respectively. At least 1 frozen tumor tissue was available for 423 (94%), 431 (96%), and 334 (74%) patients at baseline, week 2, and surgery, respectively. After 2 extraction cycles, 629 and 516 baseline frozen samples were processed for RNA and DNA extraction, respectively. The ESP was 71% (58% when RIN considered) and 80% for downstream RNAand DNA-based analyses, respectively. Incorrect material, inappropriate sample processing and low or absent tumor cellularity were some of the factors affecting the ESP. Conclusions: These results show that careful upfront logistic and technical planning in NEOALTTO had a significant impact on the compliance and the quality of collected material, which may ultimately result in valuable research data. Clinical trial information: NCT00553358.

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3013


EGF-based cancer vaccine: Optimizing predictive and surrogate biomarkers. Presenting Author: Tania Crombet Ramos, Center of Molecular Immunology, Havana, Cuba Background: EGFR is overexpressed in many epithelial tumors. EGF is one of the most important growth factors that stimulates EGFR, in a paracrine way. CIMAvax-EGF is a therapeutic cancer vaccine intended to induce antibodies against EGF. It is composed by recombinant EGF conjugated to P64 from N.Meningitides as a carrier and Montanide, as adjuvant. Methods: Two controlled trials were done in advanced NSCLC and castrationresistant prostate cancer patients (CRPC). A multicentric, randomized Phase III trial was designed to assess the efficacy, immunogenicity, and safety of CIMAVAx-EGF in advanced NSCLC patients. Patients with histology- or cytology-proven NSCLC at stage IIIB/ IV were enrolled. All subjects received 4 platinum-based cycles before entering the study. On the other hand, a multicentric, randomized Phase II trial was designed to assess the immunogenicity and safety of the vaccine in CRPC patients. The EGF cancer vaccine was administered in combination with mitoxantrone and prednisone. Results: 405 patients bearing NSCLC and 200 men with CRPC were enrolled in the 2 trials. In both studies the vaccine was immunogenic. Antibody titers against EGF increased with vaccination and EGF concentration in sera showed a fast reduction after immunization. The anti-EGF antibody response was directly correlated with overall survival. CIMAVax-EGF was safe and most prevalent adverse events were grade 1-2 injection site pain, fever, headache, nausea, vomiting, and chills. The vaccine significantly increased the survival of the NSCLC patients while it did not augment significantly the overall survival of the CRPC patients. In both studies, EGF concentration was measured at baseline and it was found to be much higher than in normal subjects. High EGF concentration predicted greater benefit after vaccination. On the contrary, NSCLC and prostate control patients with high levels of EGF had a poorer outcome. Conclusions: Antibody response against EGF is a surrogate marker of survival. High EGF concentration might be a predictive marker of vaccine efficacy and a poor prognostic biomarker for non-vaccinated NSCLC and CRPC patients. The predictive and prognostic value of the EGF concentration will be validated prospectively. Clinical trial information: IIC EC 081.

3015


Immune gene expression in primary melanomas to predict lower risk of recurrence and death. Presenting Author: Shanthi Sivendran, Hematology/ Oncology Medical Specialists, Lancaster General Health, Lancaster, PA

Targeting CD137 to enhance the antitumor efficacy of cetuximab by stimulation of innate and adaptive immunity. Presenting Author: Holbrook Edwin Kohrt, Stanford Cancer Institute, Stanford, CA

Background: Improved biomarkers are needed to define recurrence risk in patients with completely resected skin melanomas. Standard prognostic indicators used in staging, including depth, ulceration, and mitotic rate, while useful, often fail to accurately predict recurrence for individual patients. The immune system may prevent recurrence in this population, but no evidence-based immune biomarkers are in clinical use. Biomarker development has been hindered by clinical standards necessitating that the entire specimen be formalin fixed and paraffin embedded (FFPE) for morphology evaluation, a process damaging to RNA. Methods: To define a biomarker for melanoma recurrence, mRNA copy number of immunerelated genes from FFPE melanoma was measured using NanoString, a hybridization assay suited for analysis of partially degraded RNA. Genes predictive of non-recurrence were defined using receiver operating characteristic (ROC) curves in a training cohort and then validated in an independent patient cohort. Results: A panel of 21 genes predictive of non-recurrence were defined using ROC curves in a training cohort (N⫽44). This result was validated in an independent patient cohort (N⫽37, AUC⫽0.794). Protein levels of the most differentially expressed gene, CD2, also associated with non-recurrence (p⬍0.001). The immune gene panel and CD2 staining associated with prolonged survival (p⬍0.001 and p⫽0.019, respectively). Conclusions: mRNA copy number of immunerelated genes in primary FFPE melanomas predicts non-recurrence and prolonged survival. This data highlights the impact of immunosurveillance in primary human melanoma and the identified gene panel may be a useful tool for patient stratification for adjuvant immunotherapy studies.

Background: Cetuximab therapy results in beneficial, yet limited, clinical improvement for patients with KRAS wildtype (WT) colorectal (CRC) and head and neck (HN) cancer. The efficacy of cetuximab, an IgG1 monoclonal antibody against EGFR, is due in part to antibody-dependent cellmediated cytotoxicity (ADCC) by natural killer (NK) cells. CD137 is a costimulatory molecule expressed following activation on NK and memory, antigen-specific, CD8 T cells. Methods: We investigated the hypothesis that the combination of cetuximab with anti-CD137 mAb will enhance innate and adaptive immunity, thereby improving cetuximab’s anti-tumor efficacy in preclinical models and a prospective trial, NCT01114256. Results: NK cells increased their expression of CD137 by a factor of 30-40 when exposed to cetuximab-coated, EGFR-expressing HN and CRC cell lines. An agonistic anti-CD137 mAb enhanced NK cell degranulation and cytotoxicity 2-fold (~45 to 90% tumor lysis assayed by chromium release). The combination of cetuximab and anti-CD137 mAbs was synergistic in a syngeneic, human-EGFR-transfected murine tumor leading to complete tumor resolution and prolonged survival. NK cell depletion, significantly, and CD8 T cell depletion, partly, abrogated the anti-tumor efficacy of this combination. A series of HN and both KRAS WT and mutant CRC xenotransplant models demonstrated synergy with cetuximab and antiCD137 mAbs. In our clinical trial, 54 patients with HN cancer receiving cetuximab therapy, circulating and intratumoral NK cells upregulated CD137 with amplitude influenced by duration post-cetuximab and host FcyRIIIa polymorphism. Interestingly, in 10 HLA-A2⫹ patients, following cetuximab, an increase in EGFR-specific, CD137-expressing, CD8 T cells directly correlated with the percent increase in CD137-expressing NK cells. Conclusions: Our results demonstrate the synergy of combining an agonistic mAb, anti-CD137, augmenting ADCC and T cell memory following a tumor-targeting mAb, cetuximab, in HN and KRAS mutant and WT CRC cancer. These results support a novel, sequential antibody approach by targeting first the tumor and then the host innate and adaptive immune system. Clinical trial information: NCT01114256.




Association of tumor PD-L1 expression and immune biomarkers with clinical activity in patients (pts) with advanced solid tumors treated with nivolumab (anti-PD-1; BMS-936558; ONO-4538). Presenting Author: Joseph Grosso, Bristol-Myers Squibb, Princeton, NJ Background: The immune checkpoint receptor programmed death-1 (PD-1) negatively regulates T-cell activation. In a phase I study, nivolumab, a PD-1 receptor blocking antibody, demonstrated durable clinical activity. Evaluation of the expression of the PD-1 ligand, PD-L1, by IHC with the 5H1 Ab suggested a correlation between pretreatment tumor PD-L1 expression and clinical response (Topalian et al, NEJM 2012). Methods: 304 pts with non-small cell lung cancer (NSCLC, n⫽127), melanoma (MEL, n⫽107), renal cell (RCC, n⫽34), colorectal (n⫽19) or prostate cancer (n⫽17) received nivolumab between 2008-2012 (0.1⫺10 mg/kg IV Q2W) during dose escalation and/or cohort expansion. Formalin-fixed paraffin-embedded tumor tissue and peripheral blood mononuclear cells (PBMC) were analyzed to explore potential pharmacodynamic/ predictive biomarkers associated with nivolumab therapy. Tumor surface PD-L1 expression was evaluated by IHC using an automated assay based on a sensitive and specific PD-L1 mAb (28-8) distinct from 5H1. PD-L1 positivity (PD-L1⫹) was defined as ⱖ5% cell membrane staining of any intensity. Lymphocyte subsets in PBMC were measured using flow cytometry. Results: Tumor membrane PD-L1 was measured in 101 MEL and NSCLC pts. 17/38 (45%) of MEL and 31/63 (49%) of NSCLC biopsies were PD-L1⫹. A numerically higher objective response rate (ORR), longer progression-free survival (PFS), and overall survival (OS) was seen with PD-L1⫹ in MEL pts (Table).Analysis of the association of PD-L1 expression with ORR, PFS and OS in NSCLC is ongoing. A correlative analysis of pt response with pre-/post-dose levels of lymphocytes will be presented. Conclusions: These data, using a novel, automated PD-L1 IHC assay and mAb, support the hypothesis of tumor PDL1⫹ predicting activity of nivolumab in advanced cancer, which is being prospectively assessed in phase III trials. Clinical trial information: NCT00730639. Endpoint MEL

OS PFS ORR

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PD-L1 status

N event/N subj (%)

⫹ – ⫹ – ⫹ –

8/16 (50%) 10/18 (56%) 9/16 (56%) 12/18 (67%) 7/16 (44%) 3/18 (17%)

Median, Mo (95% CI) 21.1 (9.4, -) 12.5 (8.2, -) 9.1 (1.8, -) 2.0 (1.8, 9.3)


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Ipilimumab in the real world: The U.K. expanded access programme (EAP) experience in advanced melanoma. Presenting Author: Saif Ahmad, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom Background: Since publication of the registration trial in 2010 (Hodi et al, NEJM 2010;363:711-23), real world use of ipilimumab (Ipi) in previously treated advanced melanoma patients has extended beyond the specific trial entry criteria of ECOG PS 0-1. We undertook a review of UK patients (pts) treated in the international EAP prior to European licensing of Ipi in August 2011, to compare real world survival outcomes. Methods: UK clinicians registered in the EAP provided anonymised data using pre-specified variable fields for all pts. The EAP stipulated pts should have previously treated, unresectable stage III or IV metastatic melanoma and receive Ipi 3 mg/kg, 3 weekly IV, for up to 4 cycles. Response using RECIST criteria was assessed 12 weekly. Grade ⱖ3 adverse events (AEs) using CTCAE v3.0 were collected. Results: To date, information on 162 pts has been received from 16 UK sites. Primary sites were: 78% cutaneous, 4% ocular, 1% mucosal, 17% unknown. 78% pts had M1c disease, 14% had brain metastases. No prior therapies ranged from 0-4, 72% pts received 1 prior therapy. Median age was 60 years, men⬎women (1.6:1). ECOG PS was: 38% 0, 47% 1, 14% 2, 1% 3. BRAF status was known in 38% cases and WT in 75% of these. 19% pts were on steroids at baseline. No cycles delivered was 4 in 52%, 3 in 13%, 2 in 16%, 1 in 17% pts. Most frequent reason for stopping early was clinical evidence of disease progression (71%), death (16%) or unacceptable AE (12%). 32% pts experienced a grade ⱖ3 AE, the most common being diarrhoea (13%) and fatigue (8%). Complete and partial responses were reported in 1% and 21% of treated pts. At median follow-up of 17 months, median progression free survival and overall survival (OS) were 2.8 and 5.7 months, 1 year OS was 30%. Comparing outcomes of various pt subgroups, the strongest prognostic factor for OS was ECOG PS at the start of treatment (p⬍0.0001). For pts with PS 0 or 1, median OS was 8.8 months (compared with 10 months in the registration trial). More detailed safety and efficacy data on pt subgroups will be presented. Conclusions: This review, representing the largest Ipi EAP UK dataset, reports overall poorer survival outcomes than in the registration trial, but pts with similar characteristics to the trial population lived longer.

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Nonclinical evaluation of the combination of mouse IL-21 and anti- mouse CTLA-4 or PD-1 blocking antibodies in mouse tumor models. Presenting Author: Maria Jure-Kunkel, Bristol-Myers Squibb, Princeton, NJ

Effect of anti-CTLA-4 antibody treatment on T-cell repertoire evolution in treated cancer patients. Presenting Author: Edward Cha, University of California, San Francisco, San Francisco, CA

Background: Interleukin 21 (IL-21), a ␥c chain family cytokine, is produced primarily by CD4⫹ T cells and has many effects on immune cells, including enhancing CD8⫹ T cell and NK cell proliferation and cytotoxicity. Recombinant IL-21 (rIL-21) therapy resulted in objective responses in ~20% of melanoma and renal cell carcinoma patients. In mouse models, monoclonal antibody (mAb) blockade of CTLA-4 prolongs antigen-specific T cell responses, while blockade of programmed death 1 (PD-1) reverses tumor induced T cell suppression. Ipilimumab, a CTLA-4 blocking mAb, significantly improved overall survival in patients with metastatic melanoma in 2 phase III trials, and in phase I studies a PD-1 blocking mAb (nivolumab) has antitumor activity in various cancers. Side effect profiles for each mAb have been related to their mechanism and are generally manageable. It was hypothesized that combination of IL-21 plus CTLA-4 or PD-1 blockade may enhance antitumor responses, potentially leading to improved clinical activity. Methods: Preclinical studies were conducted to test the antitumor activity of mouse IL-21 (mIL-21) in combination with an anti-mouse PD-1 (mPD-1) mAb (4H2-IgG1) or with an anti-mCTLA-4 blocking mAb (9D9IgG2b) in syngeneic mouse tumor models, including MC38, CT-26, EMT-6, and B16F10. mIL-21 was tested at doses ranging from 50-200 ␮g/dose, administered up to 3d/wk. mCTLA-4 mAb or mPD-1 mAb were administered 3-4x total at 200-300 ␮g/dose. Results: Combination treatments produced enhanced antitumor activity vs. monotherapy. In the MC38 model, mIL-21 treatment led to 30% median tumor growth inhibition (TGI) by d29, while mPD-1 mAb produced 60% median TGI and 1/10 tumor-free mice. Combination of both agents led to synergistic antitumor activity, with complete regressions (CR) in 7/10 mice and 99.9% median TGI (p⫽0.046). CTLA-4 mAb ⫹ mIL-21 also produced synergistic activity in the MC38 model. By d21, mIL-21 monotherapy induced 34% TGI while CTLA-4 mAb resulted in 28% TGI, with no CR in either group. Combination resulted in 6/8 mice with CR and 86% TGI (p⬍0.05). Conclusions: These results support the use of rIL-21⫹nivolumab and rIL-21⫹ipilimumab in recently initiated clinical trials.

Background: CTL-associated antigen 4 (CTLA-4) is an immune checkpoint expressed by T cells. While treatment with anti-CTLA-4 antibody can induce clinical responses in advanced cancer patients, its effects on the breadth of the T cell response is unknown. Methods: We used a sequencingbased method, LymphoSIGHT, to assess T cell repertoire diversity in 46 patients with metastatic castration resistant prostate cancer or metastatic melanoma. Peripheral blood mononuclear cells were obtained from patients prior to and during treatment with anti-CTLA-4 antibody. mRNA was amplified using locus-specific primer sets for T cell receptor (TCR) beta, and the amplified product was sequenced. Sequence reads were used to quantitate absolute TCR frequencies using standardized clonotype determination algorithms with normalization by spiked reference TCR sequences. Following clonotype quantitation, repertoire differences between serial samples were assessed by the Morisita index, a statistical measure of population dispersion. Results: 97 paired samples were assessed, of which 46 (47%) had increases and 22 (23%) had decreases in TCR diversity by more than 2-fold. By comparison, none of 9 untreated sample pairs underwent more than a 2-fold change in diversity (P ⫽ 0.005, Fisher’s exact test, two tailed). TCR repertoire differences between monthly samples were markedly higher than for time-matched controls. After the first treatment, median Morisita index between samples was 0.197 for treated samples versus 0.039 for untreated (P ⫽ 0.0005, Mann-Whitney U test). The median number of clones that significantly changed in abundance was 421 for treated versus 45 for controls. In patients with multiple time points, this rapid clonotype evolution continued through treatment. Despite this global turnover in repertoire, a subset of high frequency clones, including CMV-specific T cells, remained relatively constant over the course of the study. Conclusions: CTLA-4 blockade increases the global rate of T cell clonotype turnover and influences TCR diversity. This evolution of the TCR repertoire may reflect a mechanism by which CTLA-4 blockade enhances tumor-specific T cells over time.


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Correlation of PDL1 tumor expression and outcomes in renal cell carcinoma (RCC) patients (pts) treated with pazopanib (paz). Presenting Author: David J Figueroa, GlaxoSmithKline, Research Triangle Park, NC

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A phase I open-label study of Ad-RTS-hIL-12, an adenoviral vector engineered to express hIL-12 under the control of an oral activator ligand, in subjects with unresectable stage III/IV melanoma. Presenting Author: Gerald P. Linette, Washington University in St. Louis, St Louis, MO

Background: The interaction between PDL1 (B7H1) and its receptor PD-1 on activated T cells plays an important role in the inhibition of T-cell responses and contributes to suppression of antitumor immune responses. Tumor PDL1 expression has been associated with poor outcomes in RCC. This study investigates the correlation between PDL1 tumor expression and outcomes in RCC pts treated with paz. Methods: Using IHC, we retrospectively analyzed baseline FFPE tumor samples for PDL1 from 2 paz RCC studies: a single arm phase II trial and randomized placebo (pbo)controlled phase III study. PDL1 expression was analyzed by MedTox Laboratories using the anti-PDL1 MouseIgG1 clone 5H1 (Thompson) on the Leica automated IHC platform. Additional dual PDL1/CD68 staining was carried out to delineate tumor and macrophage PDL1 expression. Tumor PDL1 expression was quantified by H-Score (HS) and PDL1⫹ macrophages were assessed semi-quantitatively. Association between PDL1H scores and PFS was investigated by Kaplan-Meier analysis using optimal cutoff of PDL1tumor HS (minimum p value, log rank test). Results: The optimal cut-point of PD-L1 tumor HS, relative to PFS, was identified as HS ⬎ 3. In the phase II study (46 available samples out of 225), HS range was 0-150 and most samples had negative (HS ⫽ 0, n ⫽ 34, 74%) or low (HS 1-3, n⫽4, 9%) PDL1 expression. Pts with HS ⬎ 3 (n ⫽ 8, 17%) had significantly shorter PFS (2.6 mo) than those with HS ⱕ 3 (12 mo; p ⫽ .0005). In the phase III study (N ⫽ 160 available samples: paz, 113 of 290; pbo, 47 of 145), HS range was 0-280. Most patients had negative (n ⫽ 122/160, 76%) or low (n ⫽ 9/160, 6%) PD-L1 expression, with 18% (29/160) having HS ⬎ 3. Pbo-arm pts with HS ⬎ 3 (n ⫽ 6/47, 13%) had shorter PFS (2.3 vs 5.5 mo p ⫽ .0207). Paz-arm pts with HS ⬎ 3 (n ⫽ 23/113, 20%) trended toward shorter PFS (7.3 vs 11 mo, p ⫽ .1405). Conclusions: PDL1 appears to be a prognostic marker with PDL1 HS ⬎ 3 associated with shorter PFS. Limitations of the study include the retrospective nature of the analysis with limited pt samples available, low or negative PDL1 expression in the vast majority of pts, and use of archival samples that may not accurately reflect PDL1 status at study entry. Additional results (tumor volume, OS) will be presented.

Background: IL-12 is a pleiotropic cytokine with known antitumor activity; however, clinical use was limited by toxicity when delivered systemically. Ad-RTS-hIL-12 is an adenoviral vector engineered for controlled expression of IL-12 with the RheoSwitch Therapeutic System (RTS) and an oral activator, INXN-1001. Methods: In a phase I, 3⫹3 dose escalation study, subjects with unresectable stage III/IV melanoma were administered 1e12 viral particles (Ad-RTS-hIL-12) intratumorally on the first day of up to six 21-day cycles, and INXN-1001 (5, 20, 100, and 160 mg) orally on days 1-7 of each cycle. Results: Dose escalation is complete with 14 subjects treated. Median prior therapeutic agents was 3 (range 1-4). Common related adverse events included chills (11, 78.6%), pyrexia (11, 78.6%), fatigue (10, 71.4%), and nausea (10, 71.4%). With a biologically effective dose of 160 mg, MTD for INXN-1001 was not reached. One death unrelated to study drug was secondary to septicemia. Clinical activity was observed in 5 of 7 subjects treated at doses of INXN-1001 ⱖ100 mg, but not at ⬍100 mg, and included prominent inflammatory responses in injected and non-injected lesions, decreases in size of injected and non-injected lesions, and reduction in tumor-associated pain. One subject at the 160-mg dose had stable disease for 20 weeks. Clinical activity in dose cohorts ⱖ100 mg coincided with a 4-fold median increase from baseline in peak serum levels of IL-12 and IFN-␥ compared with lower dose cohorts. Flow cytometric analyses of PBMCs revealed 7-fold (ⱖ100 mg dose cohorts) median increases from baseline in peak levels of absolute numbers of CD3⫹ and CD8⫹ T cells. ELISPOT and T-cell proliferation assays for antigen-specific responses are ongoing. Conclusions: Intratumoral delivery of IL-12 via an adenoviral vector with RheoSwitch enabled finely-controlled expression of IL-12 levels by an oral ligand. Ad-RTShIL-12 plus INXN-1001 (160 mg) was well tolerated and induced biological and clinical activity in subjects with advanced melanoma. Phase II studies are ongoing at the biologically effective dose. Clinical trial information: NCT01397708.

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Deletion and mutation of IL10RA gene on chromosome 11q23 to avert CpG-B oligodeoxynucleotides-induced apoptosis of human chronic lymphocytic leukemia B cells. Presenting Author: Xueqing Liang, University of Minnesota, Minneapolis, MN

Anti-CD20-interferon-alpha fusion protein has superior in vivo activity against human B-cell lymphomas compared to rituximab and enhanced complement-dependent cytotoxicity in vitro. Presenting Author: Reiko E Yamada, University of California, Los Angeles, Los Angeles, CA

Background: Targeting TLR9 expressed on human CLL cells with CpG-B oligodeoxynucleotides leads to IL-10-induced tyrosine phosphorylation of STATs and apoptosis of B-CLL cells. However, B-CLL cells from a small subset of patients were resistant to CpG-B ODN treatment. Here, we investigated the molecular mechanism by which B-CLL cells are sensitive or resistant to CpG-B ODN treatment. Methods: Purified CD19⫹CD23⫹CD5⫹primary B-CLL cells were cultured for 5 days with/ without CpG-B ODN (CpG 2006, CpG 685) or rh-IL-10. B-CLL cell apoptosis were determined by viable cell counts, Annexin V/PI and TMRE staining, Western blot and intracellular staining of the activation/cleavage of caspases, PARP, Bax translocation and cytochrome c release, IL-10R1 expression and IL-10 binding by flow cytometry, IL10RA gene deletion by FISH, IL10R1 S138G mutation by Bi-PASA, The tyrosine or serine phosphorylation of STATs by Western blot. Results: Fifteen CpG-sensitive and 11 CpG-resistant primary CLL samples were comparatively studied. B-CLL cells from 15/15 CpG-sensitive samples were induced into apoptosis by either CpG-B ODNs or IL-10 in a treatment time and dose-dependent manner. Both CpG-B ODNs and IL-10 significantly increased pTyr701STAT1/pTyr705-STAT3 expression and induced apoptosis via the mitochondrial apoptotic pathway in 15 primary B-CLL cells. No IL-10RA gene deletions were detected, 13/15 patients were IL10R1 S138G AA wildtypes and 2/15 patients were AG heterozygotes. In contrast, CpG-B ODNs or IL-10 failed to induce apoptosis in 11/11 CpG-resistant B-CLL cells. Interesting, 2/11 CLL samples had IL10RA genes deletion and 7/11 had IL10R1 S138G GG homozygote mutation. IL10RA gene deletion significantly decreased the IL10R1 expression; both IL10RA gene deletion and mutation significantly decreased the IL-10 binding, abolished or reduced CpG-B ODNs or IL10-induced pTyr701-STAT1/pTyr705-STAT3 expression in B-CLL cells. Conclusion: Deletion and mutation of IL10RA gene on chromosome 11q23 averts CpG-B ODN-induced apoptosis of human B-CLL cells, which may serve as biomarker to predict sensitivity or resistance of CLL to CpG-B ODN treatment.

Background: We previously reported an anti-CD20-interferon (IFN)-alpha fusion protein able to induce apoptosis and promote in vivo eradication of a human CD20-expressing mouse B cell lymphoma (Xuan et al, Blood 2010). We now report the activity of a recombinant anti-CD20-human IFN␣ fusion protein against human non-Hodgkin B cell lymphomas (NHL). Methods: Anti-CD20-hIFN␣ was evaluated against a panel of human Burkitt, diffuse large B cell (DLBCL), and mantle cell lymphoma cell lines. Proliferation was measured by [3H]-thymidine, complement-dependent cytotoxicity (CDC) by PI flow cytometry, and antibody-dependent cellular cytotoxicity (ADCC) by LDH release using PBMC effectors. NHL xenografts were grown in SCID mice. Results: Anti-CD20-hIFN␣ induced stronger growth inhibition than rituximab, particularly against Burkitt and germinal center-type DLBCL NHLs. Tumor growth inhibition by anti-CD20-hIFN␣ was associated with substantial apoptosis in some cell lines. Anti-CD20-hIFN␣ exhibited potent ADCC activity against Daudi, Ramos, and Raji cells, identical to rituximab. Surprisingly, anti-CD20-hIFN␣ exhibited superior CDC compared to rituximab against Daudi, Ramos, and Raji cells, that was dependent upon linkage of IFN␣ to the anti-CD20 antibody, and correlated with improved complement fixation. Importantly, anti-CD20-hIFN␣ achieved superior efficacy compared to rituximab and control fusion protein against multiple NHL xenografts in SCID mice (Raji: p⫽0.002 and OCI-Ly19: p⬍0.0001). At antibody doses at which Raji xenografts progressed through rituximab, anti-CD20-hIFN␣ eradicated 50-88% of established tumors. Non-targeted control fusion protein had only minor effects on tumor growth. Conclusions: Anti-CD20-hIFN␣ has stronger direct anti-proliferative and CDC activities than rituximab against human NHL while retaining potent ADCC activity, and also has the ability to eradicate established NHL xenografts in vivo. These results support the further development of anti-CD20-hIFN␣ for the treatment of B cell NHL, and a phase I first-in-human clinical trial is currently being planned.




Phase I study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the oral inhibitor of indoleamine 2,3-dioxygenase (IDO1) INCB024360 in patients (pts) with advanced malignancies. Presenting Author: Gregory Lawrence Beatty, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA Background: INCB024360 is a potent, selective inhibitor of IDO1. As the catabolism of tryptophan (Trp) to kynurenine (Kyn) by IDO1 inhibits immune responses and IDO1 expression is elevated in many human cancers, IDO1 inhibition may potentiate effective antitumor immune responses. Methods: This dose-escalation study in adult pts with advanced malignancies used a 3⫹3 design to determine MTD, toxicity, PK, PD, and tumor response rate. Daily doses of INCB024360 were evaluated in 28-day cycles in 8 cohorts (50 mg once daily; 50 mg, 100 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 700 mg BID). Treatment continued until disease progression or unacceptable toxicity. PK and PD samples were drawn on days 1 and 15. Results: 52 pts have been treated. Tumor types included colorectal (56%), melanoma (12%), and other (33%). The most common adverse events (ⱖ20%) were fatigue, nausea, decreased appetite, vomiting, constipation, abdominal pain, diarrhea, dyspnea, back pain, and cough. The most common grade 3 or 4 adverse events were abdominal pain, hypokalemia, and fatigue (9.6% each). One DLT each was observed at 300 mg BID (grade 3 radiation pneumonitis) and 400 mg BID (grade 3 fatigue); no DLTs were observed in the 18 pts treated with 600 mg or 700 mg BID. There were no objective responses. At 56 days, stable disease was seen in 15 patients and lasted ⱖ112 days in 7 patients. Significant dose-dependent reductions in plasma Kyn/Trp ratios and Kyn levels were detected at all doses and in all pts. Maximal effects were observed at doses ⱖ300 mg BID. With repeat dosing, 700 mg BID provided an average plasma concentration ~5-fold the projected IC90. Overall, doses ⱖ300 mg BID achieved greater than 90% inhibition of IDO1 throughout the dosing period. Conclusions: INCB024360 was generally well tolerated at doses of up to 700 mg BID and there appears to be no correlation of dose with toxicity. Doses ⱖ300 mg BID were capable of ⬎90% inhibition of IDO1 activity and found to effectively normalize plasma Kyn levels. The recommended dose as monotherapy is 600 mg BID. Clinical trial information: NCT01195311.

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Recombinant adenoviral human p53 gene infusion in treatment of malignant pleural effusions and malignant ascites. Presenting Author: Kaiweng Hu, East Hospital of Beijing University of Traditional Chinese Medicine, Beijing, China Background: Malignant pleural or peritoneal effusions are frequently developed in the late-stage malignant tumors in chest or abdominal cavity. Various drainage methods and intra-cavity chemotherapy have transient and limited benefits. Here we evaluated the role of recombinant adenoviral human p53 gene (rAd-p53) infusion for patients with malignant pleural or peritoneal effusions. Methods: Thirty-two patients with historically diagnosed malignant pleural (18 cases) or peritoneal (14 cases) effusions, 19 males and 13 females with an average age of 61 years old (37– 80 years), were included this study. The malignant pleural effusions were caused by primary lung cancers (8 cases), lung metastatic tumors (4 cases), breast cancers (3 cases), pleural mesothelioma (2 cases), lymphoma (1 cases), and the peritoneal effusions were caused by ovarian cancers (5 cases), primary liver cancers (4 cases), liver metastatic tumors (2 cases), colon cancer (1 case), gastric cancer (1 case), and prostate cancer (1 case). After draining most of the fluids, 4⫻1012 viral particles (VP) of rAd-p53 diluted into 1,000 ml of saline solution for intra-abdominal cavity infusion and 2⫻1012VP of rAd-p53 diluted into 500 ml of saline solution for intra-chest cavity infusion, were given weekly for 4 weeks. The response rate was evaluated. The complete response is defined as the complete disappearance of pleural or peritoneal fluid and negative cytologic findings for ⬎4 weeks, and the partial response is defined as a decrease over 50% of the fluid without the need of drainage and negative cytologic findings for ⬎4 weeks. Results: The pleural effusion showed a complete response in 6 patients (33.3%) and a partial response in 6 patients (33.3%). The peritoneal effusion had a complete response in 3 patients (21.4%) and a partial response in 7 patients (50.0%). The overall response rate was 68.8% (22/32). The symptoms associated with the malignant effusion relieved in 27 patients (84.4%). There were no serious side effects observed except for self-limited fever found in all the cases. Conclusions: Intra-abdominal or chest cavity infusion of rAd-p53 is a safe and effective treatment for some malignant pleural or peritoneal effusions.

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A phase I study of indoximod in combination with docetaxel in metastatic solid tumors. Presenting Author: Erica Jackson, University of South Florida, Morsani College of Medicine, Tampa, FL Background: The indoleamine-2, 3-dioxygenase (IDO) pathway catabolizes tryptophan to create a state of immunosuppression. Indoximod (1-methyl(D)-tryptophan, D-1MT) is an IDO pathway modulator. Preclinical studies in MMTV-neu mouse models have shown indoximod combined with chemotherapy was more effective in causing tumor regression than either agent alone. Based on this data, a phase IB trial was designed to study the safety of the combination of docetaxel (Doc) and indoximod. The primary goal of this trial was to determine the MTD for the combination of Doc and oral indoximod. Secondary endpoints were PK data and efficacy for indoximod/Doc. Methods: This phase IB study consisted of 5 dose levels (DL). Doc was dosed IV q 3 wks at 60 mg/m2 in DL 1-4 and 75 mg/m2 at DL 5. Indoximod was dosed at 300, 600, 1,000, 2,000, and 1,200 mg PO BID continuously in DL 1-5 respectively. MTD was determined using a 3⫹3 design. The DLT rule was 1st cycle ⱖG3 non-heme AEs or ⱖG4 heme AEs despite supportive care or that delay therapy ⬎14d. The PK of indoximod and Doc was analyzed using a HPLC assay. PK was measured on C1D1 and 8. Standard eligibility/exclusion criteria applied along with exclusion of patients previously treated with ipilumimab. Treatment was continued until disease progression, intolerance, or unacceptable side effects. Results: Total # of patients treated at DL1-5 were 7, 6, 6, 2, and 6 respectively, with 22 total patients evaluable for response. DLTs included: G3 dehydration (at 300 mg), G5 neutropenic colitis (at 600 mg), G3 hypotension (at 2,000 mg) and G3 mucositis (at 2,000 mg). DL 5 was well tolerated and is the recommended phase II dose. The most frequent adverse events were fatigue (58.6%), anemia (51.7%), hyperglycemia (48.3%), infection (44.8%), and nausea (41.4%). There were 4 PRs (2 breast, 1 NSCLC, 1 thymic), 9 SD, and 9 PD. There were no drug-drug interactions, and PK was similar to Doc and indoximod single-agent studies. Conclusions: The Doc⫹ indoximod combination was well tolerated with no increase in expected toxicities or unexpected PK interactions. It was active in a pretreated population of patients with metastatic solid tumors. The RP2D is 75 mg/m2 of Doc with 1,200 mg of indoximod BID for the current phase II metastatic breast cancer trial. NCT01191216 Clinical trial information: NCT01191216.

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Adoptive T-cell therapy (ACT) with TILs for metastatic melanoma: Clinical responses and durable persistence of anticancer responses in peripheral blood. Presenting Author: Marco Donia, Center for Cancer Immune Therapy/ Department of Oncology, Copenhagen University Hospital Herlev, Herlev, Denmark Background: TIL treatment holds the promise to introduce a new treatment paradigm into oncology practice. To demonstrate the logistical feasibility of this complex approach in Europe, at Herlev Hospital, Denmark, we have initiated a trial for patients with metastatic melanoma and evaluated the melanoma-specific immunity in the peripheral blood. Methods: We present the updated results of trial NCT00937625. The study takes place in a medium-size academic center (30 in-patient oncology beds) equipped with a 36 square meters cGMP cell production lab integrated in a hematopoietic stem cell transplantation unit. Patients were treated with autologous TILs preceded by standard lymphodepleting chemotherapy but followed by attenuated regimens of IL-2 (n⫽6 low-dose s.c. for 14 days; n⫽9 i.v. intermediate decrescendo dose). Melanoma-specific responses were assessed with intracellular cytokine staining. Results: We have generated TILs from 28/31 patients, with 15 patients treated so far and many TILs cryopreserved for future use. Patients were treated with an average of ⬎50x109 CD4⫹, CD8⫹and a small but consistent fraction of ␥␦ TILs. The lower doses of IL-2 have significantly decreased the classical toxicity of the treatment associated with more harsh IL-2 regimens, and response evaluation showed the achievement of three CR lasting ⬎ 1 year and four PR. Clinical responses were associated with high numbers of tumour reactive T-cells infused. Importantly, in most responding patients we observed induction and durable persistence (up to 1 year) of antimelanoma T-cell responses in the peripheral blood. Conclusions: A high response rate including durable complete responses can be induced after treatment with TILs followed by an attenuated regimen of IL-2, which significantly reduced the occurrence of severe side effects. Effective TIL treatment is associated with induction and long-term persistence in the blood of T cells producing in vitro anticancer responses. By showing that TIL-based ACT is logistically feasible and accessible to medium-size academic centers, we open the possibility for testing this treatment in a large randomized setting in Europe. Clinical trial information: NCT00937625.


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Allogeneic dendritic cell (DC) vaccination as an “off the shelf” treatment to prevent or delay relapse in elderly acute myeloid leukemia patients: Results of phase I study. Presenting Author: Arjan A van den Loosdrecht, Department of Heamatology, Cancer Center Amsterdam, Amsterdam, Netherlands

Effect of oral cyclophosphamide on the immunogenicity of DPX-Survivac in ovarian cancer patients: Results of a phase I study. Presenting Author: Neil Lorne Berinstein, Sunnybrook Health Sciences Centre, Toronto, ON, Canada

Background: Vaccines against tumor-associated antigens represent an appealing strategy for preventing tumor recurrence. A novel immunotherapy platform is represented by the DCOne cell line, which originates from a human myeloid leukemia cell line, endogenously expresses a range of tumor associated antigens and can be differentiated into mature dendritic cells. Methods: A phase I study enrolled 12 AML patients (age range 58-71) who were either in CR1/CR2 (n⫽5) or had smouldering disease (n⫽7), at high risk of relapse and ineligible for available postremission therapies, in a 3⫹3 design, starting with 4 bi-weekly intradermal DCOne DC vaccinations of 10E6 cells (n⫽3), 25E6 (n⫽3) or 50E6 (n⫽6). Patients were monitored for clinical and immunological responses for 126 days and surviving patients were followed up after study completion. Results: Treatment was well tolerated in all patients, with expected toxicities of injection site reactions (⬍ grade 2). During the study 3 patients died: 2 from infections and 1 from leukemia. Patients who survived more than 6 months post-vaccination showed remarkable survival (22 mo after the first patient was recruited, 3 patients have been alive for 22, 20 and 16 months respectively). One patient with smouldering AML at entry achieved CR2 after vaccination; one patient who was in CR2 at entry, relapsed 8 mo after vaccination and entered CR3 following a single low dose of 5-AZA. Remarkably, 1/5 patients that were evaluable by IFNg ELIPOTs showed vaccination-induced specific T cell responses to WT-1 and PRAME, antigens present in DCOne DC. In addition, increased post vaccination delayed type hypersensitivity reactions were observed in all cohorts. Furthermore, induction of systemic immune responses, with increases in CD4⫹ and CD8⫹ T cell proliferative responses and/or seroconversion to DCOne DC and/or AML blasts was seen in 5 out of 9 patients. Conclusions: Vaccination with DCOne derived DC is feasible in AML, generated cellular and humoral immune responses, and interesting clinical responses. The hypothesis that immune responses correlate with clinical benefit will be investigated in a randomised phase II trial. Clinical trial information: NCT01373515.

Background: Survivin, a protein involved in regulation of apoptosis, is highly expressed in many tumor types and has reported prognostic value. DPX-Survivac is a cocktail of survivin HLA class I peptides (A1, A2, A3, A24 and B7) formulated in the novel adjuvanting vaccine platform DepoVax. A phase I study examined the safety and immune potency of DPX-Survivac in combination with cyclophosphamide in ovarian cancer patients. Methods: 18 of 19 advanced ovarian cancer patients treated with platinum chemotherapy and showing no disease progression completed their vaccine therapy. Cohort A (6 pts) received three 0.5 mL vaccine injections 3 weeks apart; cohorts B and C (6 pts each) received three 0.1 mL or 0.5 mL vaccine injections in combination with metronomic low dose oral cyclophosphamide. Adverse events were assessed using CTCAE v4.0. Blood was collected to study immune function (MDSCs, T regs and B cells) and vaccine-induced T cell immunity (ELISpot, tetramer analysis and multi-parametric intracellular cytokine staining). Repeated measures of immunity at baseline and after 1, 2 and 3 injections were analyzed using a general linear model. Results: DPX-Survivac was well tolerated with no significant systemic AEs. Local injection AEs occured in all patients. Grade 3 local reactions occured in 3 patients (1 pt in B and 2 pts in C). 11 of 12 patients receiving the combination therapy produced immune responses by at least 2 assays, generally established with one or two vaccinations and increased or maintained with boosters. A dose response was observed, with cohort C patients producing significantly higher magnitude responses (C vs B, P⫽.013). Low dose cyclophosphamide significantly enhanced the 0.5 ml dose (C vs A, P⫽.015). Notably, antigen specific CD8 T cells were detected ex vivoi n PBL’s using tetramers and further characterized as polyfunctional by multi-parametric ICS, suggesting a robust immune response. Conclusions: DPX-Survivac is well tolerated and immunogenic. Immune modulation with low dose oral cyclophosphamide can dramatically enhance the immunogenicity of this vaccine. The efficacy of the proposed DPX-Survivac vaccine therapy needs to be tested in a randomized phase II study. Clinical trial information: NCT01416038.

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Risk of HCC recurrence with cellular immunotherapy following radiofrequency ablation. Presenting Author: Jiuwei Cui, First Hospital of Jilin University, Changchun, China Background: Although radiofrequency ablation (RFA) has brought promising therapeutic outcome in hepatocellular carcinoma (HCC) treatment, the curative rate was compromised by high recurrence and metastasis after RFA. Immunosupression in patients with HCC is an important factor leading to its recurrence and metastasis. This study was designed to observe the efficiency and safety of application of cellular immunotherapy (CIT) after RFA for HCC patients. Methods: Sixty-two patients with HCC who were treated with radical RFA were divided into two groups: RFA alone (32 patients) and RFA/CIT (30 patients). Autologous mononuclear cells were collected from the peripheral blood and separated by apheresis, and then induced into natural killer cells, ␥␦T cells, cytokine-induced killer cells. These cells were identified by flow cytometry with their specific antibodies and then were infused intravenously to RFA/CIT patients for 3 or 6 courses. The tumor recurrent status of these patients was evaluated with computed tomography (CT) every 3 months after RFA. Progression-free survival (PFS), liver function, viral load, and adverse effects were examined. Results: The median PFS in RFA group was 12.0 (9.1-14.8) months while median PFS in RFA/CIT group has not yet been reached. It indicated that sequential RFA/CIT significantly reduced the risk of HCC recurrence [hazard ratio (HR) ⫽ 0.136]. In RFA/CIT group, six courses had better survival prognosis than three courses (P ⬍0.05). Viral load of hepatitis C decreased in two of three patients without antiviral therapy in RFA/CIT group, but was increased in RFA alone group. The RFA/CIT group maintained the hepatic function at the level before CIT. The hepatic function in 28.1% (9/32 cases) patients in RFA group was deteriorated. Only one developed fever (38.5 °C) after one infusion and recovered 2 hours later. Otherwise, there was no toxic effect in the RFA/CIT group. Conclusions: These preliminary results suggested that combination of sequential CIT with RFA for HCC patients was efficient and safe, and may be helpful in the prevention of the recurrence for the patients with HCC after RFA. It also suggested that the CIT may reduce the risk of recurrence by dual effects of anti-tumor and anti-virus.


Outcome with stereotactic radiosurgery (SRS) and ipilimumab (Ipi) for malignant melanoma brain metastases. Presenting Author: Sana Shoukat, Internal Medicine, Emory University School of Medicine, Atlanta, GA Background: SRS with Ipi for brain metastases from malignant melanoma has been explored for overall survival (OS) (Knisely JP, Yu JB, Flanigan J, et al. Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J Neurosurg. 2012;117:227-33). We present the first retrospective analysis to determine if this combination is safe and improves OS, while accounting for lactate dehydrogenase (LDH). Methods: Patients with melanoma brain metastases who underwent SRS between 1998-2010 (n⫽124) were compared with those who additionally received Ipi (n⫽11). The primary endpoint was median OS from time of SRS, calculated using Kaplan-Meier method. Cox proportional hazard model was carried out for univariate and multivariable survival analysis. The secondary endpoints were local control at initial site of SRS, anywhere intra-cranial failure, need for repeat SRS, and toxicity. Results: Median OS for the entire cohort was 6.9 months. Patients in the Ipi group had an improved median OS of 28.3 months vs. 6.8 months in the non-Ipi group (p ⫽ 0.013). No difference was noted in local control, anywhere intracranial failures, toxicity (radionecrosis, hemorrhage, patient reported memory deficits), or need for repeated SRS. MVA (Table) showed that Ipi independently predicted for improved OS even when taking into account LDH and ECOG performance status. The only confounding factor within the Ipi group was younger age of the Ipi cohort (43 vs. 55 yrs, p ⫽ 0.006). Conclusions: Use of SRS with Ipi appears to be safe and associated with an impressive increase in median OS in patients with brain metastases from malignant melanoma; this combination should be further investigated. Univariate and multivariable analysis. Univariate analysis Variables KPS

ECOG DS-GPA

Number of brain mets

Ipi LDH

⬍⫽ 60 ⬍⫽80, ⬎ 60 ⬎ 80 0 1⫹ 1 2 3 4 1 2 3⫹ Not Given Given ⬍⫽ 250 ⬎ 250

HR (95%CI)

P value

2.11 (1.16 -3.84) 1.60 (1.09 -2.35)

0.011

Multivariable analysis HR (95%CI)

P value

0.47(0.28-0.80)

0.005

0.46 (0.29-0.72)

⬍.001

2.64 (1.48 – 4.72) 1.92 (1.18 – 3.14) 1.09 (0.69-1.73)

⬍.001

0.50 (0.32 – 0.78) 0.47 (0.26 -0.83)

0.004

2.56 (1.18 – 5.51)

0.013

2.30 (1.05-5.04)

0.037

0.45 (0.27 – 0.73)

0.001

0.47 (0.29-0.78)

0.004




Intraperitoneal radioimmunotherapy (RIT) for desmoplastic small round cell tumor (DSRCT): Initial results from a phase I trial. Presenting Author: Shakeel Modak, Memorial Sloan-Kettering Cancer Center, New York, NY Background: DSRCT, a rare sarcoma of adolescents and young adults usually arising from the peritoneum, is lethal in ⬎80% of patients despite aggressive multimodality therapy. Recurrences often present as multifocal peritoneal implants, making it uniquely suited for intraperitoneal (IP) targeting. We hypothesized that targeted radiotherapy may improve local control and reduce relapses. IP RIT, by virtue of prolonged residence time and slow transfer to the circulation, may selectively target IP DSRCT while minimizing organ toxicity. The anti-4Ig-B7H3 murine monoclonal antibody 8H9 binds to 96% of primary DSRCT (Med Pediatr Oncol 39:547). 131 I-8H9 injected intra-Ommaya is safe (J Neurooncol 97:409). Methods: We initiated a phase I study to test the safety of IP RIT with 131I-8H9. Cohorts of 3-6 patients were treated with 131I-8H9 at escalated doses from 30mCi/m2-60mCi/m2 as a single IP injection. A tracer dose of 2mCi124I8H9 was given IP before 131I-8H9 to acquire PET images and biodistribution data. Pharmacokinetics (PK) was studied using serial blood draws. Results: 15 heavily prior-treated patients: 13 with DSRCT, 2 with rhabdomyosarcoma received 30, 40, 50mCi/m2 131I-8H9 (3 at each dose level) or 60mCi/m2 (n⫽6). Dose-limiting toxicity was not seen. Three patients (n⫽1 each) had transient, self-limiting, possibly therapy-related grade 3 toxicities: neutropenia, hepatic transaminase elevation and thrombocytopenia. No patient required hematopoietic stem cell rescue. Blood half life was 32.5⫾11.5h (n⫽12) and mean peritoneal residence time was 14.6h (n⫽3). Mean absorbed dose to blood based on blood sampling was 0.56⫾0.21 rad/mCi (n⫽14). Mean absorbed doses (rad/mCi) to kidney, liver, lung and spleen were 1.72, 1.92, 0.64 and 1.03 respectively (n⫽3). Dehalogenation was insignificant: ⬎80% iodine remained protein-bound in blood (n⫽10). 6/7 DSRCT patients treated without evaluable disease remain in remission at a median of 11.1 months post 131I-8H9. Conclusions: IP 131I-8H9 was safe and 124I-8H9 provided valuable PK and dosimetry data. Since maximum tolerated dose was not reached we have expanded patient accrual to a planned dose of 90mCi/m2. Clinical trial information: NCT01099644.

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Correlative biomarker analysis of sequential tumor biopsies in a ph I mode of action (MoA) study in neoadjuvant head and neck squamous cell carcinoma (HNSCC) patients (pts) treated with RG7160 (GA201), a novel dual-acting, monoclonal antibody (mAb) designed to enhance antibodydependent cellular cytotoxicity (ADCC), with cetuximab (C) as reference. Presenting Author: Christoph Mancao, F. Hoffmann-La Roche Ltd, Basel, Switzerland Background: GA201 is a novel humanized anti-epidermal growth factor receptor (EGFR) mAb with a dual MoA: glycoengineered to enhance ADCC on top of inhibition of EGFR signaling. In an open-label, multi-center trial of pts with HNSCC, an exploratory biomarker analysis of sequential tumor biopsies was performed to investigate the single/duplex marker correlation structure. Methods: Pts received 2 doses of 700 or 1,400 mg GA201 or C (day 1, 8). Tumor biopsies were taken at baseline (BL) and pre-surgery (day 15). Immunohistochemistry immune-cell counts (single/duplex markers), EGFR-pathway markers and intra-tumoral cytokines (LUMINEX) were assessed. Advanced exploratory statistical methods were used to analyse inter-relationship between BL and on treatment markers, and with response (as determined by FDG-PET). Results: All immune markers (single and duplex) presented highly heterogeneous median values at BL, but cluster analysis emphasized their strong inter-correlation. These markers were unrelated to the BL tumor EGFR and pERK expression. Strongest bivariate correlation was seen between (CD16, CD68), (CD3, 4, 8) and (CD4, NKp46). GA201 treatment induced positively correlated dynamic changes (chg) between (CD8, CD68), while C did so for (CD4, CD16) and (CD16, CD68). Strong and negative correlation between (CD56chg, PETchg) was seen only in pts treated with 1,400 mg GA201. Intra-tumoral cytokines like CXCL12 showed good correlation with BL CD3, 16 and 68 infiltration. Principle component analysis also confirmed a good association between most BL immune markers and was able to differentiate strongest PET responders in the 700 mg GA201 cohort. Conclusions: Multivariate statistical methods were used to demonstrate strong interdependencies between immune-effector markers and to highlight their promising associations with response to GA201 treatment, likely due to ADCC processes in the tumors. Clinical trial information: NCT01046266.

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HER2 evaluation process for neoadjuvant targeted therapies in breast cancer. Presenting Author: Yoshio Mizuno, Breast Oncology Center, TokyoWest Tokushukai Hospital, Tokyo, Japan Background: Treatment with a combination of HER2-targeted therapies has emerged as an addition of trastuzumab to neoadjuvant chemotherapy regimens in breast cancer patients and it goes on increasing. For clinical HER2 determination, immunohistochemical (IHC) analysis is an attractive method and all IHC 2⫹ cases are categorized as equivocal and should be reflexed to fluorescence in situ hybridization (FISH) testing. However, research in recent years with respect to false-negative cases for HER2 testing have been reported, and it comes to the question of what considering the indication for trastuzumab in the neoadjuvant chemotherapy. To clarify these controversial points in applying the results of HER2 testing in the clinical setting, we performed a retrospective analysis of core needle biopsy (CNB) and surgical specimen results. Methods: 422 patients underwent primary operations for early breast cancer at TokyoWest Tokushukai Hospital (Tokyo, Japan) from October 2008 to December 2012. Among these patients, 262 patients who received CNB prior to operation were enrolled. Those patients who received preoperative chemotherapy or had DCIS were excluded. With regard to diagnostic criteria, HER2 positivity was defined as either 3⫹ by IHC or FISH analysis amplification ratio of ⱖ2.2. In addition, if in any cases which CNB samples or surgical specimens showed HER2-positive had defined true HER2positive cases, we assessed the false-negative results of the HER2 test via IHC using CNB samples and surgical specimens. Results: In a matched cohort of 262 patients, 59 cases showed HER2-positive (five cases were CNBs negative to surgical specimens positive, 14 cases were CNBs positive to surgical specimens negative, and 40 cases were both positive). If we decide for selection of trastuzumab target cases by CNBs only, we make mistakes in indications of trastuzumab for five (8.5%) of 59 HER2-positive cases who were CNBs negative to surgical specimens positive. Conclusions: There are quite a few cases show false negatives for HER2 testing in CNB samples. In cases of considering the indication for trastuzumab in the neoadjuvant chemotherapy, even if the CNB samples resulted in negative, we consider that retesting with FISH analysis should be carried out.

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Serum lactate dehydrogenase (LDH) as a prognostic selection criterion for ipilimumab treatment in metastatic melanoma. Presenting Author: Christian U. Blank, The Netherlands Cancer Institute-Antoni Van Leeuwenhoek Hospital, Amsterdam, Netherlands Background: Ipilimumab, a CTLA4 blocking antibody, has been shown to improve survival in metastatic melanoma patients in phase III trials. However, only a subset of patients experiences long-term survival benefit. Therefore, we analysed two independent retrospective sets of patients treated in ‘real world’ settings to identify prognostic factors that correlate with better outcome after ipilimumab therapy. Methods: Advanced melanoma patients, eligible for ipilimumab therapy, were treated in the Dutch and UK Expanded Access Programs (EAP) and after European licensing on the 3mg/kg schedule. Baseline characteristics and peripheral blood parameters were assessed and patients were monitored for the occurrence of adverse events and responses. Results: A total of 166 patients were enrolled in the Dutch EAP. Best overall response rate and disease control rate were (DCR) 17% and 35%. Median follow-up was 17.9 months, with a median progression free survival of 2.9 months. Median overall survival (OS) was 7.5 months, and OS at 1 year 37.8% and at 2 years 22.9%. Univariate analysis revealed that gender, age, Breslow thickness, baseline and week 6 lymphocyte count (ALC), and prior treatment had no influence on OS, while mWHO, M stage, baseline LDH, S100, erythrocyte sedimentation rate (ESR), and the slope of ALC did. In a multivariate model only baseline LDH and ESR remained as significant independent prognostic factors. The relevance of LDH was validated in an independent cohort of 68 patients from the UK. Stratifying the patients in the NL cohort according to LDH levels (ⱕupper limit normal (ULN), 54.4% of patients versus ⬎2xULN, 16.9% of patients) separated into groups of patients observing DCR of 48% versus 14%, and median OS of 13.7 versus 3.1 months, while toxicity was similar in both groups (48% and 41%). None of the patients was alive at 15 months after treatment if baseline LDH was ⬎2xULN in both the NL and UK cohorts. Conclusions: Overall survival upon ipilimumab treatment is lower in an expanded access population as compared to phase III trials. LDH ⬎2xULN at baseline is a potential prognosticator in patients receiving ipilimumab and should be considered in guiding ipilimumab treatment initiation.


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Developmental Therapeutics—Immunotherapy General Poster Session (Board #13D), Mon, 8:00 AM-11:45 AM

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A novel method to identify and monitor endogenous tumor-reactive T cells by high expression of CD11a (LFA-1) and PD-1 (CD279) as immunologic readout for evaluating the efficacy of PD-1 blockade. Presenting Author: Haidong Dong, College of Medicine, Mayo Clinic, Rochester, MN

Relationships of peripheral blood lymphocyte counts (PBLC) with antitumor activity of NGR-hTNF given in combination with chemotherapy (CT). Presenting Author: Alessandra Bulotta, Department of Oncology, Istituto Scientifico Ospedale San Raffaele, Milan, Italy

Background: Tumor immunotherapies directed towards enhancing natural or endogenous anti-tumor T-cell immunity in patients with advanced malignancies are currently being implemented in clinic with promising results. In order to optimize therapeutic protocols and monitor the effectiveness of such therapies, a reliable T-cell marker is needed. Methods: We utilized CD11a (LFA-1, lymphocyte functional-associated antigen 1), an integrin up-regulated on effector and memory CD8 T-cells, and PD-1 (programmed death-1), an immunoregulatory receptor expressed by activated T cells, as biomarkers to identify, quantitate and monitor endogenous tumor-reactive cytotoxic lymphocytes (CTLs) in two mouse tumor models and the peripheral blood (PB) of 12 patients with stage IV melanoma. Results: High expression of CD11a and PD-1 was identified among CD8 T-cells residing within primary and metastatic murine tumor sites, as well as in spontaneous murine breast cancer tissues. In the PB of melanoma patients, tumor antigen-specific CD8 T cells were associated with a population of CD11a high CD8 T-cells which co-expressed high levels of PD-1, as opposed to eleven healthy donors who had a much lower frequency of PD-1⫹ CD11a high CD8 T-cells (p ⬍0.0001). Phenotypic analysis showed that CD11a high CD8 T-cells are proliferating (Ki67 positive) activated (CD62L low, CD69 high) T-cells. Increased CD11a high CD8 T-cells and delayed tumor growth were observed in PD-1 deficient mice, suggesting that the antitumor effector function of CD8 T cells is compromised by co-expression of elevated levels of PD-1. Conclusions: CD11a high CD8 T-cell population expresses high levels of PD-1 and is likely the cellular target of PD-1 blockade therapy. High expression of CD11a (LFA-1) and PD-1 (CD279) by CD8 T-cells may represent a novel biomarker to identify and monitor endogenous tumor-reactive CTLs. This may not only provide an immunological readout for evaluating the efficacy of therapy, but also contribute to the selection of patients with solid malignancies likely to benefit from anti-PD-1 therapy.

Background: Antitumor effects of NGR-hTNF (N), a tumor-targeted antivascular agent, are driven at low dose by an early vessel stabilization that greatly enhances both intratumoral CT uptake and T-cell infiltration. Synergism with CT was shown in immunocompetent mice, but not in nude mice lacking functional T cells. Methods: By an individual patient pooled analysis of 396 patients (pts) from 7 ph II trials in 6 tumor types, we estimated the effects of baseline PBLC on the antitumor activity of N (with or without CT) and CT alone. Low dose N (0.8 ␮g/m2) was given in combination with CT in 171 pts. Control groups of 140 and 85 pts receiving N and CT alone, respectively, were also analyzed. CT was doxorubicin or a platinum-based regimen. In all trials, response to therapy was assessed every 6 weeks by RECIST. Endpoints of interest were response rate (RR, complete plus partial response), disease control rate (DCR, RR plus stable disease), duration of response (DOR) and progressionfree survival (PFS). In logistic and Cox regression analyses, PBLC data were dichotomized in high or low levels by the median cutpoint (1.5/mL; 95% CI, 1.4-1.6). Multivariate models included age, sex, PS and tumor type as covariates. Results: In both N-alone and CT-alone groups, there was no statistically significant difference in treatment effect according to baseline PBLC. Conversely, high PBLC were related to better treatment outcome in the N plus CT group, compared to low PBLC. In this N plus CT group, high PBLC (vs low) were associated with higher RR (OR⫽2.8; 95% CI, 1.2-6.3; p⫽.01) and DCR (OR⫽2.6; 1.3-4.9; p⫽.004), and with longer DOR (HR⫽0.39; 0.16-0.96; p⫽.04) and PFS (HR⫽0.60; 0.43-0.85; p⫽.004). For high vs low PBLC, RR was 29% vs 14%, DCR 76% vs 57%, median DOR 8.2 vs 6.3 months, and median PFS 5.0 vs 3.0 months, respectively. On multivariate analyses, high PBLC remained an independent predictor of increased RR (OR⫽2.7; p⫽.01) and DCR (OR⫽2.6; p⫽.005), and improved DOR (HR⫽0.36; p⫽.04) and PFS (HR⫽0.60; p⫽.005). Conclusions: Consistently with preclinical data, these results highlight the potential value of PBLC in predicting tumor response to NGR-hTNF in combination with CT, which merits further clinical validation Clinical trial information: NCT00994097-NCT00484432-NCT00484276NCT00484211-NCT00483509-NCT00483080-NCT01358071.

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Phase I study of weekly treatment with paclitaxel injection concentrate for nanodispersion (PICN), a novel solvent and protein-free formulation of paclitaxel. Presenting Author: Minish Mahendra Jain, KEM Hospital and Research Center, Pune, India

Effect of vaccination with autologous tumor-loaded dendritic cells on intratumoral regulatory T cells in metastatic melanoma patients. Presenting Author: Massimo Guidoboni, Immunotherapy and Somatic Cell Therapy Lab, IRCCS-IRST, Meldola, Italy

Background: PICN is a novel solvent and protein-free 100-110 nm particle formulation of paclitaxel stabilized with polymer and lipid using Nanotecton Technology. Paclitaxel has shown superior safety and efficacy profile when administered on a weekly schedule. We studied safety, tolerability, and pharmacokinetics (PK) of PICN using a weekly schedule in patients with advanced solid malignancies. Methods: Patients aged18-65 years with advanced solid malignancies, ECOG performance status ⱕ 2, estimated survival ⱖ 12 weeks, and adequate organ function were enrolled. A standard phase I, 3⫹3 dose escalation design to determine the maximum tolerated dose (MTD) of PICN administered on a weekly schedule (three consecutive weeks, one week recovery) was employed. PICN dose was escalated at pre-determined fixed dose levels of 80, 100, 125, 150, 175, and 200 mg/m2. PICN was administered as a 30 min infusion without any premedication for hypersensitivity. Results: Twenty-one patients treated with PICN had a mean age of 52.1 yrs (range 35-67); 20 were female and entered with metastatic breast cancer (MBC; n⫽15), cervical cancer (n⫽3), skin cancer (n⫽2). One male had oral cancer. Doses studied were 80 (n⫽3), 100 (n⫽3), 125 (n⫽3), 150 (n⫽3), 175 (n⫽6), and 200 (n⫽3) mg/m2. Despite the lack of dexamethasone premedication, no patient receiving PICN reported hypersensitivity reaction. Two DLTs (neutropenia and febrile neutropenia; both grade 3) were reported at PICN 200 mg/m2. PICN PK (AUC0-24, AUC0-⬁, and Cmax) increased in a dose proportionate manner from 80 to 200 mg/m2. Grade 3 or worse related AEs were: neutropenia, leucopenia, peripheral neuropathy, febrile neutropenia, anemia, thrombocytopenia, fatigue, syncope, hypotension and maculopapular rash. Partial responses were observed in MBC (100, 125, 150, 175, and 200 mg/m2) and cervical cancer (80 mg/m2). Conclusions: PICN on thrice monthly schedule was tolerable in the dose range evaluated. Two DTLs were reported: neutropenia and febrile neutropenia (both grade 3). Anti-tumor activity was observed in MBC and cervical cancer. Final trial data for PICN PK, safety, and efficacy will be presented at the conference. Clinical trial information: CTRI/2011/11/002124.

Background: Vaccination with dendritic cells (DC) is still a valid experimental option for metastatic melanoma (MM). However, only a few patients experience long-lasting objective responses and the majority of clinical responders afterwards relapse and die. Which mechanisms are actually responsible for this “secondary resistance” to whole tumor antigens-loaded DC vaccines is largely unknown. It has been hypothesized that suppressive immune cell subpopulations, regulatory T cells in particular, may progressively accumulate in tumor tissues thus hampering therapy-induced antitumor immune responses along time. To elucidate this issue we evaluated changes induced by immunologically effective DC vaccination in the composition of tumor-associated T cell subpopulations. Methods: 12 patients with MM previously enrolled in a phase I/II DC vaccine trial and for which tumor tissue taken before and after at least 4 induction vaccine doses were available, were included in the study. Intratumoral lymphocytes were evaluated by CD3, CD4, CD8, FoxP3 and GrB immunostainings, and quantified by a computer-assisted method. A nonparametric two-tailed Wilcoxon signed-rank test was utilized for evaluating differences in the distribution of the number of cell positive for each marker on the total cell counts in pre- and post-vaccine biopsies. Results: Our data showed a considerable and statistically significant decrease of intratumoral FoxP3⫹regulatory T cells in melanoma tissues after DC vaccination. In addition, the concurrent increase of intratumoral activated cytotoxic T lymphocytes, as shown by CD8 and Granzyme B stainings, indicated that this decrease has likely a functional relevance. Conclusions: Our findings that vaccination with DC loaded with autologous tumor lysate strongly reduces the intratumoral content of regulatory T cells add strength to the rationale for the development of potentially more effective combination schedules where whole tumor antigen-loaded DC vaccine prime and partially activate tumor-specific low-affinity T cells in a first tumor antigenfocusing step, followed by boosting with non-maximal doses of anti-CTLA-4 antibodies.




T-regulatory cell function analysis in locally/regionally advanced melanoma patients treated with ipilimumab. Presenting Author: Robert Alan VanderWeele, University of Pittsburgh Cancer Institute, Pittsburgh, PA Background: We conducted an immunogenicity and biomarker analysis in stage IIIB-C melanoma patients treated with neoadjuvant ipilimumab (ipi) and reported a significant increase in the frequency of circulating Tregulatory cells (T-reg) (CD4⫹CD25hi⫹ Foxp3⫹; p⫽0.02 CD4⫹CD25hi⫹CD39⫹; p⫽0.001) from pre-ipi (baseline) to post-ipi (6 weeks) in treated patients (Tarhini et al., ASCO 2012). Also, increases in T-reg were associated with improved PFS (p⫽0.034; HR⫽0.57). We hypothesized that ipi induces its clinical activity in part through its effect on T-reg, and despite the observed increase in circulating T-reg frequency; their suppressor function is reduced. Methods: Patients were treated with ipi (10 mg/kg IV q3weeks x 2doses) bracketing definitive surgery. PBMC were collected at baseline and at 6 weeks. T-reg were isolated from pre-ipi (baseline) and post-ipi (6 weeks) PBMC samples utilizing Miltenyi Biotec T regulatory isolation kit (CD4⫹CD25⫹CD127dim/-). Isolated T-reg were incubated with OKT3/IL-2/CD28-stimulated and CFSE-labeled CD4⫹CD25responder T-cells from the same patient time point at 1:1, 1:2 and 1:5 ratios. Flow cytometery was used to evaluate the number of cell divisions of CFSE labeled responder cells and, therefore, the degree of T-reg proliferation suppression. Results: Thirty-five patients were enrolled in the study; of those, 18 patients had adequate PBMC samples with sufficient T-reg isolated for T-reg functional analysis. Preliminary analysis of the first 13 patients shows a trend toward decreased suppressive function of T-reg after treatment with ipi. Expressed as “percent of maximum inhibition”, pre- vs. post-ipi T-reg showed 61% vs. 47% suppressive activity (p⫽0.15) at the 1:1 ratio. Conclusions: There was a trend toward decreased suppressive function of T-reg after treatment with ipi, supporting the function modulation hypothesis. T-reg functional analysis for the remaining 5 patients is ongoing and we will perform comparative studies of changes in T-reg function with changes in T-reg frequency and clinical outcomes in the entire cohort.

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Investigating genes and micro-RNAs that may predict clinical benefits of anti-CTLA-4 therapy. Presenting Author: Jianjun Gao, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Blockade of T cell co-inhibitory receptor CTLA-4 with a monoclonal antibody, ipilimumab, has led to augmented anti-tumor immune responses, clinical benefit, and FDA approval of ipilimumab for the treatment of metastatic melanoma. Only a subset of patients benefit from anti-CTLA-4 therapy. In order to identify genes, microRNAs, and signaling pathways that are modulated by anti-CTLA-4, which may be used for potential correlation with clinical outcomes or provide additional targets for therapy, we purified and analyzed CD4⫹T cells from patients treated with anti-CTLA-4 for changes in gene and microRNA expression profiles. Methods: On an IRB-approved phase Ia presurgical clinical trial, 6 patients with localized bladder cancer were treated with two doses of ipilimumab at 10 mg/kg at weeks 1 and 4. Pre-therapy and post-therapy blood samples were collected for CD4⫹ T cell enrichment by using the T cell isolation kit from Miltenyi Biotec (Auburn, CA). RNA and microRNA were isolated from purified CD4⫹T cells using Qiagen RNA isolation kits for Affymetrix microarray and micoRNA array analyses. Microarray data were then analyzed using Ingenuity iReport (Redwood City, CA). RT-PCR and Western blot were used to confirm significant changes in genes or pathways identified in microarray analyses. Results: Anti-CTLA-4 treatment resulted in modulation of differentially expressed genes (DEGs). After two doses of treatment, anti-CTLA-4 significantly changed expression of a total of 289 DEGs. Further pathway analyses indicated that anti-CTLA-4 induced a variety of pathways involved in cell proliferation and immune modulation, including PI3K/AKT, MAP/ERK, and IFN/JAK-STAT pathways. We have also identified 9 microRNAs that potentially regulate the expression of genes changed by anti-CTLA-4 therapy. Conclusions: Anti-CTLA-4 treatment results in modulation of multiple genes, microRNAs, and pathways, which likely play important roles in anti-tumor immune responses. We are currently testing a number of these identified genes and microRNAs as potential predictive biomarkers for anti-CTLA-4 therapy in a small cohort of patients who had complete response vs. progression of disease after anti-CTLA-4 therapy.

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Circulating endothelial microparticles (EMP) modifications as predictive biomarkers of resistance to chemotherapy for breast cancer (BC). Presenting Author: Elisa Garcia-Garre, Hematology and Medical Oncology Department, University Hospital Morales Meseguer, Murcia, Spain Background: Growing evidence indicates that EMP may both modulate angiogenesis and endothelial injury in cancer and cardiovascular disease. However, it has not been shown whether in vivo release of EMP might reflect the tumor response or the antiangiogenic effects of chemotherapy (CT). The aim of this work was to evaluate the relationship between the levels of small-size EMP (sEMP) and resistance to CT in locally advanced and metastatic BC. Methods: Citrated platelet-free plasma was obtained from BC patients before and after 3-4 cycles of chemotherapy. Small-size CD144⫹ sEMP (0.1-0.5 ␮m diameter) were prospectively quantified using a high resolution Apogee A50 flow cytometer. Association of EMP with clinical variables, response to CT and survival was analyzed. Response (partial or complete) was defined by RECIST criteria. Results: 45 BC patients were included (20, metastatic; 25, locally advanced). Treatment included anthracyclines in 66.7% of patients and taxanes in 15.5%. Small-size EMP baseline counts were higher in premenopausal women (p⫽0.008), but no association with other clinical or pathological characteristic was found. A significant decrease of circulating sEMP was observed after treatment with CT in the whole group of patients with paired samples available (n⫽33): pre-CT: 416.2 ⫾ 365 vs. post-CT: 340.7 ⫾ 458 (p⫽0.005). Lower chemotherapy-induced sEMP decrease was associated to treatment resistance: ROC analysis demonstrated a 66.7% sensitivity and 72.2% specificity of lower sEMP decrease for lack of response to CT using a decline cut-point of -40 sEMP (close to median decrease: -47). With the same cut-point of low sEMP decrease, odds ratio for treatment resistance was 5.2 (95% confidence interval, 1.17-23.04; p⫽0.03). No clear association of the degree of sEMP decrease was found for disease or progression free survival in the neoadjuvant or in the metastatic setting. Conclusions: This study suggests that circulating sEMP decrease after CT and are tightly associated with treatment resistance in BC patients. These findings indicate pathophysiological roles for sEMP in BC and support their potential role as treatment resistance biomarkers.

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Clinical and pharmacodynamic (PD) results of a phase I trial with AMP-224 (B7-DC Fc) that binds to the PD-1 receptor. Presenting Author: Jeffrey R. Infante, Sarah Cannon Research Institute; Tennessee Oncology, Nashville, TN Background: PD-1/B7-H1 (PD-L1) axis blockade can reinvigorate T cells, and overcome tumor immune evasion of multiple tumor types. AMP-224 is the first recombinant B7-DC-Fc fusion protein tested in patients that binds to and modulates the PD-1 axis through a unique MOA. The MoA hypothesis for AMP-224 is depletion of PD-1high expressing T-cells representing exhausted effector cells. Subsequent replenishment of the T-cell pool with functional T-cells may restore immune function. Methods: Patients with advanced solid tumors received low dose CTX on Day 0, followed by AMP-224 (IV infusion) on Days 1 and 15 of each 28-day cycle in doses ranging from 0.3 to 30 mg/kg. Blood samples were assessed serially for changes in lymphocyte subsets, PD-1HIT cells and T cell effector function. IHC staining of paired biopsies for B7-H1, CD8, PD-1, CD4 and FoxP3 was performed to assess immunological status of the tumor at baseline and following treatment and then relative to peripheral readouts. Results: 42 patients (83% melanoma) were treated with varying doses of AMP-224 [0.3 mg/kg (n ⫽ 6); 1 mg/kg (n⫽4); 3 mg/kg (n ⫽ 4); 10 mg/kg (n ⫽ 22); 30 mg/kg (n ⫽ 6)]. Infusion reactions were common (69% across dose cohorts) and occurred mostly at higher doses (86% at the 10 mg/kg dose). No drug-related inflammatory adverse events were identified contrary to PD-1 blocking antibodies. Fresh pre-treatment biopsies were collected from 33/42 (78.5%) patients and paired biopsies have been collected thus far from 19/36 (52.7%) patients on study. 31% of baseline tumors were B7-H1⫹. Several PD readouts in the periphery showed reductions in PD-1HIcells and emergence of a functional T cell response (increases in IFNg⫹, TNFa⫹, IL-2⫹ CD4 and CD8 T cells) in individual patients where partial response, stable disease, and mixed responses were seen. Conclusions: Data from peripheral readouts is consistent with hypothesized AMP-224 MoA. B7-H1⫹ was not always predictive of functional response to AMP-224 immunotherapy. Comprehensive PD readouts and evaluation of PK/PD relationships will be presented and may ultimately predict restoration of immune competence even in the presence of initial disease progression. Clinical trial information: NCT01352884.


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A trial of autologous ex vivo expanded NK cell-enriched lymphocytes with docetaxel in patients with advanced NSCLC as second- or third-line treatment: Phase IIa study. Presenting Author: Suk-Young Park, The Catholic University of Korea, Daejeon St. Mary’s Hospital, Daejeon, South Korea Background: Cancer immunotherapy has been attractive for a long time with diverse clinical attempts and results. In particular, NK cells have received considerable attention because of their potential role in immune surveillance in vivo. MICA/B on tumor cells, known as the representative ligand for NKG2D receptor on NK cell, has been reported to be modulated by a variety of stresses including some chemotherapeutic agents and it is anticipated that enhancing MICA/B expression is contributory to anti-cancer treatment. With recent development of expanding autologous ex-vivo NK cell enriched lymphocytes (NKL), we designed a trial to augment the anti-cancer effect by co-administering NKL and docetaxel (D), one of the second-line agents in patients with advanced NSCLC. Methods: We first identified some chemotherapeutic agents, such as cisplatin and D, that induce peak MICA/B expression on HeLa cell during the 24-36 hours and designed a trial of combination of NKL with D administered within the same day. Eligible patients were 20-75 years old, ECOG PS 0-2, previously received one chemotherapy, and had stage IIIB/IV histologically proven NSCLC with measurable lesions. NKL were prepared and provided from NKBIO CO. Feasibility, adverse effect, and PFS were evaluated and compared with historical control of weekly D. Results: 19 patients were enrolled before early closure. NKL production and administration were feasible in all cases even with disseminated disease. No additional AE was observed in addition to that reported in D alone. PFS 3M and RR 10.5% with 2 PR were observed and similar to historical control (PFS 2.9M, RR 8.8%). Conclusions: To our knowledge, it seems to be the first report on the combination of NKL with D in patients with advanced NSCLC. Autologous NKL production and co-administration with D were feasible without further toxicity or complication. Benefit in PFS and RR, as compared with historical control, was not detected in this study population with advanced NSCLC, but further study to see whether the combination of NKL and chemotherapy has anti-cancer effect is desirable to be performed in low tumor burden state, such as less advanced or remission induced state.

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Therapeutic superiority of a TCR-like antibody to an intracellular WT1 oncogene peptide compared with the tyrosine kinase inhibitor imatinib in a mouse model of Philadelphia chromosome positive (Phⴙ) ALL. Presenting Author: Leonid Dubrovsky, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Acute and chronic leukemias demonstrate significantly increased expression of the Wilms tumor gene 1 (WT1) product, including ⫹ CD34 CML stem cells, making WT1 an attractive therapeutic target. However, WT1 protein is intracellular and currently un-druggable. ESKM is a fully human IgG1 antibody that targets a 9 amino acid sequence (RMF) of the protein WT1 in the context of HLA-A0201. Methods: BV173 is an HLA-A0201 positive Ph⫹ ALL cell line. It over-expresses WT1 and binds strongly to ESKM. We evaluated the in vitro and in vivo efficacy of ESKM in combination with TKIs. Antibody-dependent cell-mediated cytotoxicity (ADCC) was evaluated in vitro by chromium release assay, utilizing human PBMC effectors. In vivo tumor growth was assessed in NSG mice bearing disseminated luciferase tagged BV173 with bioluminescence imaging and flow cytometry of the bone marrow after sacrifice. Imatinib was used at maximum tolerated doses for these mice as determined in pilot studies. Results: The addition of imatinib in vitro did not affect the ability of ESKM to perform ADCC. The BV173 engrafted NSG mice treated with ESKM with and without TKIs showed tumor regression one week after beginning therapy, clearing leukemia from the liver and spleen. Mice relapsed primarily in the bone marrow, with increasing luciferase signal after two weeks of therapy. Compared to untreated control animals, after 5 weeks of therapy, imatinib alone only reduced tumor growth by 45%; ESKM alone reduced growth by 81%, and the combination of ESKM and imatinib reduced growth by more than 95%. Flow cytometry of cells remaining after treatment showed binding of ESKM, suggesting escape was not due to down regulation of the epitope. Conclusions: In this mouse model of Ph⫹ ALL, ESKM antibody therapy is superior to imatinib and the combination of both modalities is additive. This antibody is efficacious in vitro and in vivo against WT1 overexpressing leukemias, in context of HLA-A0201. This combination holds promise as a therapy for leukemias in patients who are HLA-A0201 positive, with the potential of improved cytoreduction in patients with Ph⫹ leukemias.

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Up-regulation of stromal cell-derived factor by il-17 and il-18 via PI3K dependent pathway. Presenting Author: Inhye Ahn, The Methodist Hospital, Houston, TX Background: Stromal cell-derived factor-1 (SDF-1) is a versatile chemotactic cytokine and a sole ligand of CXCR4. SDF-1-CXCR4 axis is the most commonly expressed pathway in cancer cells, and is also responsible for metastasis, homing of stem cell, HIV infection, and autoimmune diseases. Interleukin (IL)-17 plays a key role in the pathogenesis of inflammation by inducing SDF-1 to propagate inflammation and vascular endothelial growth factor to provoke angiogenesis. Recent studies revealed that IL-17 pathway is interwoven with multiple cytokines and downstream pathways. Members of the IL-1␤ family, including IL-18, have recently gained attention. By measuring SDF-1 production regulated by individual and simultaneous cytokine stimulations, two cytokines were explored to define their effects, their downstream signal transduction pathways, and the impact of their antibodies. Methods: Synovial tissue was obtained from patients with rheumatoid arthritis and their age- and sex-matched controls with osteoarthritis. Fibroblast-like synoviocytes (FLS) were isolated and stimulated with a combination of IL-17 and IL-18 and quantified SDF-1 production with ELISA and their transcripts with RT-PCR. Another subset of FLS were preconditioned with PI3K inhibitor, 100 nM wortmannin, and stimulated with either 5 ng/mL of IL-17, 10 ng/mL of IL-18, or combination of both cytokines. Mann-Whitney test was adopted for statistical analysis. Results: Both IL-17 and IL-18 increased SDF-1 level and its mRNA transcript, not only individually but also synergistically (p ⬍0.05). In the group where PI3K inihibitor was applied, the individual and synergistic promotion of SDF-1 production by IL-17 and IL-18 were inhibited (p⬍0.05). Concomitant application of anti-IL-17 and anti-IL-18 led to further decline of SDF-1 production (p⬍0.01). Conclusions: This is the first report of PI3Kdependent synergism between IL-18 and IL-17, and adds a novel perspective of the role of IL-18 in immune regulation. The individual effects of these two cytokines, and their interaction through PI3K, suggest an interrelationship between the IL-1 family and IL-17.

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Pharmacokinetics (PK) of blinatumomab and its clinical implications. Presenting Author: Benjamin Wu, Pharmacokinetics & Drug Metabolism, Amgen Inc., Thousand Oaks, CA Background: Blinatumomab is an investigational, bispecific, single-chain T cell engaging (BiTE) antibody of 55 kD that targets CD19 on B cells and CD3 on T cells. Blinatumomab induces polyclonal T cell activation and proliferation, resulting in redirected lysis of CD19⫹target cells. Comprehensive analysis of its PK and the clinical implications is presented. Methods: PK data from 131 patients enrolled in 3 phase 1 or 2 studies of non-Hodgkin lymphoma (NHL; N⫽76), relapsed/refractory acute lymphoblastic leukemia (r/r ALL; N⫽36), and ALL with minimal residual disease (MRD; N⫽19) were analyzed. Blinatumomab was given by constant IV (cIV) infusion at 0.5, 1.5, 3, 5, 10, 15, 30, 60 and 90 ␮g/m2/d over 4 weeks/cycle. Serum blinatumomab concentrations were assessed using a validated bioassay. PK parameters, including volume of distribution (V), half-life (t1/2) and clearance (CL), were analyzed with noncompartmental methods. CL was derived by dividing infusion rate by blinatumomab concentration at steady state (Css). Mean CL from each patient was used to determine disease heterogeneity and for covariate analyses. Effective dose was assessed with PK, in vitroand clinical B cell data. Results: At the doses tested, blinatumomab had linear PK that was stable over time. V (~5 L) approximated that of monoclonal antibodies. Blinatumomab had a t1/2 of ~2 h, with systemic CL of ~2 L/h. Minute blinatumomab concentrations were detected in the urine of 3 (of 13) NHL patients at a dose of 60 ␮g/m2/d. There was no trend of NHL, r/r ALL or ALL with MRD; CrCL, age, gender, weight, or body surface area (BSA) influencing CL. Preliminary analysis showed comparable mean CL values in patients with CrCL ⱖ30 mL/min, ranging from 1.9 to 2.6 L/h. To achieve Css above the in vitro EC90 value for leukemia cell lines (470 pg/mL) and complete B cell suppression in patients, 15 ␮g/m2/d of blinatumomab given as cIV over 4 weeks/cycle is desired for ALL treatment. Conclusions: Blinatumomab PK was linear, stable, and independent of NHL, r/r ALL or ALL with MRD. Kidney involvement in its excretion was limited at the investigated doses. cIV administration is required due to the short t1/2. Flat or BSA-based dosing can be used in adults. A cIV dose of ⱖ15 ␮g/m2/d provides adequate exposure for ALL treatment. Clinical trial information: NCT00274742, NCT01209826, NCT00560794.




Phase II study of dendritic cell vaccination combined with recombinant adenovirus-p53 in treatment for patients with advanced pancreatic carcinoma. Presenting Author: K Chai, Center of Tumor Biological Therapy, Jingdu Hopital, NanJing, JiangSu, China, Nanjing, China Background: There are few choices of treatments for advanced pancreatic carcinoma (PC) due to the resistances to chemo- or radio-therapy. Immunotherapy based on dendritic cell (DC) vaccines and p53-based gene therapy are two promising therapeutic modalities. They also demonstrated favorable safety profiles. In this study, we compared the immunological and clinical response between DC vaccine therapy and DC vaccine combined with recombinant adenovirus-p53 (rAd-p53) gene therapy. Methods: Thirtysix patients with a stage IV pancreatic cancer, 21 men and 15 women with an average age of 56.2 years old, were included in this study and randomly assigned to two groups: 16 patients in DC group (DCG) and 20 in DC plus rAd-p53 group (DPG). The DCG patients received autologous antigenloaded DC (antigen from isolated pancreatic cancer cells) and the DPG patients received both DC and rAd-p53. DC vaccines were injected intra-dermally once every week for 4 injections and rAd-p53 were given by intravenous injections once per 3 days for 5 times at a dose of 3 x 1012viral particles. The response, safety and peripheral blood lymphocyte subsets were investigated. Results: The post-treatment CD3⫹, CD3⫹CD4⫹, CD4⫹/ CD8⫹ ratio of patients’ peripheral blood in both groups were increased. But the percent of CD4⫹CD25⫹ regulatory T cells were significantly decreases. In DPG, 5 patients had a partial response (PR) and 4 patients had stable disease (SD) according to the RECIST standard. The 3 and 3 DCG patients achieved a PR and SD, respectively. The disease control rates (PR⫹SD) were 45.0% and 37.5% for DPG and DCG, respectively. The 6-month overall survival rates were 50.0% and 43.8% for DPG and DCG, respectively. The median survival times were 6.8 and 5.5 months for DPG and DCG, respectively. Mild to medium grade fever was observed in most of the patients in the two groups. No serious adverse events were found. Conclusions: DC-based immunotherapy and p53 gene therapy are safe and appropriate treatments for patients with advanced pancreatic carcinoma. The combined treatments showed more beneficial results than the DC immunotherapy alone.

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Blinatumomab exposure and pharmacodynamic response in patients with non-Hodgkin lymphoma (NHL). Presenting Author: Youssef Hijazi, Amgen Research (Munich) GmbH, Munich, Germany Background: Blinatumomab (AMG 103) is an investigational, bispecific, T cell engaging (BiTE) antibody targeting CD19-expressing B cells. We describe the exposure-pharmacodynamic (PD) response of blinatumomab in patients with NHL, using a quantitative pharmacology approach. Methods: In a phase 1 study, 76 patients with NHL received blinatumomab by continuous intravenous infusion (cIV) at doses of 0.5 to 90 ␮g/m2/d in 4or 8-week cycles. Pharmacokinetics (PK) was determined. PD responses evaluated included lymphocytes and cytokines measured during treatment, and sum of the products of the greatest diameters of tumor size in lymph nodes (SPD) at the end of treatment. Blinatumomab concentration at steady state (Css) and the cumulative area under the concentration (AUCcum)–time curve over the period before the evaluation of SPD were used to evaluate the exposure-SPD relationship. Results: Blinatumomab showed linear PK. Early PD responses were characterized by B cell depletion, T cell redistribution, and transient cytokine release. Following cIV at doses from 0.5 to 90 ␮g/m2/d, B cells declined at a first-order rate with a dose-dependent rate constant, ranging from 0.16 to 1.0 h-1. Complete B cell depletion was achieved within 48 hours at doses ⱖ5 ␮g/m2/d. A dose-independent decrease in T cell counts was observed within 24 hours after dosing, and T cells returned to baseline within 2 weeks of treatment. Cytokine elevation occurred in some patients and was dose-dependent. Blinatumomab exposure-SPD relationship was best described by an inhibitory Emax model (E ⫽ E0-(Imax*C)/(IC50⫹C)). According to the model estimation, a 50% reduction in SPD would be achieved when Css is 2141 pg/mL and AUCcum is 1381 h*␮g/L, equivalent to a blinatumomab dose of 54 ␮g/m2/d given over 27 days. Conclusions: B lymphocytes were completely depleted from the circulation at blinatumomab doses ⱖ5 ␮g/m2/d. Depletion was faster at higher doses. Higher blinatumomab Css and AUCcum were associated with better tumor reduction. Tissue accessibility may explain the higher dose requirement for SPD reduction versus peripheral B cell depletion. The PK/PD model has utility for the design of future studies of blinatumomab in NHL. Clinical trial information: NCT00274742.

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Clinical guideline on the prophylactic use of G-CSF on neutropenia by chemotherapy. Presenting Author: Roberto Rivera-Luna, Instituto Nacional de Pediatria, Mexico City, Mexico Background: Febrile neutropenia (FN) is common in patients with chemotherapy. It requires conventional treatment, however, many studies have reported that G-CSF reduces the incidence of FN; the results were not clear and the physicians use it at their discretion. In this guideline we evaluated the efficacy and safety of the prophylactic use of G-CSF. Methods: We analyzed controlled trials (G-CSF, pegylated form or placebo) given to adult or pediatric patients with chemotherapy for leukemia (LEU), lymphoma and solid tumors (L&ST) or stem cell transplant (SCT), without infections and large radiation ports. Two independent reviewers applied CONSORT to determine the methodological quality; for ranking the evidence we used GRADE and the recommendations were developed by Delphi method. We developed subgroups according to age and type of intervention to analyze the outcomes (risk, duration, severity of FN and adverse events). We performed random-effects or fixed-effects meta-analysis methods according to their heterogeneity. Results: Of 1,776 studies,112 were included. For the risk of FN between C-GSF or pegylated form vs placebo found that G-CSF reduces the risk in adults with LEU (RR 0.89, 95% CI 0.81-0.98; p⫽0.024), L&ST (RR 0.758, 95% CI 0.68-0.84; p⫽0.000) and SCT (RR 0.85, 95% CI 0.74 – 0.97, p⫽0.017). The risk of developing severe neutropenia reduces in the adults with L&ST with the factor (RR 0.79, 95% CI 0.71-0.88; p⫽0.000) and pediatric patients with LEU (RR 0.789, 95% CI 0.71-0.88; p⫽0.000). While the duration of neutropenia in children with L&ST the time reduces with the factor (SMD -0.559; 95% CI -0.841 to -0.28; p⫽0.000). The G-CSF vs pegylated form, the evidence was inconclusive. Conclusions: When the risk and duration of neutropenia is present we suggest the use of G-CSF in adult and pediatric patients. For adults, we suggest the use of pegylated form, but for pediatric patients we do not have a specific suggestion because the evidence is nonexistent, so it is necessary to carry out clinical trials to obtain evidence.

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Double-loaded mature dendritic cell (DC) therapy for non-HLA-restricted patients with advanced ovarian cancer: Final results of a clinical phase I study. Presenting Author: Marianne Imhof, Life Research Technologies, Wien, Austria Background: Prognosis of ovarian cancer remains poor after initial responsiveness to surgery and chemotherapy followed by high recurrence and mortality rates and new experimental approaches are warranted. Our goal was to evaluate a novel DC-based vaccine, which exploits a unique dual loading strategy to amplify specific anti-tumor short- and long-term immune responses to delay or even prevent recurrent and metastatic disease. Methods: Monocytes were collected via apheresis, matured into DCs and pulsed with two universal tumor associated antigens (uTAA) in our GMP facility. DCs were loaded with TERT and Survivin via two different pathways (mRNA and peptide) to elicit CD8⫹ and CD4⫹T cells directly. Endpoints of the study were tolerability and safety, immunological and clinical responses. T cell responses against the IMP and loaded antigens were evaluated by cytokine bead array (CBA) and intracellular staining assays. Results: 15 non HLA-restricted patients with advanced ovarian cancer were enrolled 8 weeks after standard treatment (surgery and chemotherapy). Each patient was vaccinated intradermally on a weekly or fortnightly basis with a maximum of 8 doses of 13*106 double loaded DCs. The majority of treatment related side effects were grade 1 fever and erythema. Overall the therapy was well tolerated. Immune response data is available for 14/15 patients, 1 was withdrawn after the first administration. The IMP leads to strong immune responses with high frequency (⬎90%), which is proven for both uTAAs in CD8⫹ as well as CD4⫹ T cells. A clear positive trend in progression free survival is demonstrated compared to matched historical control. Conclusions: Therapy with our unique double loaded DC vaccine was feasible, safe and well-tolerated by patients. The vaccine was highly immune stimulatory and elicited both, long-term and short-term anti-tumor immune responses, establishing a promising platform for immune therapy for ovarian cancer and all solid tumors in general. The first two authors contributed equally. Clinical trial information: NCT01456065.


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Awareness and understanding of cancer immunotherapy in Europe. Presenting Author: Hakan Mellstedt, Karolinska Institute, Stockholm, Sweden Background: Use of immunotherapies in the treatment of cancer is growing and a range of new immunotherapeutic strategies are being evaluated. It is important that healthcare providers (HCP) understand these treatments and how they compare with and may complement established therapies. As part of the activities of the POINT expert group, we commissioned a survey of current awareness, attitudes and perceptions of cancer immunotherapy in Europe. Methods: From August-September 2011, 426 healthcare professionals (HCPs: oncologists, surgeons and oncology nurses) from France, Germany, Italy, Spain and the UK (~85 respondents/country) completed online interviews. Representatives of patient advocacy groups (PAGs) in each country were surveyed by telephone interview. Results: Nearly all (98%) HCPs were aware of cancer immunotherapy. While 68% of HCPs indicated a high level of interest, knowledge levels were lower. Only 24% of the HCPs had direct experience with cancer immunotherapies, while others reported they knew a lot (12%), a reasonable amount (28%) or little (34%) about immunotherapy strategies but had not used them (76%). Overall perceptions of cancer immunotherapy among HCPs were largely positive (60%) and rarely negative (3%). The key advantages of cancer immunotherapy were perceived to be good safety and tolerability (75%), a targeted mechanism of action (61%) and good efficacy (48%). The leading barriers to use of immunotherapies were costs of treatment (58%), past clinical trial failures (45%) and access/formulary restrictions (44%). Most (75%) HCPs had already discussed cancer immunotherapy with their patients and 70% of patients were reported as being receptive to the concept. The majority of PAGs indicated they were currently unable to advise patients about cancer immunotherapy due to a lack of or confusing information and poor understanding. Conclusions: Awareness of cancer immunotherapy in Europe is high and it is generally perceived as a positive addition to established treatment options. However, the understanding varies and the direct experience is limited. There is a clear need for further educational activities concerning cancer immunotherapy, as well as further clinical data on long-term efficacy and safety.

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Rituximab pharmacokinetics in children and adolescents with de novo intermediate and advanced mature B-cell lymphoma/leukemia: A Children’s Oncology Group (COG) report. Presenting Author: Matthew John Barth, Roswell Park Cancer Institute, Buffalo, NY Background: The COG trial ANHL01P1 was undertaken to determine pharmacokinetics (PK) and safety following the addition of rituximab (R) to FAB/LMB 96 chemotherapy in children and adolescents with stage III/IV mature B-NHL and B-ALL⫾CNS disease. Methods: Patients received R (375mg/m2) on day -2 and 0 of two induction cycles and day 0 of two consolidation cycles. R levels were measured prior to any antibody infusion, during induction cycles (1 hour prior and 30-60 minutes after each R dose) and following consolidation cycles (1, 3, 6 and 9 months after last R dose). R was measured by ELISA with goat anti-rituximab antibody as the capture reagent and goat anti-mouse IgG-conjugated to horseradish peroxidase as the detection reagent. R terminal half-life (t½) was calculated if at least 3 time points after the last dose were measurable in an individual subject. Results: Serum R levels are reported in the Table. Highest peak levels were achieved following the second dose of each induction cycle with sustained troughs and a t½ of 26-29 days. Group C patients tended to have lower R levels than Group B. Patients with LDH ⱖ2xULN were noted to have lower R levels during induction 1 compared to those with LDH ⬍2xULN. Children (⬍13 years) exhibited higher peak concentrations, similar trough levels and a shorter t½ than adolescents (ⱖ13 years). None of these differences reached significance after adjusting for multiple comparisons. Conclusions: R can be safely added to FAB chemotherapy with high early R peak/trough levels and a long terminal half-life. The efficacy of R combined with FAB chemotherapy is currently being investigated in an ongoing international intergroup trial. Clinical trial information: NCT00057811.

Trough1 Peak1 Trough2 Peak2 Trough3 Peak3 Trough4 Peak4 1mo 3mo 6mo 9mo

N

Group B MeanⴞSEM (␮g/mL)

N

Group C MeanⴞSEM (␮g/mL)

21 17 20 18 16 15 17 15 20 16 18 14

0⫾0 208.3⫾8.3 147.1⫾15.3 299.2⫾18.7 106.6⫾32.1 267.5⫾15.0 190.3⫾11.3 383.5⫾24.5 72.7⫾8.3 15.5⫾2.7 2.9⫾0.6 1.3⫾0.4

15 14 14 11 9 9 9 8 10 11 7 0

0⫾0 182.6⫾8.9 119.1⫾21.3 245.2⫾31.1 54.8⫾8.4 252.8⫾10.5 174.6⫾14.0 321.1⫾32.4 56.3⫾6.2 16.9⫾3.1 1.3⫾0.5 -

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An Fc-optimized NKG2D-Ig fusion protein for induction of NK cell reactivity against breast cancer. Presenting Author: Julia Steinbacher, Department of Hematology and Oncology, Eberhard Karls University Tuebingen, Tuebingen, Germany Background: The anti-tumor activity and clinical success of the monoclonal antibody trastuzumab, approved for treatment of HER2/neu-overexpressing breast cancer, is at least partially mediated by induction of antibody dependent cellular cytotoxicity (ADCC). However, only about 20% of patients show HER2/neu overexpression, and trastuzumab treatment is associated with side effects. The ligands of the activating immunoreceptor NKG2D (NKG2DL) are widely expressed on malignant cells, but generally absent on healthy tissue. We aimed to take advantage of this tumorrestricted expression by using NKG2DL as target-antigens on breast cancer cells. To this end we generated NKG2D-Ig fusion proteins with modified Fc moieties and studied their ability to induce NK cell anti-tumor reactivity. Methods: The Fc parts within the constructs were modified by amino acid exchange as previously described (Lazar 2006; Armour 1999). Direct effects on tumor cell viability as well as induction of NK cell activation, degranulation, cytotoxicity and IFN-␥ release in cultures with breast cancer cell lines expressing different HER2/neu levels were determined. Results: Compared to NKG2D-Fc containing a wildtype Fc part (NKG2D-Fc-WT) or trastuzumab, our mutants (S239D/I332E and E233P/L234V/L235A/ ⌬G236/A327G/A330S) displayed highly enhanced (NKG2D-Fc-ADCC) and abrogated (NKG2D-Fc-KO) affinity to the NK cell Fc receptor, respectively. In contrast to trastuzumab, no direct effect of the constructs on tumor cell viability was observed. In cultures of NK cells and breast cancer cells, NKG2D-Fc-KO significantly reduced NK reactivity due to blocking immunostimulatory NKG2D-NKG2DL interaction. NKG2D-Fc-WT substantially enhanced NK reactivity by induction of ADCC, while the effects of NKG2D-FcADCC by far exceeded that of NKG2D-Fc-WT and, in case of HER2/neu-low targets also that of Herceptin. Conclusions: Fc-engineered NKG2D-Ig fusion protein effectively target breast cancer cells for NK anti-tumor reactivity. Due to the tumor-restricted expression of NKG2DL, NKG2D-FcADCC may constitute an attractive means for immunotherapy especially of HER2/neu-low or -negative breast cancer.

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Generation of tumor-specific cytotoxic T-lymphocytes from peripheral blood of colorectal cancer patients for adoptive immunotherapy. Presenting Author: Marco Bregni, Ospedale di Busto Arsizio, Busto Arsizio, Italy Background: Adoptive T-cell transfer (ACT) using autologous TIL, grown ex vivo and then infused into the cancer patient after lymphoablative chemotherapy, has emerged as an effective treatment for patients with metastatic melanoma. However, this approach has been hampered by the difficulty of isolating TILs from tumors other than melanoma, and of amplifying a sufficient quantity of autologous tumor-reactive T cells. So we decided to adopt a recently described procedure for generating in vitro large numbers of anti-tumor HLA-restricted CTLs, by stimulating patient’s CD8-enriched peripheral blood mononuclear cells (PBMCs) with DCs pulsed with apoptotic solid tumor cells (TCs) as a source of tumor antigens. Methods: 61 patients affected by CRC were enrolled. Tumor biopsies were obtained at surgery, together with 100 ml of heparinized peripheral blood. Tumors were dissociated to a single-cell suspension and cultured in order to obtain tumor cell line from each patient. Dendritic cells (DCs) were generated from previously separated PBMCs, using a magnetic positive selection of CD14⫹ monocytes, cultured in presence of Interleukin-4 and recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). Antitumor cytotoxic T lymphocytes (CTLs) were elicited using DCs as antigenpresenting cells, autologous apoptotic tumor cells as source of antigens and T CD-8 lymphocytes enriched effectors, with weekly stimulation. To evaluate the cytotoxic activity of CTLs, interferon-␥ (IFN-␥) secretion was assessed by ELISPOT. Results: Tumor cell lines and DCs were obtained from 19 out of 61 patients. ELISPOT was performed so far for 6 patients: strong IFN-␥ secretion was detected at the third, fourth and fifth stimulations for one patient and at the second for another patient, whereas for three patients a weak secretion was detected during the second and the third stimulations. CTLs from one patient did not react to the stimulations. Conclusions: Generation of CTLs suitable for ACT immunotherapy is feasible from peripheral blood in patients with CRC.




A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with capecitabine for advanced solid tumors (including patients with progressive or recurrent HER2-negative metastatic breast cancer). Presenting Author: Ellis Glenn Levine, Roswell Park Cancer Institute, Buffalo, NY Background: CD105 (endoglin) is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels that is essential for angiogenesis and upregulated by hypoxia and VEGF inhibition. TRC105 is an anti-CD105 monoclonal antibody being studied in phase II trials that potentiates chemotherapy in preclinical models. Methods: Pts with advanced solid tumors (for purposes of dose escalation) or pts with metastatic HER2-negative breast cancer (following completion of dose escalation), ECOG PS 0-1, and normal organ function were treated with intravenously administered TRC105 wkly plus capecitabine at 1,000 mg/m2 BID for 14 of every 21 days, and assessed for safety, PK, and response. Results: Fourteen patients (median age ⫽ 52; M:F 4:10; median of 3 prior regimens; 10 with breast and 4 with colorectal cancer) were enrolled. Dose escalation proceeded from 7.5 mg/kg TRC105 to the recommended single agent phase II dose of 10 mg/kg of TRC105 in combination with capecitabine, without development of dose limiting toxicity. Fourteen pts were treated at 7.5 mg/kg (n⫽4) or 10 mg/kg (n⫽10) TRC105 wkly ⫹ 1,000 mg/m2 BID/14d capecitabine of repeating 21 day cycles. Patients experienced expected TRC105 related adverse events of grade 1 or grade 2 infusion reaction, epistaxis, gingival bleeding, telangiectasia, headache, rash, and fatigue. Grade 3 headache and grade 3 vomiting were each seen in one patient. Adverse events characteristic of each individual drug were not increased in frequency or severity when the two drugs were administered together. Mucocutaneous telangiectasia, a marker of TRC105 target modulation, was observed at both dose levels. A heavily pretreated male breast cancer patient remained on study for 9 months with a RECISTdefined partial response. Stable disease beyond 9 weeks was observed in three patients. Conclusions: The recommended single agent phase II dose of 10 mg/kg TRC105 wkly was well tolerated in combination with capecitabine. The combination treatment could be advanced in HER2negative breast or colorectal cancer. Clinical trial information: NCT01326481.

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Immunomodulatory effects of a dipeptidyl peptidase inhibitor, ARI-4175, and NK cell activation in a colon cancer model. Presenting Author: Alexander Macfarlane, Fox Chase Cancer Center, Philadelphia, PA Background: A possible mechanism of the antitumor effect of therapeutic antibodies is antibody-dependent cellular cytotoxicity (ADCC). We reported that an inhibitor of dipeptidyl peptidase (DPP)4-like serine proteases, Ari-4175, significantly slowed the growth of KRAS-mutated HCT-116 xenografts in nude mice, either as a single agent or with cetuximab (Ctx). Ari-4175 is not cytotoxic in vitro, and since it was able to overcome the resistance to Ctx due to the KRAS mutation in the HCT-116 line, we hypothesized that the antitumor activity involves the activation of NK cells and enhancement of ADCC. Methods: Ari-4175 was administered orally to nude mice at 200 ␮g q.d. x5 days/week. Peripheral blood or spleens were assayed for immune parameters, ex vivo, at various time points. Expression of surface markers on myeloid and NK cells were monitored by flow. Natural cytotoxicity and ADCC were assayed using HCT116 cells and Ctx using a flow based assay. Cytokines were measured using Luminex assays. Results: Ari-4175 induced upregulation of CD69 on NK cells on day 2, followed by upregulation of CD16 on day 7. Coordinate with these changes in peripheral blood, splenocytes from treated mice exhibited significantly increased in vitro cytotoxicity toward the HCT116 cells. Increased serum levels of inflammatory cytokines, including IL-1b, IL-6, MCP-1, GCSF, and IL-2 were seen. A significant expansion of a distinct CD45⫹CD14⫹Gr1⫹MHC-II-CDllb⫹CD11cvariable myeloid cell population in both peripheral blood and spleens of mice was also seen after one week of treatment. Conclusions: Ari-4175 showed dramatic anti-tumor effect in KRAS-mutant CRC xengrafts when given alone or in combination with Ctx. In vitro data suggest that the therapeutic effect of 4175 might partially be due to the augmentation of ADCC through elevated expression of CD16 on NK cells. In addition, Ari-4175 appears, in vivo, to expand a unique myeloid cell population, which may be responsible for an inflammatory cytokine response and subsequent activation of NK cells. Our study provides a mechanistic rationale for testing Ari-4175 in a clinical trial and possible biomarker endpoints for evaluation in peripheral blood samples.

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A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with bevacizumab (BEV) for advanced solid tumors. Presenting Author: Lee S. Rosen, UCLA Santa Monica Hematology-Oncology, Santa Monica, CA

An engineered immunotherapy (NKTR-214) with altered selectivity toward the IL2 receptor: Efficacy and tolerability in a murine tumor model. Presenting Author: Deborah H. Charych, Nektar Therapeutics, San Francisco, CA

Background: CD105 (endoglin) is an endothelial cell membrane receptor highly expressed on angiogenic tumor vessels that is essential for angiogenesis and upregulated by hypoxia and VEGF inhibition. TRC105 is an anti-CD105 monoclonal antibody that potentiates VEGF inhibitors in preclinical models. This study assessed safety, PK and preliminary efficacy of TRC105 in combination with BEV. Methods: Pts with advanced solid tumors, ECOG PS 0-1, and normal organ function were treated with escalating doses of IV TRC105 (3, 6, 8 or 10 mg/kg/wk) plus bevacizumab (BEV) at 15 mg/kg q3wk or 10 mg/kg q2wk. Results: Thirty one pts (median age ⫽ 62; M:F 14:17; median 4 prior regimens; primarily metastatic colorectal or ovarian cancer) were treated with TRC105 wkly ⫹ BEV. TRC105 3 mg/kg wkly ⫹ 15 mg/kg q3wk BEV was well tolerated. Concurrent administration of TRC105 6 mg/kg wkly ⫹ 15 mg/kg BEV q3wk resulted in headaches in 4 of 5 pts on cycle 1 day 1 (two grade 3). Dose escalation to the recommended single-agent phase II dose of 10 mg/kg TRC105 weekly ⫹ BEV (10 mg/kg q2wk) was tolerated when the initial TRC105 dose was introduced one week after BEV dosing and administered over 2 days. Headache was the only serious adverse drug reaction observed. Adverse events characteristic of each individual drug were not increased in frequency or severity. Target TRC105 serum concentrations were achieved at 6 mg/kg. Mucocutaneous telangiectasia, a marker of TRC105 target modulation, was observed beginning at 6 mg/kg and was dose proportional. Five of 19 heavily pretreated, BEV or VEGF receptor tyrosine kinase inhibitor (TKI) refractory pts with colorectal and ovarian cancer, each with marked tumor burden, experienced radiographic reductions in tumor volume (10-17%). Three of these patients remained on study longer than the prior VEGF inhibitor treatment and two are ongoing. Seven ongoing patients have been treated for 2-8 months. Conclusions: TRC105 10 mg/kg wkly was well tolerated with BEV 10 mg/kg q2wk. The combination demonstrated activity in BEV and VEGF TKI refractory pts. Randomized phase II trials of BEV ⫹/- TRC105 have commenced in renal cell cancer and glioblastoma. Clinical trial information: NCT01332721.

Background: Cytokine-based immunotherapy has been successful for the treatment of cancer, with potential for durable responses in multiple indications. One approach towards stimulating the immune system is to target the heterotrimeric interleukin2 receptor, IL2R. NKTR-214 uses polymer technology to alter receptor subunit selectivity to favor expansion of CD8⫹ memory effector T cells (CD8T) in the tumor over CD4⫹ regulatory T cells (Treg). In addition, polymer conjugation is designed to improve exposure and enhance tumor localization, significantly improving efficacy, modulating vascular leak syndrome (VLS) and allowing flexible dosing regimens. Methods: C57BL/6 mice bearing established subcutaneous B16F10 melanoma were treated with NKTR-214 at a variety of doses (0.25-4.0 mg/kg) and schedules (q5dx3 to q14dx2). Mice treated with clinically validated IL2 were administered 3mg/kg, bidx5 for 2 cycles. Efficacy was measured by monitoring tumor volumes. Tolerability was evaluated by survival. VLS was measured by injection of Evans Blue dye followed by colorimetry in lungs. Tumor immunotyping, by flow cytometry. Results: Tumors from mice receiving NKTR-214 had a CD8/Treg ratio of over 1,000 versus 14 for IL2. NKTR-214 administered at 2 mg/kg, q9dx3 was identified as the optimal regimen and showed tumor growth delay of 26 days compared to 9 days for optimally dosed IL2. 90% of NKTR-214 treated mice tolerated treatment compared to 67% for IL2. VLS was completely resolved prior to administration of the next dose of NKTR-214, unlike IL2. NKTR-214 was well tolerated in rats at two schedules, at MTD. Conclusions: NKTR-214 is a highly differentiated cytokine with a new mechanism of action that may provide options for cancer immunotherapy. Polymer conjugation of a clinically validated cytokine alters the IL2R selectivity to favor expansion of tumor killing immune cells (CD8T) over regulatory immune cells (Treg) in the tumor. The conjugate is also designed to improve exposure and enhance tumor localization, offering more options of dose and schedule. The optimal dose and schedule is cytokine-sparing, provides substantial tumor growth delay, and reduces toxicity.


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Antitumor activity of concurrent blockade of immune checkpoint molecules CTLA-4 and PD-1 in preclinical models. Presenting Author: Mark Selby, Bristol-Myers Squibb, Redwood City, CA Background: Interaction of immune checkpoint molecules PD-1 and CTLA-4 and their respective ligands attenuates antitumor T cell responses. In clinical studies, PD-1 blocking antibody (Ab) nivolumab (BMS-936558) or the CTLA-4 blocking Ab ipilimumab result in durable responses in multiple human malignancies. We describe the evaluation of concurrent treatment with anti-PD-1 and anti-CTLA-4 mAbs in preclinical models. Methods: Antitumor activity of treatment with murine homologs of anti-PD-1 (4H2mIgG1) and anti-CTLA-4 (9D9-mIgG2b) was evaluated in MC38, a murine colon adenocarcinoma model. The effects of concurrent treatment on T cell infiltration of tumors, tumoral expression of PD-L1 and cytokine levels were explored. The preclinical safety profile of concurrent nivolumab ⫹ ipilimumab was assessed in a cynomolgus macaque model. Results: Concurrent treatment of MC38 tumors with 4H2-mIgG1 ⫹ 9D9-mIgG2b (10 mg/kg Q3d x 3) results in synergistic antitumor activity whereas efficacy with sequential dosing was similar to either agent alone. With concurrent treatment, dose reductions of one Ab relative to a fixed dose of the other resulted in retention of some antitumor activity. Anti-PD-1 enhanced CD8⫹ T cell infiltration of MC38 tumors and increased tumor PD-L1 expression. Anti-CTLA-4 treatment increased intratumoral CD8⫹ T cells and reduced intratumoral T regulatory cells. While concurrent treatment did not result in further increases in T cell infiltration, it increased expression of intratumoral cytokines. Anti-PD-1 resulted in down regulation of cell surface and intracellular levels of PD-1 in CD8⫹ T cells. In cynomolgus macaques, concurrent nivolumab ⫹ ipilimumab resulted in dose-dependent gastrointestinal toxicities (diarrhea; body weight loss) not observed in earlier cynomolgus studies with nivolumab and rarely with ipilimumab. These preclinical observations provided the rationale for a dose escalation trial (NCT01024231) of combined nivolumab ⫹ ipilimumab in advanced melanoma. Conclusions: Concurrent treatment with anti-PD-1/anti-CTLA-4 resulted in synergistic antitumor activity in preclinical models and supports the evaluation of the combination in clinical studies.

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Circulating myeloid-derived suppressor cells (MDSC) and correlation to poor prognosis, Th2-polarization, inflammation, and nutritional damages in patients with gastric cancer. Presenting Author: Kenji Gonda, Fukushima Medical University, Fukushima, Japan Background: Recent studies have shown that myeloid-derived suppressor cells (MDSC), which have been identified in most patients, are potent suppressors of T cell activation. MDSC have been reported to be correlated with tumorigenesis and the progression of tumors. We have previously reported significant correlations of MDSC with nutritional damage and inflammation in many types of cancer. In this study the quantitative detection of MDSC in peripheral blood was analyzed in the prognosis in patients with gastric cancer. Methods: We tested PBMCs from 29 preoperative patients with gastric cancer and 18 healthy volunteers using flow cytometric analysis (CD14-CD11b⫹CD33⫹). Markers for nutritional status (serum levels of total protein), inflammation (NLR: neurphil/lymphocyte ratio, serum levels of vascular endothelial growth factor: VEGF) and Th2-polarization (PBMC’s production of IL-6 and IL-10) were measured in this study. The prognosis of the patients was assessed by Kaplan-Meier tests for correlation with levels of MDSC. Results: MDSC levels in 29 preoperative patients with gastric cancer were significantly higher than in normal volunteers. These levels were not associated with pathological characteristics. However they were significantly correlated with the production of IL-6 and IL-10, VEGF levels and NLR. A significant inverse correlation with levels of total protein was obtained. MDSCs were increased in stage IV patients compared with healthy volunteer and 2-year survival rate of the patients with higher levels of MDSC (⬎ 1.104%PBMC) was significantly poorer (median OS, 498 vs 473 days; p ⫽ 0.048), while there was no significant difference in patients with stages I, II, and III. Conclusions: These data suggest that increased MDSC is an effective biomarker for immunosuppression due to Th2-polarization, nutritional impairment, systemic inflammation and poor prognosis in advanced patients with gastric cancer.

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Phase I clinical trial of a genetically modified and oncolytic vaccinia virus GL-ONC1 with green fluorescent protein imaging (NCT009794131). Presenting Author: Khurum Hayat Khan, The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom Background: GL-ONC is a genetically engineered virus attenuated by insertion of the ruc-gfp (Renilla luciferase and Aequorea green fluorescent protein fusion gene), beta-galactosidase (lacZ) and beta-glucuronidase (gusA) reporter genes into the FL14.5L, J2R (thymidine kinase) and A56R (hemagglutinin) loci, respectively. A phase I trial of intravenous (i.v) GL-ONC1 was pursued to evaluate safety, tolerability, tumour delivery, neutralising antibody development and antitumor activity. Methods: GLONC1 was administered at escalating doses (1x105, 1x106, 1x107, 1x108, 1x109, 3x109 plaque forming units (pfu) on day 1; 1.667x107 and 1.667x108, 1.667x109pfu on days 1-3) utilizing a 28-day cycle and a 3⫹3 dose escalation design. Paired biopsies before treatment and on day 8 for pharmacodynamic and viral delivery evaluation were obtained. Green flourescent protein (GFP) imaging was performed on skin rash and mucosal tumour lesions at baseline and after each cycle. Results: To date, 33 patients (pts) across 8 cohorts have been treated with 1 dose limiting toxicty reported of grade 3 transaminitis after a single infusion at 1x109pfu. Other reported adverse events (n) included pyrexia (26), musculoskeletal pain (10), fatigue (8), nausea and vomiting (4). 2 pts had transient transaminitis; both had liver metastases, which may have contributed to this. 2 pts developed minimally symptomatic poxvirus skin pustules, which appeared green by GFP and were positive to viral plaque assay (VPA). Overall, stable disease (SD) by RECIST was seen at ⬎24 weeks (n⫽6) and 8-12 weeks (n⫽5). 2 out of 4 pts in cohort 8 (one with cholangiocarcinoma and another with non-small cell lung caner) achieved SD for median 5.5 months, with a drop in tumour markers at the time of infusions. Conclusions: GL-ONC1 is well tolerated; more frequent delivery of the virus (2 weekly, at the same dose) is planned in an attempt to increase agent exposure. Clinical trial information: NCT009794131.

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Biologic meshes in cancer patients: A double-edged sword—Differences in production of IL6 and IL12 caused by acellular dermal matrices in human immune cells. Presenting Author: Maria Margarete Guenthner-Biller, Department of Obstetrics and Gynecology, Klinikum der Ludwig-MaximiliansUniversitaet, Muenchen, Germany Background: Acellular dermal matrices (ADM) have been used in different fields of surgery for almost 20 years. In 2005 Breuing et al first described its use in breast cancer patients. It is assumed that it is safe to use in an oncologic setting, but data from controlled studies are still missing. Because of its lack of cells ADM are considered not to cause an immune reaction. With increasing knowledge about the importance of immunology in breast cancer more information about ADM on different immune cell populations is needed. IL6 and IL12 are two central cytokines and key regulators of immune supression and activation. Methods: Strattice (ST; LifeCell) CollaMend (CM; Bard Davol), Biodesign (BD; Cook Biotec) as well as TiLoop a synthetic mesh (TL; pfm medical) were used in this study. We isolated myeloid dendritic cells (MDC), untouched plasmacytoid dendritic cells (PDC), naïve B-cells and CD8⫹ T-cells using the MACS System and co-cultered them with the biologic meshes or TL. For positive controls, we used CpG ODN 2216 3 ␮g/ml and LPS in a concentration of 100 ng/ml. Cytokine concentration of IL12p70 and IL6 were determined after seven days by using sandwich Elisa sets. Statistical significance was determined by the nonparametric Friedman-Test. The single hypothesis was calculated with a paired Wilcoxon Test. Results: There was a highly significant difference between the different ADM and TL in the immunologic response. The statistical difference for IL 6 was p⫽ 0.0006131 for B cells and p⫽ 0.00418 for T cells between TL and ADM. ST also caused significantly more IL6 than CM and BD. We found similar differences in IL 12 with p⫽ 0.00194 for B cells and p⫽ 0.003636 in T cells in regard to the difference between TL and ADM. For IL 12 there was no statistical difference between the ADM. We didn´t see any significant differences in the cytokine profile between the various ADM/TL in the MDC and PDC subpopulations. Conclusions: Despite the assumed lack of immune answer to ADM, immune cells reacted in our study with significantly different cytokine profiles. These findings can have implications regarding the activation or suppression of effector cells in a cancer patient.


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Immunotherapy with CpG-ODN in neoplastic meningitis: A phase I trial. Presenting Author: Renata Ursu, Department of Neurology, Hôpital Avicenne, AP-HP, Bobigny, France Background: TLR9 agonists, such as phosphorothioate oligodeoxynucleotides containing CpG motifs (CpG-ODNs), are immunostimulating agents with antitumor effects in animal models. Neoplastic meningitis is a devastating disease, with no efficient therapeutic available. A phase I trial was conducted in patients with neoplastic meningitis to define the safety profile of subcutaneous injections, combined or not with intra-CSF administration of a CpG ODN. Methods: The diagnostic of neoplastic meningitis was based on a positive CSF cytology or on the association of clinical symptoms with meningeal enhancement on MRI. Cohorts of 3-6 patients were treated for 5 weeks with escalating doses of CpG-28 (level 1 and 2: 0.1and 0.3 mg/kg/week subcutaneously (sc); level 3 to 6: 0.3mg/kg sc associated with 3/7/12/18 mg intrathecally every other week). Concomittant treaments with radiotherapy or chemotherapy were allowed. The primary endpoint was tolerance. Secondary endpoints were time until neurological progression and survival. Results: Twenty-nine (29) patients were included. Primary cancer was malignant glioma (n⫽15), lung carcinoma (n⫽7), breast cancer (n⫽3), melanoma or melanocytoma (n⫽2), ependymoma (n⫽1), and colorectal cancer (n⫽1). At diagnosis median age was 56 years and median KPS was 70%. The treatment was well tolerated. Adverse effects possibly or probably related to the studied drug consisted in grade 2 lymphopenia, anemia and neutropenia (n⫽19), local erythema at injection sites (n⫽14), fever (n⫽10) and seizure (n⫽11). Two serious adverse events were considered as possibly or probably related to the protocol: one local infection and one intra-cerebral haemorrhage. Interestingly, median survival was higher in patients (n⫽8) who were concomitantly treated with bevacizumab a time of protocol (19 weeks vs 15 weeks, p⫽0.11). Conclusions: CpG-28 was well tolerated at doses up to 0.3mg/kg subcutaneously and 18 mg intrathecally. Main side effects were limited to local erythema, lymphopenia and fever. Combination with bevacizumab warrants further clinical investigations. Clinical trial information: P060301.

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Use of an antibody-drug conjugate targeting tissue factor to induce complete tumor regression in xenograft models with heterogeneous target expression. Presenting Author: Esther CW Breij, Genmab, Utrecht, Netherlands Background: Tissue factor (TF) is the main initiator of coagulation, that starts when circulating factor VII(a) (FVII(a)) binds membrane bound TF. In addition, the TF:FVIIa complex can initiate a pro-angiogenic signaling pathway by activation of PAR-2. TF is aberrantly expressed in many solid tumors, and expression has been associated with poor prognosis. TF-011vcMMAE, an antibody-drug conjugate (ADC) under development for the treatment of solid tumors, is composed of a human TF specific antibody (TF-011), a proteaseEcleavable valine-citrulline (vc) linker and the microtubule disrupting agent monomethyl auristatin E (MMAE). Methods: TF011 and TF-011-vcMMAE were functionally characterized using in vitro assays. In vivo anti-tumor activity of TF-011-vcMMAE was assessed in human biopsy derived xenograft models, which genetically and histologically resemble human tumors. TF expression in xenografts was assessed using immunohistochemistry. Results: TF-011 inhibited TF:FVIIa induced intracellular signaling and efficiently killed tumor cells by antibody dependent cell-mediated cytoxicity in vitro, but showed only minor inhibition of TF procoagulant activity. TF-011 was rapidly internalized and targeted to the lysosomes, a prerequisite for intracellular MMAE release and subsequent tumor cell killing by the ADC. Indeed, TF-011-vcMMAE efficiently and specifically killed TF-positive tumors in vitro and in vivo. Importantly, TF-011-vcMMAE showed excellent anti-tumor activity in human biopsyEderived xenograft models derived from bladder, lung, pancreas, prostate, ovarian and cervical cancer (n⫽7). TF expression in these models was heterogeneous, ranging from 25-100% of tumor cells. Complete tumor regression was observed in all models, including cervical and ovarian cancer xenografts that showed only 25-50% TF positive tumor cells. Conclusions: TF-011-vcMMAE is a promising new ADC with potent antitumor activity in xenograft models that represent the heterogeneity of human tumors, including heterogeneous TF expression. The functional characteristics of TF-011-vcMMAE allow efficient tumor targeting, with minimal impact on coagulation.

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Novel heteroclitic XBP1 peptides evoking antigen-specific cytotoxic T lymphocytes targeting various solid tumors. Presenting Author: Jooeun Bae, Dana-Farber Cancer Institute, Boston, MA

AFM11, a CD19/CD3 bispecific tandab, to facilitate T-cell-mediated killing of CD19ⴙ cells. Presenting Author: Eugene Zhukovsky, Affimed Therapeutics AG, Heidelberg, Germany

Background: Activation of the unfolded protein response (UPR) allows for tumor cells to survive prolonged endoplasmic reticulum stress and hypoxic conditions. XBP1 is an upstream element and a critical transcriptional activator of the UPR, and its up-regulation in a variety of human solid tumor cancers makes it as a promising immunotherapeutic target. The purpose of these studies was to evaluate immunogenic HLA-A2 XBP1-specific peptides for their ability to elicit cytotoxic T lymphocytes (CTL) against a variety of solid tumor cell lines. Methods: Upon the validation of XBP1 peptides for their strong HLA-A2 bindings and stabilities, peptide-specific CTL were generated ex vivo by repeated stimulation of CD3⫹ T lymphocytes obtained from HLA-A2⫹normal donors with XBP1 peptides-pulsed antigen-presenting cells, either dendritic cells or T2 cells. Results: A cocktail of heteroclitic XBP1 US184-192 (YISPWILAV) and heteroclitic XBP1 SP367-375 (YLFPQLISV) peptides with significantly improved HLA-A2 affinity and stability from their native counterparts were used to evoke XBP1 antigen-specific CTL. The CTL were predominantly CD3⫹CD8⫹ T cells (⬎80%) containing a high percentage of Effector Memory (EM; CCR7-CD45RO⫹) cells, which were distinctively evoked by repeated stimulation with the XBP1 peptides. In addition, the XBP1-CTL displayed a high level of cellular activation (CD69⫹/CD3⫹CD8⫹). The XBP1-CTL demonstrated effective anti-tumor responses including cell proliferation and IFN-g production, as well as degranulation (cytotoxic activity) against HLA-A2⫹breast cancer (MB231, MCF7), colon cancer (LS180, SW480) and pancreatic cancer (8902, Panc1, PL45) cell lines, which over-express both unspliced and spliced XBP1 antigens. Importantly, the specific anti-tumor activities were detected primarily in the EM CTL subset. Conclusions: These results suggest the immunotherapeutic potential of a cocktail of heteroclitic XBP1 US184192 and XBP1 SP367-375 peptides to elicit effective anti-tumor responses against various solid tumors, and provide the framework for clinical development of vaccine trials to improve patient outcome.

Background: CD19, due to broader expression on B cell subtypes, is an attractive alternative to CD20 as a target for treatment of B cell malignancies. T cells are potent tumor-killing effectors that cannot be recruited by full length antibodies, however TandAb technology harnesses their cytotoxic nature for oncology indications. The CD3 RECRUIT TandAb AFM11 enables T cells to potently and specifically kill CD19⫹ tumors and possesses advantageous PK properties enabling intravenous dosing. Methods: We constructed AFM11, a human bispecific tetravalent antibody with two binding sites for both CD3 and CD19. In vitro efficacy and safety were evaluated on CD19⫹ cell lines and primary tumors. In vivo efficacy was evaluated in a murine NOD/scid xenograft model reconstituted with human PBMC. Results: In vitro assays demonstrate higher potency and efficacy of target cell lysis by AFM11 relative to a bispecific tandem scFv. CD8⫹ T cells dominate early cytotoxicity (4 hrs) while after 24 hrs both CD4⫹ and CD8⫹ T cells equally contribute to tumor lysis with EC50 of 0.5 – 5 pM; cytotoxicity is independent of cell CD19 density. AFM11 exhibits similar cytotoxicity at Effector:Target ratios from 5:1 to 1:5 and facilitates T cell serial killing of its targets. AFM11 activates T cells only in the presence of CD19⫹ cells. In PBMC cultures AFM11 induces CD69 and CD25 expression, T cell proliferation, and production of IFN-␥, TNF-␣, IL-2, IL-6, and IL-10. Depletion of CD19⫹ cells from PBMC abrogates these effects, and indicates strict CD19⫹ target-dependent T cell activation. Thus, AFM11 should not elicit the devastating cytokine release observed when full length antibodies bind CD3. Cell lysis by AFM11 is restricted to CD19⫹ targets asCD19- bystanders are not lysed in co-culture assays. Up to one week co-incubation with AFM11 does not inhibit T cell cytotoxicity and thus it does not induce anergy. In vivo AFM11 exhibits a dose-dependent growth inhibition of Raji tumors; a single dose of AFM11 exhibits similar efficacy as 5 daily injections. Conclusions: AFM11 is a highly efficacious novel drug candidate for the treatment of CD19⫹ malignancies with an advantageous safety profile and anticipated dosing regimen.


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A phase I study of ad.p53 DC vaccine in combination with indoximod in metastatic solid tumors. Presenting Author: Hatem Hussein Soliman, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL

A phase II study of NPC-1C: A novel therapeutic monoclonal antibody (mab) to treat pancreatic (P) and colorectal (CR) cancers. Presenting Author: Michael Morse, Duke University Medical Center, Durham, NC

Background: Indeolamine 2,3 dioxygenase (IDO) is an inducible tryptophancatabolizing enzyme that downregulates the immune system. Many tumor cell types overexpress IDO to avoid elimination by infiltrating cytotoxic T cells. 1-methyl-D-tryptophan (1-MT, indoximod) is an IDO pathway modulator. Published preclinical data suggested that blockade of IDO with indoximod enhances the immunologic response to dendritic cell (DC) vaccines. Ad.p53 is an adenovirus used for generating DC vaccines directed against p53 epitopes. Ad.p53 when given to previously treated SCLC patients significantly increased their response rate to subsequent chemotherapy. The primary goal in phase I is the MTD of indoximod ⫹Ad.p53. Methods: This phase 1 study used a 3⫹3 design with 7 indoximod dose levels (DL) (100 mg, 200 mg, 400 mg, 800 mg QD then 800 mg, 1,200 mg, and 1,600 mg PO BID)⫹up to 6 fixed dose Ad.p53 DC vaccinations q2wks. Standard eligibility/exclusion criteria applied along with exclusion of patients previously treated with ipilimumab. Treatment will continue until disease progression or unacceptable toxicity. DLT rules are 1st cycle ⱖG3 AE related to treatment. Results: Total patients accrued to phase I⫽32. Types treated were 22 breast, 3 colon, 2 gastric, 1 ovarian, 1 NSCLC, 1 oropharynx, 1 sarcoma. No. of patients treated at DL 1-7 were 3, 3, 4, 6, 6, 3, 6, respectively. Toxicities possibly related to therapy were G1-2 fatigue, nausea, constipation, diarrhea, photosensitivity, hyponatremia, hyperglycemia, AST elevation. The MAD was 1,600 mg BID of indoximod with no DLTs noted. All discontinuations were due to progression of disease. No objective responses to study therapy were noted, but 6/10 breast patients treated with carboplatin/gemcitabine or gemcitabine alone responded to salvage therapy. Conclusions: The combination of indoximod⫹Ad.p53DC vaccine was well tolerated.The RP2D of indoximod is 1,600 mg BID ⫹ Ad.p53DC vaccine. There may be a chemosensitizing effect of Ad.p53DC⫹indoximod with chemo. The phase II trial in metastatic breast is looking at the response rate of indoximod⫹Ad.p53DC vaccine followed by salvage carboplatin/gemcitabine in previously treated patients. NCT01042535 Clinical trial information: NCT01042535.

Background: NPC-1C is a chimeric mab developed to treat P and CR cancers. This mab was selected from a panel of hybridomas derived from biologically screened, pooled human allogeneic colon cancer tissues. The NPC-1C target appears to be a variant of MUC5AC expressed specifically by human P and CR tumors with minimal cross-reactivity to normal GI mucosa. Methods: A phase IIa study with NPC-1C is enrolling patients (pts) with advanced P and CR cancer refractory to standard therapy. Primary objectives are to measure efficacy by analysis of CT scans pre- and post-therapy, clinical lab tests, and physical examinations. Secondary objectives are to determine safety, pharmacokinetics (PK), and select immune responses to the mab. Analyses of pts peripheral blood mononuclear cells (PBMCs) for antibody-dependent cell-mediated cytotoxicity (ADCC) and immune cytokine profiling utilizing the Milliplex MAP Human Cytokine/Chemokine Panel are planned to assess for immunologic outcome and correlation with clinical benefit. Results: Pts received 1.5 mg/kg IV of NPC-1C every two weeks. 10 subjects (8 colorectal, 2 pancreatic) have enrolled on study (2/10 non-evaluable). Treatment was well tolerated with grade 1 and 2 constitutional symptoms noted. Coombs positivity was reported in 4/8 pts shortly after the infusions, but only grade 1 hemolysis was reported (in 2/8 patients). There was 1 episode of each of the following grade 3 AE’s: weakness, increased bilirubin, and abdominal pain, possibly related to NPC-1C. 5 of 19 pts treated in this and the phase Ia study demonstrated stable disease (SD) on scans after completing the first course of treatment (4 doses). Conclusions: Preliminary results with NPC-1C show signs of clinical activity based on SD in heavily pretreated pts with P and CR cancer. Safety has been established at the 1.5 mg/kg dose. A new lot of NPC-1C, produced with improved sterility and purification procedures and demonstrating no red cell agglutination, has been manufactured under GMP conditions. We plan to introduce this new lot at the current 1.5 mg/kg dose level. If there are no dose limiting toxicities, we plan to dose escalate to a higher MTD at which we will re-evaluate clinical efficacy. Clinical trial information: NCT01040000.

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Anti-60S ribosomal protein L29 antibody: New anticancer agent discovered from human sera. Presenting Author: Yasuhiro Miyake, Department of Gastroenterology & Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

Multicenter trial for assessing tolerability of combination therapy with cisplatin, irinotecan, and PSK in extensive-stage small-cell lung cancer: RNCLC-01 study. Presenting Author: Tatsuhiko Kashii, Toyama University Hospital, Toyama, Japan

Background: Incidence of hepatocellular carcinoma (HCC) is lower in autoimmune hepatitis (AIH) than chronic viral hepatitis. In AIH, serum immunoglobulin G (IgG) levels are associated with the clinical features. In this study, we searched IgG showing anti-tumor effect in sera of AIH patients. Methods: Total IgG was extracted from sera of AIH patients by using protein G. Anti-tumor effects of the total IgG were evaluated by MTT assay using human HCC Huh7 cells and PLC/PRF/5 cells. Autoantigens in membrane proteins of Huh7 cells were screened by immunoprecipitation followed by liquid chromatography-mass spectrometry (LC-MS) shotgun analysis. Results: In one AIH patient without any cancers, addition of total IgG extracted from her serum to the culture inhibited the proliferation of Huh7 cells and PLC/PRF/5 cells, and decreased intracellular levels of ␤-Catenin and Cyclin-D1. In this patient, autoantigens in membrane proteins were screened, and 60S ribosomal protein L29 (RPL29) was identified from the MS/MS spectra and the SwissProt database using the Mascot Search engine. RPL29 expression in human HCC cell lines including Huh7, PLC/PRF/5, Hep3B, HepG2, HLE, HLF and SK-Hep-1 were identified by Western blot. Next, in the other 25 AIH patients, we investigated the correlation between serum anti-RPL29 levels by indirect ELISA using recombinant RPL29 and anti-tumor effects of total IgG extracted from their sera. Serum anti-RPL29 levels were significantly correlated with anti-tumor effects of total IgG extracted from their sera (P ⬍0.0001). On the other hand, addition of recombinant RPL29 to the culture canceled anti-tumor effects of total IgG extracted from sera of AIH patients showing higher serum anti-RPL29 levels. Additionally, these anti-tumor effects of total IgG extracted from sera of AIH patients were shown by MTT assay using human pancreatic cancer AsPC-1 cells and Panc-1 cells. Conclusions: Anti-RPL29 antibodies showing anti-tumor effect were discovered from human sera. Anti-RPL29 inhibits cancer cell proliferation via down-regulation of Wnt/␤-Catenin signaling pathway. Serum anti-RPL29 may be one of immune systems by which the human does not develop cancers.

Background: Polysaccharide-K (PSK, Krestin) is a protein-bound polysaccharide, extracted from cultured mycelium of Coriplus versicolor, and is associated with immunostimulatory activity. Although combination use of PSK with chemotherapy has been shown to prolong the response period in patients with small-cell lung cancer (SCLC), the efficacy of PSK in combination chemotherapy including cisplatin has been less examined. We examined safety and efficacy of combination therapy with cisplatin, irinotecan, and PSK in extensive-stage (ED) SCLC. Methods: Eligible pts included: histologically confirmed ED-SCLC without prior chemotherapy, age under 75 years, ECOG performance status ⱕ 1, with evaluable disease and adequate organ function. Treatment: irinotecan 60 mg/m2 on days 1, 8, and 15 and cisplatin 60 mg/m2 on day 1 every 4 weeks for 4 to 6 courses, and oral PSK 3,000 mg/body daily. The treatment with PSK was continued after the end of cisplatin and irinotecan administrations, and was combined as a part of second-line therapy after exacerbations. Results: Between January 2008 and July 2010, 17 patients were enrolled, and the efficacy and prognosis were evaluated in 15 of 17 patients. Response rate was 66.6%, one-year survival rate was 66.6%, and two-year survival rate was 33.2%. The major toxicities were diarrhea and myelosuppression, and the common toxicity of PSK-containing combination chemotherapy was not observed. Conclusions: The combination chemotherapy with cisplatin, irinotecan, and PSK was effective and well tolerated in ED-SCLC. Clinical trial information: NCT00546130.




A randomized phase II/III study of naptumomab estafenatox plus IFN-␣ versus IFN-␣ in advanced renal cell carcinoma. Presenting Author: Robert E. Hawkins, The Christie Hospital NHS Foundation Trust, Manchester, United Kingdom Background: Naptumomab estafenatox/ANYARA (Nap) is a fusion protein of an antibody (5T4) and a superantigen (SEA/E-120). After phase I studies (Borghaei. J Clin Oncol. 2009, 27:4116) a prospective, randomized phase II/III trial of Nap ⫹ IFN-␣ (A) vs IFN-␣ (I) was conducted. Methods: Patients (pts) with RCC were randomized in an open label study to receive A or I. The primary endpoint was OS. Secondary endpoints were PFS, response rate and safety. Baseline (bl) plasma IL-6 was predictive of pazopanib (Tran. Lancet Oncol. 2012, 13:827) and MVA-5T4 vaccine (Harrop. Cancer Immunol Immunother. 2012, 61:2283) benefit in RCC pts. IL-6 and anti-SEA/E-120 antibodies (a-S) were analyzed. A subgroup SG1 had bl levels below median for IL-6 (⬍7 pg/ml) and a-S. Another subgroup SG2 had IL-6 below 13 pg/ml (Tran. Lancet Oncol. 2012, 13:827) and excluding upper quartile of a-S according to phase 1 levels (Borghaei. J Clin Oncol. 2009, 27:4116). Results: From 5/2007 to 10/2010 513 pts were treated (ITT) with a median follow-up time for censored pts of 43 months. Unexpectedly, pts in certain territories had increased bl a-S (median of 61 pmol/ml in Russia vs 34 in UK). The table summarizes efficacy results. The primary endpoint was not met. Multivariate analysis adjusted for risk scores and subsequent TKI usage verified Nap benefit in pts with low IL-6 and normal a-S. Nap was well tolerated. Pyrexia (A:46%/I:18%), nausea (21%/11%), back pain (18%/6%), vomiting (16%/7%) and chills (12%/ 4%) were more common after Nap. Conclusions: The study did not meet primary endpoint. In pts with low IL-6 and normal levels of a-S, addition of Nap to IFN-␣ improves OS and PFS. The results warrant further studies with Nap in sequence or combo with e.g. TKIs in this subgroup. More generally, as bl IL-6 appears to be prognostic and predictive of outcome on treatment with TKIs and immunotherapies this may be a stratification factor for RCC studies. Clinical trial information: NCT00420888. Treatment

N

Response CRⴙPR

SG1

A I A

253 260 67

35 (14%) 40 (15%) 19 (28%)

SG2

I A

63 68

10 (16%) 13 (19%)

I

63

11 (17%)

Population ITT

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PFS median months 5.8 5.8 13.7 (p⫽0.016) 5.8 8.5 (p⫽0.162) 5.8

HR (95% CI) 0.92 (0.77, 1.11) 0.62 ( 0.42, 0.92) 0.75 (0.51, 1.10)

OS Median months 17.1 17.5 63.3 (p⫽0.020) 31.1 30.4 (p⫽0.036) 21.7

HR (95% CI) 1.08 (0.88, 1.33) 0.59 (0.37, 0.95) 0.65 (0.42, 0.99)


Physicochemical, functional, and pharmacologic comparability between the proposed biosimilar rituximab GP2013 and originator rituximab as the foundation for biosimilarity. Presenting Author: Antonio da Silva, Sandoz Biopharmaceuticals, Holzkirchen, Germany Background: Development of a biosimilar involves extensive characterization of the originator product and a target-directed iterative development process ensuring comparability to the originator with similar clinical efficacy, safety and quality. Here we report the physicochemical, functional and pre-clinical pharmacological characterization of a proposed rituximab biosimilar (GP2013). Methods: A variety of physicochemical methods were used to analyze primary and higher order structure, post-translational modifications and size heterogeneity. Functional characterization included a series of bioassays (in vitro target binding, ADCC, CDC and apoptosis) and SPR-based Fc receptor binding assays. Comparative PK and PD were assessed in cynomolgus monkeys, the pharmacologically most relevant species. Results: GP2013 has the same primary amino acid sequence and higher order structure as the originator rituximab and both were comparable with regard to charge variants, specific amino acid modifications, glycan pattern and size heterogeneity (low- and high-molecular weight variants & particles). Functionally GP2013 could not be distinguished from originator rituximab preclinically. In primates, PK analysis confirmed bioequivalence between GP2013 and originator rituximab with nearly identical AUC values and 90% CIs entirely within the standard acceptance range of 0.8-1.25. Bioequivalence of PD response was also shown, with 95% CIs of areas under the effect-time curves (AUEC) ratios for relative change from baseline in B-cell populations within the 0.8-1.25 acceptance range. Conclusions: Using a broad panel of analytical methods it was shown that GP2013 is highly similar to originator rituximab at the physicochemical level. In addition, the preclinical comparability exercise confirmed that GP2013 and originator rituximab are pharmacologically similar with regard to FcR and CD20 binding, ADCC, CDC and apoptosis potency, PK exposure and B-cell depletion. As such, we anticipate that the ongoing clinical trials will help provide confirmatory evidence of similar efficacy and safety to the originator product.

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A phase II study of Recchia’s immunomodulatory schedule (RIS) as a maintenance therapy in high-risk tumors after a response. Presenting Author: Manuel Sureda, Plataforma de Oncología, Hospital Quiron Torrevieja, Torrevieja, Spain Background: F. Recchia et al. (Interleukin-2 and 13-cis retinoic acid in the treatment of minimal residual disease: A phase II study. Int J Oncol. 20: 1275-1282, 2002) previously defined the possibility of achieving a chronic immune stimulation through a prolonged low dose sc interleukin 2 (IL2)-based schedule, leading to a prolongation of PFS in advanced cancer patients (pts). A confirmatory phase II study was started. Methods: Pts diagnosed of high risk solid tumors in response to chemotherapy were included. RIS consisted in low dose IL2 (1.8 MU sc per day, 5 days per week, 3 weeks per month) plus oral isotreonin (CRA, 0.5 mg/kg) the same days of IL2 and/or sc PEG-interferon (50 ␮g per week of treatment). No Chx was allowed with RIS, but concurrent maintenance with TKI or Hx was permitted. Results: Since 08/2007 to 01/2013, 69 pts (39 M/30 F, median age 60 y, range 31-78) were included. 51 pts were treated with stage IV disease. 36 pts entered in complete response (CR), 29 in partial response (PR), 1 with progressive disease, 3 adjuvant. 4/69 grade 3/4 toxicity, (6%): 1 fatal poliserositis resistant to cortisone after 20 months of RIS, 1 stopped RIS for reaction requiring steroids, 1 for multiinfarction dementia, 1 for grade 3 liver toxicity. 3 pts presented other alterations managed along the course of the RIS (1 PVT, 1 ITP, 1 angina resolved after stent placement). Grade 1-2 fever, fatigue and joint pain were commonly observed but usually controlled with NSAIDs. Among the 68 pts evaluable for response, one pt progressed, 26 presented stable disease (median TTP 3 mo, range 2-28), 3 presented PR (1 melanoma, 1 prostatic ca, 1 ovarian ca; 9, 11 and 28 mo respectively), and 38 maintained or presented CR (median TTP 19 mo, range 2-62⫹). Three pts in PR were converted to a CR during RIS (1 pancreatic ca, 1 ovarian ca, 1 larynx ca). Conclusions: In this study we confirm the previous results reported by F. Recchia et al. RIS represents a good alternative for high risk pts with solid tumors after systemic chemotherapy induced response with acceptable tolerability and offers in selected pts a possibility of obtaining a CR after a PR. Further validation and randomized studies are warranted.

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High hydrostatic pressure to induce immunogenic cell death in human tumor cells. Presenting Author: Iva Truxova, Sotio a.s., Prague, Czech Republic Background: Recent studies have identified molecular events characteristic of immunogenic cell death. These include surface exposure of calreticulin, HSP70 and HSP90, release of intranuclear HMGB1 and secretion of ATP from dying cells. Several chemotherapeutic agents, including anthracyclins, oxaliplatin and bortezomib, and hypericin-based photodynamic therapy have been described to induce the immunogenic cell death in human tumor cells. We investigated the potential of high hydrostatic pressure (HHP) to induce immunogenic cell death in human tumor cells. Methods: Prostate and ovarian cancer cell lines and primary tumor cells were treated by HHP and we analyzed the kinetics of the expression of immunogenic cell death markers. HHP killed tumor cells expressing immunogenic cell death markers were tested for their ability to activate dendritic cells (DCs), to induce tumor specific T cells and regulatory T cells. Results: HHP induced rapid expression of HSP70, HSP90 and calreticulin on the cell surface of all tested cell lines and primary tumor cells. HHP also induced release of HMGB1 and ATP from treated cells. The kinetics of expression was similar to doxorubicin, HHP, however, induced 1.5-2 fold higher expression of HSP70, HSP90 and calreticulin. The interaction of DCs with HHP-treated tumor cells led to the faster rate of phagocytosis, significant upregulation of CD83, CD86 and HLA-DR and release of IL-6, IL-12p70 and TNF␣. The ability of HHP-killed tumor cells to promote DCs maturation was cell contact dependent. DCs pulsed with tumor cells killed by HHP induced high numbers of tumor-specific CD4⫹ and CD8⫹IFN-gproducing T cells even in the absence of additional maturation stimulus. DCs pulsed with HHP treated tumor cells also induced the lowest number of regulatory T cells among the tested conditions. Cells treated by HHP can by cryopreserved in liquid nitrogen and retain their immunogenic properties upon thawing thus allowing for their convenient use in the manufacturing of cancer immunotherapy products. Conclusions: High hydrostatic pressure is a reliable and very potent inducer of immunogenic cell death in the wide range of human tumor cell lines and primary tumor cells.


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VTX-2337, a TLR8 agonist, plus chemotherapy in recurrent ovarian cancer: Preclinical and phase I data by the Gynecologic Oncology Group. Presenting Author: Bradley J. Monk, Creighton University School of Medicine at St. Joseph’s Hospital and Medical Center, Phoenix, AZ

Prognostic factors for the efficacy of catumaxomab in patients (pts) with malignant ascites (MA): Meta-analysis from two phase III studies. Presenting Author: Hilke Friccius-Quecke, Fresenius Biotech GmbH, Munich, Germany

Background: Given the absence of clear molecular drivers in high-grade serous ovarian cancer, targeting the tumor micro-environment with immunotherapy is an emerging approach. VTX-2337 is a potent, small molecule agonist of TLR8 which stimulates the innate immune response, and was previously evaluated as a single agent in cancer patients. We report data combining VTX-2337 with chemotherapy in recurrent ovarian cancer. Methods: VTX-2337 was tested in an ovarian cancer mouse model with an intact human immune system. Additionally, an open-label phase I study of VTX-2337 ⫹ pegylated liposomal doxorubicin (PLD) in recurrent ovarian cancer (NCT01294293, N⫽13) was performed. PLD (40 mg/m2) was given on day 1 of a 28-day cycle. Three dose levels of VTX-2337 (2.5, 3.0, 3.5 mg/m2, N⫽13) were serially tested and given by SC injection on days 3, 10, and 17. VTX-2337 (3.0 mg/m2) was also tested with paclitaxel (80 mg/m2; N⫽7) given on days 1, 8, and 15 of a 28 day cycle. Responses were evaluated using RECIST1.1. PK and serum immune cytokines were measured. Patients remained on therapy until toxicity or progression. Results: In the mouse model, clinical responses to PLD were increased. Innate immunity along with CD8⫹ T cell responses were also induced. In humans, treatment with PLD ⫹ VTX-2337 increased various cytokines and chemokines (G-CSF, MCP-1, MIP-1␤, TNF-␣). The PK of PLD was not affected by VTXE2337. The combination was well tolerated with no DLTs. AEs consisted of those seen with single-agent PLD (Gr 3/4 toxicities, N⫽6) or VTXE2337 (Gr 1/2 injection site reaction, transient fever, flu-like symptoms). There was 1 partial response (13%) and 63% had stable disease. Paclitaxel ⫹ VTX-2337 was also well tolerated. Conclusions: VTX-2337 enhances the effect of PLD in a preclinical model of ovarian cancer, and the combination is well-tolerated in patients. Clinical data and biomarkers consistent with immunostimulation, provide rationale for the on-going randomized, placebo-controlled, phase II trial comparing PLD vs PLD ⫹ VTX-2337 (GOG-3003, NCT01666444). Clinical trial information: NCT01666444.

Background: Data from two phase III studies (IP-REM-AC-01 and CASIMAS) were used for a meta-analysis to identify factors with a potential impact on the efficacy of catumaxomab (CATU) in pts with MA. Methods: 389 pts treated with CATU plus paracentesis and 88 control pts (paracentesis only) were included. Efficacy parameters were overall survival (OS), puncture-free survival (PuFS) and time to first puncture (TTPu). The impact of the prognostic factors Karnofsky Index (KI), total serum protein (protein) and presence/absence of distant metastases (metastases) at inclusion was analysed for these parameters. Results: Pts treated with CATU showed a significant prolongation of PuFS (44 vs 11 d, HR 0.34, p⬍0.0001), TTPu (88 vs 13 d, HR 0.26, p⬍0.0001) and OS (88 vs 68 d, HR 0.62, p⫽0.007) compared to control pts. Pts treated with CATU and a KI of 80 –100 at inclusion had significantly better OS compared to those with a KI of 60 –79 (120 vs 57 d, HR 0.55, p⬍0.001) and improved PuFS (55 vs 27 d, HR 0.61, p⬍0.001) but not improved TTPu (88 vs 96 d, HR 0.80, p⫽0.186). Linear Cox regression of KI as a co-variable showed a significantly positive impact of high KI on catumaxomab efficacy for OS (HR 0.97, p⬍0.001) and PuFS (HR 0.98, p⬍0.001) but not TTPu (HR 0.99, p⫽0.054). Cox regression analysis of the presence of distant metastases and low (⬍ normal) total serum protein on CATU efficacy showed a negative impact on OS (metastases: HR 1.43; p⬍0.001; protein: HR 1.39, p⫽0.002), PuFS (metastases: HR 1.37, p⫽0.003; protein: HR 1.45, p⬍0.001) and TTPu (metastases: HR 1.28, p⫽0.069; protein: HR 1.41, p⫽ 0.011). Treatment effects on PuFS and TTPu were observed in all subgroups for all factors but the effect on OS compared to controls was only found in pts with KI 80 –100 and in those with no distant metastases and with normal/high total serum protein. Conclusions: Karnofsky Index, distant metastases and total serum protein at screening were identified as factors having a significant impact on OS in CATU-treated pts and better prognostic pts compared to controls. In contrast, the effect of CATU on ascites control (PuFS, TTPu) was observed in all subgroups irrespective of whether the pts were in the good or poor prognostic group.

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Targeting myeloid-derived suppressor cells and the PD-1/PD-L1 axis to enhance immunotherapy with anti-CEA designer T cells for the treatment of colorectal liver metastases. Presenting Author: Rachel A. Burga, Roger Williams Medical Center, Surgical Immunotherapy, Providence, RI Background: Immunotherapy for colorectal cancer liver metastases (CRCLM) is limited by the intrahepatic immunosuppressive environment mediated in part by myeloid derived suppressor cells (MDSC), which expand in response to tumor. T cell suppression can be mediated by programmed death ligand-1 (PD-L1, CD274) on MDSC binding to programmed death-1 (PD-1, CD279) on T cells. We hypothesize blocking PD-L1 will improve adoptive cellular therapy efficacy for CRCLM through inhibition of MDSC-mediated T cell suppression. Methods: “Designer” T cells (dTc) were produced from activated murine splenocytes transduced with chimeric antigen receptor (CAR) specific for CEA. C57BL/6 mice were injected with CEA⫹ MC38 tumor cells via spleen, and liver MDSC (CD11b⫹Gr1⫹) were purified with immunomagnetic beads after two weeks. MDSC were co-cultured with stimulated dTc with or without in vitro PD-L1 blockade. Results: MDSC expanded 2.4-fold in response to CRCLM, and expressed high levels of PD-L1 (63.8% PD-L1⫹). PD-L1 was equally expressed on both monocytic (CD11b⫹Ly6G-Ly6C⫹) and granulocytic (CD11b⫹Ly6G⫹) MDSC subsets (43.6% PD-L1⫹ and 27.9% PD-L1⫹, respectively). Expression of related ligand, PD-L2 was found to be negligible in both subsets. The cognate inhibitory receptor, PD-1, was expressed on dTc (23.8% PD-1⫹) and native T cells (37.3% PD-1⫹). Increasing endogenous T cell expression of PD-1 significantly correlated with MDSC expansion (r⫽0.9774, p⬍0.0001) in response to CRCLM. Co-culture of dTc with MDSC demonstrated the suppressive effect of MDSC on dTc proliferation which was abrogated with in vitro targeting of PD-L1. The percentage of dTc proliferating in the presence of CEA⫹ tumor decreased from 72.2% to 29.3% (p⬍0.001) with the addition of MDSC, and immunosuppression was reversed with blockade of PD-L1, which resulted in a 1.6-fold increase in dTc proliferation (p⫽0.01 ). Conclusions: Liver MDSC expand in the presence of CRCLM and mediate suppression of anti-CEA dTc via PD-L1. Our results indicate that blockade of PD-L1:PD-1 engagement is a viable strategy for enhancing the efficacy of adoptive cell therapy for liver metastases.


Effect of therapeutic targeting of EMP2 on breast and endometrial cancer stem cells. Presenting Author: Madhuri Wadehra, DGSOM at UCLA, Los Angeles, CA Background: There is increasing evidence that tumor-initiating cancer stem cells (CSCs) contribute to tumor metastasis and therapeutic resistance. In breast and endometrial cancers, metastatic CSCs are defined as CD44⫹/ CD24- and ALDH⫹, and in this study, we define another marker epithelial membrane protein-2 (EMP2) as a novel target for this population of cells. EMP2 is an oncogene whose expression has been shown to correlate with tumor progression and survival in a number of human cancers including triple-negative breast, ovarian, and endometrial tumors. Methods: A number of cancer cell lines were utilized both in vitro and in vivo to determine if EMP2 expression levels alter the number and expression of CSC markers. To translate this work, EMP2 and ALDH expression were correlated in primary human endometrial and breast cancers. To determine the therapeutic efficacy of our fully-human EMP2 IgG1 antibody, xenografts from breast or uterine cancer were treated, removed, and then reinjected into secondary mice. Results: In this study, we show new evidence that EMP2 is highly expressed in CSCs. High levels of EMP2 increase the tumor forming potential of both endometrial and breast cancer lines. In tumors created from these cells, high levels of ALDH⫹ expression were also observed. In contrast, reduction in EMP2 decreased CD44 expression and ALDH activity both in vitro and in vivo, with the net consequence of poorly vascularized and slow growing tumors. We have recently developed a novel monoclonal antibody to EMP2 and have started testing its therapeutic efficacy. In vitro treatment with EMP2 IgG1 reduced HIF-1a, CD44, and ALDH levels, ultimately leading to caspase mediated apoptosis. Treatment of breast cancer cells with EMP2 IgG1 reduced tumor load in both subcutaneous and metastatic models of breast and endometrial cancer resulting in a significant improvement in survival. Reinjection of these cells post treatment into secondary mice failed to efficiently form, and histological examination of the tumors revealed significant necrosis and elimination of ALDH⫹ CSCs. Conclusions: These results suggest that targeting EMP2 may reduce CSCs and represent an attractive target for further therapeutic development.




Novel murine anti-HER2 monoclonal antibodies to induce apoptosis and regulate miR-21 in breast cancer cell. Presenting Author: Alice Y. Kim, City of Hope, Duarte, CA

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Phase I clinical study of NK105, paclitaxel-encapsulating micelles, on a weekly schedule, in patients with malignant tumors (dose-escalation phase). Presenting Author: Ken Kato, Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan

Background: MicroRNAs play critical roles in biological and pathological processes. Of these, miR-21 is frequently observed to be overexpressed in various cancers. However, treatment of breast cancer cells with trastuzumab enhances the level of miR-21 by a relative fold of 2.26 (Ichikawa, PLos ONE, 2012, p.5). In this study, we demonstrate that two murine anti-HER2 mAbs, 10H8 and 8H11, while inhibiting cell proliferation and inducing apoptosis, do not perturb the level of miR-21 in the same way as trastuzumab. To understand the differential effects of trastuzmab and the two mAbs, epitope mapping studies were also conducted. Methods: SKBR3 cells were used to confirm HER2 binding and determine the antibodies’ impact on proliferation, apoptosis, and miRNA expression. Cell proliferation upon a 3-day antibody treatment (10 to 15 ␮g/ml) was measured using MTS and Crystal Violet Assays. Apoptotic cells were identified using Annexin V-FITC flow cytometry. To determine their epitope mapping, cells were grown on coverslips overnight, fixed, blocked, and incubated in AF488-mAb or AF555-mAb, and images were captured with IX81. QRTPCR was used to measure the relative levels of miR-21, using miR-16 as the endogenous control Results: Cell proliferation assays showed that the treatment of 10H8 resulted in a better growth inhibition in SKBr3 cells than that of trastuzumab (ex: 80.2% vs 84%, respectively). Combining 10H8 and 8H11 produced less viable cells and more early- and postapoptotic cells than those treated with trastuzumab alone. In addition, whereas trastuzumab increased the relative quantity of the known oncogene, both 10H8 and 8H11 maintained a steady level of miR-21 (0.99 and 1.2, respectively). Conclusions: Initial results indicate that 10H8 and 8H11 inhibit cell proliferation and induce apoptosis in HER2-overexpressing cells. However, unlike trastuzumab, 10H8 and 8H11 do not involve miR-21 up-regulation. Moreover, the three mAbs do not have overlapping epitopes on HER2. Further investigations of the antibodies’ impact on intracellular signaling pathways and the structural determination of the HER2 binding sites would provide further understanding of the therapeutic potentials of these two mAbs.

Background: NK105 is the formulation of a novel drug delivery system that encapsulates paclitaxel (PTX) in polymeric micelles and possibly resolves the safety issues associated with the additives contained in the conventional PTX formulation. In the phase II study of NK105 administered to gastric cancer patients on a 150Emg/m2 triweekly schedule, peripheral sensory neuropathy was mitigated compared to prior data for conventional PTX, without any reduction in efficacy. Based on the dose-density theory, we conducted a phase I study of NK105 on a weekly schedule to determine the dose-limiting toxicity (DLT) and recommended dosage (RD), and to evaluate the pharmacokinetic profile. Methods: Patients with advanced solid tumors refractory to standard therapy received NK105 at dosage levels of 50-100 mg/m2 as a 30-min infusion without premedication, once a week for three weeks, followed by one week of rest. Pharmacokinetic analysis was conducted in cycles 1 and 2. Results: Sixteen patients were enrolled in the study. In the 100Emg/m2 cohort (n⫽7), one patient experienced DLT (grade 4 neutropenia lasting 5 days), and dose reduction or delay was necessary in 4 of the 7 patients during the first course due to neutropenia. It was decided that 100 mg/m2 was the maximum tolerated dosage, and the RD was set at 80 mg/m2. Grade 3 or more severe adverse drug reactions reported for the 80Emg/m2 cohort were neutropenia, anemia, fatigue, hearing impaired and ataxia. Comparison of the pharmacokinetic parameters of NK105 with those of PTX at the same dosage (100 mg/m2) showed that the AUC0-inf. and Vdss of NK105 were approximately 50-fold and 1/15 of the reported PTX values, respectively. A refractory gastric cancer patient and an esophageal cancer patient each showed a partial response, at dosages of 80 mg/m2 and 100 mg/m2, respectively. Conclusions: 80Emg/m2 weekly administration of NK105 was well tolerated and showed anti-tumor activity, including partial responses and several occurrences of stable disease. The expansion phase of the study is ongoing at the RD of 80 mg/m2. Clinical trial information: JapicCTI-101233.

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Superparamagnetic nanoparticles targeting cancer cells invading the extracellular matrix. Presenting Author: Samar Elachy, Faculty of Medicine, Alexandria University, Alexandria, Egypt

The effect of copper nanoparticles on the progression of tumor in vivo. Presenting Author: Polina Sergeevna Kachesova, Rostov Scientific Research Institute of Oncology, Rostov-on-Don, Russia

Background: Metastatic cancer cells secrete matrix metalloproteinases (MMP), which allow cancer cells to burrow their way to the nearby vasculature. Therefore, MMPs are potential targets for anticancer treatment. Nanoparticles (NPs) can be crafted to adhere to the ECM and subsequently be released in response to advance of invasive cells. The objective of the study is to elucidate the interaction of cancer cells in a three-dimensional culture, with functionalized SPIONS targeted to the extracellular matrix around them. Methods: SPIONS, 15-20 nm in size were functionalized using different coatings: ficoll 400, sucrose, lysinearginine, dextran50,000. Cellular uptake studies using cervical adenocarcinoma HeLa cell lines were performed to determine the optimum formulation taken up by the cells, using electron microscopy and Prussian blue staining for optical microscopy. Two types of extracellular matrices were used: Rat-tail Collagen type I and ECM gel from Engelbreth-HolmSwarm murine sarcoma with NPs embedded in them. To assess the capability of cells to invade the matrix, cells were grown on the surface of the matrices for 1 week To evaluate the ability to grow, expand and migrate inside the matrix, cells were embedded within the matrix and left for 14 days. Comparison was made in the presence or absence of SPIONS. Results: Sucrose-coated SPIONS were taken up the best by HeLa cell lines as evaluated by MRI. MMP-1 Secretion allowed HeLa cell invasion of collagen type-1 matrix unidirectionally. Cells could adhere, proliferate, differentiate and migrate in the absence of SPIONS. Cells positive for MMP-9 invaded ECM gel from Engelbreth-Hol-Swarm murine sarcoma matrix also only in the absence of SPIONS. Cells that were found engulfing SPIONS showed morphological features of apoptosis as nuclear pyknosis and karryorhexis. Conclusions: Targeting NPs to the ECM surrounding cancer cells that have developed a metastatic potential represents an attractive platform for cancer therapeutics. The findings show a great promise for development of new theranostic agents, that can be directed to the tumor environment using external magnetic fields, with subsequent suppression of invasion and even destroying malignant cells.

Background: The study of the anticancer activity of copper nanoparticles (CuNP) measuring 70-75 nm in rats transplantable tumors. Methods: Experiments were carried out on white outbreed male rats with transplanted sarcoma 45 (9.10-dimethyl-1.2-benzanthracene-induced fusiform cell fibrosarcoma, S-45) and Pliss’s lymphosarcoma (Pliss). 0.5 ml of tumor tissue suspension (1x106 cells) in saline was inoculated subcutaneously in rat dorsal region for induction of sarcoma 45 or Pliss’s lymphosarcoma. 7-8 days after tumors transplantation the animals were divided into three groups. Group 1: control (rats received 0.3 ml of saline only). Group 2: CuNP in 0.9% w/v of NaCl were injected intratumorally (1.25 mg/kg bodyweight). Group 3: The same amount of CuNP was injected intraperitonially. Animals received nanoparticles four times a week for one week, then after a week’s break, the procedure was repeated. The associated nanoparticles are spherical in shape and have an oxide film on its surface. CuNP effect on tumor growth was determined by the mass (M) and size (V) of tumors. Results: The analysis of the received data showed that administration of CuNP to rats with S-45 caused reduced growth rates or cases with complete regression (8 of 17 cases) in 67.0% of experimental animals independently of injection way (V⫽0.81⫾0.3 cm3, M⫽0.91⫾0.3 g). The other 33% of rats with S-45 showed tumor growth (V⫽7.58⫾1.3 cm3, M⫽9.2⫾1.6 g). Overall, for the entire group of animals with S-45, nanoparticles inhibited tumor growth of 45%. In the control group there was an increase of tumor growth (V⫽9.0⫾1.8 cm3, M⫽10.4⫾2.5 g). CuNP introduction to animals with Pliss caused a delay in tumor growth and partial or complete regression (12 of 28 eight cases) in 40.0-48.0% of the rats in the route of Cu injection (V⫽1.4⫾0.8 cm3, M⫽10.4⫾2.5g). Observation of the remaining animals revealed tumor growth (V⫽60.6⫾5.93 cm3, M⫽67.13⫾8.7 g). In the whole group tumor growth inhibition was 50.0%. In the control group we observed increase of tumor growth (V⫽62.1⫾5.21 cm3, M⫽75.9⫾8.2 g). Conclusions: Thus the study showed that the copper nanoparticles possess antiproliferative activity, can inhibit the growth of transplanted tumors in rats and may be potentially used in anticancer medical therapy.


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Preclinical testing using novel CT20p petide-nanoparticle combination in breast cancer. Presenting Author: Priya Vishnubhotla, VA Medical Center, Orlando, FL

Active immunotherapy in patients with progressive disease (PD) after first-line therapy: Racotumomab experience. Presenting Author: Roberto E Gomez, Laboratorio ELEA, Buenos Aires, Argentina

Background: Patients with metastatic breast cancer may be initially responsive to treatment, but a significant number develop refractory disease. There is a critical unmet need to develop effective therapeutic approaches given the unique metabolism of tumor cells. Methods: We examined the cytotoxic properties of a novel peptide, CT20p, derived from the C-terminus of Bax. For delivery to cells, the amphipathic nature of CT20p allowed it to be encapsulated in polymeric nanoparticles (NPs). NPs were made using aliphatic hyperbranched polyester (HBPE) that incorporated surface carboxylic groups and interior hydrophobic cavities for encapsulation of CT20p. To examine the cytotoxic potential and targeting capacity of CT20p-NP-HBPE, we treated MDA-MB-231 and MCF-10A breast cancer cell lines with the combination and measured changes in mitochondrial function, cell metabolism and induction of cell death. The ability of CT20p-NP-HBPE to cause tumor regression was examined by subcutaneously implanting MDA-MB-231 cells in nude mice. Results: Initial results showed that CT20p caused the release of calcein from mitochondrial-like lipid vesicles, without disrupting vesicle integrity, and, when expressed as a fusion protein in cells, localized to mitochondria. While the peptide alone had little effect upon intact cells, when encapsulated and delivered by nanoparticles, CT20p-HBPE-NPs proved an effective killer of breast cancer cells. CT20p-NP-HBPE initiated non-apoptotic cell death within 3 hours of treatment by targeting mitochondria and deregulating cellular metabolism. Nanoparticles alone or nanoparticles encapsulating a control peptide had minimal effects. The cytotoxicity of CT20p-NP-HPBE was most pronounced in breast cancer cells, sparing normal, epithelial cells. In implanted breast tumors, CT20p-NP-HBPE accumulated in tumors within 24 hours and reduced tumor burden by 50-80%. Conclusions: These results reveal the innovative features of CT20p that allow nanoparticle-mediated delivery to tumors and the potential application in combination therapies that target the unique metabolism of cancer cells.

Background: Racotumomab is a therapeutic vaccine that induces a cellular and humoral immune response against NeuGc-containing gangliosides expressed in several tumors but not in normal human tissues. A previous randomized, double blinded, placebo-controlled trial has demonstrated low toxicity of racotumomab and a statistically significant benefit in overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC) who had achieved partial or complete response or disease stabilization after first line therapy. Methods: An open, non-randomized study was performed to evaluate if racotumomab could also be beneficial in patients with progressive disease. Patients with recurrent and advanced stages (IIIB/IV) of NSCLC, in progression after completion of first-line onco-specific treatment as per the NCCN Oncology Therapeutic Guidelines (surgery, chemotherapy and/or radiotherapy) were included in the study. Most of them had received 4 to 6 cycles of cisplatin/vinblastin. Vaccination consisted of 5 intradermic doses of racotumomab (1 every 14 days), followed by 1 dose every 28 days until patient refusal or worsening of ECOG status. The patients did not receive second-line therapy. Results: 180 patients were included in an intent to treat (ITT) survival analysis (Kaplan Meier estimate), after at least 10 months of follow-up. Median survival was 8.06 months. OS rate (%) at 24 months was 21%. A control group of 85 consecutive patients treated at the same institution by the same investigators, who did not receive second-line therapy or racotumomab showed a median survival of 6.26 months (log rank test p⫽ 0.011). OS rate (%) at 24 months was only 7%. A per protocol survival analysis including only the 124 patients (68.8%) who received ⱖ 5 doses of racotumomab showed a median survival of 12 months. OS rate (%) at 24 months was 30%. Conclusions: Patients with PD after first-line treatment show favorable results in survival when vaccinated with racotumomab. This result is similar to previous clinical trials where racotumomab was administered to patients with objective response (partial or complete) or stable disease after first line therapy.

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Effect of an adjuvant breast cancer vaccine on disease-specific survival of breast cancer patients with depressed lymphocyte immunity. Presenting Author: Robert Lange Elliott, Elliott Elliott Head Breast Cancer Research & Treatment Center, Baton Rouge, LA Background: Breast cancer patients were vaccinated in the adjuvant setting with an autologous, allogeneic whole cell vaccine to evaluate the effect on host lymphocyte immunity and disease-specific survival. Methods: We began preparing whole cell preparations for a vaccine study in 1995. Stage I and II breast cancer patients had host lymphocyte immunity against tumors associated antigens evaluated before and after vaccination. Those patients with depressed immunity, determined by a lymphocyte blastogenesis assay (LBA), were offered the whole cell vaccine. Patients were given six intradermal injections (three weekly followed by three monthly). Ten weeks after the last injection the LBA was repeated. Thirty-seven patients were vaccinated in the adjuvant setting with the whole cell autologous, allogeneic vaccine. Results: The vaccine was well tolerated with no severe toxicities. Some patients experienced slight pain and swelling at the injection site and slight chills and fever. The vaccinated patients had a mean follow-up of 12.7 years with mean follow-up of 8.9 and 9.2 years for the patients with normal and depressed immunity, respectively, in the historic control. The 10-year survival was 95% (20 of 21 patients) in the normal immunity historic control, 59% (33 of 56 patients) in the depressed immunity historic control and 89% (33 of 37 patients) in the patients with depressed immunity that were vaccinated in the present clinical trial. Conclusions: The disease-specific survival of the vaccinated patients with depressed immunity in this trial is significantly greater than that of the historic controls of unvaccinated patients with depressed immunity to their tumor associated antigens. This study confirms the importance of maintaining good host lymphocyte immunity after completion of standard therapy and validates the value of cancer immunotherapy in the adjuvant setting.


A phase II study of intratumoral administration of the autologous immature dendritic cell (DC) vaccine used after lesion photodynamic therapy (PhDT) and immunomodulation with cyclophosphamide (Cy) in pretreated patients with disseminated malignant melanoma. Presenting Author: Alexey Viktorovich Novik, N. N. Petrov Research Institute of Oncology, St. Petersburg, Russia Background: Immature DC can be loaded in vivo with tumor-specific antigens after tissue destruction and induce specific immune response even in pretreated patients with unfavorable prognosis. We assess clinical efficacy of this approach in melanoma patients after at least 1 line of drug therapy in metastatic setting. Methods: Totally, 14 pts were enrolled: 11 men, 3 women. Stage M1a in 4 (28%) pts, M1b in 1 (7%) and M1c was in 9 (64%) pts. Patient received Cy 300 mg IM at D0, photoditasine (PH) at D3, PhDT therapy on injectable lesion 2 hrs after PH (662 nm, 300 J). The immature DC derived from peripheral blood stem-cells were injected in irradiated lesion 6 hrs after photodynamic therapy at D3 and daily until D7 of the 21-day cycle. Vaccine dose was 60-100*10^6 cells. Toxicity was measured by CTC AE v4, efficacy by RECIST 1.0. Primary endpoint was clinical benefit rate (CBR), secondary – overall survival (OS), response rate (RR), time to progression (TTP) and toxicity. Results: 14 pts were evaluable for toxicity, 13 for response. 37 cycles of therapy were performed. 2 patients achieved PR lasting 393 and 218⫹ days. 5 patients were stable for 33⫹, 108, 113, 168 and 239 days. RR was 15 (95% CI 2-39)%, CBR – 54 (95% CI 27-81)%. Median OS was 334 days, TTP – 113 days. RR was well correlated with OS (p⫽0,014). No SAE or AE of 4th degree occurred. The only grade 3 toxicity was fever. All grade 1-2 AEs were immune-related: fever (the most frequent AE), pain in the lesions, flu-like reactions, myalgia as well as high serum ALT, AST and bilirubin in patients with liver metastases. Conclusions: Thus, using the described approach for immunotherapy of melanoma has clinical efficacy and worth further developing.




A phase I study of an MVA vaccine targeting p53 in cancer. Presenting Author: Vincent M. Chung, City of Hope, Duarte, CA Background: Despite chemotherapy, survival for most patients with metastatic gastrointestinal cancer is ⬍2 years. These dismal statistics reflect lack of effective therapy. We are conducting a first-in-human trial of modified vaccinia Ankara (MVA), an attenuated viral vaccine that targets wild-type (wt) p53. This approach applies to the majority of p53-involved tumors, since the bulk of the p53 sequence is identical, except for individual point mutations. Our phase I study evaluates the safety and tolerability of the vaccine. Methods: Patients with metastatic colon, gastric and pancreas cancer that failed standard treatment were eligible for vaccination if ⬎10% of the cells stained strongly positive for p53. A standard 3⫹3 design was employed and patients were accrued to either the 108 pfu or 5.6 x 108pfu dose levels. A total of 3 injections were given, each spaced apart by 3 weeks and patients were evaluated for dose limiting toxicities. Results: Three patients were accrued to the 108 pfu dose level; 2 patients with colon cancer and 1 patient with pancreatic cancer. There were no dose limiting toxicities and the injection was well tolerated and only local irritation at the injection site was seen. The dose was escalated to 5.6 x 108 pfu; 3 patients were accrued, 1 with colon cancer and 2 with pancreatic cancer. There were no dose limiting toxicities observed in the 3 patients. Grade 2 toxicities that were at least possibly related to the vaccine include injection site reaction and fatigue seen in one patient each. One patient with pancreatic cancer had stable disease on CT after completion of the 3 injections. This dose level is being expanded to accrue an additional 6 patients to evaluate safety and immunogenicity using cytokine flow cytometry to characterize p53-specific CD4⫹ and CD8⫹ T cell response. Of the cell-surface markers employed, PD1 showed extraordinary strong expression prior to vaccine injection. All patients had a humoral response to the MVA backbone. Conclusions: Our MVA p53 vaccine is well tolerated with minimal grade 1-2 toxicities. The highest dose tested is 5.6 x 108 pfu and additional patients are being accrued to evaluate immunogenicity. Since many cancers have mutant p53, this is an attractive target and may potentially be used with many other cancers. Clinical trial information: NCT01191684.

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A phase I/II randomized trial using GM-CSF-producing and CD40Lexpressing bystander cell line (GM.CD40L) vaccine in combination with CCL21 in stage IV lung adenocarcinoma: Preliminary results. Presenting Author: Jhanelle Elaine Gray, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL Background: Our GM.CD40L vaccine (an allogeneic tumor cell-based vaccine generated from human bystander cell line) recruits and activates dendritic cells, which then migrate to regional lymph nodes, where T cell activation occurs, leading to systemic tumor cell killing. The CCL21 chemokine helps to recruit T cells and leads to enhanced T cell responses. The GM.CD40L.CCL21 combination has demonstrated additive effects in NSCLC mouse models. Methods: We initiated a phase I/II randomized study to evaluate GM.CD40L (Arm A) vs. GM.CD40L.CCL21 (Arm B) in patients with lung adenocarcinoma who had failed first-line therapy. Primary endpoints were safety and tolerability of Arm B in phase I and progressionfree survival (PFS) in phase II; secondary endpoints included anti-tumor immune responses/T-cell responses by ELISpot assay on PBMC. Immunerelated response criteria as determined by the investigator served to determine discontinuation from study treatment. Intradermal vaccines were administered every 14 days for 3 doses and then monthly X3. A two-stage minimax design was used. Results: In phase I, 3 patients received GM.CD40L.CCL21; no dose-limiting toxicities occurred. Between 4/2012 and 12/2012, Arm A enrolled 11 and Arm B enrolled 16 patients, including those in phase I (median age: 70/67.5 years, females: 45.5%/ 37.5%, PS1: 54.5%/75%, median prior regimens: 3/5 for Arm A vs. Arm B, respectively). Most common toxicities for Arm A vs. Arm B were injection site reaction (45.5%/43.8%), fatigue (9.1%/37.5%), anorexia (0%/ 12.5%), and pain in extremity (0%/12.5%). Median PFS for Arm A vs. B was 4.4 vs. 4.4 months (p⫽0.37). Of the 6 patients who remained on study post RECIST v1.1 progression, all demonstrated further progression on subsequent scans and were removed from the study. Of patients evaluable for efficacy, stable disease was 3/7 and progressive disease was 6/7 for Arm A vs. Arm B, respectively. Analyses of ELISpot assay on the PBMC are underway. Conclusions: GM.CD40L.CCL21 vaccine is well tolerated; thus far, median PFS results are similar to GM.CD40L vaccine. Updated results of the phase II trial will be presented. Clinical trial information: NCT01433172.

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VXM01, an oral T-cell vaccine targeting the tumor vasculature: Results from a randomized, controlled, first-in-man study in pancreatic cancer patients. Presenting Author: Friedrich Hubertus Schmitz-Winnenthal, Clinic for General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany Background: VXM01 is an orally available, bacterially transmitted DNA vaccine targeting VEGFR-2. Pre-clinically, VXM01 showed anti-tumor activity in multiple tumor types. This first-in-human study was designed to evaluate the safety and tolerability of VXM01. Secondary endpoints included VEGFR-2 specific T-cell responses, tumor perfusion changes, and related biomarkers. Methods: A randomized, double-blinded, placebocontrolled, dose-escalation study was conducted in 45 patients with advanced pancreatic cancer. VXM01 or placebo was given on days 1, 3, 5, and 7. Doses were escalated from 10(6) CFU to 10(10) CFU over 5 dose groups, each including 6 VXM01 and 3 placebo patients. VEGFR-2 specific T-cell activity was monitored by ELISpot and T(reg) specificity assays before, during and after the vaccination course. Tumor perfusion was assessed by DCE-MRI on days 0 and 38. Biomarkers included CA19-9, VEGF-A and collagen IV. Results: Patients were enrolled from 12/2011 to 10/2012. Most commonly observed AEs were leukopenia, abdominal pain, and diarrhea, which were all equally distributed between treatment and placebo group. While a mild elevation in average blood pressure was observed in the VXM01 group over the placebo group, the hypertension adverse event rate did not differ between both groups. No DLTs were observed. VEGFR-2 specific effector T-cell response was increased in 57% of evaluable VXM01 treated patients, during and after the vaccination course. In 25% of the VXM01 group, the T-cell response score postvaccination was higher than maximum placebo levels. In contrast, VEGFR-2 specific T(reg) responses were overall reduced in vaccinated patients. DCE-MRI data indicated a ⬎33% drop in K(trans)/tumor perfusion in 35% of evaluable VXM01 treated patients vs. 10% in the placebo group. Mean changes were -4% (VXM01) and ⫹15% (placebo). Reduced tumor perfusion correlated with VEGFR-2 specific T-cell responses and biomarker responses. Conclusions: VXM01 appeared safe and was well tolerated without DLTs across 5 tested dose levels. The data suggest further that VXM01 induces and enhances a VEGFR-2 specific T-cell response and impacts tumor perfusion. Clinical trial information: ISRCTN68809279.

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Systematic approach for development of new immunotherapeutics for lung cancers through cancer genomics analysis. Presenting Author: Yataro Daigo, Institute of Medical Science, University of Tokyo, Tokyo, Japan Background: Oncoantigens are defined to be proteins that are very specifically expressed in cancer cells and that have the oncogenic activity and high immunogenicity, and are considered to be promising targets for immunotherapy such as therapeutic cancer vaccines. Methods: We have established a strategy as follows to identify new oncoantigens; i) screening of highly transactivated genes in the majority of 120 lung cancers using cDNA microarray representing 27,648 genes coupled with enrichment of tumor cells by laser microdissection, ii) verification of no expression of each candidate gene in normal tissues by northern-blot analysis, iii) validation of the clinicopathological significance of its high level of expression with tissue microarray containing 300 lung cancers, iv) verification of a critical role of each gene in the growth or invasiveness of cancer cells by RNAi and cell growth/invasion assays, v) screening of the epitope peptides recognized by HLA-A*0201- or A*2402-restricted cytotoxic T lymphocyte (CTL). We conducted phase I clinical trials of these therapeutic peptide vaccines for lung cancer patients. Results: We identified 35 oncoantigens and screened dozens of 10-amino-acid peptides, each of which corresponded to a part of TTK, LY6K, IMP-3, CDCA1, KIF20A, CDC45L, and FOXM1, and was a candidate to be presented on the surface of HLA-A*0201 or HLA-A*2402 that induced in vitro CTL response. Phase I clinical studies indicated that five epitope peptides could strongly induce the CTL activity in cancer patients. For example, we conducted a phase I study for HLA-A*2402positive, advanced non-small cell lung cancer patients who failed to standard therapy, using the combination of 1, 2 or 3 mg/body of each peptides from LY6K, CDCA1, and KIF20A mixed with adjuvant once a week. This cancer vaccine therapy demonstrated tolerability and had very high immunogenicity of even 1 mg/body dose to induce antigen-specific CTLs in cancer patients. Conclusions: Through systematic genomics-based approach and clinical study, we have identified five epitope peptides, which could induce CTLs very effectively in cancer patients, and therefore it warrants further clinical studies. Clinical trial information: NCT01069575.


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Evaluation of cyclophosphamide as an immune enhancer for the NY-ESO-1/ ISCOMATRIX vaccine in patients with metastatic melanoma. Presenting Author: Oliver Klein, Ludwig Institute for Cancer Research, Melbourne, Australia Background: We have previously demonstrated potent immunogenicity of the NY-ESO-1/ISCOMATRIX vaccine in patients with resected melanoma; however the same vaccine induced only a few vaccine antigen specific immune responses in patients with advanced disease. Therefore, we have enrolled a second cohort of patients with advanced melanoma in the clinical trial LUD2002-013 to investigate whether pre-treatment with the immune-modulator cyclophosphamide could improve the immunogenicity of the NY-ESO-1/ISCOMATRIX vaccine. Methods: LUD2002-013 was an open-label phase II study intended to evaluate the safety and immunogenicity of the NY-ESO-1/ISCOMATRIX vaccine in patients with advanced melanoma. The first cohort of patients received vaccine alone; a second cohort with 19 patients was added after evaluation of responses in Cohort 1 and received vaccine in combination with low-dose cyclophosphamide. Patients received 3 injections of NY-ESO-1 ISCOMATRIX preceded, in Cohort 2, by cyclophosphamide at a dose of 300 mg/m2 every four weeks. Assessment of clinical and immunological responses was undertaken at week 11. Results: Fifteen patients of Cohort 2 completed at least one cycle of vaccination. No objective responses were observed with three patients having stable disease for more than three months. The inclusion of cyclophosphamide into the vaccination protocol did not lead to any significant toxicity. Seven of fourteen patients in Cohort 2 developed a vaccine induced NY-ESO-1 specific CD4 T cell response, a significant increase compared to cohort 1 (p⫽0.019). No differences were observed in the frequency of vaccine induced antibody or CD8 T cell responses. No change in the frequency of peripheral blood regulatory T cells or myeloid derived suppressor cells was detected. Conclusions: The administration of low dose cyclophosphamide has significantly increased the NY-ESO-1 specific CD4 T cell response of the NY-ESO-1/ISCOMATRIX vaccine in patients with metastatic melanoma. Given the emerging importance of CD4 T cells in tumour regression, the present findings warrant further clinical exploration of combining cyclophosphamide with vaccines and other immune-modulatory agents. Clinical trial information: NCT00518206.

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NfP2X7, a novel target for immune therapeutic approaches in cancer treatment. Presenting Author: Jan Nesselhut, Praxisgemeinschaft fuer Zelltherapie, Duderstadt, Germany Background: P2X7 receptor, a ligand-gated channel, is activated by extracellular ATP and mediates ATP induced apoptosis. Several polymorphisms leading to loss of function of P2X7 have been described. Overexpression of non-functioning P2X7 receptor (nfP2X7), able to form a Ca2⫹channel but not an apoptotic pore, is found on every type of cancer cell but no normal cells, making it a perfectly selective target for immune therapy approaches. Methods: Samples from various tumor types were analyzed for the expression of nfP2X7 using immunohistochemistry. MoDC from n⫽6 patients with advanced metastatic sarcoma (2 osteosarcoma, 4 soft tissue sarcoma) with disease progression after failure of extensive standard therapies were primed against the nfP2X7using a specific peptide. MoDC were harvested, analyzed by flow cytometry and applied to the patient intradermaly. Specific T-cell response was analyzed by IFN-gamma Elispot. Results: nfP2X7 is overexpressed in essentially all analyzed tumor samples from all cell types: epithelial, mesenchymal, neural, germinal examined in large numbers (n ⫽ 5 to ⬎1,000). The uniquely displayed epitope associated with the ATP binding site exposed on nfP2X7 but hidden in P2X7 was found on the cancer cell surface but not on the surface of any normal cells. MoDC primed with a specific peptide against nfP2X7 show a distinct DC morphology and an up-regulation of the maturation marker CD83. Patients are 6-9 months (onset June 2012) under treatment at time of abstract submission. 2 patients have a disease stabilization. One further patient with a metastatic, rapidly growing osteosarcoma showed a mixed response. IFN-gamma Elispot, which was exemplarily performed, shows a nfP2X7specific T-cell response. Conclusions: Efficient inductions of an antitumor response by dendritic cell therapy require the definition and choice of an optimal target, being expressed in almost all kinds of tumors. nfP2X7, a set of non-functioning forms of the P2X7 receptor unable to initiate apoptosis but maintaining channel activity, could therefore be an optimal universal candidate. The efficacy of dendritic-cell based therapy may be improved by priming the MoDC against nfP2X7 and thus may improve the clinical outcome.

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Booster inoculations of the AE37 peptide vaccine enhance immunological responses in a phase II study. Presenting Author: Eleftheria A Anastasopoulou, Cancer Immunology and Immunotherapy Center Saint Savas Cancer Hospital, Athens, Greece

Safety and efficacy of the HER2-derived GP2 peptide vaccine in combination with trastuzumab for breast cancer patients in the adjuvant setting. Presenting Author: Ritesh Patil, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY

Background: We are conducting a multicenter randomized phase II trial of AE37, the Ii-Key hybrid peptide of HER2 776-790 (AE36). The purpose of the study is to determine if the AE37 vaccine can prevent recurrence in disease-free conventionally treated node-positive (NP) and high-risk nodenegative (NN) breast cancer patients at significant risk for recurrence. Since clinical efficacy is anticipated to occur as the result of long lasting memory immune responses induced by vaccination, repeated booster inoculations were scheduled as part of the trial. Here we present data on immune responses in patients who received boosters up to 24 months after completion of the primary vaccination series (PVS). Methods: The trial is enrolling NP or high-risk NN patients with any degree of HER2 expression (IHC 1-3⫹ or FISH ⬎ 1.2) rendered disease-free following standard of care therapy. The vaccine group (VG) received AE37⫹GM-CSF and control group (CG) GM-CSF alone in 6 monthly i.d. inoculations followed by boosters administered every 6 months x 4. Immunologic responses were assessed in vivo by dermal reactions at the inoculation site, and in vitro, against the AE36 peptide, with proliferation and IFN-␥ ELISPOT assays. Results: 25 patients in the VG and 23 in the CG have completed their boosters. After the last booster (BRC24), 100%, 54% and 54% in the VG (vs. 9%, 18% and 27% in the CG) responded by dermal reaction, proliferation and IFN-␥ ELISPOT, respectively. Mean dermal reactions (orthogonal mean in mm) in vaccinated patients was 25.9⫾3.13 at completion of the PVS (R6) and increased to 35.47⫾4.35 at BRC24 (p⫽0.01). VG patients increased their proliferation response (stimulation index, SI) to AE36 from 0.97⫾0.046 at baseline (R0) before vaccination to 2.27⫾0.57 at R6 (p⫽0.0003) which was maintained until BRC24 (SI 2.21⫾0,33, p⬍0.0001). The number of IFN-␥ specific spots/106 PBMC increased from 26.88⫾12.36 at R0 to 40.35⫾17.02 (p⫽0.07) at R6, up to 62⫾16.82 (p⫽0.0076) at BRC24. Conclusions: Our data demonstrate that AE37 vaccine boosters enhance the immune responses against HER elicited during the PVS, thus sustaining long lasting immunity, a prerequisite for possible clinical efficacy which is currently being evaluated. Clinical trial information: NCT00524277.

Background: GP2 is a 9 amino acid HLA-A2/A3 restricted HER2-derived peptide. GP2 ⫹ GM-CSF has been shown to be safe and effective in eliciting anti-HER2 immune response in breast cancer patients. Preclinical data has demonstrated that pretreatment of cells with trastuzumab (Tz) enhances susceptibility to lysis by GP2-specific cytotoxic T lymphocytes (CTLs). We conducted a phase Ib study to evaluate the combination of the GP2 vaccine and Tz. Methods: HLA-A2/A3 ⫹ patients with HER2 overexpressing breast cancer receiving Tz as standard therapy were enrolled. The study was designed as a 3⫹3 dose escalation trial with an expansion cohort evaluating 4 dose levels of the vaccine administered as 6 inoculations given every 3 weeks in combination with Tz (6mg/kg). Toxicity was graded 48-72 hr post vaccination using NCI Toxicity Criteria. Ejection fraction (EF) was monitored every 3 mo. Immunologic response was assessed in vivo by injection site local reaction (LR) and in vitro by quantifying the number of GP2-specific CTLs by HLA-A2: IgG dimer assays and their functional activity by ELISPOT. Results: 19 patients enrolled (median age 47 yr, mean tumor size 3.4 cm, 74% were grade 3, 53% ER/PR⫹, 63% node positive, 74% received anthracycline based therapy). Maximum local toxicities were grade 1 (77% of patients) and grade 2 (6%), and maximum systemic toxicities were grade 1 (24%) and grade 2 (5%). There were no grade 3 or 4 local or systemic toxicities. There was no significant change in EF at 3 mo (57⫾ 1%, p⫽0.23) or 6 mo (59⫾1%, p⫽0.8) compared to baseline (58⫾0.9%). Mean post-vaccine series LR was significantly larger than initial vaccination LR (68.2 ⫾ 8.6 mm vs 28.0 ⫾ 10.3 mm, p⫽0.0004). In vitro assays demonstrated an increase in the maximal number of postversus pre-vaccination GP2-specific CTLs by dimer assay (1.45 ⫾ 0.19 vs 0.96 ⫾ 0.19%, p⫽0.06) and increased ELISPOT activity [median 86 range (3-194) vs 34 (range 0-295) spots/106 cells]. Conclusions: GP2 vaccine in combination with Tz is both safe and immunogenic in HER2overexpressing breast cancer patients in the adjuvant setting. Toxicity was limited to mild local and systemic reactions. There were no dose limiting toxicities or cardiac events.




Risk factors for development of delayed urticarial reactions in the phase II trial of HER2 peptide vaccines plus GM-CSF versus GM-CSF alone in high-risk breast cancer patients to prevent recurrence. Presenting Author: Alfred F Trappey, Brooke Army Medical Center, San Antonio, TX Background: We are monitoring the incidence of delayed urticarial reactions (DURs) in our phase II trial evaluating adjuvant HER2-specific vaccines (AE37 and GP2) for the prevention of breast cancer recurrence. Here, we characterize DURs and analyze risk factors for their development. Methods: After completion of standard of care therapy, disease-free node-positive or high-risk node-negative patients (pts) were randomized to receive either a peptide⫹GM-CSF (VG) or GM-CSF (CG). Pts receive 6 monthly intradermal inoculations during the primary vaccine series (PVS) then four boosters (B) every 6 mos. Immune response is measured by delayed type hypersensitivity (DTH) pre- (R0) and post-PVS (R6) and local reaction (LR) at R1 – R6. Results: Twenty-four (6.1%) of 393 initiated patients report a DUR; 13 VG (vDUR), and 11 CG (cDUR); vDUR - 9 AE37, 4 GP2. Time to onset of symptoms is 9⫾5 days (d) and is similar in vDUR/cDUR (p ⫽ 0.27). DURs manifest as hives/pruritis in all patients. Average duration of symptoms is 32.6 d ⫾ 8.8 d (no difference in vDUR/cDUR [p ⫽ 0.23]). Episodes have resolved with antihistamines or IV/oral steroids. Ten (4 cDUR, 6 vDUR) patients have had recurrent episodes that have resolved similarly. 75% of first episodes occur between R6-B3. For DUR patients v. those who have not had a DUR (noDUR), there are no differences in demographics. DTH response is similar in vDUR pts v. noDUR VG pts (R0- p ⫽ 0.34; R6p⫽0.40). cDUR pts had a greater DTH response v. CG noDUR pts at R6 (13.2 v 4.7 mm, p⫽0.01). LRs are greater in DUR pts compared to noDUR pts after the second vaccination (R2 – 66.2 v 48.2 mm, p⫽0.02). LR for DUR pts decrease and are less than noDUR at R6 (45.4 v 57.4 mm, p⫽0.09). Relative risk for developing DUR for LR ⬎ 100 mm at R2 is 3.49 (1.58-7.68, 95% CI [p⫽0.004]). At 29.9 months median follow-up, there have been no recurrences in VG and CG DUR v. 75.9% DFS for noDUR (p⫽0.05). Conclusions: DURs occur infrequently and without long-term sequelae. Pts at risk for developing DUR are identified early in the vaccine series using LR. Robust immune response in DUR may explain the survival benefit demonstrated here. Clinical trial information: NCT00524277.

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Phase I/II clinical trial of a genetically modified and oncolytic vaccinia virus GL-ONC1 in patients with unresactable, chemotherapy-resistant peritoneal carcinomatosis. Presenting Author: Ulrich Lauer, Department of Gastroenterology & Hepatology, Medical University Hospital, Tübingen, Germany, Tuebingen, Germany Background: For therapy-resistant peritoneal carcinomatosis (PC) viruses exhibiting oncolytic properties open up new perspectives. Our phase I/II study in patients with refractory PC (NCT01443260) is designed to assess the safety, MTD, and anti-tumor activity of GL-ONC1, a recombinant vaccinia virus (VACV) genetically engineered to selectively replicate in and destroy cancer cells. Methods: GL-ONC1 was administered intraperitoneally up to 4 times every 28 days under a standard 3⫹3 dose escalation design. Safety was assessed using CTCAEv4.0. Anti-tumor activity was determined by “fluid biopsies” obtained via repetitive paracenteses and by serial PET-CT scans. Patient samples were collected for pharmacokinetics, pharmacodynamics and viral shedding analysis. Results: Up to now, 4 patients have received 10 doses of GL-ONC1 ranging from 107 to 108 infectious viral particles per application.Adverse events have generally been limited to grade 1/2, being mostly transient flu-like symptoms as well as increased abdominal pain resulting from treatment-induced peritonitis. No DLT was reported. No viral shedding was observed. In one gastric cancer patient, effective intraperitoneal replication of GL-ONC1 was demonstrated for more than 3 weeks. Using either anti-EpCAM or anti-VACV specific antibodies, around 5% of all ascitic cells were found to be EpCAM-positive 3 days after treatment in this patient, and only around 5-10% of these cancer cells were VACV positive at the same time point. In contrast, 4 days later (i.e. 7 days after virotherapeutic treatment), less than 2% of all ascitic cells were still EpCAM-positive, and more than 90% of these cancer cells were VACV positive. Of note, VACV-positive cancer cells morphologically showed significant degenerative changes. Conclusions: Preliminary data demonstrate that GL-ONC1 is well tolerated when infused intraperitoneally. Importantly, a single intraperitoneal delivery of GL-ONC1 was found to be sufficient to cause a dramatic decline in the number of malignant cells in the ascitic fluid, suggesting that GL-ONC1 effectively removes tumor cells in the ascites of patients with PC. Clinical trial information: NCT01443260.

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A phase I trial of intratumoral administration of HF10 in patients with refractory superficial cancer: Immune correlates of virus injection. Presenting Author: Neil Gildener-Leapman, University of Pittsburgh Medical Center, Pittsburgh, PA

Role of mesenchymal stem cells in delivering Newcastle disease virus to glioma cells and glioma stem cells and enhancing the oncolytic effect of the virus by secreting TRAIL. Presenting Author: Shimon Slavin, International Center for Cell Therapy and Cancer Immunotherapy, Tel Aviv, Israel

Background: HF10 is a spontaneously occurring, oncolytic, mutant Herpes Simplex Virus type 1 (HSV-1). Several deletions/insertions in its genome render it nonpathogenic. HF10 has been tested in solid tumors accessible for injection. Methods: We report correlative studies from an open label, non-randomized, multicenter, single dose escalation phase I study in patients with refractory superficial cancer. The study was a “3 ⫹ 3” design with 4-dose cohorts at escalating doses of HF10 (1 x 105 TCID50/dose with incremental dose escalations up to 1 x 107 TCID50/dose), which has been completed. Body fluids (qPCR), peripheral blood (flow cytometry) and serum (30-plex cytokine assay) were examined for viral levels, quantitative immune cell variation, and cytokines, respectively. Results: Seventeen patients were enrolled and 15 treated (9 H/N; 4 melanoma; 1 colon; 1 sarcoma). Best response was stable disease in six patients and progressive disease in nine patients. Three of the 15 patients had an adverse event possibly related to the study therapy. These AEs were grade 1 hypotension (1) and flu-like symptoms (2): typical of treatment with oncolytic viruses. qPCR analysis transiently revealed virus in the saliva of two patients (day 2 and day 22); viral clearance was achieved after 1 and 7 days respectively. Comparing the two highest and two lowest dose HF10 cohorts, CD8⫹PD1⫹ cells were decreased with increasing HF10 dose (p⫽0.023). Increased monocyte population (CD14⫹CD11c⫹) appeared to correlate with increased HF10 dose (p⫽0.063). IL-8 increased in all samples (p⫽0.0078 Wilcoxon Signed rank test) post injection. Conclusions: Single dose intratumoral injection was well tolerated with mild-drug related AEs and rapid viral clearance. Six patients achieved stable disease during the study period. There appears to be a generalized IL-8 related inflammatory response coincident with increased peripheral blood monocytes after HF10 administration. Decreased CD8⫹PD1⫹ cells may indicate a shift towards a non-exhausted, functional CTL phenotype. These results justify the currently accruing study of multiple administrations of HF10 at the highest administered dose. Clinical trial information: NCT01017185.

Background: Newcastle disease virus (NDV), an avian paramyxovirus, is tumor selective and oncolytic by induction of apoptosis. Preclinical and clinical studies in patients with glioblastoma (GBM) using NDV demonstrated occasional clinical benefits with no major side effects. Limitations to the use of NDV as virotherapy of GBM is the inefficient delivery into cancer cells in the brain. Methods: Mesenchymal stromal cells (MSCs) can migrate towards cancer cells. We examined potential delivery of oncolytic effect of NDV (MTH-68/H) against glioma cell lines and glioma stem cells (GSCs) and the ability of MSCs to deliver NDV to glioma cells and GSCs in culture. Results: NDV induced a dose-dependent cell death in the glioma cells U87, A172 and U251 with maximal effects at 10 MOI. In contrast, we found only small level of apoptosis or changes in self-renewal in three GSCs infected with NDV. We found that MSCs derived from bone marrow, adipose tissue and cord were successfully infected by NDV and were able to deliver the virus to co-cultured glioma cells and GSCs. In addition, treatment of glioma cells and GSCs with culture supernatant of infected MSCs increase apoptosis of glioma cells as compared to the effect of direct infection of glioma cells. Moreover, the culture supernatants of the infected MSCs induced cell death in GSCs that were resistant to the oncolytic effect of NDV, suggesting that factor(s) secreted by the infected MSCs sensitized the glioma cells and GSCs to the cytotoxic effects of NDV. Using antibody array and ELISA we identified TRAIL as the factor secreted from infected MSCs. Indeed, treatment of infected glioma cells with TRAIL increased the cytotoxic effect of NDV and sensitized GSCs to the oncolytic effects of NDV. Conclusions: MSCs can be employed to deliver NDV to GBM. In addition, MSCs can also sensitize glioma cells and GSCs to oncolysis by NDV. Considering the resistance of GSCs to chemotherapy and radiation therapy, treatment of GBM with MSC-mediated targeted oncolytic NDV may provide a new clinical tool for treatment of GBM and eradication of GSCs.


198s 3101


Activity of PU-H71, a novel HSP90 inhibitor, and bortezomib in Ewing sarcoma preclinical models. Presenting Author: Srikanth R. Ambati, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Heat shock protein (HSP) 90 regulates the disposition and activity of a large number of deregulated proteins in Ewing sarcoma. We have shown pre-clinical efficacy of PU-H71, a novel HSP90 inhibitor developed at MSKCC, in Ewing sarcoma. Unfolded proteins as a result of HSP90 inhibition are degraded via the ubiquitin-proteasome pathway or the autophagy pathway. We investigated the effects of combined inhibition of HSP90 and the proteasome pathway. Methods: We studied the effects of PU-H71 and bortezomib alone and in combination on cell proliferation and viability in multiple Ewing cell lines, benign stromal cells and hematopoietic stem cells. We performed cell cycle analysis, clonogenic assay, immunoblot analysis, reverse phase protein array and in vivo experiments in NOD/SCID IL2R gamma null (NSG) mice using the A673 cell line transduced with GFP luciferase. Using A673 metastatic model in NSG mice, we investigated the disease burden when treated with PU-H71, bortezomib and in combination. Results: In vitro, PU-H71 and bortezomib treatment resulted in caspase mediated cell death in a dose-dependent and time-dependent manner. Using PU-H71 beads we showed that some of the critical proteins, including IGF1R, hTERT and EWS-FLI1, are stabilized by HSP90. Exposure to PU-H71 resulted in depletion of AKT, ERK, MYC, C-kit, IGF1R and EWS-FLI1. Combination index (CI)-Fa plots and normalized isobolograms indicated synergism between PU-H71 and bortezomib. We noted increased expression of cleaved PARP and cleaved caspase 3 when Ewing cell lines were exposed to a combination of PU-H71 and bortezomib. Based on PK studies we treated mice (4 groups) using vehicle, PU-H71 75mg/kg i.p three times/wk, bortezomib 0.8mg/kg i.v twice/wk or a combination of PU-H71 and bortezomib for 4 wk. Ewing xenografts were significantly inhibited when treated with combination of PU-H71 and bortezomib compared to vehicle or either drug alone. Conclusions: Both PU-H71 and bortezomib have single agent activity against Ewing sarcoma. However they exhibit synergism when combined in in vitro and in vivo models providing a strong rationale for clinical evaluation in Ewing sarcoma.

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Do ascorbic acid and viscum album improve PFS in NSCLC? Presenting Author: Fatima Zehra Raza, University of Louisville, Louisville, KY Background: Intravenous vitamin C achieves 70 times higher plasma concentrations of ascorbate as a similar oral dose. Such pharmacologic concentrations(0.3-20mM) kill cancer cells but not normal cells, through extracellular H2O2 generation. Ascorbate treatment depleted ATP and induced autophagy in prostate cancer cells; gemcitabine with ascorbate resulted in 50% inhibition of growth in pancreatic tumor xenografts in mice models. A phase I/II study for pancreatic cancer patients is underway. Viscum album (mistletoe) is widely used in Europe as complementary therapy. Its cytotoxic and immunomodulatory effects are poorly understood. Additional treatment with subcutaneous mistletoe injections improved quality of life in gastric cancer patients in a study. Methods: We report the case of a 54 year old male smoker with adenocarcinoma of the lung (pT4N2M1a), EGFR/RAS/ALK negative. After 5 cycles of chemotherapy (carboplatin/taxol x 3, then carboplatin/pemetrexed x 2) scans showed continued progression. The patient made an informed decision to stop further chemotherapy and initiated complementary medical means, receiving high dose IV vitamin C (75 g, 2 x week) and subcutaneous mistletoe injections every other day, for the last seven months. Results: Six months into the non-standard therapy, a PET/CT shows a PR by RECIST and decreased FDG activity of the biopsy proven primary and metastatic site. The patient feels well, a year now after being diagnosed with advanced NSCLC. Conclusions: Whether the PR and the surprisingly long PFS is due to IV ascorbic acid and/or mistletoe is unknown. A review of the literature reveals reports of similar astonishing clinical results after treatment with either agent. A registry and biorepository of cases treated with alternative modalities may discover markers and biological mechanisms to explain these surprising reports.

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Economic analysis of pharmacokinetic (PK) studies in phase I clinical trials. Presenting Author: Badi Edmond El Osta, Department of Investigational Cancer Therapeutics, Phase I Clinical Trials Program, The University of Texas MD Anderson Cancer Cent, Houston, TX

Systematic analysis of potential targets for immunotherapy in acute myeloid leukemia. Presenting Author: Christopher Simon Hourigan, Myeloid Malignancies Section, Hematology Branch, National Heart, Lung and Blood Institute, Bethesda, MD

Background: Although PK evaluation is a prevalent and critical component of cancer drug development, optimization of the cost-value relationship of PK studies has not been evaluated. Methods: We reviewed 26 phase I protocols that were activated and performed in the Clinical & Translational Research Center at U.T. MD Anderson Cancer Center from 2010 to 2012. 23 protocols met the residual analysis criteria of a normal and independent distribution. We collected protocol-specific data including medication, route, frequency, mechanism of action, number of enrolled patients, number of PK time points, and PK charges. Results: All 23 protocols were funded by industry sponsors. During 2010-2012: the total number of patients was 560; the median number of patients enrolled per protocol at our site was 18 (range 3-84); the median number of total PK studies per patient performed on each protocol was 19.46 (4.11-36.92); the median charge of PK time points was $42.33 (35.02-80.00); the median charge of all PK time points per patient on a protocol was $813.00 (329.001676.00); the median number of total PK studies per patient on a protocol during cycle 1 was 15.20 (2.40-27.47); the median charge of PK studies during cycle 1 was $43.24 (36.93-80). The number of PK time points and the amount of PK charges did not significantly correlate with monotherapy vs. combination regimens, oral vs. parenteral route, or small molecules vs. other (cytotoxic, vaccine, monoclonal antibodies). However, protocols (all cycles combined) with small molecules had a trend of lower PK time point median charges (41.97 vs. 52.67; p⫽0.09). Analysis of PKs in cycle 1 demonstrated that protocols with small molecules had a trend of higher PK time point median charges (61.33 vs. 42.38; p⫽0.08). Conclusions: The number and charges of PK studies was independent of the study drug or route. Future studies comparing budgeted vs. performed PKs and industry vs. investigator-initiated trials are warranted.

Background: The ability to target myeloid malignancies using immunotherapy, without allogeneic transplantation, depends on the capability to target leukemic clones while sparing normal tissues. A variety of putative leukemia associated antigens (LAA) have been identified but an evidencebased list of targets for acute myeloid leukemia (AML) has not yet been established. Methods: De-identified, clinically annotated, samples of peripheral blood and/or bone marrow aspirate from untreated AML patients were collected under IRB-approved protocols from three NCCN cancer centers. Samples were analyzed for commonly observed somatic mutations in ASXL1, DNMT3A, FLT3, IDH1/2, KIT, NPM1, NRAS, RUNX1, TET2, and WT1. Gene expression of 75 consensus LAAs were determined using a custom-designed RT-PCR array. 12 samples underwent extended LAA analysis by flow sorting into “bulk leukemia” and “stem cell enriched” populations. LAA expression was normalized using the geometric mean of three control genes. Results: Samples from 48 AML patients (30 blood, 22 marrow) were suitable for analysis. Average age of patients was 53 (24-86), 50% were female. Cytogenetics were favorable (17%), intermediate (65%) or adverse (19%); 29% presented with a white blood cell count ⬎50,000. Over 10,000 individual data-points were collected. Five distinct patterns of LAA expression were observed in blood from AML patients compared to healthy donors. Conclusions: Understanding the heterogeneity and patterns of AML LAA expression between individuals allows the rational prioritization of potential targets for immunotherapy. Based on our data we predict that targeting any single LAA will likely often be ineffective but that it may be possible to create an inclusive panel of multiple targets with coverage of most AMLs, eliminating the need for individualized personalization of therapy. Such AML antigen signatures may also have utility for minimal residual disease monitoring. 1) Common, often highly overexpressed 2) Common, rarely highly overexpressed 3) Rare, but highly overexpressed 4) Rare, and rarely highly overexpressed 5) Not overexpressed

Cyclin A1, WT1 BAALC, PR3 PRAME, MSLN, MECOM Survivin, RHAMM AURKA, EXOSC5, MAGE A1/A3/C1, NUDCD1, RPSA, SSX2IP


Developmental Therapeutics—Immunotherapy TPS3105^


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Clinical and preclinical activity of SL-401, a targeted therapy directed to the interleukin-3 receptor on cancer stem cells and tumor bulk of hematologic malignancies, against blastic plasmacytoid dendritic cell neoplasm (BPDCN). Presenting Author: Arthur E. Frankel, University of Texas Southwestern, Dallas, TX

A phase I study of lirilumab (BMS-986015), an anti-KIR monoclonal antibody, administered in combination with ipilimumab, an anti-CTLA4 monoclonal antibody, in patients (Pts) with select advanced solid tumors. Presenting Author: Naiyer A. Rizvi, Memorial Sloan-Kettering Cancer Center, New York, NY

Background: Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), a rare and aggressive dendritic cell-derived hematologic malignancy that typically involves the skin and invariably progresses to a leukemic phase, has a dismal prognosis with a median survival of approximately 14 months. Since BPDCN cells express high levels of the interleukin-3 receptor (IL-3R), SL-401, a novel targeted therapy directed to IL-3R, is being developed to treat BPDCN and other IL-3R-expressing hematologic malignancies. SL401 is a recombinant biologic comprised of IL-3 conjugated to a truncated diphtheria toxin, a potent inhibitor of protein synthesis (Frankel et al, Prot Eng 13, 575, 2000). SL-401 is cytotoxic in vitro to IL-3R-expressing leukemia blasts (Frankel et al, Leukemia 14, 576, 2000) and inhibits tumor growth in vivo (Black et al, Leukemia 17, 155, 2003). Recently, SL-401 demonstrated ultra-high anti-tumor potency against BPDCN cells in the femtomolar (10-15 M) range (Angelot-Delettre et al, Blood 118 Suppl 2588, 2011). Methods: In a Phase I/II trial of SL-401 in patients with IL-3R-expressing advanced hematologic malignancies, 4 patients with heavily pretreated BPDCN received a single cycle of SL-401 as a 15minute infusion daily for 5 days. Results: All patients had CD4⫹/CD56⫹/ CD123⫹ (IL-3Ralpha) expressing blasts and had failed previous combination chemotherapy regimens and allogeneic bone marrow transplantation. There were no serious adverse events. Three patients treated with SL-401 at 12.5 ␮g/kg/day (the planned pivotal Phase IIb trial dose) experienced complete responses (CRs). The CRs included disappearance of BPDCN in the skin, bone marrow, peripheral blood, spleen and lymph nodes. CR durations are 5, 3⫹, and 1⫹ months to date. Conclusions: Given these robust clinical responses, as well as the mechanistic rationale for SL-401 in BPDCN, additional BPDCN patients are being evaluated in the study and a pivotal Phase IIb multi-cycle trial in this ultra-orphan indication is being planned. Clinical trial information: NCT00397579.

Background: Immune checkpoint blockade represents a novel form of cancer immunotherapy. Killer cell immunoglobulin-like receptors (KIR) and cytotoxic T lymphocyte antigen-4 (CTLA-4) are immune receptors that down-regulate NK and T cell activity, respectively. The anti-KIR antibody, lirilumab (BMSE986015), potentiates innate immunity by blocking signaling through inhibitory KIRs and has demonstrated modest side effects in a Phase I trial. The anti-CTLA-4 antibody, ipilimumab, potentiates adaptive immunity and has demonstrated improved overall survival in pts with advanced melanoma and preliminary evidence of clinical activity in Phase I and II trials. We hypothesized that coordinate modulation of innate and adaptive immunity by combining anti-KIR and anti-CTLA4 antibodies could achieve enhanced biologic and clinical activity compared to either agent alone. Here, we describe a Phase I study of lirilumab plus ipilimumab in pts with selected advanced solid tumors. Methods: This study will be performed in two parts and enroll approximately 150 pts. During dose escalation, pts with advanced melanoma, non-small cell lung cancer and castrate resistant prostate cancer, will be enrolled. During cohort expansion, 20 pts with each tumor type will be enrolled at the maximum tolerated dose (MTD), or the maximum administered dose, if no MTD is defined. The primary study objectives are to delineate the safety and tolerability, dose limiting toxicities, and MTD of this combination. Secondary objectives are to assess preliminary anti-tumor activity, pharmacokinetics, and immunogenicity of this combination in all pts, and the pharmacodynamic effects on tumor infiltrating lymphocytes in a cohort of melanoma pts. Exploratory objectives include a thorough assessment of the modulation of innate and adaptive immunity by this combination in peripheral blood and/or tumor specimens, and preliminary evaluation of the association of these changes with clinical outcome. Clinical trial registration number: NCT01750580 Clinical trial information: NCT01750580.

TPS3107

TPS3108


A phase I study of the safety, tolerability, pharmacokinetics, and immunoregulatory activity of urelumab (BMS-663513) in subjects with advanced and/or metastatic solid tumors and relapsed/refractory B-cell nonHodgkin’s lymphoma (B-NHL). Presenting Author: Ignacio Melero, Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain Background: CD137 (4-1BB) is a costimulatory molecule that belongs to the TNF superfamily. It is upregulated on activated lymphocytes, NK cells and dendritic cells and plays an important role in the potentiation of antigen-specific immune responses in T-cell directed therapy as well as in antibody-dependent cell-mediated cytotoxicity. Urelumab is an agonistic antibody targeting CD137 which has demonstrated antitumor activity against a variety of cancers in pre-clinical and clinical studies. We describe a phase I study to investigate the clinical and biologic effects of treatment with urelumab in patients with advanced solid tumors and B-cell nonHodgkin’s lymphoma (B-NHL). Methods: This phase I study (n⫽70) will include dose escalation (Part 1) using a 6⫹9 design, cohort expansion (Part 2), and tumor-specific cohort expansion (Part 3). In Part 1, successive cohorts of pts with advanced solid tumors will be treated as follows: Cohort 1 (0.1 mg/kg q3weeks) and Cohort 2 (0.3 mg/kg q3weeks). In Part 2, both cohorts (1 ⫹2) will expand to 20 patients with advanced solid tumors. In Part 3, additional tumor-specific cohorts with B-NHL, colorectal cancer, and head and neck cancer (10 subjects each) will be enrolled at the highest tolerated dose. The primary objective of this study is to evaluate the safety and to define the MTD of the respective doses of 0.1 and 0.3 mg/kg administered every 3 weeks with special attention to hepatic toxicity. Secondary objectives include assessment of the preliminary antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunoregulatory activity in peripheral blood and paired tumor biopsy specimens and associations with clinical outcome. Part 1 (dose escalation) has been completed without any DLTs. Clinical trial information: NCT01471210.


A phase Ib, open-label, multicenter study of urelumab (BMS-663513) in combination with rituximab in subjects with relapsed/refractory B-cell malignancies. Presenting Author: Holbrook Edwin Kohrt, Stanford Cancer Institute, Stanford, CA Background: CD137 (4-1BB) is a costimulatory molecule that belongs to the TNF superfamily. It is upregulated on activated lymphocytes, NK cells and dendritic cells and plays an important role in the potentiation of antigen-specific immune responses as well as in antibody-dependent cell-mediated cytotoxicity (ADCC). Urelumab is an agonistic antibody targeting the CD137 receptor. Preclinical evidence has shown that there is modulation of CD137 expression on NK cells after exposure to rituximab. Anti-CD137 agonist monoclonal antibody has been shown to have singleagent anti-lymphoma activity and to potentiate the anti-lymphoma activity of rituximab through enhancing ADCC. We hypothesized that upregulation of CD137 on NK cells by rituximab followed by urelumab could afford a mechanism-based approach to achieve enhanced biologic and/or clinical activity compared to either single agent alone. Here we describe a phase Ib study to investigate the clinical and biologic effects of combined treatment with urelumab and rituximab in patients with relapsed/refractory B-cell malignancies. Methods: This phase I study (n⫽100) will include dose escalation (Part 1) using a 3⫹3⫹3 design and cohort expansion (Part 2). In Part 1, successive cohorts of patients with relapsed/refractory B-NHL will be treated as follows: Cohort 1 (0.1 mg/kg q3weeks) and Cohort 2 (0.3 mg/kg q3weeks) with both cohorts in combination with rituximab 375 mg/m2 given weekly for the first 4 weeks of each 12 week cycle. In Part 2, cohorts of CLL (n⫽30), follicular lymphoma (FL) (n⫽30), and diffuse large B-cell lymphoma (DLBCL) (n⫽20) will be treated at the dose level found to be safe for the urelumab/rituximab combination. The primary objective of the study is to evaluate the safety and define a safe and effective dose of the urelumab/rituximab combination. Secondary objectives include assessment of the antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunoregulatory activity of this combination in peripheral blood and paired tumor biopsy specimens and the association of these effects with clinical response/ toxicity. Clinical trial information: NCT01775631.


200s TPS3109


TPS3110


Phase I dose escalation study of recombinant interleukin-21 (rIL-21, BMS-982470) in combination with ipilimumab (Ipi) in patients (pts) with advanced or metastatic melanoma (MM). Presenting Author: Shailender Bhatia, University of Washington Medical Center/Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance, Seattle, WA

A phase I dose-escalation and cohort expansion study of lirilumab (antiKIR; BMS-986015) administered in combination with nivolumab (antiPD-1; BMS-936558; ONO-4538) in patients (Pts) with advanced refractory solid tumors. Presenting Author: Rachel E. Sanborn, Earle A. Chiles Research Institute and Providence Cancer Center, Portland, OR

Background: Ipilimumab is a monoclonal anti-CTLA-4 antibody that promotes T-cell activation and has been approved for the treatment of pts with advanced melanoma. The cytokine rIL-21 is a T-cell and NK-cell growth factor that has also demonstrated antitumor activity in selected solid tumors including MM. We hypothesize that coordinated stimulation of T and/or NK cell function with rIL-21 in conjunction with T-cell checkpoint inhibitor blockade with Ipi will achieve enhanced biologic and clinical activity compared to either agent alone. Here we describe an ongoing phase Ib study to investigate the clinical and biologic effects of combined treatment with rIL-21 and Ipi in pts with MM. Methods: The phase I study includes dose escalation (Part 1) using a 6 ⫹ 6 design and cohort expansion (Part 2). In Part 1 (n⫽48), successive cohorts of pts with melanoma will be treated with rIL-21 in combination with Ipi as follows: Arm A, rIL-21 (10, 30, or 50 ␮g/kg daily x 5) ⫹ Ipi (3 or 10 mg/kg Q3W) in a 3 week cycle; or Arm B, rIL-21 (30, 100, or 150 ␮g/kg weekly) ⫹ Ipi (3 or 10 mg/kg Q3W) in a 3 week cycle. In Part 1, all subjects will receive an initial cycle with rIL-21 monotherapy (lead-in) for biomarker and PK assessment that will be the same as the dose of rIL-21 specified for the cohort. Four cycles of combination treatment will follow the lead-in with restaging evaluation after 4 combination cycles. Subjects with initial benefit are eligible for retreatment at progression. In Part 2, pts (n⫽25/ arm) will be randomly assigned to one of 3 cohorts: Ipi monotherapy at 3 mg/kg Q3W or Ipi ⫹ weekly rIL-21 or Ipi ⫹ daily rIL-21 at the MTD determined for each schedule in Part 1. The primary objectives of this study are to evaluate the safety of rIL-21 ⫹ Ipi and to define the MTD of the respective rIL-21 ⫹ Ipi regimens. Secondary objectives include assessment of the preliminary antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunologic effects of this combination in peripheral blood and paired tumor biopsy specimens, and the association of these effects with clinical outcome. Clinical trial information: NCT01489059.

Background: Immune checkpoint blockade represents a novel form of cancer immunotherapy. Killer cell immunoglobulin-like receptor (KIR) and programmed death-1 (PD-1) are immune receptors that down-regulate NK and T cell activity, respectively. Lirilumab, an anti-KIR antibody that potentiates innate immunity, has demonstrated modest side effects in a phase I monotherapy trial. Nivolumab, a PD-1 receptor blocking antibody that potentiates adaptive immunity, has shown clinical activity with various solid tumors in phase I and II trials. We hypothesized that coordinate modulation of innate and adaptive immunity with anti-KIR and anti-PD-1 antibodies could achieve more favorable biologic and clinical activity than either agent alone. Here, we describe a phase I study of lirilumab plus nivolumab in pts with advanced solid tumors, the first collaborative clinical trial being conducted by the International Immuno-Oncology Network (II-ON). Methods: This study will be performed in two parts and enroll approximately 150 pts. During dose escalation, pts with any solid tumor, except primary central nervous system tumors, will be enrolled. During cohort expansion, pts (N⫽16/cohort) with non-small cell lung carcinoma – squamous and non-squamous histology, renal cell carcinoma, melanoma, colorectal carcinoma, or ovarian carcinoma will be enrolled at the maximum tolerated dose (MTD), or the maximum administered dose, if no MTD is defined. The primary study objectives are to delineate the safety and tolerability, dose limiting toxicities, and MTD of this combination. Secondary objectives are to assess preliminary anti-tumor activity, pharmacokinetics, and immunogenicity in all pts, and pharmacodynamic effect on tumor infiltrating lymphocyte subsets from melanoma pts. Exploratory objectives include a thorough assessment of innate and adaptive immunity modulation by this combination in peripheral blood and/or tumor specimens, as well as preliminary associations with clinical outcome. As of Feb 1, 2013, three pts have started therapy. Clinical trial registration number: NCT01714739. Clinical trial information: NCT01714739.

TPS3111

TPS3112


Phase I dose escalation study of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with advanced hepatocellular carcinoma (HCC) with or without chronic viral hepatitis. Presenting Author: Bruno Sangro, Clinica Universidad de Navarra and CIBEREHD, Pamplona, Spain Background: Pts with advanced HCC have limited treatment options. Sorafenib, the current standard of care, achieves only modest overall survival improvements. There is a clear etiologic association between HCC and prior/concurrent hepatitis B (HBV) or C (HCV) infection. Programmed death-1 (PD-1) is an immune checkpoint receptor that inhibits T-cell activation when bound by ligands including PD-L1/L2. PD-L1 overexpression has been noted on HCC tumors, and PD-1/PD-L1 interaction may contribute to viral hepatitis induced T-cell exhaustion. Nivolumab, a PD-1 receptor blocking antibody, has shown efficacy against various solid tumor types in Ph 1 trials. We hypothesized that blockade of PD-1/PD-L1 interaction could enhance T-cell activation and mediate antitumor and/or antiviral activity in HCC pts. We describe a phase I, dose-escalation study of nivolumab in advanced HCC pts. Methods: Successive pt cohorts with histologically confirmed advanced HCC with/without HBV or HCV infection (N⫽72 max) will be treated on 3 distinct arms with IV nivolumab at 0.3, 1 and 3.0 mg/kg (uninfected or HCV-infected pts) or 0.1, 0.3, 1 and 3.0 mg/kg (HBV-infected pts) every 2 weeks using a 3⫹3 escalation scheme. Pts must have progressive disease or intolerance after ⱖ1 line of therapy or have refused sorafenib treatment, and a Child-Pugh class A. HBV-infected pts must be receiving antiviral therapy (viral DNA ⬍100 IU/mL) for ⱖ3 months. Pts with brain metastasis, encephalopathy, prior/current ascites requiring paracentesis, history of recent variceal bleeding, active coinfection with HIV, or both HBV and HCV, or concurrent hepatitis D and HBV infection will be excluded. Primary endpoints include characterization of safety, tolerability, dose-limiting toxicities and maximum tolerated dose of nivolumab. Secondary endpoints include assessment of the preliminary antitumor activity (per modified RECIST for HCC), PK and immunogenicity. Exploratory endpoints include evaluation of the relationship between tumor PD-L1 expression and clinical outcome, and nivolumab’s antiviral and immunoregulatory activity in peripheral blood and/or tumor specimens. Clinical trial information: NCT01658878.


Phase I dose escalation study of recombinant interleukin-21 (rIL-21; BMS-982470) in combination with nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with advanced or metastatic solid tumors. Presenting Author: Laura Quan Man Chow, University of Washington/Fred Hutchinson Cancer Research Center, Seattle, WA Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that attenuates T-cell activation by binding to its ligands, PD-L1 and PD-L2. Nivolumab, a PD-1 receptor blocking antibody, has shown durable antitumor activity in pts with various solid tumors in two phase I clinical trials. The cytokine rIL-21 has also shown antitumor activity in selected solid tumors. We hypothesized that combining rIL-21-induced stimulation of T-cell and NK-cell function in conjunction with T-cell checkpoint blockade using nivolumab could enhance biologic activity resulting in improved clinical outcomes, as compared with either agent alone. We describe a novel phase I study investigating the biologic activity and clinical outcomes of the combination in pts with advanced solid tumors. Methods: This ongoing study (N⫽160) includes a dose escalation phase (Part 1) using a 3 ⫹ 3 design followed by an expansion phase (Part 2). In Part 1 (N⫽60), successive pt cohorts with advanced solid tumors are being treated with escalating doses of rIL-21 (10, 30, 50, 75, or 100 ␮g/kg IV) on two distinct schedules (Arms A and B) in combination with fixed-dose nivolumab (3 mg/kg q 2 weeks) in 6 week cycles. Arm A administers rIL-21 on a weekly schedule, given on day 1 in weeks 1– 4 of the 6 week cycle. Arm B administers rIL-21 at 3x per week during weeks 1 and 3 of the 6 week cycle. In Part 2, pts with renal cell carcinoma (N⫽50) or non-small cell lung carcinoma (N⫽50) will each be randomized to treatment at the maximum tolerated dose (MTD) or maximum administered dose, if no MTD is determined, for Arm A or Arm B. Therapy for pts who are stable or responding in Parts 1 and 2 may be continued for up to 2 years or until treatment discontinuation criteria are met. Primary objectives are to evaluate the safety of rIL-21 ⫹ nivolumab, and to define the MTD of the 2 schedules. Secondary and exploratory objectives include a preliminary assessment of the antitumor activity, pharmacokinetics, immunoregulatory activity (peripheral blood, tumor) and immunogenicity of this combination. Clinical trial information: NCT01629758.


Developmental Therapeutics—Immunotherapy TPS3113


A phase I dose-escalation study evaluating the effects of nivolumab (anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with select relapsed or refractory hematologic malignancies. Presenting Author: Alexander M. Lesokhin, Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York, NY Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that inhibits T-cell activation upon interaction with its ligands PD-L1 or PD-L2. Increased PD-L1 expression has been reported with various hematologic malignancies and may prevent the host immune response from exerting an antitumor effect on the malignant cells. Nivolumab, a fully human IgG4 monoclonal PD-1 receptor blocking antibody, has demonstrated antitumor activity in pts with solid tumors including melanoma, renal cell carcinoma, and non-small cell lung carcinoma. We hypothesized that nivolumab could also mediate antitumor activity in pts with hematologic malignancies, a significant area of unmet medical need. We describe a phase I study to evaluate the effects of nivolumab in pts with select hematologic malignancies. Methods: This open-label, two-part study will enroll approximately 100 pts. During dose escalation, successive cohorts of pts with relapsed or refractory hematologic malignancies will be treated using a 6⫹3 escalation design. Pts will receive 1 or 3 mg/kg nivolumab IV every 2 weeks (wks) (the first dose will be followed by a 3-wk evaluation period), for 2 years, with the potential for an additional year of therapy for pts who progress during the follow-up period. Subsequently, 5 tumorspecific cohorts of 16 pts will be enrolled at the maximum tolerated dose (MTD) for multiple myeloma, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma/primary mediastinal B-cell lymphoma, and chronic myelogenous leukemia. Response will be assessed at wks 4, 8, 16, 24, and every 16 wks thereafter. The primary study objective is to establish dose limiting toxicities, the MTD, and the recommended phase II nivolumab dose. Secondary objectives are to characterize nivolumab pharmacokinetics, immunogenicity, preliminary antitumor activity, and the potential association between PD-L1 expression on tumor cells and clinical efficacy. Exploratory objectives include investigation of the immunoregulatory effects of nivolumab in peripheral blood, bone marrow, and/or tumor. Pts are currently being enrolled at 3 mg/kg. Clinical trial information: NCT01592370.

TPS3115


Chimeric antigen receptor (CARⴙ) modified T cells targeting prostate specific membrane antigen (PSMA) in patients (pts) with castrate metastatic prostate cancer (CMPC). Presenting Author: Susan F. Slovin, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University; Memorial Sloan-Kettering Cancer Center, New York, NY Background: A phase I dose-escalating study to assess safety, dose and targeting efficiency of genetically modified autologous human T cells targeted to PSMA was initiated. Preclinical models demonstrated antitumor activity and accumulation, migration, and persistence of these cells to tumor. The autologous PSMA-targeted T cells utilizes the P28z second generation chimeric antigen receptor following iv cyclophosphamide (Cy). For safety, the herpes simplex virus-1 thymidine kinase (hsvtk) gene is co-expressed with the P28z receptor, rendering T cells sensitive to ganciclovir for immediate T cell elimination. The expression of hsvtk enables PET imaging using radiolabeled FIAU to localize these T cells Methods: Autologous T cells are activated from a leukapheresis product using anti-CD3/CD28 Dynabeads. Release criteria include mean vector copy number by Q-PCR and vector identity by Southern blot, absence of Replication Competent Retrovirus and residual Dynabeads. Pts were dosed from 107 to 3 x 107 CAR⫹ T cells/kg.All 7 pts received 300mg/m2 of Cy one day before infusion. Baseline and post treatment imaging included FDG, FDHT and 18F-FIAU PET scans. Results: Three pts in cohort 1 received 1 x 107 CAR⫹ T cells/kg safely. A fourth pt received the same dose with a modified vector with higher copy number. One pt had stable disease for ⬎ 6 months; a second pt has stable scans for ⬎ 20 months; the third and fourth patients progressed. Of 3 pts in cohort 2, one received 1.5 x 107 CAR⫹ T cells/kg and 2 received 3 x 107 CAR⫹ cell/kg. All 3 had intermittent fever spikes up to 39oC associated with increased levels of IL-4, IL-8, IP-10, sIL-2ra and IL-6 suggesting T cell activation. CAR⫹ cells persisted in the circulation for up to 2 weeks. Scans with 18F-FIAU labeling suggests that imaging may be cell dose dependent. Conclusions: We have shown that pts can be safely treated with an ex vivo transduction, expansion and therapeutic protocol for the generation of PSMA targeted T cells. Cytokine production suggests in vivo activation and persistence of T cells in blood for up to 2 weeks. Ongoing imaging with 18F may be suboptimal; a second cohort of pts will be studied with 124I-FIAU. Clinical trial information: NCTO1140373.

TPS3114

201s


An exploratory study of the biologic effects of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) treatment in patients (pts) with advanced (unresectable or metastatic) melanoma (MEL). Presenting Author: Jeffrey Alan Sosman, Vanderbilt-Ingram Cancer Center, Nashville, TN Background: Programmed death-1 (PD-1) is an immune checkpoint receptor expressed by T cells that negatively regulates T-cell activity and may promote tumor immune evasion by binding to its ligands (PD-L1/L2) on tumor cells and/or antigen-presenting cells. Nivolumab is a fully human IgG4 PD-1 receptor blocking monoclonal antibody that has shown antitumor activity in phase I trials in pts with solid tumors, including advanced MEL. Objective responses were observed in pts whose diseases were refractory to multiple prior therapies. We describe an ongoing exploratory, open-label, multicenter translational study designed to further investigate the immunoregulatory activity and mechanisms of action of nivolumab in advanced MEL, including ipilimumab (anti-CTLA-4) naïve and refractory pts. Methods: This study is enrolling advanced MEL pts who are either ipilimumab naive (n⫽40) or refractory (n⫽40). Eligible pts must not have received ⬎3 prior therapies for metastatic disease and must consent to pre-and on-treatment biopsy (after 2 doses of nivolumab [Day 28]) of an accessible tumor. Nivolumab will be administered IV every 2 weeks (wks) at a dose of 3mg/kg and may continue for up to 13 cycles (104 wks) until clinically significant progression or treatment discontinuation criteria are met. Tumor responses will be assessed every 8 wks using RECIST 1.1 criteria. The primary objective is to investigate the pharmacodynamic (immunoregulatory) activity of nivolumab in the peripheral blood (PB), tumor, and tumor microenvironment. Secondary objectives include evaluation of safety and tolerability, preliminary antitumor activity, and immunogenicity of nivolumab, as well as the association between tumor PD-L1 expression and clinical efficacy. Exploratory objectives include characterization of pharmacokinetics (PK) and evaluation of the potential association between selected PB and/or tumor biomarkers and PK, clinical safety, and efficacy (eg, progression-free and overall survival). Clinical trial information: NCT01621490.

TPS3116


A phase I/II study of multiple peptides cocktail vaccine for advanced/ recurrent ovarian cancer. Presenting Author: Satoshi Takeuchi, Iwate Medical University School of Medicine, Morioka, Japan Background: Despite improvement in chemotherapy including the molecular targeting agents, advanced or recurrent ovarian cancer (A/ROC) are still incurable. Some tumor associated proteins, hypoxia-inducible protein 2 (HIG2), and tumor related vascular endothelial growth factor receptor 1,2 (VEGFR1,VEGFR2) were found to be candidates as new targets, and their epitope peptides have been shown to have the ability to induce specific cytotoxic T lymphocyte ( CTL) responses. We conducted a phase I/II study of these peptides cocktail vaccine (PCV) in patients with A/ROC in order to evaluate toxicity, immunological response, and tumor response. Methods: 23 patients positive for human leukocyte antigen (HLA)-A2402 (A24) and 15 patients with HLA-A0201(A02) were enrolled in this study. Enrollment is still on going up to 30 evaluable patients in each group. PCV for A24 comprises FOXM1(Forkhead Box M1), MELK(maternal embryonic leucine zipper kinase), HJURP(Holliday junction recognition protein), VEGFR1 and VEGFR2. As for A02- PCV comprises HIG2, VEGFR1and VEGFR2. Cocktails were made at a dose of 1mg of each peptide with GMP grade-adjuvant, MONTANIDE ISA51. Vaccination schedule included weekly subcutaneous administration for first 12 weeks, then bi-weekly administration for next 16 weeks, then further vaccination was done monthly for 8 times and 3-6 months as a maintenance step according to patient’s need. Pre- and post-vaccination blood samples were obtained from the patients for toxicity assessment and immunological evaluation. Clinical responses were evaluated every three months by RECIST v 1.1. Results: PCV were generally well tolerated with no major adverse events, and most of the patients developed specific CTL responses. One patient showed complete response, two showed partial response and 10 showed stable disease in 22 evaluable patients. At the time of the analysis, median overall survival was 5 months (from 30 to 623 days) and 9 months(from 54 to 921 days),in A24 and A02, respectively. 11 patients remained alive with median follow up of 9 months. Conclusions: These findings suggest these peptides cocktail vaccines are safe and applicable for advanced/recurrent ovarian cancer. Clinical trial information: UMIN000003862, UMIN000003860.


202s TPS3117^


Intergroup ALFA/GOELAMS randomized phase II trial of lirilumab anti-KIR monoclonal antibody (IPH2102/BMS986015) as maintenance treatment in elderly patients with acute myeloid leukemia (EFFIKIR trial). Presenting Author: Norbert Vey, Institut Paoli Calmettes, Marseilles, France Background: Inhibitory killer immunoglobulin-like receptors (KIR) negatively regulate natural killer (NK) cell–mediated killing of HLA class I– expressing tumors. Lack of KIR-HLA class I interactions has been associated with potent NK cell-mediated antitumor efficacy and increased survival in patients with acute myeloid leukemia (AML) upon haploidentical stem cell transplantation from KIR-mismatched donors(Ruggeri, Blood 2007). Anti-KIR antibody treatment resulted in long-term survival in SCID mice inoculated with lethal autologous AML cells (Romagne, Blood 2009). Lirilumab is a second generation fully human monoclonal antibody targeting the major inhibitory KIR on NK cells. The objectives of this study are to determine if maintenance therapy with lirilumab can improve leukemiafree survival (LFS) of elderly patients in first complete remission (CR1) of AML and to assess two dose schedules leading to either intermittent or continuous KIR occupancy. Methods: EFFIKIR is a randomized doubleblind 3-arm placebo controlled trial of lirilumab in elderly patients in CR1 of AML. Patients aged 60 to 80 in CR1 of AML following standard induction and consolidation programs are randomly allocated to receive placebo or lirilumab given at either 0.1 mg/kg q 12 weeks or 1 mg/kg q 4 weeks according to a minimization algorithm adjusting for center, primary vs. secondary AML, no. of consolidation cycles (1 vs. 2) and cytogenetics (intermediate vs. high risk). Patients are to receive up to 2 yrs of therapy. ECOG performance status of 0-1, adequate hematologic, liver and renal function, and recovery from toxicities of prior chemotherapies are required. Patients are excluded if they are eligible for bone marrow transplantation and if the time interval since last consolidation exceeds 3 mos. The primary endpoint is LFS based on independent central review. The trial will accrue 50 patients in each arm and is powered (80%) to detect an improvement in LFS with a hazard ratio of 0.60 and a one-sided alpha of 0.05. Each dose schedule will be compared to placebo using a Hochberg procedure. The first patient was randomized on 12/11/2012. Clinical trial information: NCT01687387.

TPS3119^


TPS3118^


Evaluation of the safety and immunogenicity of intratumoral injection of interferon gamma (IFNg) during vaccination in patients with subcutaneous or cutaneous metastases of melanoma (Mel51; NCT00977145). Presenting Author: Craig L. Slingluff, University of Virginia School of Medicine, Charlottesville, VA Background: One mechanism to improve immunologic outcomes of vaccine therapy, and other immune therapies, is to optimize T cell trafficking to sites of tumor. CXCR3 is expressed by Th1 and Tc1 T cells and directs them to sites of inflammation by following the chemokine gradient. The ligands for CXCR3 (CXCL9 (MIG), CXCL10 (IP-10) and CXCL11 (I-TAC)) are induced by interferon gamma (IFNg). This protocol tests whether administering peptide vaccine activates circulating tumor antigen-specific CD8⫹ CXCR3⫹ T cells, followed by intratumoral IFNg to increase CXCR3 ligands (CXCL9-11) at the tumor site and thus to recruit the CXCR3⫹T cells. Methods: This pilot clinical trial is enrolling patients (n⫽14) with subcutaneous or cutaneous metastases of melanoma (stage IIIB-IV), who have adequate accessible tumor in 1-4 lesions to provide 100-300 mm3 tumor on each of the three biopsy days, and with at least one lesion amenable to intratumoral IFNg injection. Patients must also express HLA-A1, A2, A3, or A11. Patients undergo tumor biopsy d1, then are vaccinated days 1, 8, and 15 with a multipeptide vaccine. A biopsy day 22 provides information on the effect of vaccination alone on T cell infiltration into tumor. IFNg (up to 2 million units) is injected into at least 1 metastasis, which is biopsied day 24. Additional vaccines are given days 24, 43, and 64. Primary goals are to determine the safety of intratumoral interferon gamma (IFNg) plus a multipeptide melanoma vaccine, and to evaluate the biological effects of vaccine plus IFN-g at the tumor site, to include expression of CXCR3 ligands (CXCL9, CXCL10 & CXCL11) and the magnitude of infiltration of CD8⫹ CXCR3⫹ T cells and vaccine-specific T cells. Secondary goals include evaluating effects of vaccine on CXCR3 expression by circulating antigen-experienced CD4 and CD8 T cells, estimating the effects of vaccine plus IFNg on changes in the percentage of FoxP3⫹ CD25hi CD4⫹(putative regulatory T cells, Tregs) among tumor infiltrating T cells and to obtain preliminary data on the clinical response of cutaneous or subcutaneous metastases of melanoma to the proposed combination regimen. Clinical trial information: NCT00977145.

TPS3120


Results of the CARMA study to investigate catumaxomab therapy for ascites related to peritoneal carcinomatosis in clinical practice. Presenting Author: Christian M. Kurbacher, Medical Centre Bonn Friedensplatz, Bonn, Germany

A pilot study of preoperative, single-dose ipilimumab (Ipi) and/or cryoablation (Cryo) in women (pts) with early stage/resectable breast cancer (ESBC). Presenting Author: Adi Diab, Memorial Sloan-Kettering Cancer Center, New York, NY

Background: The trifunctional antibody CATU (catumaxomab) is approved in the EU for intraperitoneal (IP) treatment of malignant ascites (MA) in patients (pts) with EpCAM-positive carcinomas. Clinical data for CATU are based on 2 phase III and several phase I/II trials. However, the routine use of CATU has not been evaluated systematically. Therefore, a prospective observational study (CARMA) was started in 2010 investigating the administration of CATU in a total of 160 pts with MA under routine conditions. Participating centers were hospitals and oncologic practices in Germany and Austria. Hereby, we report on the results of the 2nd interim CARMA analysis. Methods: This analysis included 103 pts with MA due to EpCAM-positive carcinomas: ovarian, n⫽37; gastric, n⫽13; pancreatic, n⫽10; colorectal, n⫽6, miscellaneous, n⫽37. Pts were treated with CATU at a routine setting at 4 increasing dosages over a 2-week interval. The primary endpoint was puncture-free interval (PFI), secondary endpoints included safety and overall survival (OS). Results: The study population mainly comprised pts with advanced-stage disease. In 65% distant metastases were present. Therapy was given in 24 hospitals (73 %) and 9 outpatient facilities (27 %). Pts suffered from typical MA related symptoms such as abdominal swelling (77%), pain (56%), dyspnea (27%), anorexia (31%), constipation (13%). In 67 pts (65%), CATU was given as planned, 36 pts (35%) received ⬍4 infusions. Most frequent adverse events (AE) were fever (20%), nausea (14%) and diarrhea (6%).The median PFI was 57 days (d), the median OS was 100 d. For the subgroups ovar/non-ovar, a median PFI of 93/41 d and a median OS of 115/72 d was observed. Conclusion: CARMA represents the first systematic evaluation of CATU therapy given for MA under routine conditions. In accordance to previous prospective trials, the presented 2nd interim-analysis was able to demonstrate a clinically meaningful benefit of CATU, particularly impressive in ovarian cancer pts. CATU showed an acceptable safety profile, thus allowing for treatment at an outpatient setting in an adequately selected group of pts. The final CARMA analysis after including 160 pts is thus eagerly awaited. Clinical trial information: DRKS00000458.

Background: Intratumoral cryo combined with immune modulation generates a potent systemic anti-tumor immune response that might improve recurrence-free survival in ESBC. Cryo-mediated tumor destruction results in necrosis and immunogenic cell death which exposes dendritic cells (DC) to sufficient quantities of tumor antigens and inflammatory cytokines to induce their maturation and activation and elicit tumor specific T cell responses. To further amplify this immune response we use ipi, a human monoclonal antibody that blocks cytotoxic T lymphocyte antigen-4 (CTLA4). In preclinical murine models, the combination of cryo with CTLA4 blockade successfully mediates rejection of metastatic prostate cancer lesions and prevents growth of secondary tumors. We therefore hypothesize that this strategy could confer long-term immunity for pts with ESBC. In this study, we evaluate the safety of pre-op cryo and/or immune modulation with single dose ipi (at 10 mg/kg) in pts with ESBC. Methods: Pts are sequentially assigned to receive pre-op: cryo alone (Group A), ipi alone (B), or ipi with cryo (C). Cryo is administered 7-10 d prior to surgery. Ipi is administered 8-15 d prior to surgery (1-5 d prior to cryo). If at least 5/6 pts in each group proceed with surgery without delay, the regimen will be considered safe/tolerable.Primary aim: To evaluate the safety of pre-op cryo and/or ipi (10mg/kg) in pts with ESBC.Seconday aims: To characterize pre- and post-intervention radiographic and immunological (peripheral blood and tumor tissue) correlates. Eligibility: Pts ⱖ18y of age with operable ⱖ1.5 cm invasive ESBC, no history of autoimmune disease and planned mastectomy. Study status: As of January 25, 2013 7/7 pts were enrolled to Group A (expanded after 1 pt had suspected incomplete cryo) and 5/6 pts were enrolled to Group B. Enrollment to Group C will open when the pts in Group B meet the safety endpoint 30 d (⫹/-10 d) after surgery. Toxicity evaluation continues for 12 wks after ipi administration for Groups B and C. Clinical trial information: NCT01502592.


Developmental Therapeutics—Immunotherapy TPS3121


TPS3122

203s


A phase II study of live-attenuated Listeria monocytogenes immunotherapy (ADXS11-001) in the treatment of persistent or recurrent cancer of the cervix (GOG-0265). Presenting Author: Warner King Huh, University of Alabama at Birmingham, Birmingham, AL

Novel combination of toll-like receptor (TLR)-7 agonist imiquimod and local radiotherapy in the treatment of breast cancer chest wall recurrences or skin metastases. Presenting Author: Maxwell Dale Janosky, NYU, New York, NY

Background: This is a GOG/NCI-sponsored phase II study (NCT01266460, GOG 0265) of ADXS11-001 in patients with persistent or recurrent cancer of the cervix. ADXS11-001 is a live attenuated Listeria monocytogenes (Lm) immunotherapy bioengineered to secret a HPV-E7 fusion protein targeting HPV-E7 transformed cells. A previous phase I dose escalation study determined the safety of ADXS11-001 in patients with late stage cervical cancer (Maciag PA. Vaccine. 2009 Jun 18;27(30):3975-83). The primary objectives of this study are to evaluate the tolerability and safety of ADXS11-001, and to assess the activity of ADXS11-001 in patients with persistent or recurrent cancer of the cervix. Secondary objectives are progression-free survival, overall survival and objective tumor response. Methods: Patient eligibility criteria: Females age ⱖ 18 years with persistent or recurrent squamous or non-squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix with documented disease progression (disease not amenable to curative therapy). Patients must have measurable disease as defined by RECIST 1.1; at least one “target lesion” as defined by RECIST 1.1; have had one prior systemic chemotherapeutic regimen for management of their disease; have adequate organ function and must be free of active infection and not on antibiotics. This protocol is a 2-stage design with 12-month survival as the primary endpoint and with a planned sample size of up to 67 patients. Patients will receive ADXS11001 at a dose of 1x109 CFU on Day 1 and repeat every 28 days for 3 total doses in the absence of disease progression or unacceptable toxicity, with each dose followed at 72 hours by a 7 day course of ampicillin, 500 mg QID. Tumor tissue and serum samples may be collected periodically for translational research. After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 3 years. As of January 31, 2013, enrollment has been completed in the 6-patient safety lead-in portion of the study. Clinical trial information: NCT01266460.

Background: To assess the local and systemic effects of the novel combination of local radiotherapy (RT) with imiquimod (IMQ) applied topically to breast cancer metastatic to skin, and measure immunologic correlates (clinicaltrials.gov NCT01421017). Breast cancer is the 2nd most common tumor to metastasize to the skin. Current therapies for unresectable skin lesions are rarely curative. Patients ultimately die of visceral metastases, necessitating more effective therapies. IMQ, a synthetic TLR-7 agonist has profound effects on the tumor immune microenvironment and can lead to regression of cutaneous breast cancer metastases (Adams, Clin Ca Res, 2012). The trial was designed based on accumulated data supporting the synergy of combined RT/immunotherapy (Formenti, JNCI, 2013), and pre-clinical data demonstrating the synergy of topical IMQ and local RT in a mouse model of mammary adenocarcinoma which ulcerates through the skin, and mimics a chest wall recurrence. In the mouse model, the combination was superior with complete regressions of the treated tumors, responses at untreated sites and improved survival (Dewan, Clin Ca Res, 2012). Methods: Eligibility: patients with biopsy-confirmed breast cancer, measurable disease and skin metastases, ECOG PS 0-2 and adequate organ/marrow function. RT is delivered to 1 area of skin metastases in 5 fractions of 6 Gy (days 1, 3, 5, 8, 10). IMQ cream is applied topically 5 nights/week for 8 weeks, beginning on day 1. Following a brief phase I portion to allow dose optimization in the event of unanticipated adverse events (3-3 design), the phase II study evaluates efficacy with 25 additional patients planned. Primary endpoint is the response rate in untreated distant metastases, assessed by immune-related response criteria. The local tumor responses and safety of the combination will also be determined; tumor biopsies will be studied for immune-mediated rejection signatures and peripheral lymphocytes for antigen-specific T and B cell responses. To date, 10 patients have been enrolled. The phase I portion has been successfully completed with 6 patients without DLT. Phase II enrollment has begun. Clinical trial information: NCT01421017.

TPS3123

TPS3124^


Trial proactive: A prospective, randomized, multicenter, open label phase III study of active specific immunotherapy with racotumomab plus best support treatment versus best support treatment in patients with advanced non-small cell lung cancer. Presenting Author: Roberto E Gomez, Laboratorio ELEA, Buenos Aires, Argentina Background: Gangliosides, especially NeuGc-GM3, are attractive targets for cancer immunotherapy. They are not expressed in normal human cells but are overexpressed and involved in tumor growth in several tumors (melanoma, neuroectodermal pediatric tumors and breast cancer). More than 70% of non-small cell lung cancers (NSCLC) express NeuGc-GM3. Racotumomab is an anti-idiotypic monoclonal antibody that mimics NeuGc gangliosides. Administered as a therapeutic vaccine it acts as an antigen, inducing a cellular and humoral immune response against NeuGc-GM3 and other gangliosides. Previous trials have shown its low toxicity and high immunogenicity. Recently, a multicenter, randomized, placebo controlled, double-blind trial in 176 NSCLC (IIIB and IV) patients with at least stable disease after first line therapy and progression free at inclusion showed a statistical significant survival benefit in favor of racotumomab. Methods: This phase III, multinational, randomized (1:1), open label trial will evaluate efficacy and safety of racotumomab plus best supportive care (BSC) versus BSC. 1,082 patients with NSCLC (stages III or IV) showing response or stable disease after standard first-line therapy (platinum-based chemotherapy and radiotherapy) are eligible if they remain free of progression and have a PS ⱕ 1. Vaccination consists of an induction period (5 doses, 1 every 14 days) followed by a maintenance period (1 dose every 28 days, until worsening of the PS or unacceptable toxicity occur). Upon progression other onco-specific therapies may be used and vaccination can continue. Overall survival (OS) will be compared using a two-sided log rank test at a significance level (alpha) of 0.05 with 90% power to detect a hazard ratio of 0.79. There will be 3 interim analyses and a final analysis when 758 deaths occur. So far 190 patients have been randomized. An Independent Data Monitoring Committee oversees the study and has so far (last meeting September 2012) concluded that the trial can continue. The trial is registered in ClinicalTrials.gov under NCT01460472. Clinical trial information: NCT01460472.


A randomized, double-blind, placebo-controlled, multicenter, multinational, phase II trial immunotherapy with L-BLP25 (tecemotide) in patients with colorectal carcinoma following R0/R1 hepatic metastasectomy. Presenting Author: Stefan Kasper, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University DuisburgEssen, Essen, Germany Background: 15-20% of all patients (pts) diagnosed with colorectal cancer (crc) develop metastases (mets) surgical resection remains the only potentially curative treatment available. Current 5-year survival rate following R0 resection of liver mets lies between 28-39%, recurrence occurs in up to 70% of pts. To date, adjuvant chemotherapy has not significantly improved clinical outcomes. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active MUC1-specific cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in crc pts following R0/R1 resection of liver mets known to highly express MUC1 glycoprotein. Phase III data from L-BLP25 in NSCLC will be reported at this meeting. Methods: This is a multinational, phase II, multicenter, randomized, double-blind, placebocontrolled trial with a sample size of 159 pts from 20 centers in 3 countries. Pts must have stage IV cr adenocarcinoma limited to liver mets. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous mets, eligible pts are randomized 2:1 to receive either L-BLP25 or placebo. L-BLP25 arm receives a single dose of 300 mg/m2 cyclophosphamide (CPA) 3 d before 1st L-BLP25 dose, then primary treatment with sc L-BLP25 930 ␮g weekly for 8 weeks, followed by sc L-BLP25 930 ␮g maintenance doses at 6-week (year 1 and 2) and 12-week (year 3) intervals until recurrence. Control arm: CPA is replaced by saline solution and L-BLP25 by placebo. Primary endpoint (PE) is RFS time. Secondary endpoints: Overall survival (OS), safety, tolerance, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. Study start was in Q3 2011. 19 centers were initialized and 36 patients recruited, no SUSARs occurred. Study recruitment will end Q3 2013: follow-up until Q3 2017. PE assessment is in Q3 2016. Interim analyses are not planned.No major practical issues were identified during setup and early conduct of the study. Clinical trial information: 2011000218-20.


204s TPS3125


A multipeptide vaccine plus toll-like receptor agonists in melanoma patients, with evaluation of the vaccine site microenvironment and sentinel immunized node (Mel58; NCT01585350). Presenting Author: Craig L. Slingluff, University of Virginia School of Medicine, Charlottesville, VA

TPS3126


Biomarker correlation to clinical response in phase I/II trials of the adjuvant breast cancer vaccine neuvax (nelipepimut-S or E75). Presenting Author: John S. Berry, Brooke Army Medical Center, San Antonio, TX

Background: Recent data show clinical activity of cancer vaccines containing a defined cancer antigen, and a peptide vaccine for melanoma. However, immune responses to peptide vaccines are often transient and of low magnitude. The most common adjuvant for peptide vaccines for melanoma has been an incomplete Freund’s adjuvant (IFA), which may have suboptimal adjuvant properties. Toll-like receptor (TLR) agonists offer the potential to improve the magnitude and persistence of antitumor T cell responses, either in combination with IFA or alone. CD40 ligation at the vaccine site microenvironment (VSME) may also improve adjuvant activity of TLR agonists and may be provided by CD4 T cell activation. We report a clinical trial of a multipeptide vaccine using TLR agonists and IFA, with correlative studies in 3 immunologic compartments. Methods: This trial is enrolling patients with resected stage IIB-IV melanoma (n⫽48) and is designed to evaluate the safety and immunogenicity of vaccination with peptides and either of 2 toll-like receptor agonists (TLR3 agonist polyICLC; TLR4 agonist endotoxin), with or without IFA. Patients are vaccinated 6 times over 12 weeks with 12 Class I MHC-restricted nonamer peptides. An immunogenic tetanus helper peptide is included to activate CD4 T cells in the VSME and secondarily to ligate CD40. Goals include safety assessment, measures of CD8 T cell responses, and characterization of cellular and molecular events induced in the blood, VSME and vaccine-draining node (sentinel immunized node, SIN), as well as a preliminary assessment of whether vaccination with TLR agonists improves the persistence of CD8 and CD4 T cell responses to melanoma antigens compared to prior studies with IFA. This includes a first-in-humans evaluation of the safety and immunogenicity of LPS, a classic TLR4 agonist, as a vaccine adjuvant. Thus, there is a novel dose-escalation phase with this adjuvant, which has been safely administered in other settings by intravenous and inhalation routes. An aim of this study is to identify an improved adjuvant for use in future trials combining peptides with other immune therapies. Clinical trial information: NCT01585350.

Background: We completed phase I/II clinical trials with NeuVax (nelipepimut-S), a HLA-A2/A3-restricted, HER2-derived peptide vaccine. The vaccine was administered in the adjuvant setting to prevent recurrence in breast cancer patients rendered disease-free with standard-of-care therapy. Here, we examine the relationship between in vitro immunologic response (IR) and clinical recurrence (CR) after 5-year follow-up. Methods: The phase I/II trials were performed as dose-escalation/schedule-optimization trials enrolling node positive and high-risk, node-negative patients (pts) with tumors expressing any level of HER2 (IHC 1⫹,2⫹,or 3⫹). HLA-A2/A3⫹ pts were enrolled in the vaccine group (VG) while HLA-A2/A3- pts were followed prospectively as an untreated control group (CG). The VG was given 4-6 monthly intradermal inoculations of nelipepimut-S⫹GMCSF (immunoadjuvant) during the primary vaccine series (PVS). In vitro IR was assessed for E75-specific, cytotoxic T lymphocyte clonal expansion by HLA-A2:IgG dimer assay and expressed as mean dimer index (mdi) at baseline, after PVS (R6), and six months after the PVS. HER2 underexpression was defined as an IHC 1/2, and a FISH ⬍ 2.2. VG and CG pts were followed for CR over 60 months. P-values were calculated using the Fisher’s exact test. Results: Of the 195 pts enrolled, 8 withdrew, leaving 187 evaluable pts; 108 in the VG and 79 in the CG. R6 dimer assays were available for 86 pts in the VG. The mean R6 dimer in the VG is 0.63 mdi⫹.08. Of the 30 pts with an R6 dimer above the mean, only one recurred, compared to eight of the 56 below the mean (p⫽.09). The difference between baseline and maximum mdi was available in 56 HER2 under-expressing VG pts. Of the 26 pts above the mean difference (1.08 mdi ⫹.17), one recurred, compared to six CR in the 30 pts below the mean (p⫽.06). There were no CR in pts with HER2 under expression with a mean difference ranked in the top third. Conclusions: In prospective, completed phase I/II trials of NeuVax (nelipepimut-S), patients who exhibit robust in vitro IR have lower recurrence rates. This finding suggests that nelipepimutspecific CTL clonal expansion is a valid biomarker for CR in pts treated with NeuVax. Clinical trial information: NCT00841399.

TPS3127

TPS3128


A phase II study of a yeast-based therapeutic cancer vaccine, GI-6207, targeting CEA in patients with minimally symptomatic, metastatic medullary thyroid cancer. Presenting Author: Ravi Amrit Madan, Laboratory of Tumor Immunology and Biology, Medical Oncology Branch, National Cancer Institute, Bethesda, MD Background: Saccharomyces cerevisiae has been genetically modified to express CEA protein and developed under a CRADA with GlobeImmune/NCI as a heat-killed immune-stimulating, therapeutic cancer vaccine (GI6207). A phase I study with GI-6207 demonstrated safety, biomarker stabilization and enhanced immune response in some patients. CEA is over-expressed in multiple malignancies, including medullary thyroid cancer (MTC). Two therapies recently approved by the FDA for metastatic MTC (vandetanib, cabozantinib) come with toxicity and should be reserved for symptomatic/progressive disease. However, a large population of asymptomatic MTC patients has small tumor burden and/or disease that is more indolent. The standard management of these patients is observation. Preliminary data suggest that tumor growth measured by the rate of CEA and calcitonin increase can be quantified in a 3-6 months. Retrospective data from prostate cancer studies suggest vaccines can alter growth rates within 3-4 months. We hypothesize that GI-6207 can alter tumor growth rates in MTC and impact long-term outcome. Methods: A phase II study will evaluate the effect of GI-6207 onthe rates ofincrease in calcitonin in metastatic MTC. 34 patients with minimally symptomatic, radiographically evaluable, metastatic MTC will be randomized 1:1. Arm A will receive vaccine for a year from the time of enrollment. Arm B will receive vaccine after 6 months of surveillance. GI-6207 will be administered subcutaneously at 4 sites (10 yeast units/site), every 2 weeks for 3 months, then monthly up to 1 year. The primary endpoint will compare the effect of GI-6207 on calcitonin kinetics between the vaccine and surveillance arms in the first 6 months. Secondary endpoints include immunologic responses (including antigen-specific T cell responses), objective responses, time to progression, and changes in CEA kinetics. If this trial can prospectively demonstrate that vaccines can alter tumor growth rates, and if such changes are associated with clinical outcomes, then changes in tumor growth rates may become a clinical metric to evaluate vaccine efficacy in MTC and other populations.


CALM study: A phase II study of intratumoral coxsackievirus A21 in patients with stage IIIc and stage IV malignant melanoma. Presenting Author: Robert Hans Ingemar Andtbacka, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT Background: Coxsackievirus A21 (CVA21: CAVATAK) is a naturally occurring ⬙common cold⬙ virus. CVA21 displays potent oncolytic activity against both in vitro cultures of cancer cells and against in vivo xenografts of human cancers in mouse models of melanoma, prostate cancer, breast cancer and multiple myeloma, all which exhibit high surface ICAM-1 expression, which is used for viral entry. In mouse human melanoma xenograft CVA21 challenge models, progeny virus released from infected cells is capable of targeting adjacent cells, entering the systemic circulation, and destroying micro-metastatic foci. In a phase 1 study, two intralesional injections of CVA21 were shown to reduce or stabilize the growth of injected melanoma lesions. Methods: The CALM study investigates the efficacy and safety of intratumoral CVA21 in approximately 63 pts with treated or untreated unresectable Stage IIIC-IVM1c melanoma. Pts are treated with up to 3 x 108 TCID50 intratumorally on study days 1, 3, 5 and 8 and then every three weeks for a further 6 injections. Key eligibility criteria are ⱖ 18 yrs old, ECOG 0-1, and at least 1 injectable cutaneous, sc, or nodal tumor ⬎1.0 cm. The primary endpoint is irPFS at 6 months following tx; secondary endpoints include durable response rate and OS. A 2-stage Simon’s minimax design will be employed. Based on data from previous trials and literature, a target overall irPFS at 6 months of 22.5% versus a projected rate of 10% in the target population is selected. With an alpha level of 5% and 80% of power, a total of 54 evaluable patients will be required to test the null hypothesis that the true irPFS rate is ⬍10% versus the alternative hypothesis that the true irPFS rate is at least 22.5%. Thirty-five patients will be treated at Stage I. If 3 or more objective responses (CR or PR) are achieved by modified RECIST 1.1 criteria in the first 35 patients, then the study will complete enrollment. Results: Currently, 21 patients have been enrolled on the study and treated with CVA21 injections. The treatment has been well tolerated. The Stage I interim efficacy endpoint of ⬎ 3 objective responses has been achieved, and the second stage of the study is proceeding with a planned enrollment of a total of 63 patients. Clinical trial information: NCT01227551.


Gastrointestinal (Colorectal) Cancer 3500


Effect of 3-5 years of scheduled CEA and CT follow-up to detect recurrence of colorectal cancer: FACS randomized controlled trial. Presenting Author: David Mant, University of Oxford, Oxford, United Kingdom Background: Intensive long-term follow-up after surgery for colorectal cancer is common practice but neither the actual benefit nor the optimal methodology is known. Methods: Pragmatic factorial randomised controlled trial in 39 UK hospitals, comparing minimum follow-up (which included a single CT scan at 12-18 months) with 3-6 monthly blood carcinoembryonic antigen (CEA) testing and 6-12 monthly computerised tomography (CT) imaging of the chest, abdomen and pelvis following 1202 participants for 3-5 (mean 3.7) years. Results: The proportion of participants with recurrence treated surgically with curative intent was lower than predicted (6.0% overall) but was about 3x higher in the more intensive than minimum follow-up arms (p⫽0.019). The adjusted odds were 2.7 for CEA only (p⫽0.035) and 3.4 for CT only (p⫽0.007); the absolute differences in detection rate in the more intensive arms compared to minimum follow-up were 4.3-5.7% (5.8-8.0% per protocol). Combining CEA and CT provided no additional benefit (adjusted odds for CT⫹CEA arm ⫽ 2.9). The absolute difference in the proportion of participants with recurrence treated surgically with curative intent in the factorial comparison was 1.4% for CEA (p⫽0.28) and 2.8% for CT (p⫽0.04). There was no statistical difference in colorectal cancer deaths nor overall deaths in the minimum compared to the intensive follow-up arms. Conclusions: Both regular CEA measurement and CT scanning result in significantly higher rates of diagnosis of operable recurrent colorectal cancer compared to minimal follow up. There is no benefit in monitoring with both CEA and CT. To date no difference in the overall mortality has been demonstrated. CEA monitoring combined with a single CT scan at 12-18 months seems likely to be cost effective. Clinical trial information: 41458548.

3501

Background: Cumulative neurotoxicity commonly leads to early discontinuation of oxaliplatin-based therapy. In a relatively small, prematurelydiscontinued, randomized study, IV CaMg was associated with reduced oxaliplatin-induced sNT (Grothey, JCO, 2011). N08CB was designed to definitively test whether IV CaMg significantly decreases cumulative oxaliplatin-related sNT. Methods: 353 pts with colon cancer undergoing adjuvant therapy with FOLFOX were randomized to 3 arms: IV CaMg (1g calcium gluconate, 1g magnesium sulfate) before and after oxaliplatin vs PL before and after vs CaMg before and PL after. The primary endpoint was cumulative sNT repeatedly measured by the sensory subscale of the EORTC QLQ-CIPN20. Secondary endpoints, using CTCAE 4.0 and an oxaliplatin specific neurotoxicity scale, were also assessed. Acute neuropathy data were also collected for 5 days following each oxaliplatin dose. The area under the curve (AUC) of the sensory subscale during the treatment cycles was used as summary measures for comparison. The Wilcoxon rank-sum tests were conducted for each treatment versus placebo arm, at 2.5%, adjusting for multiplicity using Bonferroni’s approach. Results: CaMg did not reduce cumulative sNT. Primary and secondary analyses data are summarized in the Table. In addition, there were no significant differences between arms regarding oxaliplatin administered doses or chemotherapy discontinuation rates. Also, there were no substantial differences in acute neuropathy scores or side-effects between study arms. Conclusions: This study does not demonstrate any activity of IV CaMg as a neuroprotectant against oxaliplatin-induced neurotoxicity. Clinical trial information: NCT01099449. Primary endpoint: CIPN-20 sensory scale mean AUC (sd) (higher scores better) CTCAE, median days to grade 2 sNT Oxaliplatin- specific neuropathy scale, median days to grade 2 sNT


Maintenance treatment with capecitabine and bevacizumab versus observation after induction treatment with chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC): The phase III CAIRO3 study of the Dutch Colorectal Cancer Group (DCCG). Presenting Author: Miriam Koopman, University Medical Center Utrecht, Utrecht, Netherlands Background: The optimal duration of chemotherapy and bevacizumab in mCRC is not well established. The CAIRO3 study investigated the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation in mCRC pts not progressing during induction treatment with capecitabine, oxaliplatin and bevacizumab (CAPOX-B). Methods: Previously untreated mCRC pts, PS 0-1, with stable disease or better after 6 cycles of CAPOX-B, not eligible for metastasectomy and eligible for future treatment with oxaliplatin, were randomized between observation (arm A) or maintenance treatment with capecitabine 625 mg/m2 bid dailycontinuouslyand bevacizumab 7.5 mg/kg iv q 3 weeks (arm B). Upon first progression (PFS1), pts in both arms were treated with CAPOX-B until second progression (PFS2, primary endpoint). For pts not able to receive CAPOX-B upon PFS1, PFS2 was considered equal to PFS1. Secondary endpoints were overall survival (OS) and time to second progression (TTP2), which was defined as the time to progression or death on any treatment following PFS1. All endpoints were calculated from the time of randomization. Results: A total of 558 pts were randomized. Median follow-up is 33 months. The median number of maintenance cycles in arm B was 9 (range 1-54). The median PFS1 in arm A vs B was 4.1 vs 7.4 months (HR 0.44, 95% CI 0.37-0.54, p⬍0.0001). Upon PFS1, 72% of pts received CAPOX-B in arm A and 44% in arm B. The median PFS2 was 10.4 vs 10.4 months (HR 0.86, 95% CI 0.7-1.04, p⫽0.12). The median TTP2 in arm A vs B was 11.5 vs 15.4 months (HR 0.58, 95% CI 0.48-0.72, p⬍0.0001), and the median OS was 17.9 vs 21.7 months (HR 0.77, 95% CI 0.62-0.96, p⫽0.02), respectively. Conclusions: Maintenance treatment with capecitabine plus bevacizumab after 6 cycles CAPOX-B did not significantly prolong PFS2, which may be due to the lower number of pts in arm B that received CAPOX-B following PFS1. Maintenance treatment significantly prolonged PFS1, TTP2 and OS. Our data support the use of bevacizumab plus capecitabine until progression or unacceptable toxicity. Updated results will be presented. Clinical trial information: NCT00442637.


Phase III randomized, placebo (PL)-controlled, double-blind study of intravenous calcium/magnesium (CaMg) to prevent oxaliplatin-induced sensory neurotoxicity (sNT), N08CB: An alliance for clinical trials in oncology study. Presenting Author: Charles L. Loprinzi, Mayo Clinic, Rochester, MN

Arm/measure

3502

205s

3503

CaMg/CaMg (nⴝ118)

CaMg/PL (nⴝ116)

PL/PL (nⴝ119)

P value between CaMg/CaMg vs PL/PL

P value between CaMg/PL vs PL/PL

89.2 (8.5)

87.1 (9.9)

88.3 (9.7)

0.727

0.292

171 140

171 139

173 148

0.748 0.953

0.848 0.942


Bevacizumab continuation versus no continuation after first-line chemobevacizumab therapy in patients with metastatic colorectal cancer: A randomized phase III noninferiority trial (SAKK 41/06). Presenting Author: Dieter Koeberle, Kantonsspital St. Gallen, St. Gallen, Switzerland Background: Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after stop of first-line chemotherapy. Methods: In an open-label, phase 3 multicenter study conducted in Switzerland, patients with unresectable metastatic colorectal cancer having non-progressive disease after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned in a 1:1 ratio to continuing bevacizumab (7.5 mg/kg every 3 weeks) or no treatment. CT scans were done every 6 weeks between randomization and disease progression. The primary endpoint was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significant level of 10% and a statistical power of 85%. Results: The per-protocol population comprised 262 patients. Median follow-up is 28.6 months (range, 0.6-54.9 months). Median TTP was 17.9 weeks (95% CI 13.3-23.4) for bevacizumab continuation and 12.6 weeks (95% CI 12.0-16.4) for no continuation; HR 0.72 (95% CI 0.56-0.92). Median progression free-survival and overall survival, both measured from start of first-line treatment, was 9.5 months and 24.9 months for bevacizumab continuation and 8.5 months (HR 0.73 (95% CI 0.57 - 0.94)) and 22.8 months (HR 0.87 (95% CI 0.64 – 1.18)) for no continuation. Median time from randomization to second-line treatment was 5.9 months for bevacizumab and 4.8 for no continuation. Grade 3-4 adverse events in the bevacizumab continuation arm were uncommon. Conclusions: Noninferiority could not be demonstrated. The 95% confidence intervals for the TTP HR indicate superiority of bevacizumab continuation after stop of first-line chemotherapy. The median differences in TTP and in time between randomization and start of second-line treatment were of moderate magnitude being less than 6 weeks. The results of an accompanying cost analysis will be presented at the meeting. Clinical trial information: NCT00544700.


206s 3504

Gastrointestinal (Colorectal) Cancer Oral Abstract Session, Sat, 3:00 PM-6:00 PM

3505


A randomized clinical trial of chemotherapy compared to chemotherapy in combination with cetuximab in k-RAS wild-type patients with operable metastases from colorectal cancer: The new EPOC study. Presenting Author: John Neil Primrose, Southampton General Hospital, Southampton, United Kingdom

FOLFOXIRI/bevacizumab (bev) versus FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): Results of the phase III TRIBE trial by GONO group. Presenting Author: Alfredo Falcone, U.O. Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy

Background: Resection of liver metastases from colorectal cancer with or without neoadjuvant chemotherapy is the standard of care. The EPOC study (Nordlinger et al, Lancet 2008) randomised patients between surgery and surgery with chemotherapy and demonstrated an improvement in 3 year progression free survival (PFS) of 7·3% (from 28·1% to 35·4%). As a rational extension to the EPOC study data, the New EPOC study evaluates the benefit of cetuximab, an EGF receptor antibody, in addition to standard chemotherapy in patients with operable liver metastases. Methods: 272 patients were randomised between February 2007 and November 2012 into the New EPOC study. Eligible patients were required to be k-RAS wild type, have operable liver metastases and to be sufficiently fit for chemotherapy and surgery. Patients with the primary tumour in situ, and those who required short course rectal radiation were eligible. Patients were randomised to receive a fluoropyrimidine and oxaliplatin plus or minus cetuximab for 12 weeks before, then 12 weeks following surgery. Patients who had been treated with adjuvant oxaliplatin could receive irinotecan and 5 – fluorouracil. Results: Following a recommendation from the Independent Data Monitoring Committee on 19/11/2012, the New EPOC study was stopped when the study met a protocol pre-defined futility analysis. With 45.3% (96/212) of the expected events observed, progression free survival was significantly worse in the cetuximab arm (14.8 vs 24.2 months, HR (95%CI) 1.50037 (1.000707 to 2.249517) p⬍ 0.048). The result of a pre-planned analysis excluding the 23 patients treated with irinotecan based chemotherapy was similar (15.2 vs 24.2 months, HR 1.565546 (1.014967-2.414793) P⬍0.043). Conclusions: Although the data are immature, the accumulation of more events is unlikely to change this result. In patients with resectable liver metastases and K-RAS wt tumours the addition of cetuximab to chemotherapy is not beneficial. Clinical trial information: ISRCTN22944367.

Background: Doublets plus bev are a standard option for the first-line treatment of mCRC. First-line FOLFOXIRI demonstrated superior RR, PFS and OS compared to FOLFIRI. A phase II study of FOLFOXIRI/bev showed promising activity and manageable toxicities. The objective of the TRIBE trial was to confirm the superiority of FOLFOXIRI vs FOLFIRI when bev is added to chemotherapy (CT). Methods: Eligibility criteria included: measurable and unresectable mCRC, age 18-75 years, no prior CT for advanced disease. Pts were randomized to either FOLFIRI/bev (arm A) or FOLFOXIRI/ bev (arm B). Both treatments were administered for a maximum of 12 cycles followed by 5FU/bev until progression. Primary endpoint was PFS. Results: Between July 2008 and May 2011 508 pts were randomized. Pts characteristics were (arm A/arm B): median age 60/61, ECOG PS 1-2 11%/10%, synchronous metastases 81%/79%, multiple sites of disease 74%/70%, liver-only disease 18%/23%, prior adjuvant (adj) 12%/12%. At a median follow-up of 26.6 mos 424 pts progressed and 244 died. Median PFS and OS in the intention to treat (ITT) population were 10.9 and 30.9 mos. FOLFOXIRI/bev significantly increased PFS (median 9.7 vs 12.2 mos, HR 0.73 [0.60-0.88] p⫽0.0012). Subgroup analyses based on stratification factors (PS, prior adj) and baseline characteristics (site of primary, liver only disease, resection of primary, Kohne score) did not evidence significant interactions between treatment and analyzed factors. A trend toward a more consistent effect of FOLFOXIRI/bev was reported in no prior adj (HR 0.68 [0.55-0.83]) compared to prior adj group (HR 1.18 [0.67-2.08], p for interaction⫽0.071). Response rate (RECIST) was also significantly improved (53% vs 65% p⫽0.006). FOLFOXIRI/bev did not increase the R0 secondary resection rate in the ITT population (12% vs 15%, p⫽0.327), or in the liver-only subgroup (28% vs 32%, p⫽0.823). Conclusions: FOLFOXIRI/bev compared to FOLFIRI/bev, significantly increases PFS and response rate. Subgroup analysis suggests a possible interaction between prior adj CT and PFS benefit. Secondary resection rate does not differ between treatment arms. Clinical trial information: NCT00719797.

LBA3506

3507



Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). Presenting Author: Volker Heinemann, Department of Hematology and Oncology, Klinikum Grosshadern and Comprehensive Cancer Center, LMU Munich, Munich, Germany

Pharmacodynamic and efficacy analysis of the BRAF inhibitor dabrafenib (GSK436) in combination with the MEK inhibitor trametinib (GSK212) in patients with BRAFV600 mutant colorectal cancer (CRC). Presenting Author: Ryan Bruce Corcoran, Massachusetts General Hospital Cancer Center, Boston, MA

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Saturday June, 1, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.

Background: TheBRAF V600 mutation occurs in 5-10% of metastatic CRC, predicts poor prognosis, and may predict lack of response to standard therapy. The combination of inhibitors of BRAF (dabrafenib; D) and MEK (trametinib; T) has shown significant efficacy in BRAF-mutant melanoma. The safety, efficacy, and pharmacodynamic effects of this combination were studied in BRAF-mutant CRC patients (pts). Methods: BRAF mutant CRC pts were enrolled to an initial efficacy cohort of 26 pts and a subsequent pharmacodynamic (PD) expansion cohort that included biopsies of 15 pts at screening and at steady state. So far, 36 pts have enrolled, including 10 in the PD cohort. Eligible pts had previously-treated BRAFV600E mutant stage IV CRC. Pts were treated with D (150mg BID) and T (2mg QD). Additional analyses were performed on available archival tissues. Results: Data are available for 36 pts: ECOG performance status 0 (58%) or 1 (42%), 81% had received ⱖ 2 prior chemotherapy regimens, 36% had received prior EGFR inhibitor treatment, and 83% had ⱖ 1 biologic therapy. Among 34 pts with ⬎1 restaging assessment as of November 2012, 1 (3%) achieved a complete response (confirmed, on study ⬎12m), 3 (9%) achieved a partial response (1 confirmed to date), and 18 (53%) had stable disease (SD). Minor responses were seen in 7/18 pts (39%) with SD. Median PFS was 3.5 mo (95% CI: 1.8-4.9); overall duration on study range: 0.03–15.2 mo 7 pts (24%) remained on study for ⱖ6 cycles with 9 pts still on study. The most frequent AEs, any grade, included pyrexia (67%), nausea (56%), fatigue (53%), chills (47%), vomiting (39%), headache (31%), peripheral edema (31%), anemia (28%), and decreased appetite (28%). 2 pts (6%) discontinued due to AEs. Decreased pERK staining vs pre-dose samples was seen in all post-dose samples leading to absolute (49% ⫾29%) and relative (69% ⫾28%, normalized to total ERK) reduction in pERK. Conclusions: Further investigation is needed, as this combination is tolerable at full monotherapy doses of each drug, with manageable toxicities, and has activity in a subset of BRAF mutant pts. Updated safety, efficacy, and correlative data will be presented. Clinical trial information: NCT01072175.




A randomized, placebo-controlled, phase I/II study of tivantinib (ARQ 197) in combination with cetuximab and irinotecan in patients (pts) with KRAS wild-type (WT) metastatic colorectal cancer (CRC) who had received previous front-line systemic therapy. Presenting Author: Cathy Eng, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Tivantinib (ARQ 197) selectively inhibits the MET receptor tyrosine kinase, which is implicated in tumor cell migration, invasion, and metastasis. Resistance to EGFR inhibitors has been associated with activation of alternative pathways including MET. Methods: Pts with advanced KRAS WT CRC that progressed on or after 1 prior line of chemotherapy and no previous treatment with an EGFR inhibitor were eligible. Pts were randomized 1:1 to receive cetuximab (500 mg/m2) and irinotecan (180 mg/m2) on days 1 and 15 every 28 days, plus oral tivantinib (360 mg twice daily [BID]) or placebo. The primary endpoint was progression-free survival (PFS); additional endpoints include safety, objective response rate, overall survival (OS) and exploratory biomarker analyses. Results: Between Jul 2010 and Feb 2012, 122 pts were randomized; 117 pts were eligible for analysis (60 tivantinib, 57 placebo). Mean age was 57 years (range, 27-79 years); ECOG PS 0/1 55%/45%; and 81% received prior oxaliplatin. Median PFS was 8.3 months in the tivantinib arm vs 7.3 months in the placebo arm (hazard ratio [HR] ⫽ 0.85; 95% CI, 0.55-1.33; P ⫽ 0.38). Objective response rate (95% CI) was 45% (33%-58%) in the tivantinib arm and 33% (23%-46%) in the placebo arm. Median OS has not yet been reached but is trending in favor of tivantinib vs placebo (HR ⫽ 0.67). Among pts with prior oxaliplatin therapy, median PFS was 8.4 months for tivantinib and 7.2 months for placebo (HR ⫽ 0.67; 95% CI, 0.44-1.00; P⫽ 0.1). The most common grade 3/4 adverse events (ⱖ 10%) were neutropenia, diarrhea, and nausea. Correlation of clinical outcomes with additional factors including mutation status and immunohistochemical analysis of tumor MET expression will be presented. Conclusions: Outcomes in this trial trended towards improvement with tivantinib (360 mg BID) plus cetuximab and irinotecan, particularly in the subgroup who had previous oxaliplatin. Further studies are needed to identify the CRC population most likely to benefit from addition of tivantinib to standard therapy. Clinical trial information: NCT01075048.

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Validation of DPYD variants DPYD*2A, I560S, and D949V as predictors of 5-fluorouracil (5-FU)-related toxicity in stage III colon cancer (CC) patients from adjuvant trial NCCTG N0147. Presenting Author: Adam Lee, Mayo Clinic, Rochester, MN Background: Prediction of 5-FU-related adverse events (5FU-AEs) continues to be problematic. Pharmacogenetic studies on the rate-limiting enzyme in 5-FU metabolism, dihydropyrimidine dehydrogenase (DPD), suggest a link between three variants and both decreased enzyme activity and increased toxicity: c.1905⫹1 G⬎A (DPYD*2A; rs3918290), c.1679 T⬎G (I560S; DPYD*13; rs55886062), and c.2846A⬎T (D949V; rs67376798). Since the adverse impact of DPYD variants on 5-FU toxicity remains controversial, we determined associations between the three known DPYD variants and 5FU-AEs in stage III CC patients receiving FOLFOX or FOLFIRI (⫹ cetuximab) after curative resection. Methods: 2886 patients were genotyped by multiplexed single-base extension assays using the IPLEX Gold Kit and analyzed on the Sequenom MassARRAY system. Grade 3⫹ AEs were recorded per CTCAE v3. Fisher’s exact test, unequal variance two-sample t-test, and Wilcoxon rank sum test were used to compare categorical variables, continuous variables, and counts between patients with wild-type and mutant status. Logistic regressions were used to assess univariate and multivariate associations. Results: Patients displayed the following characteristics: male gender 53.2%, median age 58 [19-86], proficient DNA mismatch repair status 88.6%, PS-0 76.6%, ⫹ irinotecan 8.1%, and ⫹ cetuximab 45.9%. A total of 27 (0.9%), 4 (0.1%), and 32 (1.1%) patients carried the DPYD*2A, I560S, and D949V variants, respectively. Analysis identified significant associations between DPYD*2A and D949V variants and toxicity, with grade 3⫹ 5FU-AEs identified in 22 DPYD*2A carriers (OR⫽11.9, 95% CI 4.0-32.7, p⬍0.0001) and 22 D949V carriers (OR⫽5.5, 95% CI 2.5-12.1, p⬍ 0.0001). No interaction effect was found between DPYD*2Aand D949V on grade 3⫹ 5FU-AEs (p ⫽ 0.98), nor on overall grade 3⫹ AEs (p ⫽ 0.97). No significant association was identified between I560S and grade 3⫹ 5FU-AEs. Conclusions: In the largest study to date, statistically significant associations were found between DPYD*2A and D949V variants and increased incidence of grade 3⫹ 5FU-AEs, suggesting utility in 5-FU toxicity prediction.

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Comprehensive pharmacogenetic profiling of advanced colorectal cancer. Presenting Author: Ayman Madi, Northern Centre for Cancer Care, Newcastle Upon Tyne, United Kingdom Background: Inherited genetic factors may influence a patient’s response to, and side effects from, chemotherapy and biological therapies. Here, we sought to generate a comprehensive inherited pharmacogenetic profile for advanced colorectal cancer (aCRC). Methods: We analysed 260 potentially functional coding region and promoter variants in genes within the 5-FU, capecitabine, oxaliplatin, EGFR and DNA repair pathways in 2183 patients with aCRC treated with oxaliplatin-fluoropyrimidine chemotherapy ⫾ cetuximab (from the MRC COIN and COIN-B trials). Primary outcomes assessed were 12-week response, skin rash (SR) (for those receiving cetuximab), dose-reduction or delay in treatment due to any toxicity and peripheral neuropathy (PN). Results: For variants with minor allele frequencies ⬎20%, we had ⬎85% power to detect an effect on response / toxicity with an OR of 1.3. In patients treated with chemotherapy ⫹ cetuximab, 5 and 4 coding region variants in the EGFR pathway were associated with response and SR, respectively. The most significant associations were with variants in members of phosphatidylinositol 3-kinase regulatory subunit. In patients treated with chemotherapy ⫾ cetuximab, 8 coding region variants in the 5-FU, capecitabine, oxaliplatin or DNA repair pathways were associated with response, 8 with any toxicity and 5 with PN. The most significant associations for response were with variants in DNA repair genes and, for any toxicity, with common variants in DPYD. Conclusions: Our study highlights the difficulty in identifying inherited biomarkers for the treatment of aCRC - despite using samples from the largest reported randomised trial for aCRC, with considerable power to detect alleles of small effects, none of the associations remained significant after rigorous correction for multiple testing.

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Analysis of KRAS/NRAS and BRAF mutations in the phase III PRIME study of panitumumab (pmab) plus FOLFOX versus FOLFOX as first-line treatment (tx) for metastatic colorectal cancer (mCRC). Presenting Author: Kelly S. Oliner, Amgen, Inc., Thousand Oaks, CA Background: Analysis of a phase III pmab monotherapy study indicated that KRAS and NRAS mutations beyond KRAS exon 2 may be predictive of pmab efficacy (Peeters et al, 2013). Methods: The primary objective of this prospectively defined retrospective analysis of PRIME was to assess the effect of pmab ⫹ FOLFOX vs FOLFOX on overall survival (OS) in pts with mCRC based on RAS (KRAS or NRAS) or BRAF mutation status. ⬙Gold standard⬙ bidirectional Sanger sequencing and WAVE-based SURVEYOR Scan Kits from Transgenomic (conducted independently) were used to detect mutations in KRAS exon 3, exon 4; NRAS exon 2, exon 3, exon 4; and BRAF exon 15. Results: RAS ascertainment rate was 90%. Tx HRs for pts with WT RAS were 0.78 (95% CI, 0.62 - 0.99; p ⫽ 0.04) for OS (median gain of 5.8 months in the pmab arm) and 0.72 (95% CI, 0.58 - 0.90; p ⫽ ⬍ 0.01) for PFS. Tx HRs for WT KRAS exon 2/mutant (MT) other RAS were 1.29 (95% CI, 0.79 - 2.10; p ⫽ 0.31) for OS and 1.28 (95% CI, 0.79 - 2.07; p ⫽ 0.32) for PFS. Tx HRs for pts with WT or MT BRAF were inconsistent with a predictive biomarker (Table). Prognostic effects of the tested biomarkers will be presented. Conclusions: A statistically significant OS benefit was observed in pts with WT RAS mCRC treated with pmab ⫹ FOLFOX vs FOLFOX. Pmab is unlikely to benefit pts with any RAS mutations. In this analysis, BRAF mutation had no predictive value. Clinical trial information: NCT00364013. WT RASa - n Median OS - mos (95% CI) Median PFS - mos (95% CI) MT RASb - n Median OS - mos (95% CI) Median PFS - mos (95% CI) WT RAS and BRAF - n Median OS - mos (95% CI) Median PFS - mos (95% CI) MT BRAF - n Median OS - mos (95% CI) Median PFS - mos (95% CI) aWT

Pmab ⴙ FOLFOX (N ⴝ 320)

FOLFOX (N ⴝ 321)

259 26.0 (21.7 - 30.4) 10.1 (9.3 - 12.0) 272 15.6 (13.4 - 17.9) 7.3 (6.3 - 7.9) 228 28.3 (23.7 - not estimable) 10.8 (9.4 - 12.4) 24 10.5 (6.4 - 18.9) 6.1 (3.7 - 10.7)

253 20.2 (17.7 - 23.1) 7.9 (7.2 - 9.3) 276 19.2 (16.7 - 21.8) 8.7 (7.6 - 9.4) 218 20.9 (18.4 - 23.8) 9.2 (7.4 - 9.6) 29 9.2 (8.0 - 15.7) 5.4 (3.3 - 6.2)

in KRAS and NRAS exons 2, 3, and 4.

bMT

HR (95% CI)

0.78 (0.62 - 0.99) 0.72 (0.58 - 0.90)

Descriptive p value

0.04 ⬍ 0.01

1.25 (1.02 - 1.55) 1.31 (1.07 - 1.60)

0.04

0.74 (0.57 - 0.96) 0.68 (0.54 - 0.87)

0.02

0.90 (0.46 - 1.76) 0.58 (0.29 - 1.15)

0.01

⬍ 0.01 0.76 0.12

in any KRAS or NRAS exon 2, 3, or 4.


208s 3512

Gastrointestinal (Colorectal) Cancer Poster Discussion Session (Board #4), Tue, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

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Heterogeneity of acquired KRAS and EGFR mutations in colorectal cancer patients treated with anti-EGFR monoclonal antibodies. Presenting Author: M. Pia Morelli, The University of Texas MD Anderson Cancer Center, Houston, TX

EGFR and KRAS mutations during anti-EGFR monoclonal antibody treatment in metastatic colorectal cancer: Clinically relevant? Presenting Author: Lucie Karayan-Tapon, Department of Molecular Oncology, Poitiers, France

Background: Although KRAS and EGFR extracellular domain acquired mutations were detected in two small cohorts and correlated with acquired resistance to anti-EGFR monoclonal antibodies (MAb), the frequency, co-occurrence, and distribution of these acquired mutations is unknown. In this study we evaluated the presence of acquired KRAS and EGFR mutations in cfDNA from CRC patients (pts) treated with anti-EGFR monoclonal antibody. Methods: Plasma was collected from EGFR-MAb refractory mCRC pts as part of the ATTACC (Assessment of Targeted Therapies Against Colorectal Cancer) program. Eligible pts had documentation of pre-treatment KRAS wild type tumor. The cfDNA was extracted from the plasma and analyzed by BEAMing technology for acquired KRAS and EGFR mutation. Results: The plasma from 55 patients was analyzed for EGFR and KRAS mutation. The S492R EGFR mutation was detected in 4 pts (7%) treated with cetuximab. Acquired KRAS mutations were detected in 26 of the 55 KRAS wt samples analyzed (47%). Although codon 61 and 146 mutations are rare in untreated CRCs (2% and 1% of the MDACC population, respectively), these atypical KRAS mutations predominated in acquired resistance (Q61H⫽33% and A146T⫽10%). Mutations in more than one KRAS codon are exceedingly rare in the primary tumor. In our study we detected more than one KRAS or EGFR mutation in 30% of the population (p⬍0.001), suggesting the development of multiple independent clones in individual patients. Compared to 8 patients with known KRAS mutations, the average number of mutant reads in the 26 patients with acquired mutation was substantially lower (p⬍0.01) despite similar tumor burden. Of note, acquired concomitant KRAS mutations were also found in a BRAF V600 mutant patient previously treated with anti-EGFR MAb and a BRAF inhibitor. Conclusions: KRAS and EGFR acquired mutation are present at low concentrations in cfDNA from mCRC pts refractory to anti-EGFR MAb and they are not mutually exclusive, suggesting heterogeneity of the resistant clones. Anti-EGFR MAb refractory patients showed a higher incidence of atypical KRAS mutation and higher incidence of multiple codon KRAS mutations compared with overall CRC patient.

Background: It is well-established that only patients with wild-type KRAS metastatic colorectal cancer (mCRC) benefit from treatment with an epidermal growth factor receptor monoclonal antibody (anti-EGFR mAb). Recently, in patients with tumor progression after anti-EGFR mAb, occurrence of EGFR mutation (n⫽2/10) [Montagut C et al., Nat Med 2012] or KRAS mutation (n⫽6/10) [Misale S et al., Nature 2012] in metastases has been identified. These mutations could explain treatment resistance but still need to be confirmed with simultaneous analysis of KRAS and EGFR mutations. Methods: We analyzed 37 tumor samples after anti-EGFR mAb treatment for mCRC (34 from metastasis lesions and 3 from primary tumors). We analyzed KRAS (codons 12 and 13), BRAFV600E and EGFRS492R mutations using a highly sensitive technique, pyrosequencing (TheraScreen KRAS Pyro Kit, Qiagen). All tumors were KRAS, BRAFV600E and EGFRS492Rwild-type before anti-EGFR mAb treatment. Results: The majority of patients were treated using anti-EGFR mAb in first-line chemotherapy (70%) and combined with cytotoxic chemotherapy (96%). Cetuximab was used in 86% and panitumumab in 14% of the cases. Among the 37 tumor specimens, 8 were collected after disease progression, and the others after disease control. No EGFRS492R mutation was detected. No tumors developed BRAF mutation but one tumor acquired a KRAS mutation. Nevertheless, the KRAS mutation in this patient (G12V) was detected, after 5-fluorouracil plus cetuximab therapy, only in the primary tumor in the colon but not in the liver metastasis. Moreover, there was a disease control (partial response). Conclusions: Our results suggest that EGFRS492R and acquired KRAS mutations during anti-EGFR mAb therapy are not the only factors accounting for anti-EGFR resistance. Moreover, occurrence of KRAS mutation during anti-EGFR therapy could differ between primary tumor and metastases.

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Analysis of plasma protein biomarkers from the CORRECT phase III study of regorafenib for metastatic colorectal cancer. Presenting Author: HeinzJosef Lenz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA Background: In the CORRECT phase III trial, the multikinase inhibitor regorafenib (REG) demonstrated significant improvement in overall survival (OS) and progression-free survival (PFS) vs placebo (Pla) in patients with metastatic colorectal cancer (mCRC) whose disease had progressed on other standard therapies. An exploratory biomarker subanalysis was conducted to identify protein biomarkers with potential predictive or prognostic value. Methods: Fifteen proteins of interest, many of which are involved in angiogenesis, were quantified by multiplex immunoassay or ELISA in baseline plasma samples collected at study entry from 80% (611/760) of patients. Potential predictive and prognostic effects were evaluated. Results: The biomarker subpopulation was representative of the overall study population in terms of OS and PFS. Using OS as the clinical endpoint, Tie-1 was the only protein whose level demonstrated significant correlation with efficacy (low protein group: REG/Pla, HR 0.87; high protein group, HR 0.56; interaction, p⫽0.035). Using PFS as the clinical endpoint, von Willebrand factor (VWF) was the only protein whose level demonstrated significant correlation with efficacy (low protein group: REG/Pla, HR 0.39; high protein group, HR 0.60; interaction, p⫽0.02). Following correction for multiple testing, neither Tie-1 nor VWF data retained statistical significance. Baseline levels of IL-8 and placental growth factor (PlGF) were found to have prognostic value for OS (IL-8: high/low protein levels, HR 3.48, p⬍0.001; PIGF: HR 1.81, p⫽0.002). IL-8 was also prognostic for PFS (high/low protein levels: HR 1.63, p⬍0.001). Conclusions: None of the plasma proteins examined showed significant predictive value for REG efficacy after multiple testing correction. The association between baseline levels of Tie-1/VWF and REG efficacy may be a hypothesis to be tested in further trials. Clinical trial information: NCT01103323.


Maintenance therapy with bevacizumab with or without erlotinib in metastatic colorectal cancer (mCRC) according to KRAS: Results of the GERCOR DREAM phase III trial. Presenting Author: Christophe Tournigand, Hopital Henri Mondor, UPEC, Creteil, France Background: The primary analysis of DREAM demonstrated that a maintenance therapy (MT) with bevacizumab (Bev) ⫹ EGFR TKI erlotinib (E) significantly improved progression-free survival (PFS) after a 1st-line Bev-based induction therapy (IT) in patients (pts) with unresectable mCRC. Methods: Pts were randomized to MT after an IT with FOLFOX-bev or XELOX-bev or FOLFIRI-bev between Bev alone (Bev 7.5 mg/kg q3w; arm A) or Bev⫹E (Bev 7.5 mg/kg q3w, E 150 mg/d ; arm B) until PD or unacceptable toxicity. Primary endpoint was PFS on MT. Secondary endpoints included PFS from inclusion, overall survival (OS) and safety. The impact of KRAS tumor status on treatment efficacy was evaluated in an exploratory analysis. Results: 700 pts were registered and 452 pts were randomized (228 in arm A, 224 in arm B). KRAS status was available for 413/452 (91%) pts. The median duration of MT was 3.6 m. Results for MT are presented below (Table). In the registered population, median OS was 24.9m (22.5 – 27.3). Conclusions: Maintenance treatment with bev ⫹ erlotinib increases PFS over maintenance with bev alone in pts with mCRC but does not prolong OS. Further follow-up will determine the impact of 2nd or 3rd line anti-EGFR Mabs in this study. Contrasting with anti-EGFR Mabs, KRAS tumor status is not mandatory to select pts with mCRC for treatment with erlotinib. Clinical trial information: NCT00265824. GERCOR DREAM study: KRAS analysis. Endpoints, months (95% CI)

Arm A

Arm B

Maintenance population (MP) (n ⴝ 452) Median maintenance PFS Median PFS Median OS

n ⫽ 228

n ⫽ 224

HR (95% CI)

P value

4.8 (4.1 - 5.7) 9.3 (8.7 – 10.1) 27.9 (24.1 – 31.1)

5.9 (4.5 - 6.4) 10.2 (9.5 – 11.5) 28.5 (25.1 – 33.9)

0.76 (0.61-0.94) 0.76 (0.61 - 0.94) 0.89 (0.70-1.12)

0.010 0.009 0.312

MP - WT KRAS Median maintenance PFS Median PFS Median OS

n ⫽ 111 5.9 (4.0 – 6.5) 9.7 (8.7 – 11.0) 31.5 (27.5 – 38.0)

n ⫽ 129 6.0 (4.5 – 7.8) 10.9 (9.8 – 12.6) 31.8 (26.6 – 37.8)

0.86 (0.64-0.1.16) 0.83 (0.61 - 1.11) 0.92 (0.66 – 1.30)

0.135 0.197 0.644

MP - Mut KRAS (n ⴝ 173) Median maintenance PFS Median PFS Median OS

n ⫽ 95 4.4 (3.9 – 5.3) 9.9 (8.6 – 10.8) 26.9 (22.4 – 33.2)

n ⫽ 78 4.7 (3.6 – 7.1) 9.8 (8.4 – 12.2) 26.3 (21.0 – 34.4)

0.77 (0.54 – 1.08) 0.80 (0.57 – 1.13) 1.06 (0.72 - 1.55)

0.124 0.212 0.767




FOLFIRI plus bevacizumab (bev) as second-line therapy in patients (pts) with metastatic colorectal cancer (mCRC) who have failed first-line bev plus oxaliplatin-based therapy: The randomized phase III EAGLE study. Presenting Author: Hiroshi Tamagawa, Department of Surgery, Osaka General Medical Center, Osaka, Japan Background: The phase III ML18147 study (NCT00700102) showed a survival benefit for the continuation of bev after 1st-line bev-containing therapy in pts with mCRC. Continuation of bev beyond disease progression in this setting was approved by the FDA in Jan 2013. In the randomized, phase II SPIRITT study (NCT00418938) assessing 2nd-line treatment for mCRC, progression-free survival (PFS) was longer in the bev arm compared with the panitumumab arm, but the difference was not statistically significant. We describe the results of EAGLE, a multicenter, randomized phase III study evaluating the optimal dose of 2nd-line bev in Japan (UMIN000002557). Methods: Pts were randomized 1:1 to receive bev 5 mg/kg (Arm A) or 10 mg/kg (Arm B) plus FOLFIRI Q2W. Key eligibility criteria: age ⱖ20 years, mCRC, ECOG PS ⱕ1, and treatment failure to prior 1st-line bev plus oxaliplatin-based therapy (ⱖ4 cycles). The primary endpoint was PFS. Secondary endpoints included time to treatment failure (TTF), PFS from 1st-line therapy, response rate (RR) and safety. The planned sample size was 370 pts to detect 30% risk reduction with 90% power assuming a two-sided significance level of 0.05. Results: 387 pts were randomized between Sep 2009 and Jan 2012; 367 pts formed the full analysis set (Arm A 179 pts; Arm B 188 pts). Baseline characteristics were well balanced between the treatment arms. Respectively for Arm A and B, PFS was 6.2 and 6.3 months (HR 1.03, 95% CI: 0.82-1.30; p⫽0.815), TTF 5.3 and 5.3 months (HR 1.08, 95% CI: 0.87-1.33; p⫽0.485), PFS from 1st-line therapy 17.6 and 17.8 months (HR 0.99, 95% CI: 0.78-1.25; p⫽0.919) and RR 11.7% and 10.1%. Frequently reported AEs in Arm A and B, respectively, were: hypertension (13.0%, 18.1%), proteinurea (36.8%, 35.2%), GI perforation (4.7%, 3.1%), grade 3/4 neutropenia (46.1%, 39.9%), grade 3/4 fatigue (7.8%, 10.9%), and grade 3/4 anorexia (5.7%, 5.2%). Treatment-related deaths occurred in 2 pts in each arm. Conclusions: The study did not meet its primary endpoint. PFS in Arm A was comparable to that reported in the ML18147 study. Safety in both arms was consistent with previously reported studies. Clinical trial information: UMIN000002557.

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Noninferiority of S-1 to UFT/LV as adjuvant chemotherapy for stage III colon cancer: A randomized phase III trial (ACTS-CC). Presenting Author: Yoshihiko Nakamoto, Department of Surgery, Kobe City Medical Center West Hospital, Hyogo, Japan Background: The ACTS-CC trial is a phase III trial designed to validate non-inferiority of S-1 to UFT/LV, a standard treatment in Japan as adjuvant chemotherapy for stage III colon cancer. This is the first report which evaluated the efficacy of S-1 as adjuvant therapy for colon cancer. Methods: 20-80 aged patients with stage III colon cancer who underwent curative surgery were randomly assigned to receive S-1 (80, 100, or 120 mg/day according to BSA on days 1 to 28, followed by 14 days rest, 4 courses) or UFT/LV (UFT: 300 to 600 mg/day according to BSA and, LV: 75 mg/day on days 1 to 28, followed by 7 days rest, 5 courses). Primary endpoint was DFS. Sample size was 1,480 determined with one-sided alpha of 0.05, power of 0.80, and non-inferiority margin of hazard ratio (HR) of 1.29. Results: Among 1535 enrolled patients between Apr. 2009 and Jun. 2010, 1518 patients (758 in S-1 group, 760 in UFT/LV group) were included in the efficacy analysis. Median follow-up was 41.3 months, the mean age at enrollment was 64.5 years, wide lymph node dissection (D3) was done in 79.8%, the median number of dissected lymph nodes was 17, and stage IIIA/IIIB/IIIC were 15%/71%/14%. The 3-year DFS rate was 75.5% in S-1 group and 72.5% in UFT/LV group. The HR of DFS was 0.85 (95%CI: 0.70-1.03) and non-inferiority of S-1 was demonstrated (p⬍0.0001). The completion rate of the protocol treatment was 76.5% in S-1 group and 72.5% in UFT/LV group. The overall incidence of grade ⱖ3 adverse events (AEs) in S-1 group and UFT/LV group were 16.0% and 14.4%: 4.4% and 5.5% for diarrhea, 4.9% and 3.5% for anorexia, 0.7% and 0.4% for leucopenia, 0.9% and 0.1% for anemia, 0.1% and 0.4% for thrombocytopenia, 1.2% and 1.5% for hyperbilirubinemia, 0.8% and 2.1% for AST elevation, and 1.1% and 3.3% for ALT elevation, respectively. Conclusions: Adjuvant therapy of S-1 for stage III colon cancer was demonstrated to be non-inferior in DFS to that of UFT/LV. Although AE profiles differed between S-1 group and UFT/LV group in this trial, incidence and degree of AEs were acceptable, and the completion rate of the protocol treatment was high. Adjuvant chemotherapy using S-1 will be a treatment option for stage III colon cancer. Clinical trial information: NCT00660894.

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Effectiveness of bevacizumab added to gold standard chemotherapy in metastatic colorectal cancer (mCRC): Final results from the Itaca randomized clinical trial. Presenting Author: Alessandro Passardi, IRCCS Istitituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy Background: Evidence from available RCTs indicates that the addition of bevacizumab (B) to chemotherapy (CT) results into an improved survival in metastatic colorectal cancer (mCRC). However, the magnitude of this effect is different across trials, with marginal benefit observed when gold standard CT regimens are used. With these premises we performed a phase III randomized clinical study to evaluate the effectiveness of gold standard mCRC first line CT ⫹ B. This study was funded by the Italian Ministry of Health. Methods: mCRC patients candidate were randomized to receive first line CT ⫹B or first line CT alone. CT regimens included FOLFOX4 (oxaliplatin 85 mg/m2 d1, folinic acid FA 100 mg/m2 dd1,2, 5FU 400 mg/m2 iv bolus dd 1,2 plus 5FU 600 mg/m2 22-h ic dd1,2 – Q14 days) or FOLFIRI (irinotecan 180 mg/m2d1, FA and 5FU as in FOLFOX4, Q 14 days); B 5 mg/kg was administered Q 14 days. The primary end point was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Response Rate (ORR) and safety. Three hundreds ten events were required to statistically differentiate PFS between groups with 80% power. Results: Between 11/2007 and 03/2012, 376 patients were randomized. Patient characteristics were well balanced between the two arms. FOLFOX4 was used in 60% of the patients and FOLFIRI in 40%. After a median follow up of 18.4 months, 313 progressions and 179 deaths were observed. No statistically significant differences in PFS, OS and ORR were observed (see table). B containg regimens were associated with more frequent hypertension, bleeding, proteinuria and asthenia. Conclusions: The addition of B to a gold standard CT for mCRCdoes not result into an improved prognosis in terms ofPFS, ORR, OS. ITACA’s results (control arm) suggest that the chemotherapeutic schedules used in some of the previously published bevacizumab trials might be suboptimal. Clinical trial information: 2007-004539-44. CTⴙBeva CT HR (95% CI) (nⴝ179) (nⴝ197) P value Median PFS mos (95%CI) Median OS mos (95%CI) ORR % (95% CI)

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9.2 (8.0-10.0) 20.6 (15.3-22.6) 54.2 (46.7-62.3)

8.4 (7.0-8.9) 20.6 (18.2-23.3) 48.1 (40.8-55.4)

0.88 (0.70-1.10) 0.265 1.18(0.88-1.58), 0.278 0.286


A randomized phase III trial of S-1/oxaliplatin (SOX) plus bevacizumab versus 5-FU/l-LV/oxaliplatin (mFOLFOX6) plus bevacizmab in patients with metastatic colorectal cancer: The SOFT study. Presenting Author: Daisuke Takahari, Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan Background: Several studies of oxaliplatin plus S-1 combination therapy (SOX) conducted in Asia have shown promising efficacy and safety for metastatic colorectal cancer (mCRC), suggesting the potential to replace mFOLFOX6. We performed a randomized phase III trial to determine whether SOX plus bevacizmab (SOX⫹Bev) is non-inferior to mFOLFOX6 plus bevacizmab (mFOLFOX6⫹Bev) in terms of progression-free survival (PFS). Methods: The SOFT study was a randomized, open-label, phase III trial. Chemotherapy-naïve patients (pts) with mCRC, an ECOG PS of 0-1, and adequate organ functions were randomized to receive either mFOLFOX6⫹Bev (5 mg/kg of bevacizumab, followed by 200 mg/m2 of l-leucovorin given simultaneously with 85 mg/m2 of oxaliplatin, followed by a 400 mg/m2 bolus of 5-FU on day 1 and then 2,400 mg/m2 of 5-FU over 46 h, every 2 weeks) or SOX⫹Bev (7.5 mg/kg of bevacizumab, 130 mg/m2 of oxaliplatin on day 1, and 40⫺60 mg of S-1 twice daily for 2 weeks, followed by a 1-week rest). The primary endpoint was PFS. A sample size of 225 pts per group was estimated to be necessary based on a median PFS of 10.0 months in each group and an 80% power to demonstrate noninferiority of SOX⫹Bev with a 2.5-month margin (hazard ratio, HR ⫽ 1.33) and a 2-sided alpha of 0.05. Results: A total of 512 pts were enrolled from February 2009 to March 2011. Data were analyzed after confirming ⬎388 events as planned. Demographic factors were well balanced. Pts received a median of 12 cycles (1 cycle ⫽ 2 weeks) of mFOLFOX6⫹Bev and 8 cycles (1 cycle ⫽ 3 weeks) of SOX⫹Bev (range: 1⫺16). Median PFS was 11.5 months (95% CI: 10.7⫺13.2) with mFOLFOX6⫹Bev and 11.7 months (95% CI: 10.7⫺12.9) with SOX⫹Bev. The adjusted HR for PFS was 1.043 (95% CI: 0.860⫺1.266), and the p value for non-inferiority was 0.0139. Response rate was 62.7% with mFOLFOX6⫹Bev and 61.5% with SOX⫹Bev. Grade 3/4 toxicities (%) with mFOLFOX6⫹Bev/SOX⫹Bev were leukopenia 8.4/2.4, neutropenia 33.7/8.8, anorexia 1.2/5.2, and diarrhea 2.8/9.2. Conclusions: SOX⫹Bev is non-inferior to mFOLFOX6⫹Bev with respect to PFS as 1st-line treatment for mCRC and thus can replace mFOLFOX6⫹Bev. Clinical trial information: JapicCTI-090699.


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Prognostic value of early objective tumor response (EOTR) to first-line systemic therapy in metastatic colorectal cancer (mCRC): Individual patient data (IPD) meta-analysis of randomized trials from the ARCAD database. Presenting Author: Dirkje Willemien Sommeijer, NHMRC Clinical Trials Centre, University of Sydney, Camperdown, Australia

Efficacy and safety according to age subgroups in AVEX, a randomized phase III trial of bevacizumab in combination with capecitabine for the first-line treatment of elderly patients with metastatic colorectal cancer. Presenting Author: Mark P. Saunders, Christie Hospital NHS Foundation Trust, Withington, United Kingdom

Background: EOTR has been suggested as a potential surrogate for overall survival (OS) in patients (pts) with mCRC and allows early assessment of treatment efficacy, facilitating adaptive trial design. We assessed at the individual patient level, the correlation between EOTR (complete or partial response) at 6, 8 and 12 weeks (wk), OS and progression free survival (PFS) in pts with mCRC treated with 1stline chemotherapy with or without a targeted agent as a first step in a surrogacy demonstration. Methods: IPD from 13,949 pts enrolled on 15 randomized Phase III trials in 1st line mCRC were used; 8 trials included targeted (anti-angiogenic and antiEGFR) agents. EOTR prognostic value was assessed by landmark analyses using Cox models stratified by treatment assignment. P-values ⬍0.01 were considered statistically significant to account for multiple comparisons. Results: Of 13,949 pts, 11,987 had sufficient response data to be included in the analysis. Median OS was 21.7 months (mo) in pts with an EOTR vs. 16.5 mo without EOTR at 6 wk (p⬍.0001, Hazard Ratio [HR] 0.64, 95% confidence interval [CI] 0.58-0.70, c statistic [c] 0.55). HRs were similar whether pts were treated with targeted therapies (p⬍.0001, HR 0.68, 95% CI 0.58-0.80, x 0.54) or non-targeted therapies (p⬍.0001, HR 0.61, 95% CI 0.55-0.69, x 0.55). Median PFS was 8.4 mo in pts with EOTR at 6 wk vs. 7.0 mo in pts without EOTR (p⬍.0001, HR 0.79, 95% CI 0.73-0.85). EOTR at 8 and 12 wks were also significantly associated with longer OS and PFS. The prognostic value of EOTR at 6, 8 and 12 wks remained significant (p⬍0.0001) after adjusting for age, gender, performance statusand location of metastatic disease (lung or liver). Overall tumor response (to 26 wk) however provided superior OS prediction (p⬍.0001, HR 0.51, 95% CI, 0.47-0.56, CS 0.61) vs. EOTR. Conclusions: Early response measured at 6, 8 or 12 wk after starting 1st line treatment was a strong and independent predictor of both OS and PFS in patient with mCRC and warrants further consideration as a potential endpoint for future trials, particularly randomized phase II trials.

Background: Elderly patients (pts) are underrepresented in clinical trials. The open-label phase III trial AVEX evaluated the benefit of adding bevacizumab (BEV) to capecitabine (cape) in elderly pts with previously untreated metastatic colorectal cancer (mCRC). This analysis explores clinical outcomes by age subgroup. Methods: In AVEX, 280 pts ⱖ70 y with mCRC for whom single-agent chemotherapy was deemed appropriate, were randomized to first-line cape (1000 mg/m2bid days 1–14) alone (n⫽140) or with BEV (7.5 mg/kg) q3w (n⫽140). The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), overall response rate, and safety. The study was powered to show a difference in PFS but not OS. A post hoc analysis was conducted to assess PFS, OS, and safety in pts 70 –74 y, 75–79 y, and ⱖ80 y. Results: Median age was 76 y (range, 70 – 87). In the overall population, BEV ⫹ cape significantly prolonged PFS compared with cape (median 9.1 vs 5.1 mo; hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.41– 0.69; p⬍.001). Differences in OS did not reach statistical significance in the overall population (HR, 0.79; 95% CI, 0.57–1.09; p⫽.182). Treatment was well tolerated. Results according to age are shown (Table). Conclusions: The addition of BEV to cape was associated with significant improvements in PFS in the overall elderly mCRC population and within age subgroups. The safety profile of BEV ⫹ cape was consistent across age groups. Clinical trial information: NCT00484939. 70–74 y Cape ⴙ BEV nⴝ55 Median PFS, mo (95% CI) PFS HR (95% CI) Log-rank p Median OS, mo (95% CI) OS HR (95% CI) Log-rank p Best ORR (%) Fisher’s exact p Grade >3 adverse events, %

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75–79 y Cape nⴝ46

7.6 5.0 (6.0–11.8) (4.0–6.5) 0.52 (0.32–0.83) ⬍.001 20.7 (13.7–26.1)

22.2 (9.7–42.7) 0.91 (0.50-1.66) .55 25.5 10.9 .076 n⫽54 n⫽46 63.0 41.3

Cape ⴙ BEV nⴝ57

>80 y Cape nⴝ66

9.8 5.1 (7.1–11.4) (4.1–7.4) 0.60 (0.40–0.89) .016 19.8 17.4 (13.8–27.3) (11.9–23.0) 0.79 (0.48-1.30) .37 15.8 12.1 .607 n⫽53 n⫽64 54.7 40.6

Cape ⴙ BEV nⴝ28

Cape nⴝ28

10.5 5.1 (5.0–14.5) (2.2–7.1) 0.36 (0.19–0.71) .003 19.7 12.6 (7.5–26.9) (6.6–17.0) 0.62 (0.31-1.24) .24 14.3 3.6 .352 n⫽27 n⫽26 59.3 57.7


BRAF and KRAS mutations as additional risk factors in the context of clinical parameters of patients with colorectal cancer. Presenting Author: Vlad Calin Popovici, SIB Swiss Institute of Bioinfromatics, Lausanne, Switzerland

Prognostic impact of KRAS and BRAFV600E mutations stratified by tumor site in resected stage III colon cancer patients treated with adjuvant mFOLFOX6 with or without cetuximab: NCCTG N0147 (Alliance). Presenting Author: Frank A. Sinicrope, Mayo Clinic, Rochester, MN

Background: The BRAF and KRAS mutations have been proposed as prognostic markers in colorectal cancer (CRC). Of them, only the BRAF V600E mutation has been validated as prognostic for overall survival and survival after relapse, while the value of KRAS mutation is still unclear. Methods: In a cohort of 1423 stage II-III patients from the PETACC-3 clinical trial, the prognostic value of the BRAF and KRAS mutations was retrospectively assessed in all possible stratifications defined by the 5 factors (T and N stage, tumor site and grade, and microsatellite instability status), by log rank test for overall survival (OS), relapse-free survival (RFS), and survival after relapse (SAR). The presence of interactions was tested by Wald test. The significance level was set to 0.01 for Bonferroni-adjusted p-values (P*), and a second level for a trend towards statistical significance was set at 0.05 for unadjusted p-values (P). Results: BRAF mutation was a marker of poor OS only in microsatellite stable (MSS) and left-sided tumors, with no prognostic value in microsatellite instable (MSI-H) or right-sided tumors. In MSS/left-sided tumors, BRAF mutation represents a marker of higher risk than previously reported: OS HR⫽6.4 [95% CI: 3.6-11.5], P* ⬍ 0.0001. For SAR, BRAF was prognostic in more stratifications, with higher risk in MSS/left-sided tumors (HR⫽3.9 [95% CI: 2.1-7.2], P* ⫽ 0.0002) than in MSS/right-sided (HR⫽2.3 [95% CI: 1.2-4.4], P⫽0.01). A novel observation was that BRAF mutation was prognostic also for RFS, but only in MSS/left-sided tumors (HR⫽3.6 [95% CI:2-6.3], P*⫽0.0005]). Additionally, heterogeneity in OS and RFS among BRAF mutants was observed. In general, KRAS mutation did not reach the significance level required, but showed a trend to become a prognostic marker for RFS in MSS tumors with early lymph node involvement (N1) (HR⫽1.6 [95% CI:1.1-2.2], P⫽0.01). Conclusions: The prognostic utility of the BRAF and KRAS mutations has to be interpreted in the context of other factors. For the BRAF mutation, a clear interaction with MSI status and tumor site was observed, with BRAF mutation indicating a much higher risk in MSS/left-sided tumors than previously considered.

Background: The association of KRAS or BRAFV600E mutations with prognosis in colon cancers has been inconsistent. Since primary tumor site may influence outcome, we analyzed KRAS and BRAFV600E stratified by tumor site in resected stage III colon cancers from a randomized adjuvant trial of mFOLFOX6 ⫹ cetuximab chemotherapy (N⫽ 2,686) where no survival difference by treatment was found. Methods: 2,580 tumors were analyzed for mutations in BRAFV600E (exon 15) or KRAS (codons 12, 13), and for deficient DNA mismatch repair (dMMR). Cox models were used, adjusting for mutation status, age, sex, treatment, T-stage, histologic grade, nodal status, tumor site, and MMR. After study initiation, eligibility was restricted to patients (pts) with KRAS wild-type (WT) tumors. At a median follow-up 4.1 yrs, 83% of pts are alive. Results: KRAS and BRAFV600E mutations were detected in 716 (28%) and 346 (14%) tumors, respectively; dMMR was found in 314 (12%). Proximal (to splenic flexure) tumors (50%) were associated with older age and were more likely to be high grade (33 vs 18%), T-stage3,4 (88 vs 82%), mutated for KRAS (33 vs 23%) or BRAFV600E (23 vs 4%), and dMMR (21 vs 3%)[all p ⬍0.02]. Pts with distal vs proximal tumors showed improved disease-free survival (DFS)[ HR 0.7, 95% CI (0.6-0.9); p⬍0.01 unadjusted for KRAS or BRAF;]. Mutant KRAS [HR⫽1.5 (1.2-1.7); p⬍.0001] or mutant BRAF [HR⫽1.4 (1.1-1.7); p⫽0.02] were each independently associated with worse DFS. The KRAS and tumor site interaction was significant (unadjusted pinteraction⫽0.02; adjusted pinteraction⫽0.07), with poorer DFS among distal tumors having mutant KRAS [HR 1.7 (1.3-2.2); p⬍.0001]. No interaction was observed for BRAFV600E and tumor site, despite worse DFS for mutant BRAFV600E among proximal tumors [HR 1.3 (1-1.8); p⫽0.04]. Conclusions: The adverse prognostic impact of KRAS, but not BRAFV600E, mutations was confined to the distal colon. This finding underscores the importance of tumor site in the interpretation of the prognostic impact of KRAS status, and motivates similar analyses in pts with advanced disease.



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3525^ Poster Discussion Session (Board #17), Tue, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

Effect of adding oxaliplatin to adjuvant 5-fluorouracil/leucovorin (5FU/LV) in patients with defective mismatch repair (dMMR) colon cancer stage II and III included in the MOSIAC study. Presenting Author: Jean-François Flejou, Department of Pathology, Hospital Saint-Antoine, AP-HP, Paris, France Background: The MOSAIC study (André T, N Engl J Med, 2004) demonstrated that adding oxaliplatin to adjuvant 5FU and LV improved three-year disease-free survival (DFS) in stage II and III resected CC. Efficacy of FOLFOX4 in pts with dMMR stage III was suggested in a retrospective study (Zaanan A, Ann Oncol 2010). Methods: Of the 2,246 pts included in MOSAIC study, formalin-fixed, paraffin-embedded (FFPE) tissue blocks or slides from 1,019 pts were obtained. Thirty-three samples with insufficient tumor tissue were excluded from this translational study. MMR status was determined by immunohistochemistry (IHC) analysis of the protein products of MLH1, MSH2, PMS2, and MSH6 genes. Results: A total of 986 pts (44%) were evaluable for MMR status and MMR status was not evaluable for 1,260 pts (56%). Relapse-free survival (RFS), DFS and overall survival (OS) were similar in both, MMR and MMR not evaluable population. Ninety (9.1%) and 896 (90.9%) pts had dMMR and proficient MMR (pMMR) CC, respectively. Of the patients with 90 dMMR CC, 45 pts had stage II and 45 stage III. Hazard Ratios (HRs) for stage II and III dMMR are 0.52 (0.21–1.28) for RFS, 0.52 (0.24 –1.14) for DFS, and 0.45 (0.19 –1.05) for OS, respectively. HR for stage III dMMR are 0.56 (0.19 –1.61) for RFS, 0.51 (0.18 –1.41) for DFS, and 0.44 (0.15–1.34) for OS, respectively. HR for stage II dMMR are 0.64 (0.11–3.70) for RFS, 0.60 (0.17–2.09) for DFS, and 0.52 (0.13–2.10) for OS, respectively. Conclusions: Analyses ofcolon cancerMMR status in pts included in the MOSAIC study support the use of FOLFOX4 in pts with dMMR stage III cancer. Clinical trial information: NCT00275210.

Subgroup analyses results of the PETACC8 phase III trial comparing adjuvant FOLFOX4 with or without cetuximab (CTX) in resected stage III colon cancer (CC). Presenting Author: Julien Taïeb, Georges Pompidou European Hospital, Paris, France

Three-year RFS and DFS and 5- and 10-year OS for patients with dMMR CC. Stage II and III dMMR (nⴝ90) FOLFOX4 (nⴝ40) LV5FU2 (nⴝ50) Stage III dMMR(nⴝ45) FOLFOX4 (nⴝ17) LV5FU2 (nⴝ28) Stage II dMMR (nⴝ45) FOLFOX4 (nⴝ23) LV5FU2 (nⴝ22)

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3-year RFS

3-year DFS

5-year OS

10-year OS

90.0% ⫾ 4.7% 79.8% ⫾ 5.7%

87.5% ⫾ 5.2% 78.0% ⫾ 5.9%

90.0% ⫾ 4.7% 82.0% ⫾ 5.5%

87.2% ⫾ 5.4% 70.9% ⫾ 6.6%

82.4% ⫾ 9.2% 67.9% ⫾ 8.8%

82.4% ⫾ 9.2% 67.9% ⫾ 8.8%

88.2% ⫾ 7.8% 71.3% ⫾ 8.6%

88.2% ⫾ 7.8% 63.0% ⫾ 9.4%

95.7% ⫾ 4.2% 95.2% ⫾ 4.6%

91.3% ⫾ 5.8% 90.9% ⫾ 6.3%

91.3% ⫾ 5.8% 95.5% ⫾ 4.4%

87.0% ⫾ 7% 81% ⫾ 8.6%


Proximal and distal colon tumors as distinct biologic entities with different prognoses. Presenting Author: Edoardo Missiaglia, SIB Swiss Institute of Bioinfromatics, Lausanne, Switzerland Background: It has been shown that tumors arising in the proximal and distal colon, defined by the embryological midgut and hindgut, have distinctive clinical and molecular features, but very little is known concerning the differences in the mechanism of tumorigenesis and the effect that this could have on therapy. Methods: The distribution of clinico-pathological and molecular features was evaluated between proximal (N ⫽ 1110 - Caecum to hepatic flexure) and distal colon (N ⫽ 1728 splenic flexure down to sigmoid) in patients included in the PETACC3 trial. Gene expression profile was also available from 783 tumors and 32 normal colon. A further set of 473 metastatic patients treated with cetuximab combined with chemotherapy (De Roock Lancet Oncol. 2010) was used to test tumor location with response. Results: Pathological features, such as tumor differentiation, and mucinous histology as well as molecular characteristics, such as MSI status, BRAF, PIK3Ca mutations and LOH18q loss show higher frequency in proximal compared to distal colon (N ⫽ 1214; Fisher test, P⬍0.001). Proximal tumors showed a significantly worse overall survival (N⫽ 2838; HR⫽1.4 [1.18 - 1.64] P⬍0.001) and survival after relapse (N ⫽ 861; HR⫽1.97 [1.65 - 2.35] P ⬍0.001) only if they were stage III at diagnosis, while no difference was observed for relapse free survival. Microarray profiling identified 997 genes differentially expressed between the two anatomical sites, after adjustment for age, gender, mucinous histology, BRAF, KRAS and MSI status. Only 20 of those were present in normal colon site comparison indicating tumor specificity. Data mining analysis of the differentially expressed genes showed that the distal colon is characterized by an enrichment for MAPK activated pathways as well as for the cetuximab response gene signature (Khambata-Ford JCO 2007). In fact, cetuximab treated KRAS/BRAF wild-type tumors in distal colon had prolonged PFS and a 2-fold higher response rate then proximal. Conclusions: Proximal and distal colon tumors have distinctive patterns of clinical-pathological and molecular features. These biological differences likely have significant prognostic and therapeutic implications.

Background: Potential benefit of adding CTX to the current standard treatment for stage III CC, was assessed. Subgroup analyses of demographic, clinical and molecular data may improve our understanding of this patient population. Methods: Patients (pts) were randomized 28-56 days following resection. They received 12 biweekly cycles of oxaliplatin 85 mg/m2 day (d) 1, with leucovorin 200 mg/m2, 5-FU 400 mg/m2 bolus IV, followed by 5-FU 600 mg/m2 22-hr IV on d1-2 (FOLFOX4), without (arm A) or with weekly CTX (arm B) 250 mg/m2 (initial dose 400 mg/m2). Primary endpoint was disease free survival time (DFS). Secondary endpoints included overall survival (OS), treatment compliance and safety. Enrolment was restricted to KRAS wt pts in 06/2008. Planned accrual of 1,407 KRAS wild-type (wt) pts provided 90% power to detect a hazard ratio (HR) of 0.75 with 2-sided ␣⫽0.05, with interim analyses after 65% of planned events. Preplanned subgroup analyses were performed. Results: 1,602 KRAS wt pts (811 arm A, 791 arm B) and 742 mutated (m) KRAS (prior to the amendment), were randomized. BRAF status was determined in 1134 (71%) KRAS wt pts. Median follow-up was 40 months. This interim analysis showed no difference between arms for DFS (HR 1.05, 95% CI 0.85-1.29; p⫽0.66) or OS (HR 1.09, 95% CI 0.81-1.47; p⫽0.55) in KRAS wt pts or for DFS (HR 0.99, 95% CI 0.75-1.28; p⫽0.91) or OS (HR 0.98, 95% CI 0.67-1.44; p⫽0.92) in KRAS/BRAF wt pts (n⫽984). Similar results were seen in KRAS mutant (mt) pts without any detrimental effect. In KRAS wt pts worse outcomes were seen with CTX in pts ⬎70 years (n⫽149, DFS: HR 1.97, 95% CI 0.99-3.93; p⫽0.05), in females (n⫽666, HR 1.45, 95% CI 1.03-2.03; p⫽0.03) and in pts with right-sided CC (n⫽570, HR 1.40, 95% CI 1.01-1.94; p⫽0.04). Conversely, a better outcome was seen in pts with pT4pN2 CC (n⫽146, HR 0.55, 95% CI 0.35-0.89; p⫽0.01). Conclusions: Adding CTX to FOLFOX4 offered no benefit to pts with resected stage III KRAS wt, KRAS/BRAF wt and KRAS mt CC. Subgroup analyses suggest that KRAS wt pts with pT4pN2 tumors may derive benefit from CTX. MSI status determination is ongoing to explore its potential interaction with poor outcome in female and/or with right-sided tumors pts. Clinical trial information: NCT00265811.

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Gene expression profiles and tumor locations in colorectal cancer (left vs. right vs. rectum). Presenting Author: Martin K. H. Maus, Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany Background: Recent data suggests that CRC from different locations show distinct genetic profiles. Right-sided tumors have a worse prognosis and may have less benefit from targeted therapies. We investigated the tumor locations and genetic profiles (KRAS and BRAF mutation status and ERCC1, TS, EGFR and VEGFR2 mRNA expression) in 580 CRC tumors. Methods: FFPE tumor specimen from 580 patients with advanced CRC adenocarcinoma were microdissected and DNA and RNA were extracted. Specifically designed primers and probes were used to detect 7 different base substitutions in codon 12 and 13 of KRAS, V600E mutations in BRAF and the mRNA expression levels of ERCC1, TS, EGFR and VEGFR2 by RT-PCR. These values were analyzed according to tumor location (left vs. right vs. rectum). Results: BRAF mutations were significantly more common in the right colon (15%), followed by rectum (3.8%) and left colon (2.5%). KRAS mutations occurred at similar frequencies throughout the colon. Gene expression of ERCC1 was significantly higher in right-sided than left-sided colon tumors in KRAS wild-type colon cancers. The highest expression levels for all genes were seen in rectum. These differences reached significant levels for ERCC1 (rectum vs. right and rectum vs. left, p⬍0.001), TS (rectum vs. left, p⬍0.036) and VEGFR2 (rectum vs. right and rectum vs. left, p⬍0.001). Conclusions: Tumor location in CRC is associated with specific mutation and expression profiles. Differences in chemosensitivity may be explained by mutation status and mRNA levels in right vs. left CRC. Rectum cancers showed a distinct genetic profile when compared to colon which indicates different tumor biology and may be related to differences in the microflora.


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Location of colon cancer (right-sided [RC] versus left-sided [LC]) as a predictor of benefit from cetuximab (CET): NCIC CTG CO.17. Presenting Author: Stephanie Yasmin Brule, The Ottawa Hospital, Ottawa, ON, Canada Background: RC and LC differ with respect to biology, pathology, and epidemiology. Further, recent SEER data suggests a mortality difference between RC and LC that varies by stage: stage II and III RC having lower and higher mortality, respectively. We examined if the primary tumour site can also predict for outcome in pre-treated, chemotherapy refractory, metastatic colon cancer (MCC). We compared RC vs. LC as a predictor for efficacy of EGFR inhibition with CET. Methods: Using CO.17 (CET vs. BSC), we coded the primary tumour site for 399 pts as RC (cecum to transverse colon) or LC (splenic flexure to rectosigmoid). Fisher’s exact test assessed the association between site of cancer and baseline characteristics. Univariate and multivariate analyses of overall survival (OS) and progression free survival (PFS) by site of cancer were performed using Cox regression models. Results: Pts with RC (150/399) had more poorly differentiated tumours, mutant KRAS status, and peritoneal rather than liver and lung metastases, and they more often entered the study less than two years after initial diagnosis. Among pts receiving BSC, tumour location (RC vs. LC) was not prognostic for PFS (HR 1.07 [0.79, 1.44], p⫽0.67) or OS (HR 0.96 [0.70, 1.31], p⫽0.78). Among pts with KRAS wild type tumour status, site of cancer was a predictor of benefit from CET, with much greater PFS observed for LC (interaction p⫽0.002). Conclusions: In refractory MCC, tumour location within the colon (RC vs. LC) is not a prognostic factor, but is a strong predictor of PFS benefit from CET therapy. Additional research is needed to understand the molecular differences between RC and LC and their interaction with EGFR inhibition. Median survival (months) CET vs. BSC

Benefit CET vs. BSC HR (95% C.I.), p value

Predictive effect Interaction p value

PFS LC

5.4 vs. 1.8 1.9 vs. 1.9

0.28 (0.18, 0.45), p⬍0.0001 0.73 (0.42, 1.27), p⫽0.26

0.002

RC OS LC

10.1 vs. 4.8 6.2 vs. 3.5

0.49 (0.31, 0.77), p⫽0.002 0.66 (0.36, 1.21), p⫽0.18

0.25

RC

KRAS WT subset

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MET overexpression as a hallmark of the epithelial-mesenchymal transition (EMT) phenotype in colorectal cancer. Presenting Author: Kanwal Pratap Singh Raghav, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Epithelial-mesenchymal transition (EMT) has been identified as a dominant molecular subtype of colorectal cancer (CRC). This EMT phenotype as recognized by complex gene signatures is prognostic and associated with chemoresistance, but a biomarker for EMT suitable for clinical utilization has not yet been validated. The purpose of this study was to compare MET protein expression with protein/gene expression of EMT markers and to evaluate its impact on overall survival (OS). Methods: We performed an exploratory analysis of 139 untreated primary CRC samples using data from The Cancer Genome Atlas. Protein and gene expressions were measured using reverse-phase protein array (RPPA) and RNAsequencing, respectively. MET high/overexpressed group was defined by protein level in the highest quartile. Mann-Whitney U-test and Spearman rank correlation was used to determine association between MET protein expression and protein/gene expression of EMT markers and EMT gene signature scores. Regression tree method and Kaplan-Meier estimates were used to assess overall survival (OS). Results: The MET protein distribution is right skewed, demonstrating a unique population of MET high expressing tumors (P ⬍ 0.01). Colon tumors had higher MET protein levels compared to rectal tumors (P ⬍ 0.01). MET overexpression was associated with decreased OS (HR 2.92; 95% CI: 1.45 - 5.92). MET protein expression correlated strongly with protein expressions of SLUG (transcription factor for EMT) (r ⫽ 0.6) and ERCC1 (a marker for oxaliplatin chemo-resistance) (r ⫽ 0.6) (P ⬍ 0.01). Higher MET protein levels were associated with higher gene expression of 28 EMT markers including AXL, VIM, ZEB1, ZEB2, FGF1, TGFB1I1 and MMP11 (P ⬍ 0.05). Higher MET protein levels were also associated with higher gene scores derived from three published EMT gene signatures (P ⬍ 0.05). MET protein expression did not correlate with MET gene expression (r ⫽ 0.16). Conclusions: Increased MET protein expression strongly correlates with a molecular EMT phenotype and poor survival in patients with CRC. MET protein expression may be used as a surrogate biomarker to represent and select for this unique molecular subset of CRC driven by EMT biology.

3531


Association of colorectal cancer intrinsic subtypes with prognosis, chemotherapy response, deficient mismatch repair, and epithelial to mesenchymal transition (EMT). Presenting Author: Ramon Salazar, Translational Research Laboratory and Department of Medical Oncology, Institut Catala d’Oncologia-IDIBELL, Hospitalet de Llobregat, Spain

Preoperative chemoradiotherapy and postoperative chemotherapy with capecitabine and oxaliplatin versus capecitabine alone in locally advanced rectal cancer: First results of the PETACC-6 randomized phase III trial. Presenting Author: Hans-Joachim Schmoll, Martin Luther University HalleWittenberg, Halle, Germany

Background: Unbiased genome-wide analyses of gene expression patterns have been successfully used for molecular classification of breast cancer into subtypes that have clear relevance for prognosis and treatment. A similar classification is still missing for colorectal cancer (CRC). Methods: Using full genome expression data of 188 stage I-IV CRC patients, an unsupervised clustering revealed three major subtypes (A-, B-, C-type). A molecular subtype classification was developed and validated in 543 stage II and III patients. The subtypes were analyzed for correlation to clinical information, mutations in the kinome, known molecular markers status and chemotherapy response. In addition, subtypes were determined on 173 samples from The Cancer Genome Atlas (TCGA) colon dataset with Agilent genome expression data. Results: C-type patients have the worst outcome, a mesenchymal phenotype, and show no benefit from adjuvant chemotherapy treatment. Patients having A- or B-type tumors have a better clinical outcome, a more proliferative and epithelial phenotype and benefit from adjuvant chemotherapy. A- and C-type groups are enriched for tumors having oncogenic BRAF mutations and a deficient DNA mismatch repair system. B-type tumors showed a low overall kinome mutation frequency (1.6%), while both A- and C-type patients harbor a higher mutation frequency (respectively 4.2 and 6.2%), in agreement with their mismatch repair deficiency. Finally, CRC subtyping was confirmed in the colon TCGA dataset with 26 samples classified as A-type, 110 as B-type and 37 as C-type. In agreement with the different aggressiveness of the subtypes, A-type tumors were less prevalent in stage IV while C-type were less prevalent in stage I CRC. Conclusions: The heterogeneity of the intrinsic subtypes is largely based on three biological hallmarks of the tumor: an epithelial-to-mesenchymal transition, deficiency in mismatch repair genes that result in a high mutation frequency associated with MSI, and cellular proliferation. These subtypes are clinically relevant, as they differ in their underlying biology and might require different treatment strategies.

Background: The PETACC-6 trial investigates whether the addition of oxaliplatin to preoperative oral fluoropyrimidine-based chemoradiation (CRT) followed by postoperative adjuvant fluoropyrimidine-based chemotherapy (CT) improves disease-free survival (DFS) in locally advanced rectal cancer. We present results of the early secondary endpoints. Methods: Between 11/2008 and 09/2011, patients with rectal cancer within 12 cm from the anal verge, T3/4 and/or node-positive, with no evidence of metastatic disease and considered either resectable at the time of entry or expected to become resectable after preoperative CRT, were randomly assigned to receive 5 weeks of preoperative CRT (45 Gy in 25 fractions) with capecitabine (825 mg/m² twice daily), followed by 6 cycles of adjuvant CT with capecitabine (1000 mg/m2twice daily/days 1-15 every three weeks) (arm 1) or to receive the same regimen with the addition of oxaliplatin before (50 mg/m²/days 1, 8, 15, 22, 29) and after surgery (130 mg/m²/day 1, every three weeks) (arm 2). Additional RT before surgery (5.4 Gy/days 36-38) using the same fields or as a boost with capecitabine was an option. Primary endpoint is DFS. Results: 1094 patients were randomized (547 in each arm). 98% and 92% of patients, respectively, received at least 45 Gy of preoperative RT in arm 1 and arm 2. More than 90% of full dose concurrent CT was delivered in 91% and 63% of patients, respectively, in arm 1 and arm 2. Preoperative grade 3/4 toxicity occurred in 15.1% of patients in arm 1 vs. 36.7% in arm 2; 1 vs. 3 patients died before surgery. R0 resection rate was 92.0% in arm 1 and 86.3% in arm 2. The pCR rate (ypT0N0) was equal in both arms with 11.3% in arm 1 and 13.3% in arm 2 (p⫽0.31). The anal sphincter was preserved in 70% vs. 65% (p⫽0.09) in arm 1 and 2. Postoperative complications were not different between arms (38% vs. 41%; 5 vs. 4 patients died following surgery). Definitive numbers will be presented at the congress. Conclusions: The addition of oxaliplatin to preoperative fluoropyrimidine-based CRT led to decreased treatment compliance and increased toxicity, but did not improve surgical outcome. Clinical trial information: NCT00766155.




Tumor-related and treatment-related colostomy-free survival (CFS) following chemoradiation (CRT) using mitomycin (MMC) or cisplatin (CisP), with or without maintenance 5FU/CisP chemotherapy (CT) in squamous cell carcinoma of the anus (SCCA): Results of ACT II. Presenting Author: Robert Glynne-Jones, Mount Vernon Centre for Cancer Treatment, Middlesex, United Kingdom Background: Concurrent CRT is standard treatment for patients (pts) with SCCA. We explore tumor- and treatment-related CFS in a phase III trial (ACT II), which mandated standardised radiation fields and a uniform dose (50.4Gy in 28 daily fractions of 1.8Gy). Methods: The ACT II trial (940 pts) compared both CisP (n⫽468) versus MMC (n⫽472) combined with 5-FU/CRT, and 2 cycles of maintenance CT (Maint, n⫽448) versus none (No-maint, n⫽446). We investigated the association between CFS and baseline factors (age, sex, T stage, size of tumour, nodal status) and treatment using Cox regression. CFS events included baseline colostomies not reversed at first follow up after treatment and post-treatment colostomies. Results: Median follow-up (all pts) was 5.1 years. Median age: 58 years; tumour site – canal (84%), margin (14%); stage T1-T2 (52%), T3-T4 (46%); N⫹ (32%), N0 (62%). Of 884 evaluable patients only 20/118 (17%) baseline colostomies were reversed within 8 months, and 37 later. 112 pts had a post-treatment colostomy due to persistent disease (98) or morbidity (14). The 5-year CFS rates by stage were 86% T1, 77% T2, 57% T3 and 47% T4; 72% N0, 60% N⫹; by treatment arm 68% MMC/Maint, 70% CisP/Maint, 68% MMC/No-maint and 65% CisP/Nomaint respectively. The 5-year CFS rates were 72% and 60% for N0 and N⫹ respectively. The most significant predictors of colostomy in multivariable Cox regression analyses were T stage, sex and baseline haemoglobin (p⬍0.001 for all). Men were more at risk than women (adjusted HR 1.64; 95% CI: 1.26, 2.14). Age, site of primary or treatment did not impact on CFS. Although significant in univariate analysis, nodal status did not influence CFS when adjusted for other baseline factors. Conclusions: In the largest trial in anal cancer, neither the type of CRT (5FU/CisP vs. 5FU/MMC) nor maintenance chemotherapy improved CFS. 34% (61/177) of all colostomies were baseline fashioned prior to treatment and never reversed after all treatments. The major predictive factors for CFS were T stage, sex and haemoglobin levels. Clinical trial information: NCT00025090.

3534


Randomized controlled trials (RCTs) examining continuous (CS) versus intermittent strategies (IS) of delivering systemic treatment (Tx) for untreated metastatic colorectal cancer (mCRC): A meta-analysis from the Cancer Care Ontario program in evidence-based care. Presenting Author: Scott R. Berry, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada Background: Given the varying impact on efficacy demonstrated in individual RCTs of CS vs IS of delivering systemic Tx for mCRC, a meta-analysis of the available RCTs was performed. Methods: RCTs that compared a CS versus IS of delivering systemic Tx were identified by a systematic search (MEDLINE, EMBASE and ASCO and ESMO proceedings) and review. The results of identified trials were clinically homogeneous (Table) so the data was pooled using Review Manager software (RevMan 5.2). Overall survival (OS) hazard ratios were extracted directly from the most recently reported trial results. A random effects model was used for all pooling. Results: 10 RCTs were identified (n⫽ 4,296). After an induction period, the maintenance Tx patients received during the IS was: none (5 trials, n⫽2,562), fluoropyrimidine (F) (2 trials, n⫽759), biologic (B) (2 trials, n⫽852), F⫹B (1 trial, n⫽123). Results of the meta-analysis are summarized in the Table (HR⬎1 favors CS). Sensitivity analyses performed demonstrate results are robust independent of the induction or maintenance Tx used. QOL (data from 2 trials) was either the same in both arms (single Tx induction trial with no maintenance Tx, n⫽354) or improved in the IS arm (combination tx induction trial with no maintenance Tx, n⫽1,630). Conclusions: IS of delivering systemic Tx for mCRC do not result in a statistically significant reduction in OS compared to a CS of delivery whether or not maintenance therapy is included. QOL is the same or better with an IS. All trials All trials (nⴝ4,296) Trials with no maintenance Tx (nⴝ2,562) Trials with maintenance Tx (nⴝ1,734)

OS HR (95% CI)

Test for overall effect - Z

Heterogeneity chi2 (df)

1.02 (0.95 – 1.10) 1.01 (0.89 – 1.14)

0.50 (p⫽0.62) 0.10 (p⫽0.92)

5.18 (6) (p⫽0.52) 4.38 (3) (p⫽0.22)

1.00 (0.88 – 1.14)

0.01 (p⫽0.99)

0.69 (2) (p⫽0.71)

I2(%) 0 31 0

3533

213s


Individual patient data (IPD) analysis of progression-free survival (PFS) versus overall survival (OS) as an endpoint for metastatic colorectal cancer (mCRC) in modern trials: Findings from the 16,700 patients (pts) ARCAD database. Presenting Author: Qian Shi, Mayo Clinic, Rochester, MN Background: PFS has previously been established as a surrogate for OS based on IPD from first-line mCRC trials conducted before 1999. As mCRC treatment (trt) has advanced in the last decade and OS has increased from 1 to 2 years, this surrogacy required re-examination. Methods: IPD from 16,762 pts, median age 62, 62% male, 53% ECOG PS 0 were available from 22 1st line mCRC studies conducted from 1997-2006; 12 tested targeted (anti-angiogenic and/or anti-EGFR) regimens. The relationship between PFS (first event of progression or death) and OS was evaluated at patient-, trt-arm-, and trial-levels using correlation (corr.) coefficients and 2 R (closer to 1 the better) from weighted least square (WLS) regression of arm-specific survival rates and trial-specific hazard ratios (HRs), estimated using Cox and Copula bivariate models. The concordance of significance (CoS) of the treatment effects (TEs) on both endpoints was calculated. Results: 44% pts received a targeted regimen. Median PFS was 8 and OS was18 months. The corr. between PFS and OS was modest at all three levels with low CoS in TE comparisons (see Table). Analyses limited to trials testing targeted trts, non-strategy trials, or superiority trials did not improve surrogacy. Conclusions: In modern mCRC trials, where survival post-first progression exceeds time to first progression, PFS TEs do not reliably predict TEs on OS. Nonetheless, until alternative endpoints of clinical benefit can be validated, PFS remains a relevant primary endpoint for 1st line mCRC trials, as our data demonstrate that the ability for any agent to produce an OS benefit from a single line of therapy is challenging. Class (n. of trials) Pt level Rank corr. Trt arm level [6m PFS vs. 12m OS rates] R2WLS Trial level [HRPFS vs. HROS] R2WLS R2Copula Concordance

3535

Overall (22)

Targeted (12)

Nonstrategy (18)

Superiority (16)

.51 (.50 - .52)

.55 (.54 - .56)

.53 (.52 - .54)

.51 (.50 - .52)

.69 (.58 - .79)

.70 (.48 - .91)

.73 (.62 - .83)

.71 (.59 - .83)

.54 (.33 - .75) .46 (.24 - .68) 67%

.52 (.24 - .80) .45 (.16 - .75) 64%

.54 (.32 - .76) .48 (.24 - .71) 68%

.51 (.24 - .77) .54 (.31 - .78) 63%

General Poster Session (Board #1A), Sun, 8:00 AM-11:45 AM

Prospective analysis of UGT1A1 genotyping for predicting toxicities in advanced colorectal cancer (aCRC) treated with irinotecan (IRI)-based regimens: Interim safety analysis of a Japanese observational study. Presenting Author: Wataru Ichikawa, National Defense Medical College, Tokorozawa, Japan Background: UGT1A1*6 and UGT1A1*28 are risk factors for severe IRI-related toxicities in Asians, but recommended IRI doses based on UGT1A1 genotypes and other risk factors are unclear. We conducted a prospective analysis to examine the correlation between UGT1A1 genotypes and the efficacy and safety of IRI-based regimens in Japanese aCRC patients (pts), (NCT 01039506). Methods: Pts who had histologically confirmed aCRC, PS of 0 –2, received IRI-based regimens (FOLFIRI, IRI⫹S-1, IRI monotherapy), were UGT1A1 genotyped, and provided written informed consent were included. UGT1A1 polymorphisms were analyzed and categorized into 3 groups: wild (*1/*1), hetero (*1/*6, *1/*28), and homo (*6/*6, *6/*28, *28/*28). Detailed toxicities in the first 3 months of treatment were prospectively recorded. For interim safety analysis, incidences of grade 3– 4 (severe) toxicities were compared among UGT1A1 genotypes and a logistic regression model was used to predict the risk of severe toxicities. Severe toxicities and associated risk factors were predicted using a nomogram and bootstrap validation was performed. Results: We enrolled 1376 pts between October 2009 and March 2012. At the time of abstract submission, toxicity data of 504 pts were available; 46% pts had wild, 44% hetero, and 11% homo polymorphisms. FOLFIRI was administered to 63% pts. Severe neutropenia developed during the first 3 months of treatment in 33% pts: 36% in hetero [OR, 1.5; 95% CI, 1.0 –2.3], 47% in homo (OR, 2.3; 95% CI, 1.2– 4.4), and 28% in wild. Severe diarrhea incidence was 5%, which did not correlate with UGT1A1 genotypes. Multiple logistic regression model included regimen, initial IRI dose, gender, age, UGT1A1 genotype, and PS as predictors of severe neutropenia in the first treatment cycle. The resulting nomogram demonstrated good accuracy in predicting severe neutropenia, with a bootstrapcorrected concordance index of 0.74. Conclusions: Considering UGT1A1 genotype along with other clinical factors is important for managing pts undergoing IRI-based regimens. Our presentation will provide analysis of data from more than 1000 pts. Clinical trial information: NCT01039506.


214s

Gastrointestinal (Colorectal) Cancer

3536

General Poster Session (Board #1B), Sun, 8:00 AM-11:45 AM

Prognostic factors of recurrence of colorectal cancers with microsatellite instability after curative resection: An AGEO retrospective multicenter study. Presenting Author: David Tougeron, Department of Gastroenterology, Poitiers University Hospital, Poitiers, France Background: Microsatellite instability (MSI) phenotype is found in approximately 12% of colorectal cancers (CRC). MSI CRC is associated with a low recurrence rate and 5-fluorouracil chemoresistance in adjuvant setting. Clinical and pathological prognostic factors of recurrence are wellidentified after surgery of CRC but not in the subgroup of MSI CRC. Methods: This multicenter retrospective study included patients with stage I, II and III MSI CRC. The following prognostic factors were studied: age, sex, perforation, occlusion, tumor location, tumor differentiation, T4 stage, lymph node invasion, VELIPI criteria (vascular emboli, lymphatic invasion and perinervous invasion), BRAF mutation and adjuvant chemotherapy. Disease-free survival (DFS) was calculated using the Kaplan-Meier method. Prognostic factors of DFS were analyzed in multivariate analysis using Cox model. Results: A total of 294 MSI CRC patients were analyzed, including 10%, 49% and 41% stage I, II and III, respectively. Mean age was 67.2 ⫾ 16.0 years. Occlusion was observed in 10% of cases. VELIPI criteria were found in 39%, including 26% with vascular emboli. BRAF mutation was detected in 27% of cases. All in all, 40% of patients received adjuvant chemotherapy, predominantly stage III (74%). Mean follow-up was 39.2 ⫾ 33.2 months. The disease recurrence rate was 3%, 8% and 21% in stage I, II and III patients, respectively. The 3-year DFS rate was 85%. In univariate analysis, age, occlusion, lymph node invasion, T4 stage, vascular emboli and perinervous invasion were associated with decreased DFS (p⬍0.05). In multivariate analysis, only occlusion (RR⫽3.0; 95% CI 1.2-7.7, p⫽0.02) and vascular emboli (RR⫽4.5; 95% CI 1.6-12.7, p⬍0.01) were associated with decreased DFS. Recurrence rates for MSI CRC with and without vascular emboli were respectively, 22% versus 5% for stage II and 33% versus 15% for stage III. Conclusions: Occlusion and vascular emboli were independently associated with recurrence of MSI CRC but not lymph node invasion. We advocate vascular emboli analysis in routine clinical practice to facilitate adjuvant chemotherapy decision-making in MSI CRC.

3538

General Poster Session (Board #1D), Sun, 8:00 AM-11:45 AM

Cetuximab and chemotherapy in the treatment of patients with initially “nonresectable” colorectal (CRC) liver metastases: Long-term follow-up of the CELIM trial. Presenting Author: Gunnar Folprecht, University Hospital Carl Gustav Carus, University Cancer Center / Medical Department I, Dresden, Germany Background: CRC liver metastases can be resected after downsizing with intensive chemotherapy schedules, with a strong correlation between the response and resection rates. Cetuximab plus chemotherapy has been shown to increase the rates of tumor response and resection of liver metastases. (Van Cutsem et al, JCO 2011). Methods: Patients (pts) with technically non-resectable and/or with ⬎ 4 liver metastases were randomized to treatment with FOLFOX/cetuximab (arm A) or FOLFIRI/cetuximab (arm B) and evaluated regarding resectability every 2 months. Resection was offered to all patients who became resectable during the study. K-ras and b-raf status were retrospectively evaluated. Data on tumor response and resection were reported earlier (Folprecht et al, Lancet Oncol 2010). Overall and progression free survival were analyzed in December 2012. Results: Between Dec 2004 and March 2008, 56 pts were randomized to arm A, 55 to arm B. For the current analysis, 109 pts were evaluable for overall survival (OS), and 106 patients for PFS. The median OS was 35.7 [95% CI: 27.2-44.2] months (arm A: 35.8 [28.1-43.6], arm B: 29.0 [16.0-41.9], HR 1.03 [0.66-1.61], p⫽0.9). The median PFS was 10.8 [9.3-12.2] months (Arm A: 11.2 [7.2-15.3], Arm B: 10.5 [8.9-12.2], HR 1.18 [0.79-1.74], p⫽0.4). Patients with R0 resection had a better OS (median: 53.9 [35.9-71.9] mo) than patients without R0 resection (27.3 [21.1-33.4] mo, p⫽0.002) and a better PFS (median 15.4 [11.4-19.5] and 8.9 [6.7-11.1] mo in R0 resected and not R0 resected pts, p⬍0.001). The 5 year survival in R0 resected patients is 46.2% [29.5-62.9%]. Conclusions: This study confirmed a favourable long term survival of patients with initially “nonresectable” CRC liver metastases treated in a multidisciplinary approach of neoadjuvant chemotherapy with cetuximab and subsequent metastasectomy in pts who became resectable. Clinical trial information: NCT00153998. Estimated OS and PFS. OS

SO

N

1y

2y

3y

4y

5y

OS

All pts K-RAS wt Arm A Arm B R0 resected No R0 resection All pts K-RAS wt R0 resected

109 69 54 55 36 70 106 67 36

90% 88% 89% 91% 89% 91% 43% 49% 69%

62% 68% 63% 62% 78% 54% 15% 18% 25%

48% 53% 49% 47% 64% 39% 6% 6% 11%

34% 40% 35% 34% 53% 24% 5% 5% 8%

28% 33% 28% 28% 46% 19% 5% 5% 8%

PFS

3537

General Poster Session (Board #1C), Sun, 8:00 AM-11:45 AM

Treatment outcome according to tumor ERCC1 expression status in OPUS study patients with metastatic colorectal cancer (mCRC) randomized to FOLFOX4 with/without cetuximab. Presenting Author: Carsten Bokemeyer, University Medical Center Hamburg-Eppendorf, Department of Oncology, Hematology and BMT with section of Pneumology, Hamburg, Germany Background: The OPUS study showed that the addition of cetuximab to infusional 5-fluorouracil/folinic acid ⫹ oxaliplatin (FOLFOX4) significantly improved progression-free survival (PFS) and response in the first-line treatment of patients (pts) with KRAS wild-type (wt) mCRC. High level expression in tumors of ERCC1, a protein involved in nucleotide excision repair, has been associated with resistance to platinum-based chemotherapy in a range of tumor types. This analysis assessed outcome according to ERCC1 expression level and treatment group in OPUS study pts. Methods: ERCC1 expression level was assessed by immunohistochemistry (IHC) in all available formalin-fixed paraffin-embedded tumor samples from OPUS study pts. An ERCC1 IHC score on a continuous scale of 0 –300 was calculated for each tumor, based on the intensity of nuclear staining and proportion of positive cells. The median IHC score was used to define low (⬍median) and high (ⱖmedian) ERCC1 expression levels and outcome was assessed in low vs high expression groups in both treatment arms. Results: Of 337 OPUS study intention to treat pts, 97 (29%) were evaluable for ERCC1 expression. Pts in the FOLFOX4 arm in the high ERCC1 expression group (n⫽27) had shorter PFS (median 5.8 vs 9.2 months; hazard ratio, HR 1.63, 95% CI 0.80 –3.34) and overall survival (median 11.5 vs 18.5 months; HR 1.75, 95% CI 0.90 –3.40) and a lower response rate (33.3% vs 39.1%) compared with those in the low ERCC1 expression group (n⫽23). To assess the effect of adding cetuximab to FOLFOX4 according to ERCC1 expression level, outcome was assessed in the KRAS wt subgroup of pts. Although low pt numbers precluded the drawing of definitive conclusions, PFS in the high ERCC1 expression group was longer in the FOLFOX4 ⫹ cetuximab arm (n⫽14) compared with the FOLFOX4 arm (n⫽13; median 7.7 vs 5.8 months), survival was longer (median 19.7 vs 12.0 months) and the response rate was higher (71.4% vs 30.8%). Conclusions: High tumor ERCC1 expression was associated with poor outcome in pts with mCRC receiving first-line platinum-based chemotherapy. The addition of cetuximab to FOLFOX4 may mitigate this effect in those with KRAS wt tumors. Clinical trial information: NCT00125034.

3539

General Poster Session (Board #1E), Sun, 8:00 AM-11:45 AM

A phase II study of combination epigenetic therapy in metastatic colorectal cancer (mCRC): A phase II consortium (P2C)/Stand Up 2 Cancer (SU2C) study. Presenting Author: Nilofer Saba Azad, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD Background: Therapy with decitabine and entinostat (ENT: HDAC inhibitor) shows synergistic effect in re-expression of tumor-suppressor genes and growth inhibition in CRC cell lines and in vivo studies. Methods: We conducted a phase II, multi-institutional study of SQ 5-azacitidine (AZA) and oral ENT in mCRC pts. A 28 day cycle included: AZA at 40 mg/m2 d1-5 and 8-10 with ENT 7 mg d3 and 10. Initial eligibility criteria included: ECOG PS 0-1, good end organ function, and biopsiable disease for cohort A (CoA). An interim analysis indicated that toxicity which crossed prespecified safety boundary was secondary to disease. A 2nd cohort B (CoB) with eligibility restrictions: ⬍2 prior regimens in KRAS-mutated CRC pts, ⬍3 prior regimens if KRAS wild-type, and liver disease limited to ⬍30% of volume was accrued. Serial tumor biopsies and research blood were collected to assess for methylation/expression changes in circulating tumor DNA and biopsies, respectively. The primary endpoint was response as measured by RECIST criteria using a 2-stage Simon design. Results: 47 pts were initially enrolled (24 CoA, 23 CoB). Pts received a median of 2 cycles on both cohorts (1-16 CoA, 2-6 CoB). Pts had a median of 4 prior therapies for CoA (range 2-9) and 3 for CoB (range 2-6). Gr 4 AEs attributable to treatment for CoA included hyperglycemia (1) and hypokalemia (1); other common Gr 3 AEs included anemia (3), decreased lymphocytes (7), fatigue (3), and nausea (3). CoB pts experienced grade 3 chest pain (1), neutropenia (2), leucopenia (2), urinary tract obstruction (1), and hypophosphatemia (1). No responses have been observed. Results of translational objectives will be presented at the meeting. Conclusions: SQ AZA and ENT therapy does not have clinical activity as defined by confirmed response in aCRC. Follow-up for survival, response to subsequent therapy, and correlative analysis are ongoing. Supported in part by N01-CM-2011-00099. Clinical trial information: NCT01105377. Patient outcome (Nⴝ46). Cohort

Follow-up

PD

Deaths

Median PFS*

Median* OS

A (nⴝ24)

26 mos (22-23.3) 11 mos (0.2-12)

21

22

1.8 (1.7-4)

5.6 (3.7-12.6)

19

13

1.9 (1.8-2.2)

8.3 (6.1-NA)

B (nⴝ22)

* Kaplan-Meier estimates, time in months, with 95% confidence interval.



General Poster Session (Board #1F), Sun, 8:00 AM-11:45 AM

3541

215s

General Poster Session (Board #1G), Sun, 8:00 AM-11:45 AM

Using quantitative sensory testing as an early predictor of chronic oxaliplatin neuropathy in gastrointestinal cancer patients. Presenting Author: Sangeetha Meda Reddy, Northwestern University, Feinberg School of Medicine, Chicago, IL

Beyond VEGF inhibition: Comparative efficacy analysis of novel VEGF and non-VEGF therapeutic agents in phase I trials for patients with metastatic colorectal cancer (mCRC). Presenting Author: Sukeshi R. Patel, University of Texas Health Science Center at San Antonio, San Antonio, TX

Background: Acute oxaliplatin neurotoxicity has been shown to be predictive of chronic neuropathy, a devastating irreversible adverse effect of oxaliplatin. Our study was designed to test the utility of quantitative sensory testing (QST) to measure acute oxaliplatin neurotoxicity at early time points to identify those at risk for developing chronic neuropathy. Methods: Gastrointestinal cancer patients receiving 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy were evaluated over a 1 year period for development of acute and chronic oxaliplatin neurotoxicity: before starting FOLFOX, 1 hour into oxaliplatin infusion, before cycles 2, 4 and 12, and 1 year after start of treatment. Patients underwent QST to measure thermal and mechanical sensitivities, vibration detection, pain sensation, and fine motor skills. Chronic neuropathy was measured using National Cancer Institute Common Toxicity Criteria for Adverse Events version 4. Results: We conducted analysis of 18 patients that have reached the 1 year followup period. We found thermal QST measured during cycle 1 infusion, which is indicative of acute neurotoxicity, to be predictive of 1 year neuropathy. Decreased cold detection intrainfusion during cycle 1 relative to baseline scores yielded a significant correlation to chronic neuropathy scores (rs⫽ -0.53, p⫽0.03) and predicted grade 2 or 3 neuropathy (p⫽0.048). Furthermore, decreased cold detection scores intrainfusion showed trend towards correlation to neuropathy scores (rs⫽ -0.45, p⫽0.07) and prediction of grade 2 or 3 neuropathy (p⫽0.07). Additionally, patients with higher tolerance to cold and heat intrainfusion were at higher risk for grade 1 or higher neuropathy (p⫽0.057 for cold pain, p⫽0.03 for heat pain). We also found decreased mechanical detection scores using von frey filaments as early as cycle 2 were correlated to 1 year neuropathy scores (rs⫽0.52, p⫽0.03) and predicted development of grade 2 or 3 neuropathy (p⫽0.008). Conclusions: We can use QST to identify high risk patients that are likely to develop chronic neuropathy at 1 year, allowing for targeted use of preventive measures to decrease the incidence of this debilitating adverse effect.

Background: Recently, regorafenib (RGF), an oral multikinase inhibitor, was approved for patients (pts) with mCRC who have failed standard therapies. Compared to placebo, the phase III CORRECT study showed RGF improved median overall survival (mOS) from 5.0 to 6.4 months (mo) and median progression-free survival (mPFS) from 1.7 to 1.9 mo, regardless of K-Ras status. This suggests further VEGF inhibition is crucial in controlling mCRC progression. Many mCRC pts enroll on phase I studies with efficacy reported by some; however, a collective efficacy assessment aimed solely for mCRC in relation to class of agents has not been done. Methods: A historical cohort analysis included pts with mCRC enrolled amongst 28 phase I trials at the IDD, from 7/2008 – 9/2012. PFS and OS were estimated from Kaplan-Meier curves and groups were statistically compared with the log rank test. The magnitude of association between dichotomous factors and survival was estimated with the hazard ratio (HR). Results: A total of 75 pts were included. Median age 59 (33– 80), males 61 %, K-ras mutated 39 %. ECOG PS 0 –1 96 %. ⱖ3 prior lines of therapy 68 %. Class of drugs included: VEGF Inhibitors 32 %, Cytotoxic 25 %, Microenvironment Inhibitors 13 %, Apoptosis/Autophagy Inhibitors 11 %, EGFR/Growth Factor TKIs 8 %, others 11 %. For the whole cohort of 75 pts, mPFS was 2.8 mo (95% CI: 2.0 –3.7). As of 12/1/12, among 65 pts, mOS was 5.6 mo (95% CI: 4.4-7.0). In subgroup analysis, mPFS was 3.4 (95% CI: 1.4 – 4.5) vs 2.8 months (95% CI: 2.0 –3.5) for pts on VEGF and non-VEGF Inhibitors (HR 0.79, 95% CI: 0.43–1.44, p ⫽ 0.44), respectively. VEGF Inhibitor treated pts had a mOS of 5.5 months (95% CI: 1.6 –10.0 months) vs 5.6 months (95% CI: 4.4 –7.6) with non-VEGF Inhibitors (HR 1.02, 95% CI: 0.58 –1.78, p ⫽ 0.96). Efficacy was similar regardless of K-Ras status. Conclusions: In pretreated mCRC, median PFS and OS for pts enrolled in phase I trials, irrespective of agent, was comparable to efficacy of RGF. Therefore, after failure of standard therapies, mCRC pts should be encouraged to enroll in clinical trials with efficacy reported in both VEGF and non-VEGF inhibitors.

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General Poster Session (Board #1H), Sun, 8:00 AM-11:45 AM

5FU/LV with or without irinotecan in patients with resected stage II-III rectal cancer: Final analysis of R98 intergroup study. Presenting Author: Catherine Delbaldo, Service Oncologie, Hôpital des Diaconesses, Paris, France Background: The goal of the study was to test whether adding Irinotecan to a 5-FU/LV adjuvant regimen improves disease free survival (DFS) or overall survival (OS) in optimally resected stages II-III rectal cancers. Primary end-point was DFS. Methods: Six hundred patients were planned to be randomized between 5-FU/LV (control arm) or 5-FU/LV ⫹ irinotecan (experimental arm). As only 357 patients had been included from 03/1999 to 12/2005 (178 in control and 179 in experimental arm), the IDMC recommended to close accrual. The trial was stratified by control arm: Mayo-Clinic regimen (A: LV 20 mg/m², 5-FU 425 mg/m² bolus days (d) 1- 5 reapeted at d29,57,92,127 and 162) or LV5-FU2 regimen (A’: LV 200 mg/m², 5-FU 400 mg/m² bolus and 5-FU 600 mg/m² 22-hours infusion d1-2, q 2 w for 12 cycles). The experimental arm (B) was LV5-FU2 ⫹ irinotecan 180 mg/m² d1. Results: All 357 randomized patients were evaluable for efficacy. Patient characteristics were well balanced (median age 62 years, stage II 31 %, stage III 69 %, N0 31 %, 68 % received preoperative radiotherapy, and 80 % had sphincter conservation). With follow-up of 156 months, DFS and OS are not statistically increase (81vs 92 events for DFS in experimental and control arm, hazard ratio (HR)⫽0.805, p⫽0.154;63 vs 72 events for OS, HR⫽0.874, p⫽0.433). Patients allocated to the experimental arm had more grade 3-4 neutropenia when compared with the LV5FU2 control (33 % vs 16 %, p⫽0.03), but not when compared with the Mayo Clinic arm (32% vs 36%, p⫽0.84). Grade 3-4 diarrhea tend to be higher in the experimental arm, but analyses stratified by control arm or by radiotherapy failed to show significant differences across strata (test for interaction p⫽0.44). Conclusions: In patients with resected stage II-III rectal cancer, adding irinotecan to 5FU/LV led to a non significant increase of DFS and OS. The analysis was planned to have a 60 % power to detect a significant difference with 220 events. With a long term follow up of 8 years only 173 events were observed in our trial. Lack of power and good patient prognosis (thirty one percent of node negative patients) may have impacted the results.


Phase II trial of target-guided personalized chemotherapy in first-line metastatic colorectal. Presenting Author: Antonio Cubillo, Centro Integral Oncológico Clara Campal, Madrid, Spain Background: Chemotherapy (Ch) options for patients (pts) with colorectal cancer (CRC) have increased in the last years. However, there are no validated prospective molecular markers in CRC to select which agents are better to treat any individual case. The aim of this study was to determine the efficacy in terms of progression free survival (PFS) of a biomarker panel to guide treatment selection in this setting. Methods: Treatment naive, ECOG 0-1, metastatic CRC pts were accrued. Pts were prospectively analyzed with a predefined set of 10 molecular targets, including: KRAS, BRAF, and PI3K mutations and Topoisomerase-1(Top-1), ERCC-1, Thymidylate synthase (TS) and Thymidine phosphorylase (TP) expression by inmunohistochemistry ( IHC) performed in a tumor biopsy. Ch combination schema plus Cetuximab (C) or Bevacizumab (B) at standard doses was customized based on: Topo-1 ⫹:Irinotecan (I). Topo-1- and ERCC-1 -:Oxaliplatin(O). Topo-1- and ERCC1 ⫹:investigator option (I or O). TS -:Fluoropyrimidines (FP).TS ⫹:No FP. TP -:5-FU, TP ⫹:Capecitabine. Maintenance C or B treatment was allowed. Primary outcome measure was PFS. Results: 74 pts were accrued and all of them received biomarker guide treatment. All of them began personalized. Interim analysis on 61 pts (38 males, median age 65) showed.Topo-1 ⫹ in 33 pts (54%),ERCC-1- in 36( 59%) TS ⫹ in 44 (73%), TP – in 61 ( 100%), K-ras nativein 34 ( 55%), BRaf mutated in 2 (3,2%). With a median follow up time of 9,1 months (m). Median PFS (95% CI) is 8,6 (6,2-10,9) m, with a 41,3% (27,4-55,2) 12mPFS . Overall clinical benefit (Response ⫹ Stabilizations) was 74,5% (65,6-83,4).Toxicities Grade ⱖ 3 included 18% neutropenia, 4,9% asthenia and 3,3% anemia. 12 pts (23%) received loco-regional treatment ( surgery or radiosurgery). Median Overall survival has not been reached. Conclusions: Target- Guided Personalized Ch in first line CRC pts is feasible and results in promising PFS with low toxicity. Update of final results and more detailed data will be presented. Clinical trial information: NCT01453257.


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Gastrointestinal (Colorectal) Cancer General Poster Session (Board #2B), Sun, 8:00 AM-11:45 AM

3545


Use of RAS pathway activation or KRAS mutation status to predict cetuximab response in CRC patient-derived xenografts. Presenting Author: Henry Li, Crown Bioscience, Santa Clara, CA

ALK and ROS1 gene rearrangements detected in colorectal cancer (CRC) by fluorescence in situ hybridization (FISH). Presenting Author: Andrew James Weickhardt, University of Colorado Cancer Center, Aurora, CO

Background: Cetuximab was approved for treating EGFR-expressing metastatic colorectal carcinoma (mCRC) without patient stratification. Subsequent retrospective clinical studies resulted in an exclusion criterion for patients with KRAS mutations at codons 12 and 13. However, only a fraction of patients with wtKRAS benefit from the treatment. Recent analyses indicated that patients with KRAS mutation at codon 13 can also benefit. We set out to investigate whether KRAS mutations, or any other factors, are good biomarkers for CRC-cetuximab therapy patient stratification. Methods: We have established patient derived xenografts (PDX) from treatment-naive Asian CRC patients to discover biomarker predictive of cetuximab response. We conducted a clinical trial style study (“patient avatar trial”) of cetuximab using a randomly selected cohort of 26 EGFR⫹ PDXs. The antitumor activities were analyzed against KRAS mutation status and a published expression-signature. Results: We identified 12/26 (~46%) as cetuximab responders and 14/26 non-responders (defined by 50% tumor growth inhibition threshold). All 14 non-responders are mutated for one or more of KRAS, BRAF (V600E), EGFR, AKT and PIK3CA oncogenes. In contrast, 5/11 responders analyzed are wild-type for all these genes. Importantly, 5/11 responders have activating KRAS mutations at codons 12/13, contradictory to the currently practiced clinical exclusion criteria, but consistent with more recent clinical findings. Most interestingly, the observed cetuximab activity in this cohort of 26 PDXs has a surprisingly strong correlation to a published RAS pathway score. Conclusions: Our results indicated strong predictive power of cetuximab-CRCPDX trial and RAS signature, and warrant prospective clinical studies for further confirmation.

Background: Activation of ROS1 and ALK tyrosine kinases through gene fusions lead to unchecked cell proliferation and transformation. ROS1 and ALK gene fusions were found in about 5% and 2% of lung adenocarcinomas and are highly sensitive to specific tyrosine kinase inhibitors. This study aimed at identifying the presence of ROS1 and ALKrearrangements in CRC using FISH technology. Methods: Arrayed specimens of metastatic CRC (mCRC) patients were tested with a 4-target, 4-color break-apart FISH probe set (Abbott Molecular) designed to simultaneously evaluate the genomic status of ROS1 and ALK. Fused 3’/5’ signals of each gene were considered negative for rearrangement; single 3’/single 5’ (for ROS1) and split 3’-5’ or single 3’ (for ALK) were considered positive for rearrangement. Results: Among 236 mCRC patients tested, two were positive for ROS1 (single 3’ROS1 signals in 39% and 61% of tumor cells) and one was positive for ALK rearrangement (single 3’ALK in 41% of tumor cells). The upper cut-off for positive FISH patterns in the negative specimens was identified as ⬍15% both for ROS1 and ALK. Interestingly, the ALK⫹ patient displayed intra-tumoral heterogeneity, detected in the tissue cores and confirmed in two resection blocks. The fusion partner for ALK was identified as EML4 by PCR-based tests and sequencing. The fusion partner(s) for ROS1 remains to be identified by other technologies. A small fraction of specimens presented duplicated or clustered copies of native ALK and ROS1. Conclusions: The novel FISH probe set was effective to identify the first cases of ROS1 rearrangements in CRC and re-confirm the occurrence of ALK rearrangements. This supports further evaluation of mCRC cases for ROS1 and ALK gene fusions as these may represent new targets for evaluation in clinical trials. Tumor heterogeneity in the ALK rearrangement must be addressed for screening tests. (Partially supported by research grant from Abbott Molecular and the Colorado CCSG P30CA046934).

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Stereotactic body radiotherapy response and local control rates for hepatic oligometastases. Presenting Author: Ben Goodman, Indiana University, Indianapolis, IN Background: Stereotactic body radiation therapy (SBRT) is a non-invasive, effective technique in the treatment of hepatic oligometastases from solid tumors. We present response and local control rates from our single institution experience. Methods: We treated 79 metastatic liver lesions from 64 different patients using stereotactic body radiation therapy. One colorectal cancer patient was treated three times and four patients were treated twice. Among the 79 metastatic liver lesions treated, 85% had prior chemotherapy. The primary cancer site included: Colorectal 66%, Noncolorectal GI 14%, Breast 6%, Ovarian 5%, NSCLC 3%, and other 6%. The mean GTV size was 37.3 (cc). The mean GTV diameter was 3.1 (cm). The median total dose was 54 (Gy) with the minimum and maximum total dose being 30 and 60 (Gy). Results: The overall local control rate was 94.2%, with estimates at 12, 24, 36, and 48 months being 96.1%, 87.9%, 87.9% and 87.9% following SBRT treatment. When comparing colorectal cancer patients vs all other primary cancer sites, the one year local control rate was 93.4% and 100%. The two and three year local control rates for colorectal cancer vs other primary cancer sites were 84.9% vs 90.9%. Best response was examined as a 4 level response (CR,PR,SD,PD) per the RECIST criteria. Overall, 67% of patients had a response, and less than 3% of patients had progression with SBRT treatment. For colorectal cancer patients, 79% had a response to treatment. Only 21% of colorectal cancer patients did not respond, however, the majority of these patients still had stable disease following treatment. Non-colorectal primary site cancers had a response in 50% of the lesions following SBRT treatment. The remaining 50% of non-colorectal primary cancers were stable following SBRT treatment and none progressed. The median dose for CR, PR, or SD was 54 Gy. The median dose for patients with progressive disease was less than 50 Gy. The observed CTC toxicities were limited with mostly grade 1-2 toxicity and only two grade 4 and one grade 5 toxicity. Conclusions: Stereotactic body radiation therapy is an effective treatment option for patients with hepatic oligometastases with a limited toxicity profile.


Effect of oxaliplatin-containing neoadjuvant chemotherapy on tumor volume in locally advanced rectal cancer and sensitivity of surviving tumor cells to radiotherapy. Presenting Author: Kjersti Flatmark, Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway Background: The use of oxaliplatin (OXA) is well established in adjuvant and palliative treatment of colorectal cancer (CRC), but its role in neoadjuvant treatment of locally advanced rectal cancer (LARC) is controversial. Data from the ACCORD 12/0405, STAR-01 and NSABBP R-04 trials suggest no additional clinical benefit of adding OXA to fluoropyrimidine-based preoperative chemoradiotherapy (CRT) in LARC. However, the possibility of reducing risk of systemic recurrence and the use of OXA-containing neoadjuvant chemotherapy (NACT) in liver metastasis warrant further clarification of the role of OXA in neoadjuvant treatment of LARC. Methods: We report results from a non-randomized phase II trial of neoadjuvant treatment of 72 LARC patients, receiving two courses of the Nordic FLOX regimen prior to CRT (25 x 2 Gy; weekly OXA; daily capecitabine). Tumor volumes were calculated from MRI scans taken before and after NACT and 4 weeks after CRT completion. Using OXA resistant human CRC cell lines, the impact of previous OXA exposure on radiosensitivity (1-5 Gy) was examined. Results: Median baseline tumor volume was 16.6 cm3 (1.1-293 cm3). All tumors, except one, responded to NACT, leaving a median tumor volume of 5.3 cm3 (0.2-157 cm3), representing a median volume reduction of 63%. In all but three patients, additional tumor volume reduction was observed following subsequent CRT (median tumor volume 5.3 cm3; 0.02-119 cm3; median volume reduction of 68%). Exposure of cell lines to increasing concentrations of OXA resulted in resistance towards the drug. OXA resistant models exhibited increased radiosensitivity compared to OXA sensitive counterparts. Conclusions: OXA-containing NACT led to substantial tumor volume reduction. Additional tumor volume reduction was observed in almost all cases, suggesting that pretreatment with OXAcontaining NACT did not preclude tumor response to CRT. Results from experimental models rather suggest that pretreatment with OXA might enhance radiosensitivity of surviving OXA resistant cells. Taken together, our results are in favor of continued exploration of OXA-containing NACT in LARC. Clinical trial information: NCT00278694.




Cochrane systematic review and meta-analysis of adjuvant chemotherapy for stage II colon cancer. Presenting Author: Brandon Matthew Meyers, Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada Background: Colon cancer is potentially curable by surgery in the early stages of the disease. Adjuvant chemotherapy improves disease-free and overall survival in patients with stage III disease, but the magnitude of benefit in stage II colon cancer is less clear. A previous Cochrane systematic review and meta-analysis (SR/MA) found improved disease-free, but not overall survival (Figueredo et al., 2008). An updated SR/MA was performed to determine the effects of adjuvant chemotherapy on diseasefree and overall survival in patients with stage II colon cancer. Methods: Relevant databases (MEDLINE, EMBASE, and Cochrane) were independently searched by all authors, using the same search strategy employed in the original study (1/1988 to 9/2012). Randomized trials containing data on stage II colon cancer patients undergoing adjuvant 5-fluorouracil (5FU) chemotherapy versus observation were included. Pooled results were expressed as hazard ratios (HR) whenever possible, or risk ratios (RR), with 95% confidence intervals (95%CI) using a random effects model. Results: Seven studies were identified, and included in the final SR/MA. Six of the 7 studies were included in the disease-free survival analysis (n⫽4587). Adjuvant 5FU was associated with better disease-free survival (RR 0.84 (95%CI 0.75-0.94)). All 7 studies (n⫽5353) were included in the overall survival analysis showing an improvement with adjuvant 5FU (HR 0.87 (95%CI 0.78-0.97)). There was no evidence of heterogeneity across the studies (I2 ⫽ 0% for all analyses). Conclusions: In stage II colon cancer, adjuvant 5FU chemotherapy statistically improves both disease-free and overall survival. Our SR/MA demonstrates, for the first time, an overall survival advantage with adjuvant chemotherapy in stage II colon cancer.

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The frequencies and clinical implications of mutations in 33 kinase-related genes in locally advanced rectal cancer. Presenting Author: Khairun Izlinda Abdul Jalil, Department of Medical Oncology, Beaumont Hospital, Dublin 9, Dublin, Ireland Background: Locally advanced rectal cancer, LARC (T3/4 and/or N⫹) is currently treated with pre-operative chemoradiotherapy (pCRT), but responses are not uniform. The phosphatidylinositol 3-kinase (PI3K), MAPkinase (MAPK) and related pathways have been implicated in rectal cancer tumorigenesis. Here, we investigated the association between genetic variations in these pathways and clinical outcomes in LARC. Methods: We genotyped a total of 239 Single Nucleotide Polymorphisms (SNPs) including potentially clinically relevant mutations in 33 cancer related genes including PIK3CA, PIK3R1, AKT, STK11, KRAS, BRAF, MEK, CTNNB1, EGFR, MET and NRAS using the Sequenom platform. DNA samples utilized herein were extracted from pre-treatment rectal cancer biopsies of 201 patients who were then treated with long-course pCRT followed by surgical resection. Results: 62 different mutations were detected in 15 genes, with the highest frequencies occurring in KRAS (n⫽93, 47%), PIK3CA (n⫽29, 14%), MET (n⫽27, 13%), STK11 (n⫽13, 6.3%), CTNNB1 (n⫽12, 6%), BRAF (n⫽8, 4%) and NRAS (n⫽7, 3.5%). Mutations were also detected in AKT, PIK3R1, EGFR, GNAS, MEK1, PDGFRA, ALK and TNK2, but at frequencies of less than 2%. Pathologic complete response (pCR) was associated with excellent (97%) 5-year Recurrence-Free Survival (RFS) (Hazard ratio [HR], 0.076; 95% CI, 0.01-0.50, P⫽0.001). We found: 1) Mutations in PI3K pathway-related genes (PIK3CA, AKT, STK11) were significantly associated with absence of pCR (odd ratio [OR], 5.40; 95% CI, 1.24-23.54, P⫽0.024). However, mutations in MAPK pathway-related genes (KRAS, BRAF, NRAS, MEK) was not found to be significantly associated with pCR (P⫽0.805). 2) In contrast, in patients who did not achieve pCR (non-pCR), mutations in PI3K pathway-related genes were not associated with RFS. However, KRAS G12V and KRAS G12S mutations were significantly associated with an increased risk of recurrence (HR, 2.115; 95% CI, 1.077-4.156, P⫽0.030). Conclusions: These results suggest that mutations in kinase signaling pathways may modulate treatment responsiveness and clinical outcomes in locally advanced rectal cancer and thus may constitute rational targets for novel therapies.

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Molecular characteristics and prognostic implication of mucinous histology in colorectal cancer patients treated with adjuvant FOLFOX. Presenting Author: Dae-Won Lee, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea

Proof-of-concept study of Sym004, an anti-EGFR monoclonal antibody (mAb) mixture, in patients (pts) with anti-EGFR mab-refractory KRAS wild-type (wt) metastatic colorectal cancer (mCRC). Presenting Author: Rodrigo Dienstmann, Vall d’Hebron University Hospital, Barcelona, Spain

Background: There have been controversies in prognostic impact of mucinous histology in colorectal cancer (CRC) and its implication in pts treated with adjuvant FOLFOX is unclear. This study aimed at elucidating the molecular characteristics and prognostic implication of mucinous histology in pts treated with adjuvant FOLFOX. Methods: Stage II and III CRC pts who received adjuvant FOLFOX were analyzed. Pts were grouped according to the mucinous content: ⬎ 50%, mucinous adenocarcinoma (MAC); ⬍ 50%, adenocarcinoma with intermediated mucinous component (AIM); and without any mucinous component, nonmucinous adenocarcinoma (NMA). Clinicopathologic features, MSI status (N ⫽ 518), CpG island methylator phenotype (CIMP) (N ⫽ 322) BRAF mutation (N ⫽ 269) and disease-free survival (DFS) were compared. Results: Among a total of 521 pts, 27 (5.2%) had MAC, 41 (7.9%) AIM, and 453 (86.9%) NMA. MAC and AIM had higher frequency of proximal location and lower angiolymphatic invasion. MAC had higher proportion of T4 tumors. AIM had higher frequency of age ⱖ65 years and female. In terms of molecular characteristics, MAC and AIM showed similarly higher proportion of MSI-high and CIMP-high compared to NMA. BRAF mutation also showed similar trend. In contrast to the similarities between MAC and AIM, DFS was significantly different. MAC showed significantly worse DFS compared with AIM and NMA, whereas AIM and NMA showed similar DFS. Multivariate analysis revealed MAC as an independent negative prognostic factor of DFS (adjusted HR 7.96, 95% CI 3.76-16.8). Conclusions: AIM and MAC has distinct clinico-pathologic features and molecular characteristics compared with NMA. Only MAC but not AIM has an adverse prognostic impact on stage II or III CRC treated with adjuvant FOLFOX compared with NMA.

Background: KRAS wt mCRC pts progressing on chemotherapy and antiEGFR mAbs have limited treatment options. Sym004 is a first-in-class drug mixture of two mAbs targeting non-overlapping epitopes on the EGFR, causing its internalization and degradation. With this unique mechanism of action, Sym004 overcomes acquired resistance to anti-EGFR mAbs in preclinical studies. Methods: Open-label, multicenter trial assessing safety (primary endpoint) and efficacy of 2 dose levels of Sym004 in KRAS wt mCRC pts with prior clinical benefit to anti-EGFR mAbs and subsequent progression during or within 6 months after treatment cessation. Sym004 was administered until disease progression or unacceptable toxicity. Tumor responses were evaluated centrally according to RECIST criteria. Paired skin and tumor biopsies were obtained at baseline and week 4. Results: In total, 42 pts were enrolled at 9 mg/kg (13) and 12 mg/kg (29). Median age was 66 years and median number of prior treatment lines 3. Central radiology review was performed in 12/13 (92%) pts at 9 mg/kg and 27/29 (93%) pts at 12 mg/kg. Tumor shrinkage ⬎ 10% was documented in 4/12 (33%) pts at 9 mg/kg, with partial response (PR) in 1/12 (8%) and stable disease (SD) in 9/12 (75%). At 12 mg/kg, 7/27 (26%) pts had ⬎ 10% tumor shrinkage, with PR in 3/27 (11%) and SD in 15/27 (56%). Median progression-free survival was 13.6 weeks (95% CI: 5.3-23) and 13.7 weeks (95% CI: 5.9-18.6), respectively. Duration of response for pts with PR was 5.6-17.6 weeks. Grade 3 or higher toxicity included skin rash in 26/42 (62%), hypomagnesemia in 16/42 (38%) and diarrhea in 2/42 (8%). Adverse events were manageable with dose reduction and supportive medication. There were no indications of immunogenicity. Pharmacodynamic analysis in serial tumor samples showed profound down-regulation of EGFR and reduction in proliferation marker Ki67. Conclusions: Sym004 at weekly doses of 9 and 12 mg/kg showed significant clinical activity in anti-EGFR treatment-refractory KRAS wt mCRC pts, clearly demonstrating proof-of-concept. Serial biopsies confirmed its mechanism of action. No unexpected adverse events were observed. Clinical trial information: NCT01117428.

P values Age 665

MAC (%)

AIM (%)

NMA (%)

MAC vs NMA

AIM vs NMA

AIM vs MAC

Age >65 Female Proximal T4 Angiolymphatic invasion

29.6 40.7 59.3 40.7 22.2

46.3 68.3 61.0 14.6 29.3

28.3 37.5 30.9 13.0 45.3

0.002 ⬍0.001 0.019

0.015 ⬍0.001 ⬍0.001 0.048

0.025 0.015 -

MSI-high CIMP-high BRAF mutation 3-year DFS

14.8 35.3 5.3 57

14.6 25.0 6.7 87

5.6 4.6 2.1 86

0.073 ⬍0.001 ⬍0.001

0.022 ⬍0.001 -

0.01

-, ⬎0.10


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Association of DNA promoter hypermethylation of decoy receptor 1 (DCR1) with poor response to irinotecan in metastatic colorectal cancer. Presenting Author: Wim Van Criekinge, MDxHealth, Irvine, CA Background: Heterogeneity in the biology of colorectal cancer (CRC) is associated with variable responses to standard chemotherapy. We aimed to identify DNA hypermethylated genes as predictive biomarkers for irinotecan treatment of patients with metastatic CRC. Methods: The presence of DNA methylation for a selected panel of 22 genes was assessed by methylation specific PCR (MSP) on primary tumors of 185 patients with metastatic CRC treated with first-line capecitabine (CAP, n⫽90) or a combination of capecitabine and irinotecan (CAPIRI, n⫽95) in the phase 3 CAIRO trial. Methylation status of each gene was correlated to progression free survival (PFS) by treatment regimen. Genes for which methylation status associated with response to irinotecan, were validated in 166 patients treated with first-line CAP (n⫽78) or CAPIRI (n⫽88). Results: Decoy Receptor 1 (DCR1) was identified as a novel hypermethylated gene in CRC. In CAPIRI treated patients, DCR1 methylation was correlated to a shorter PFS compared to patients with unmethylated DCR1 (hazard ratio [HR]⫽0.4 (95%CI ⫽0.3-0.7), p ⫽ 0.0009). In patients with methylated DCR1 PFS did not improve with CAPIRI treatment, compared to treatment with CAP (discovery set: HR⫽0.8 (95%CI⫽0.5-1.3, p⫽0.4); validation set: HR⫽1.1 (95%CI 0.7-1.7, p⫽0.6)), in contrast to patients with unmethylated DCR1 (discovery set: HR⫽2.5 (95%CI 1.7-3.3, p⫽0.00004); validation set: HR⫽1.7 (95%CI 1.1-2.0, p⫽0.004)). Conclusions: CRC patients with methylated DCR1 did not benefit from adding irinotecan to capecitabine therapy, indicating that DCR1 methylation status may guide selecting metastatic CRC patients for irinotecan-based therapy.

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Regular statin users and colorectal cancer (CRC) prognosis. Presenting Author: Wei-li Ma, National Taiwan University Hospital, Taipei, Taiwan Background: Statins are frequently used for the control of hyperlipidemia. Statins have multiple anti-cancer properties and may be associated with lower CRC risks among their users. This study tries to go a step further and explores whether statin use affects the prognosis of curatively resected CRC. Methods: We established a population cohort with patients (age ⱖ 40 y) who were diagnosed as having stage I or II CRC from 2004 to 2008 and received curative surgery from the database of Taiwan Cancer Registry. Data of medication prescription and co-morbidities were retrieved from the database of National Health Insurance, Taiwan. Regular statin use was defined as taking statins for ⬎ 180 days within the observation period from one year before the cancer diagnosis to one year afterward. The database of National Death Registry was used for survival outcomes. Another similar cohort consisting of patients with hepatocellular carcinoma (HCC) was used for comparison. Results: In total, 10762 patients with CRC were enrolled; 891 (8%) patients were regular stain users, 812 (8%) patients took statins but were not regular users, and 9059 (84%) patients never used statins. Regular statin users, compared to never users, were more likely to be female (p ⬍ 0.001), older (p ⬍ 0.001), have stage I disease (p ⬍ 0.001) and co-morbidities such as diabetes, coronary artery disease, and renal disease. Adjuvant therapy was less frequently administered in regular statin users. In univariate analysis, cancer-specific survival (CSS) of regular stating users was significantly longer than that of never users (5-y CSS, 87% vs. 84%, p ⫽ 0.022), but overall survival (OS) was not significantly different (5-y OS, 80% vs. 77%, p ⫽ 0.156). In multivariate analysis adjusting for age, gender, stage, adjuvant therapy, co-morbidities, and the use of aspirin, regular stating use was an independent predictor both for better CSS (hazard ratio [HR] 0.72, p ⬍ 0.001) and for better OS (HR 0.71, p⬍ 0.001). In contrast, no associations were found between statin use and CSS or OS in the HCC comparison cohort. Conclusions: Regular statin use was associated with better prognosis in CRC patients who received curative therapy. (This study was supported by grants DOH-101TD-B-111-001 and DOH-102-TD-B-111-001).

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Genetic variations in miRNA binding site of TPST1 and ZG16B associated with prognosis for patients with colorectal cancer. Presenting Author: Byung Woog Kang, Department of Oncology/Hematology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, South Korea Background: MicroRNAs (miRNA) may play important roles in tumorigenesis by regulating the expressions of proto-oncogenes or tumor suppressor genes. Single nucleotide polymorphisms (SNP) located in the 3’-UTR of miRNA target genes might affect miRNA-mediated gene regulation, thereby contributing to the susceptibility or prognosis of cancer. Accordingly, the present study analyzed SNPs located in the putative miRNA-binding sites of the 3’-UTR of various genes and their impact on the prognosis for patients with colorectal cancer by altering miRNA binding efficiency. Methods: Eight hundred and thirty-one consecutive patients (discovery cohort, n⫽309; validation cohort, n⫽522) with curatively resected colorectal adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from fresh colorectal tissue. One hundred fifty-seven SNPs were selected in Silico analysis for the current study, which was based on several miRNA database and HapMap database. The SNP genotyping was performed using the Sequenom MassARRAY. Results: The median age of all patients was 65 years, and 468 (56.3%) patients had colon cancer, while 363 (45.1%) patients had rectal cancer. The pathologic stages after the surgical resection were as follows: stage I (n⫽150, 18.1%), stage II (n⫽332, 40.0%), stage III (n⫽333, 40.1%), and stage IV (n⫽16, 1.9%). In the discovery cohort, 19 SNPs were identified as possible prognostic biomarkers in a multivariate survival analysis [disease-free survival (DFS) and/or overall survival (OS)] adjusted for age, preoperative CEA level, and pathologic stage. In the validation cohort, the TPST1 rs3757417T⬎G and ZG16B rs12373A⬎C were significantly associated with prognosis as same direction in the discovery cohort (discovery ⫹ validation cohort; TPST1 rs3757417T⬎G, DFS, p value⫽0.0007, OS, p value⫽0.0091 in recessive model; ZG16B rs12373A⬎C, DFS, p value⫽⬍0.0001, OS, p value⫽0.0009 in dominant model). Conclusions: The current study provides evidence that the rs3757417T⬎G and rs12373A⬎C polymorphism in the 3’-UTR of TPST1 and ZG16B, respectively, are possible prognostic biomarker for patients with colorectal cancer.

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Colorectal cancer gene expression profiling using nanostring nCounter analysis. Presenting Author: Kristen Keon Ciombor, Vanderbilt University Medical Center, Nashville, TN Background: A more accurate method of identifying stage 2 and 3 colorectal cancer (CRC) patients at highest risk for recurrence after surgical resection is needed. Gene expression signatures utilizing microarray-derived gene expression data from fresh frozen primary CRCs to predict risk of recurrence have been developed by us and others. Advances in technology platforms for gene expression measurements and their applicability to formalin-fixed, paraffin-embedded (FFPE) specimens offer new opportunity to develop clinically useful diagnostics based on molecular profiles. Methods: 58 patient FFPE samples of all stages stored from 1-12 years were collected from the Vanderbilt GI SPORE Translational Pathology and Imaging Core and annotated with appropriate clinicopathologic data. 414 genes were selected from our 34-gene prognostic classifier and other published CRC gene signatures, as well as gene elements associated with intestinal stem cell biology and epithelial-to-mesenchymal transition (EMT). RNA was extracted from the tumors, and gene expression analysis was completed using the nCounterplatform. Results: Quality of extracted RNA from tumor blocks was similar among the tumors and adequate for analysis. No significant differences were seen in signal strength (p⫽0.94, KruskalWallis test) or intra-class variation (correlation coefficient ⫽ 0.99) across material extracted from new and old blocks. Fold change values for the 70 most highly differentially expressed genes on the nCounter platform correlated well with Affymetrix U133 plus 2 microarray (R2⫽0.819). Genes associated with EMT clustered according to prognosis, with poorer prognoses seen in patients with high TWIST expression or low E-cadherin and SMAD4 expression. There was a trend toward better survival outcomes with high expression of E-cadherin and SMAD4 (p⫽0.072, log-rank test). Conclusions: This preliminary study demonstrates the feasibility of this approach to determine gene expression patterns in FFPE tumor tissue samples. Our data suggest that this approach may be applied to identify clinically applicable prognostic gene expression profiles that may be validated in archived patient samples that are well annotated with patient outcome data.




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Neoadjuvant chemoradiotherapy (NCRT) using concurrent S-1 and irinotecan in rectal cancer: Impact on long-term clinical outcomes and prognostic factors. Presenting Author: Atsuko Tsutsui, Kitasato University School of Medicine, Sagamihara, Japan

Genes involved in EGFR-degradation to predict for efficacy in metastatic colorectal cancer patients treated with cetuximab. Presenting Author: Sebastian Stintzing, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA

Background: To assess long-term clinical outcomes of neoadjuvant chemoradiotherapy (NCRT) of rectal cancer using concurrent irinotecan and S-1. Methods: One hundred and fifteen patients without distant metastases entered this phase II trial in cT3/T4 rectal cancer (n⫽104/11). Pelvic radiotherapy was given to 45 Gy in 25 fractions over 5 weeks with concurrent oral S-1 at 80 mg/m2 and intravenous irinotecan at 80 mg/m2 once weekly. Median follow-up term was 60 months (ranged from 20 to 96 months). Results: Adverse effect of Grade 3 was recognized in 7 patients (6%), and completion rate of this NCRT regimen was 87 %. All 115 patients (100%) could undergo R0 surgical resection. Twenty-eight patients (24%) demonstrated a pathologic complete response (ypCR). Local recurrence-free survival was 93%, disease-free survival (DFS) was 79%, and overall survival (OS) was 80%. By the multivariate proportional hazard model for DFS and OS, ypN2 was only remnant independent prognostic factor (P⫽0.0019 and P⫽0.0064, respectively). ypN2 was recognized in 9 patients (8%), and prognosis was extremely dismal (8 patients were recurred within 2 years). We again performed the multivariate analysis for 106 cases restricted to ypN0/1, which exhibited 85% of DFS, and both ypT and tumor portion were independent predictors (P⫽0.0065 and P⫽0.003, respectively). Combination of them could greatly enrich high risk patients for recurrence (P⬍0.0001), and dominant recurrences were uniquely found in lung. Conclusions: Novel NCRT regimen using S1/irinotecan demonstrated high response rates and excellent long-term survival, with acceptable adverse effects. ypN2 is a definitive indicator of dismal prognosis, and combination of ypT and tumor portion can identify high risk patients among the ypN0/1 patients.

Background: As many transmembrane receptors, the epithelial growth factor receptor (EGFR) has a highly regulated turnover leading to inactivation and recycling or degradation after activation. This process can be divided into four different phases: receptor endocytosis, ubiquitation/ neddylation, recycling and degradation. We tested whether functional significant single nucleotide polymorphisms in genes involved in the degradation pathway will predict clinical outcome (response, PFS and OS) in 108 patients with metastatic colorectal cancer enrolled in clinical trials and treated with cetuximab. Methods: Genomic DNA was isolated from blood from 108 patients treated with cetuximab enrolled in one of two clinical trials. All patients were KRAS and BRAF wildtyp. 20 SNPs were selected based on the involvement in receptor endocytosis (CBL, CIN85, endophilin) ubiquitation/neddylation, recycling and degradation (CBL, EPS15, Ubc12, UbcH7). Minor allele frequency had to by higher than 10%. PCR and product sequencing were done using standard procedures. Uni- and multivariate analyses, adjusting for age, gender, rash and racial background, were carried out. Results: In univariate analysis, rs895374 (HR: 1.69; p⫽ 0.03), which is located in the exome of UbcH7, was able to separate patient cohorts significantly in perspective of progression free survival (CC ⫽ 5.7mo, CA⫽ 3.6mo, AA⫽ 3.4mo). Using multivariate analysis, rs895375 stayed to be a significant predictor of progression free survival with a Hazard ratio of 2.08 (95% CI 1.24 – 3.48) and a p value of 0.005. UbcH7 plays a pivotal role in the process of neddylation (adding NEDD8 to the EGFR), which switch the balance between recycling and degradation of the EGFR towards degradation. Conclusions: The process of EGFR recycling is important mechanism of resistance of cetuximab in colorectal cancer. This is the first report suggesting that germline polymorphisms in the degradation process may predict efficacy of cetuximab in patients with metastatic colorectal cancer. Anti-EGFR antibody like Sym004 might overcome this resistance mechanism by preventing EGFR recycling.

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Survival after resection plus intra-operative radiofrequency ablation (IRFA) to treat colorectal liver metastases (CLM): Results of an international collaborative study. Presenting Author: Serge Evrard, Institut Bergonié, Bordeaux, France

Association between c-Met expression and tumor recurrence in colorectal cancer patients after liver resection. Presenting Author: Hirokazu Shoji, Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, Japan

Background: Adding IRFA to parenchymal resection to treat CLM is gaining increasing acceptance in specialized HPB teams treating complex, bilobar disease. Objectives were to confirm the promising results of the prospective CLOCC and ARF2003 trials on a larger international scale. Methods: Four centers combined their clinical databases regarding IRFA for CLM. Demographics, treatments, CLM characteristics, complications (Clavien-Dindo), local recurrence, and survivals (liver progression-free, LPFS, relapse-free, RFS and overall, OS) were analyzed. Results: 280 patients (38% female, median age 61y) received resection plus IRFA over 2001-2011. 205 had synchronous CLM (73%) and 247 bilateral (88%). 227 patients received pre-operative chemotherapy (173 one line, 37 two lines, 10 three lines, 7 missing); 189 received post-operative chemotherapy (103 one line, 46 two lines, 40 three lines). Median number of tumors resected was 2 (range 1-19) and ablated 2 (1-12). Median size (mm) of largest CLM ablated per patient was 8.5(0.1-50). 96 patients experienced complications: 29 G1, 19 G2, 35 G3, 10 G4, and 3 deaths. 48 patients had local recurrence of ablated CLM. 155 patients developed new CLM, 165 extra-hepatic metastases, and 119 patients died during follow-up. One-year, 3-year and median (months) RFS, LPFS and OS were respectively: RFS 41%(95CI3547), 14%(95CI9-19), 9m (95CI8-11); LPFS 53%(95CI47-59), 31%(95CI25-37), 15m (95CI11-19); OS 90%(95CI85-93), 58%(95CI5165), 40m (95CI37-50). Median follow-up was 38m (95CI34-49). Conclusions: In this difficult-to-treat group, survival results were good and comparable with rates reported after resection only. IRFA complements resection, enabling to treat more patients, and offers the advantage of sparing healthy parenchyma.

Background: c-Met is a receptor for hepatocyte growth factor that has been implicated in the pathogenesis and growth of a wide variety of human malignancies, including colorectal cancer (CRC). The aim of the present study was to clarify the correlation between c-Met protein expression in the primary lesion and relapse-free survival (RFS) in patients who had undergone curative hepatectomy for colorectal metastases. Methods: Between January 2004 and December 2009, formalin-fixed paraffin-embedded sections of surgical specimens from 108 CRC patients who had undergone hepatectomy were obtained at a single center. We performed immunohistochemical staining to detect c-Met expression. c-Met expression levels were scored dependent on staining intensity; 0, negative; 1, weak; 2, moderate; 3, strong. We defined scores 0 and 1 as c-Met-low, and scores 2 and 3 as c-Met-high. The Kaplan-Meier method and Cox proportional hazards model were used to investigate relationships between c-Met expression, patient characteristics, and RFS. Results: We identified 65 males and 43 females with a median age of 62 years. A total of 53% of patients underwent simultaneous resection of primary and metastatic liver lesions, and the others underwent metachronous resection. High levels of c-Met expression (c-Met-high) in the primary tumor were observed in 52% of patients. There were no differences in terms of size or number of metastatic liver lesions between the c-Met-low patients and the c-Met-high patients. RFS was significantly shorter in the c-Met-high patients (9.7 months) than that in the c-Met-low patients (21.1 months) in primary tumors (p⫽0.013). Multivariate analyses demonstrated that c-Met-high (hazards ratio [HR], 1.73; 95% confidence interval [95% CI], 1.08-2.79 for c-Met-high vs. c-Met-low) and hepatic resection for synchronous disease (HR, 2.17; 95% CI, 1.36-3.46 for synchronous vs. metachronous resection) were associated with worse RFS. Conclusions: High levels of c-Met expression in the primary tumor were associated with shorter RFS after hepatic metastasectomy.


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Preoperative radiotherapy (preop RT) in rectal cancer: Impact of chemotherapy on the outcome—Long-term results of the randomized 22,921 phase III trial of EORTC. Presenting Author: Jean Francois Bosset, Besançon University Hospital, Besancon, France

Efficacy and toxicity of second-line AIO plus irinotecan (IRI) after pretreatment with AIO plus oxaliplatin (L-OHP) in the sequential therapy of metastatic colorectal cancer (CRC). Presenting Author: Axel Wein, Department of Internal Medicine 1, Erlangen University, Erlangen, Germany

Background: This 2x2 factorial design clinical trial evaluated the addition of Fluorouracil-based chemotherapy (CT) to preop RT and the use of adjuvant CT in patients with resectable T3-T4 M0 rectal cancer. The 5-year results showed that adding CT preoperatively or postoperatively had no significant effect on overall survival (OS) nor on disease-free survival (DFS) but a divergence seemed to emerge respectively at 2 and 5 years in the postop CT group. We report results with a median of 10.4 years. Methods: A total of 1011 patients were allocated in four treatment arms: preop RT ; preop RT ⫹ 2 CT courses ; preop RT ⫹ 4 postop CT courses ; preop RT-CT ⫹ postop CT. Preop RT was 45 Gy over 5 weeks. A one 5-day course of CT consisted of 5-Fu 350 mg/m²/d and Leucovorin 20 mg/m²/d. The effect of preop CT and adjuvant CT on OS and DFS was assessed by Logrank test (2-sided 5% significance level) stratified respectively for postop and for preop treatment. Written informed consent was obtained from all patients before randomization. Results: There is no significant difference in OS, nor in DFS between the groups receiving preop CT or not (p ⫽ 0.91 and p ⫽ 0.38 respectively). There is no significant difference in OS nor in DFS between the groups treated by postop CT or not (p ⫽ 0.32 and p ⫽ 0.29 respectively). The 10-year cumulative incidence of local recurrences is ~9 % in all the CT groups and 17.4 % in the preop RT alone group (p ⫽ 0.0044). The 10 year cumulative incidence of distant metastases (DM) is ~35 % in all treatment groups. Conclusions: With more that 10-years follow-up there is no benefit in rectal cancer by adding Fluorouracil-based chemotherapy preoperatively nor postoperatively to preop RT in terms of OS, DFS, nor in term of DM. Clinical trial information: 00002523.

Background: The FOLFIRI followed by FOLFOX6 (or vice versa) schedule has been considered as the gold standard of sequential treatment in CRC (Tournigand C. JCO 2004). In contrast to those bi-weekly schedules, the wide-spread weekly chemotherapy administration (e.g. AIO regimen), has not been investigated as yet for second-line treatment. The AIO ⫹ IRI schedule has provided promising results in the first-line treatment of CRC (Köhne C.-H. JCO 2005). Therefore, we now investigated the efficacy and toxicity of this schedule in second-line treatment in a phase II study. Methods: From 5/02 to 6/10, 60 palliative patients (pts.) with histologically proven CRC were enrolled in an oligocentric phase II study based on the following regimen: weekly IRI (80 mg/m2 i.v.) as 1h-infusion (inf.): d1, 8, 15, 22, 29, 36, qd 57 followed by 5-FU (2000 mg/m2 i.v.) combined with sodium folinic acid (500 mg/m2, d1, 8, 15, 22, 29, 36, qd 57) as a 24h-inf. via port-a-cath. This study focused on the efficacy and toxicity of second-line treatment with AIO ⫹ IRI. Results: Last date of evaluation: November 30, 2012; evaluable for efficacy: n ⫽ 58 pts., evaluable for toxicity: n ⫽ 59 pts.; men/women: 28/72%; median age: 65y; primary tumor location: rectum/colon: 45/55%.; toxicity data: higher grade toxicity (grade 3-4): leukocytopenia: 5.1%; thrombocytopenia: 1.7%; vomiting: 3.4%; diarrhea: 13.5%; hand-foot-syndrome: 1.7%; alopecia (grade 2) 3.4%; efficacy data: PFS: 4.2 m; median OS 14.2 m, RR: 10%; AIO ⫹ IRI following AIO ⫹ L-OHP achieved a median OS of 25.0 months. Conclusions: In the field of second-linetreatment of CRC the AIO plus IRI regimen offers both a favorable toxicity profile and promising results in terms of efficacy compared with the FOLFIRI regimen.

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Hsa-miR-31-3p expression in FFPE tumor samples as a predictor of anti-EGFR response in patients with metastatic colorectal cancer. Presenting Author: Gilles Manceau, INSERM UMR-S775, Université ParisDescartes, Paris, France

Phase I study of the HSP90 inhibitor AUY922 in combination with capecitabine as treatment for patients with advanced solid tumors. Presenting Author: Shubham Pant, Stephenson Cancer Center/SCRI, Oklahoma City, OK

Background: In metastatic colorectal cancer (mCRC), KRAS mutations are associated with resistance to anti-EGFR antibodies. To identify, in wildtype KRAS mCRC patients, markers that predict response to anti-EGFR antibodies, we focused on miRNAs. Methods: Expression profile of 1145 miRNAs was done on 84 colorectal tumors and 5 normal colon mucosae. Correlations between miRNAs expression level and survival were based on frozen samples of a training set from a retrospective series of 33 patients treated by cetuximab and irinotecan and of two validation set from prospective collections of 38 patients treated by cetuximab or panitumumab based chemotherapy or by panitumumab and irinotecan as third-line, using an adjusted Cox proportional hazards model. Validation on FFPE samples was done on 39 patients treated with panitumumab and irinotecan as third-line. Results: A predictive signature of 11 miRNA linked to the PFS was identified (p⬍0.01) but only one, hsa-miR-31-3p, exhibited significant different expression level between tumor from bad prognosis and good prognosis from the training set. We tested expression of this miRNA on the training set, and found a HR of 1.9 CI95% [1.1-2.9]. In validation set, the prognostic impact of hsa-miR-31-3p the HR was estimated to 1.9 CI95% [1.1-3.1]. Using multivariate model obtained from the training set to the two validation set, we predict the PFS of the patients (accuracy of prediction: AUC ⫽ 0.77). We classified the validation set according to a free PFS score (P⫽0.005) with a specificity of 62% CI95% [38%-82%] and a sensitivity of 82% CI95% [56%-96%] for the prediction model. A nomogram, established taking into account hsa-miR-31-3p expression level, predicted the progression risk (P⬍0.0001). Confirmation of the predictive value of hsa-miR-31-3p expression on survival risk progression was done on FFPE sample (p⫽0.0006). Conclusions: This is the first tool to select individual patients with a wild-type KRAS tumor for anti-EGFR therapy from frozen or FFPE samples.

Background: Heat shock protein 90 (HSP90) is a molecular chaperone involved in the maintenance and function of client proteins, many of which are integral to key oncogenic processes. AUY922 is a competitive inhibitor of HSP90. Preclinical evidence suggests potential synergy between HSP90 inhibition and fluorouracil. This phase I study was designed to determine the maximum tolerated dose (MTD) of AUY922 in combination with standard dose of capecitabine as treatment for patients with advanced solid tumors. Methods: Pts with refractory solid tumors received AUY922 with capecitabine in a standard 3⫹3 dose escalation. Dose levels were capecitabine 1000mg/m2 PO BID d 1-14 of 21-day cycles, with escalating doses of AUY922 IV days 1, 8, and 15; the 6th dose level combined the MTD of AUY922 with capecitabine 1250mg/m2. Dose-limiting toxicities (DLTs), safety, and efficacy were evaluated. Results: 23 pts were treated at 6 dose levels: 22mg/m2 (n ⫽ 3); 28mg/m2 (n ⫽ 3); 40mg/m2 (n ⫽ 3); 55mg/m2 (n ⫽ 5); 70mg/m2 (n ⫽ 3); 70mg/m2 with capecitabine 1250mg/m2 (n⫽ 6). No DLTs were observed until the 6th dose level (grade 3 diarrhea). Related adverse events (% grade 1/2; % grade 3/4) included: diarrhea (43%; 17%), fatigue (30%; 13%), nausea (39%; 0), hand-foot skin reaction (30%; 5%), anorexia (30%; 4%), vomiting (30%; 0), and darkening vision (26%; 0). Vision darkening, a class effect of HSP90 inhibitors, was reversible with drug hold and retreatment was possible. Two pts (9%) had hematologic G 3/4 events of neutropenia. Of the 19 pts evaluable for response, partial response was noted in 4 patients (colorectal, 2; breast, 1; stomach, 1); 2 had progressed on prior fluorouracil, and remained on treatment for 13-35 wks. Stable disease was noted in 8 pts (35% [colorectal, 5; pancreas, 2; breast, 1]) with a median duration of 25.5 wks (range: 11-44⫹). All 5 colorectal pts were refractory to 5-FU. Conclusions: The addition of AUY922 to standard dose capecitabine was well-tolerated at doses of up to 70mg/m2. Preliminary efficacy is encouraging, particularly as seen in pts previously resistant to fluorouracil, and warrants further investigation of this regimen. Clinical trial information: NCT01226732.




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EGFL7 polymorphism to predict tumor response in metastatic colorectal cancer (mCRC) patients (pts) treated with FOLFIRI and bevacizumab (BV). Presenting Author: Joseph Ethan Li, USC Norris Comprehensive Cancer Center, Los Angeles, CA

Use of genetic variants in pericyte-driven tumor vessel maturation genes to predict treatment efficacy in mCRC patients treated with FOLFIRI/ bevacizumab. Presenting Author: Nico Benjamin Volz, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA

Background: Angiogenesis involves endothelial cell (EC) sprouting, proliferation, and differentiation and recruitment of mural cells to stabilize new vessels. The proteins Epidermal Growth Factor Domain-Like 7 (EGFL-7) and Activin Receptor-like Kinase 1 (ALK1) play critical roles. EC-secreted EGFL7 antagonizes Notch to promote EC proliferation, sprouting, and motility. EGFL7 also regulates mural cell recruitment and extracellular matrix deposition. ALK1 is an EC-restricted TGF-␤ Type 1 receptor with downstream repression of Vascular Endothelial Growth Factor (VEGF) signaling. ALK1 also promotes pericyte-EC adhesion. EGFL7 or ALK1 inhibition enhances antitumor efficacy when combined with BV in murine models. Both are overexpressed in many cancers and may be critical for efficacy of anti-VEGF therapy. We tested whether EGFL7 (rs1051851, rs2297538) and ALK1 polymorphisms (rs2293094, rs11169953, rs706819) will predict efficacy of BV-based therapy in mCRC pts. Methods: Genomic DNA was extracted from peripheral whole blood samples from 455 mCRC pts treated with first-line BV and FOLFIRI. SNPs were analyzed by PCR-based direct DNA sequencing and evaluated for association with tumor response rate (RR), overall survival (OS), and progression free survival (PFS). Results: Male/female: 272/183; median age: 62 (range: 25-81); median PFS and median OS: 10.9 (95%CI: 10.1-11.6) and 29.9 (95%CI: 25.9-34.6) months, respectively; response to therapy: 59% (215 pts); median follow-up:23.6 (range: 1.8-60.4) months. Pts carrying the EGFL7 rs1051851 G/G alleles had a 62% RR versus 56% in pts with A/G and 29% in patients with A/A (p⫽0.0130, Cochran-Armitage trend test). The result remained significant after adjustment for baseline pt characteristics (p⫽0.026, Multivariable logistic regression test). There was no statistically significant association between tested polymorphisms and OS or PFS. Conclusions: The EGFL7 SNP rs1051851 may predict tumor response in mCRC pts treated with FOLFIRI and BV. To our knowledge, this is the first study demonstrating predictive significance of genetic variations in EGFL7. Prospective validation of this study is warranted.

Background: Angiogenesis is maintained by the presence of PDGFB (platelet derived growth factor beta) which binds to the receptor, PDGFRB on pericytes, signaling them to stabilize stalk cells adjacent to tip cells. PDGFB signaling by endothelial tip cells promotes proliferation, migration, and stabilization of pericytes which are closely associated with endothelial cells. VEGF driven angiogenesis in response to tumor hypoxia relies on several genes. Previously, studies showed RALBP1, RGS5, and CSPG4 greatly impact the structure of blood vessels during angiogenesis. Recognizing these genes are important in angiogenesis through pericytes, we investigated the correlation between polymorphisms in these genes and clinical outcomes in patients with mCRC treated with FOLFIRI/bevacizumab (BV). Methods: Genomic DNA was extracted from 455 patients’ blood or tissue treated with first-line BV ⫹ FOLFIRI and prospectively enrolled in a prospective pharmacogenomic translational study. Median follow up is 24 months and median PFS and OS were 10.5 and 29.9 months, respectively. Eight functionally significant SNPs; RGS5 (rs1056515, rs2661280), PDGFRB (rs2229562, rs2302271), CSPG4 (rs8023621, rs1127648), and RALBP1 (rs10989, rs329007) were analyzed by PCR-based direct sequencing. All candidate SNPs were analyzed for association with tumor response rate (RR), progression free survival (PFS), and overall survival (OS). Results: Four SNPs showed significant results in the univariate analysis of either OS or PFS. PDGFRB rs2302273 remained significant upon multivariate analysis. Univariate analysis of PDGFRB rs2302273 concluded patients with any T (CT/TT) allele were significantly associated with longer PFS compared to those with CC genotypes (median 10.2 vs 11.6 months, HR⫽0.78 [95%CI: 0.63-.98], p⫽0.031, log-rank test) which remained significant upon multivariate analysis (HR⫽0.73 [95% CI: 0.57-0.92], p⫽0.008, log-rank test). Conclusions: Our results show that the PDGFRB polymorphism rs2302273 may serve as a prognostic marker for the efficacy of FOLFIRI ⫹ BV treatment in patients with mCRC. Studies to confirm and update these preliminary findings are ongoing.

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Use of genetic variants in immune response genes to predict clinical outcome in mCRC patients treated with cetuximab-based therapy. Presenting Author: Anne Maria Schultheis, USC Norris Comprehensive Cancer Center, Los Angeles, CA Background: Cetuximab is a monoclonal antibody targeting the EGF receptor. One of its anti-tumor mechanisms is the stimulation of the immune system via ADCC (Antibody-Dependent-Cell mediated Cytotoxicity). Immune response through T-cell activation may also play a role in antitumor efficacy of chemotherapy. CTLA4, PDL1, IDO1 and CD24 are inhibitory co-receptors or ligands that may downregulate the immune system through suppression of T-cell response. We tested whether Germline polymorphisms in these genes are involved in the cetuximab dependent immune response pathway and thus predict outcome in mCRC patients treated with cetuximab. Methods: DNA was isolated from blood of 108 patients with mCRC treated with either irinotecan⫹cetuximab (n⫽73) or single agent cetuximab (n⫽35). Twelve prospectively functionally relevant SNPs; IDO1(rs9657182, rs3739319, rs1010866), PD1(rs2227981, rs7421861), PDL1(rs2297137, rs2297136, rs10122089, G⬎C), CTLA4(rs231777, rs231775), and CD24(rs8734) were analyzed by PCR-based direct sequencing and evaluated for association with tumor response, overall survival (OS), and progression free survival (PFS). Results: Results are attached. There were 65 men and 43 women with a median PFS of 3.7 (95%CI: 2.8, 4.6) months and a median OS of 10.5 (95%CI:7.7, 13.3) months. Median follow up was 16.3 (range:1.2, 42.4) months. Conclusions: Our results show that immune response related SNPs may predict efficacy of cetuximab treatment in patients with mCRC. To the best of our knowledge this is the first data linking PDL1(rs2297137) to cetuximab efficacy in mCRC patients. Significant results in OS, PS, or tumor response. SNP

N

OS

P (multivariate)

Median, mo (95%CI) IDO1rs9657182 A/A A/G G/G IDO1rs3739319 A/A A/G G/G CD24rs8734 G/G G/A A/A

0.009 24 55 25

12.0 (5.7, 20.4) 15.0 (7.8, 15.9) 8.5 (5.1, 10.8)

27 51 27

10.8 (4.4, 15.0) 8.7 (6.3, 12.0) 17.9 (8.5, 26.4)

54 36 5

7.8 (5.7, 10.5) 13.1 (8.7, 17.9) 2.3 (1.8, 11.3)

0.045

0.001

PFS Median, mo (95%CI) CTLA4rs231777 C/C C/T

65 34

4.1 (3.3, 5.3) 2.6 (2.3, 4.4) Tumor response PR

0.017

PDL1rs2297137 G/G G/A A/A

60 36 9

9 (16%) 7 (19%) 5 (56%)

SD⫹PD 0.029 49 (84%) 29 (81%) 4 (44%)


Use of genetic variants in wnt signaling pathway to predict gender and tumor location dependent survival in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line FOLFIRI and bevacizumab (BEV). Presenting Author: Yan Ning, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA Background: CRC is generally characterized by aberrant Wnt signaling. Wnt signaling pathway genes AXIN2 and TCF7L2 complex control the proliferation and differentiation of intestinal epithelial cells. Previous study showed polymorphisms in TCF7L2 and AXIN2 were associated with increase risk of colon cancer. We tested the hypothesis whether single nucleotide polymorphisms (SNPs) in TCF7L2 (rs7903146) and AXIN2 (rs2240308, rs3923087) will predict clinical outcome in a cohort of mCRC pts treated with first line FOLFIRI/BEV. Methods: Genomic DNA were extracted from blood of 455 mCRC pts which prospectively enrolled in a pharmacogenetic translational study. Females(n⫽172) and males(n⫽252); Median follow up is 24 months, median PFS and OS were 10.5 and 29.9 months, respectively. Candidate SNPs were analyzed by PCR-based direct sequencing. Results: In the overall population analysis, TCF7L2 and AXIN2 polymorphisms were not associated with OS and PFS, but our data showed that 2 polymorphisms may predict clinical outcome when adjusted by pts gender and tumor location: 1) In right-sided tumors, male pts with any T allele of TCF7L2rs7903146 were associated with significantly worse PFS in comparison to those carrying C/C genotype (HR: 2.15; 95% CI: 1.09-4.22; P ⫽ 0.027, log-rank test). However, female pts with any T allele reversly showed better PFS compared with those carrying C/C variants (HR: 0.39; 95% CI: 0.17-0.94; P ⫽ 0.035, logrank test). 2) In women, pts with AXIN2 rs2240308 any A allele had better PFS and OS in right-sided tumors compared to those with any A allele but located in left side(pinteraction⫽0.047)(PFS) and (pinteraction⫽0.025)(OS), respectively. Conclusions: Our data show for the first time Wnt signaling pathway gene polymorphisms TCF7L2 rs7903146 and AXIN2 rs2240308 may predict PFS and OS in mCRC pts treated with first-line FOLFIRI/BEV. More importantly, this predictive value is dependent on gender and tumor location, suggesting a different role of Wnt signaling in female vs male and in right vs left side tumor. Our preliminary data warrants clinical trial validation.

Abbreviations: PR, partial response, SD, stable disease, PD, progressive disease.


222s

Gastrointestinal (Colorectal) Cancer

3569


Adjuvant chemotherapy (AC) outcomes in young (YP) and elderly patients (EP) with high-risk stage II colon cancer (CC). Presenting Author: Aalok Kumar, British Columbia Cancer Agency, Vancouver, BC, Canada Background: High-risk stage II CC is defined as those presenting with T4 stage, obstruction or perforation, ⬍12 lymph nodes retrieved, positive resection margins, and lymphovascular or perineural invasion. Our prior findings suggest that improved outcomes from AC are limited to specific high risk features, such as T4 disease (Kumar et al, ASCO 2012). It is unclear if this benefit is seen across all ages. Our aim was to compare patterns of AC use and outcomes in YP and EP with high risk stage II CC. Methods: All patients diagnosed with high risk stage II CC from 1999 to 2008 and evaluated at any 1 of 5 regional cancer centers in British Columbia were categorized into YP (age ⬍70 years) or EP (age ⬎/⫽70 years). Kaplan-Meier methods and Cox regression were used to correlate receipt of AC with overall survival (OS), disease specific (DSS) and relapse free survival (RFS), stratified by age group. Results: A total of 1,236 patients were identified: 636 (51%) YP and 600 (49%) EP among whom 363 (57%) and 85 (14%) received AC, respectively. Individuals who received AC in either age group had better performance status than those who did not (ECOG 0/1 47% vs. 34%, p⫽0.02). After adjusting for known prognostic factors, a significant advantage in OS, but not DSS or RFS, from AC was observed for both YP and EP (Table). The impact of AC on these outcomes was similar across age groups (p interaction of age and treatment ⫽ 0.46, 0.64 and 0.69 for OS, DSS and RFS, respectively). In the entire cohort, individuals with T4 lesions had significantly improved OS (HR 0.50, 95%CI 0.33-0.77, p⫽0.002), DSS (HR 0.59, 95%CI 0.37-0.93, p⫽0.03), and RFS (HR 0.63, 95%CI 0.42-0.95, p⫽0.03). The effect of AC in the T4 subgroup was also similar for both YP and EP in terms of OS, DSS and RFS (p interaction of age and treatment ⫽ 0.41, 0.71 and 0.77, respectively). Conclusions: In this population-based cohort of high risk stage II CC, improvements in outcomes from AC were seen mainly in those with T4 disease, regardless of age. Hazard ratios (and 95% CI) of events in patients receiving AC vs. no AC Age group YP EP

3571

OS

p value

DSS

p value

RFS

p value

0.72 (0.52-0.99) 0.59 (0.40-0.88)

0.04

0.79 (0.54-1.16) 0.69 (0.42-1.13)

0.23

0.75 (0.53-1.05) 0.84 (0.53-1.33)

0.09

0.01

0.14

0.45


3570


Adjuvant chemotherapy with oxaliplatin/5-fluorouracil/leucovorin (FOLFOX) versus 5-fluorouracil/leucovorin (FL) in patients with locally advanced rectal cancer after preoperative chemoradiotherapy followed by surgery: A randomized phase II study (The ADORE). Presenting Author: Yong Sang Hong, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea Background: Preoperative chemoradiotherapy (Pre-CRT) with fluoropyrimidines (Fp) followed by surgery is one of the standard treatments for patients (pts) with locally advanced rectal cancer (LARC); however, the role of adjuvant chemotherapy is still controversial. The aim of this study is to investigate the efficacy of adjuvant FOLFOX for LARC pts who underwent Fp-based Pre-CRT and complete total mesorectal excision (TME). Methods: This randomised phase II study accrued LARC pts whose ypStage was II (ypT3-4/ypN0) or III (any ypT/ypN1-2) after Fp-based Pre-CRT followed by TME. Pts were randomly assigned (1:1) to receive adjuvant chemotherapy either with FL (5-FU 380 mg/m2, leucovorin 20 mg/m2 on D1-5 q 4 weeks X 4 cycles) or FOLFOX (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2 on D1, 5-FU bolus 400 mg/m2 on D1, 5-FU infusion 2400 mg/m2 for 46 hours q 2 weeks X 8 cycles). The primary endpoint was disease-free survival (DFS). Results: A total of 320 pts were randomly assigned (161 FL and 159 FOLFOX) between November 2008 and June 2012, the arms were balanced. By intent-to-treat analysis, estimated 2-year DFS rate was 82.0% in FOLFOX arm and 69.4% in FL arm (HR 0.46 [95% CI, 0.28-0.76], p⫽0.002) after the median follow-up duration of 22.5 months. The statistical improvements of DFS were maintained regardless of ypStage: 2-year DFS rate was 89.7% (FOLFOX) vs 76.4% (FL) in pts (n⫽122) with ypStage II (HR 0.32 [0.10-0.98], p⫽0.035), and 78.1% (FOLFOX) vs 64.4% (FL) in pts (n⫽198) with ypStage III (HR 0.49, [0.27-0.86], p⫽0.011). All grade leucopenia (32% vs 22%), neutropenia (70% vs 46%), thrombocytopenia (26% vs 2%) and sensory neuropathy (71% vs5%) were more frequently observed in FOLFOX arm; however, grade 3/4 adverse events (AE) were not different between arms. Conclusions: Adjuvant FOLFOX improved 2-year DFS relative to FL for LARC pts whose ypStage II or III after Fp-based Pre-CRT followed by TME. Significant AEs were not different between arms. The DFS results will be updated in the presentation. Clinical trial information: NCT00807911.

3572


Tumor perivascular PDGFBR as an independent prognostic factor in metastatic colorectal cancer. Presenting Author: Maja Bradic Lindh, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden, Stockholm, Sweden

Primary tumor location and expression of mir-664 as a combined biomarker for bevacizumab effectiveness in metastatic colorectal cancer. Presenting Author: Mogens Karsboel Boisen, Department of Oncology, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark

Background: New vessel formation is an essential factor for tumor growth and metastasis. Tumor vessels show reduced and variable pericyte coverage. Several pericyte markers have been identified, including plateletderived growth factor receptor beta (PDGFbR), smooth muscle ␣-actin (ASMA) and desmin. Variability in pericyte status and its prognostic significance remains largely uncharacterized in colorectal cancer (CRC). The aim of the present study was to perform a preliminary analysis of the variability in expression of the three pericyte markers and to investigate the potential prognostic significance of perivascular PDGFbR (PV-PDGFbR). Methods: A population-based cohort was used for double-staining, performed on 100 tumors with CD34 and above-named pericyte markers. For the rest of the study a metastatic CRC (mCRC) collection from the phase III NORDIC-VII study was used. Analyses were performed on a tissue microarray with tumor material from 328 out of the 566 patients in the intention to treat population. All tumors and corresponding normal tissue were scored by immunohistochemistry (IHC) with regard to PV-PDGFbR. 255 and 97 cases were analyzed by IHC with regard to perivascular ASMA and microvessel density (MVD), respectively. Results: Analyses of the doublestaining revealed independent and variable expressions of all three pericyte markers. Analyses of the NORDIC-VII cohort revealed two prognostic groups with low and high PV-PDGFbR expression. Median OS was 14.3 mo for PV-PDGFbR-low tumors (N⫽22) vs. 22.9 mo for PV-PDGFbR-high (N⫽306) tumors (HR⫽1.95; 95% CI 1.20-3.16; log-rank p⫽0.007). Multivariate analysis, including WHO performance status, alkaline phosphatase level and BRAF mutation status confirmed PV-PDGFbR as an independent prognostic factor of OS (HR⫽1.75; 95% CI 1.07-2.84; p⫽0.025). PV-PDGFbR was not significantly linked to perivascular ASMA or MVD. PV-PDGFbR in normal tissue was not associated with survival. Conclusions: CRC display a previously un-recognized variability in pericyte characteristics. Low tumor PV-PDGFbR level is associated with worse prognosis in patients with mCRC, in a manner independent of performance status, alkaline phosphatase levels and BRAF status.

Background: We aimed to identify tissue microRNAs (miRs) that could predict outcome for patients with metastatic colorectal cancer (mCRC) treated with first line bevacizumab (BEV) and chemotherapy (CT) but not for patients treated with CT alone. Methods: Patients with mCRC treated with first line capecitabine and oxaliplatin (CT) with or without BEV at ten hospitals were identified and data was extracted retrospectively. Formalinfixed paraffin-embedded tissue samples from primary tumors were collected and RNA was purified from 3 x 10 ␮m sections, without microdissection. miR expression was measured using Applied Biosystems TaqMan Custom LDA cards profiling 22 selected miRs in duplicate. The 22 miRs were selected from a previous discovery study profiling 754 miRs. miR expression was related to time to disease progression (TTP) and overall survival (OS) in multivariate analyses using Cox proportional hazards models with adjustment for age, prior adjuvant treatment, and no. of metastatic sites. We have previously found that patients with primary tumors originating in the sigmoid colon and rectum (S⫹R) experienced a better outcome than patients with other primary tumor locations (caecum to descending colon) when treated with BEV, so our analyses were stratified by primary tumor location. Results: miR expression was measured in samples from 399 patients: 155 samples from the original CT⫹BEV discovery study, 119 samples from a new CT⫹BEV cohort, and 125 samples from a CT alone cohort. Expression of miR-664 showed a significant positive association with increasing TTP, OS, and response rate (RR), but only in the cohort of patients with sigmoid colon- and rectal primary tumors treated with CT⫹BEV (n⫽183). Conclusions: We have identified a subgroup of patients with mCRC that are likely to benefit from BEV addition to first line CT using the combined information of location of the primary tumor and expression level of miR-664. Treatment Primary tumor location MiR-664 expression level RR (CRⴙPR), % Median TTP, mo Median OS, mo

CT

CTⴙBEV

CT

CTⴙBEV

CT

CTⴙBEV

All All 8.4 16.4

All All 37 9.5 24.4

S⫹R All 8.1 16.8

S⫹R All 40 10.3 28.4

S⫹R Highest quartile 7.3 15.3

S⫹R Highest quartile 48 11.3 33.9




On-treatment progression-free survival analysis of ziv-aflibercept/FOLFIRI treatment within 28 days of end of treatment in metastatic colorectal cancer: Updated efficacy results from the VELOUR study. Presenting Author: David Ferry, New Cross Hospital, Wolverhampton, United Kingdom Background: The phase III VELOUR study demonstrated that adding the novel antiangiogenic agent ziv-aflibercept (known as aflibercept outside the United States) to FOLFIRI in patients with metastatic colorectal cancer previously treated with oxaliplatin significantly improved overall survival, progression-free survival (PFS), and overall response rate vs placebo/ FOLFIRI. We performed an additional analysis of PFS “on-treatment,” censoring events that occurred more than 28 days after last treatment dose. Methods: Patients were randomized to receive ziv-aflibercept 4 mg/kg or placebo every 2 weeks in combination with FOLFIRI. An independent review committee determined progression based on radiologic review. PFS was estimated using Kaplan-Meier analysis, with censoring of events after the last dose plus 28 days. Treatment groups were compared using a log-rank test and were stratified by Eastern Cooperative Oncology Group performance status and prior bevacizumab therapy. Hazard ratio (HR) and confidence interval (CI) were estimated using a Cox proportional hazard model. Results: On-treatment analysis showed significantly increased PFS for patients treated with ziv-aflibercept/FOLFIRI compared with placebo/ FOLFIRI (Table). More patients were censored in the ziv-aflibercept arm due to adverse events. Conclusions: The on-treatment PFS analysis demonstrates a significantly improved treatment effect of the addition of zivaflibercept to FOLFIRI (HR⫽0.55) over what was observed in the primary analysis suggesting that continuing treatment with ziv-aflibercept up to disease progression provides additional benefit. Clinical trial information: NCT00561470. PFS, months

Placebo/FOLFIRI nⴝ614

Ziv-aflibercept/FOLFIRI nⴝ612

Hazard ratio

454

393

HR⫽0.76 (95% CI, 0.66-0.87) P⫽0.00007

Median (95% CI) On-treatment PFS, number of events

4.67 (4.21-5.36) 320

6.90 (6.51-7.20) 208

Median (95% CI)

5.29 (4.37-5.49)

8.31 (7.23-9.50)

PFS per primary analysis, number of events

3575

HR⫽0.55 (95% CI, 0.46-0.66) P⬍0.00001


Results of a phase III, randomized, double-blind, placebo-controlled trial of pegfilgrastim (PEG) in patients (pts) receiving first-line FOLFOX or FOLFIRI and bevacizumab (B) for colorectal cancer (CRC). Presenting Author: Tamas Pinter, Petz Aladar Teaching Hospital, Gyor, Hungary Background: The literature reports that adding biologics to chemotherapy (ctx) may increase the incidence of clinically significant neutropenia. his trial was conducted to evaluate the efficacy of PEG in reducing the incidence of febrile neutropenia (FN) in pts with locally-advanced (LA) or metastatic (m)CRC receiving first-line treatment with either FOLFOX/B or FOLFIRI/B. Methods: Key eligibility: ⱖ 18 years old; measurable, nonresectable CRC per RECIST 1.1. Pts were randomly assigned 1:1 to either placebo or 6 mg PEG ~24 h after ctx/B. The study treatment period included four Q2W cycles, but pts could continue their assigned regimen until progression. Pts were stratified by region (North America vs rest of world), stage (LA vs mCRC), and ctx (FOLFOX vs FOLFIRI). Estimated sample size (N ⫽ 800) was based on the expected incidence of grade 3/4 FN (primary endpoint) across the first 4 cycles of ctx/B, powered for PEG superiority over placebo. Other endpoints included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: 845 pts were randomized (Nov 2009 to Jan 2012) and received study treatment; 783 pts completed 4 cycles of ctx/B. Median age was 61 years; 512 (61%) pts were male; 819 (97%) had mCRC; 414 (49%) received FOLFOX, and 431 (51%) received FOLFIRI. Grade 3/4 FN (first 4 cycles) for placebo vs PEG was 5.7% vs 2.4%; OR 0.41; p ⫽ 0.014. A similar incidence of other ⱖ grade 3 adverse events was seen in both arms (28% placebo; 27% PEG). See table for additional results. Conclusions: PEG significantly reduced the incidence of grade 3/4 FN in this pt population receiving standard ctx/B for CRC. Follow-up is ongoing. Clinical trial information: NCT00911170. Placebo (nⴝ423)

PEG (nⴝ422)

Placebo vs PEG

5.7% (3.7, 8.3)

2.4% (1.1, 4.3)

ORR* (95% CI)

238/420†; 56.7% (51.8, 61.5)

244/420†; 58.1% (53.2, 62.0)

Median PFS* (95% CI), mo Median OS* (95% CI), mo

10.1 (9.3, 11.1)

9.7 (9.2, 10.8)

24.6 (21.3, NR)

21.8 (18.5, 25.6)

Diff ⫽ -3.3% (-6.6, 0.0) OR⫽0.41 (0.19, 0.86) p⫽0.014 Diff ⫽ 1.4% (-6.5, 9.3) OR ⫽ 1.06 (0.81, 1.39) p⫽0.683 HR ⫽ 1.05 (0.88, 1.26) p⫽0.552 HR ⫽ 1.05 (0.81, 1.36) p⫽0.704

Grade 3/4 FN (95% CI)

*Immature data. †Measurable disease.

3574

223s


Analysis of overall survival and safety during the course of the phase III VELOUR trial comparing FOLFIRI and ziv-aflibercept or placebo in mCRC patients who progressed on prior oxaliplatin treatment. Presenting Author: Paul Ruff, University of Witwatersrand Faculty of Health Sciences, Johannesburg, South Africa Background: VELOUR, a large, international, randomized, placebo (pbo)controlled study, compared efficacy and safety of FOLFIRI with zivaflibercept (known as aflibercept outside the United States) or with pbo in 1,226 metastatic colorectal cancer patients who received prior oxaliplatin treatment. Ziv-aflibercept demonstrated statistically significant, clinically meaningful improvements in median overall survival (OS) (13.5 vs 12.06 mos; hazard ratio [HR]⫽0.817, P⫽0.0032), progression-free survival, and response rate. This analysis estimates treatment effect and safety over time course of the study. Methods: HRs by 6-mo time periods were estimated using piecewise Cox proportional hazard model. NCI-CTCAE v3.0 was used to grade adverse event (AE) severity. Results: HR improved over time (Table), consistent with survival curves that continue to separate past the median time point, indicating that the magnitude of ziv-aflibercept treatment effect continues to increase over time. Incidence of grade 3 AEs (45.1% vs 62.0%) was higher in the ziv-aflibercept/FOLFIRI arm; incidences of grade 4 AEs were 17.4% (pbo) vs 21.4% (ziv-aflibercept). More common AEs only occurred in a small proportion of ziv-aflibercept/FOLFIRI cycles (eg, grade ⱖ3 hypertension and diarrhea occurred in 3.6% and 2.8% of cycles, respectively). The majority of grade 3/4 AEs occurred in early treatment (first 3-4 cycles). Most patients experienced only a single episode of grade ⱖ3 AEs with ziv-aflibercept/FOLFIRI. Importantly, AEs in VELOUR did not impact patients’ ability to receive chemotherapy. Conclusions: Treatment with ziv-aflibercept/FOLFIRI showed continuous, consistent improvement in OS over time. While combined grade 3/4 AEs were higher with ziv-aflibercept, AEs occurred early in treatment in a small proportion of total cycles; the majority were single-episode in nature. Clinical trial information: NCT00561470. OS (mos), piecewise Cox model with predefined intervals (per 6 mos) (ITT population). Parameter OS OS OS OS

3576

Time (mos)

HR (95% CI vs pbo ⴙ FOLFIRI)

tⱕ6 6 ⬍ t ⱕ 12 12 ⬍ t ⱕ 18 t ⬎ 18

0.860 (0.664-1.114) 0.838 (0.673-1.043) 0.782 (0.582-1.050) 0.676 (0.463-0.988)


Detection of the BRAFV600E protein in human colon carcinomas by a mutation-specific antibody. Presenting Author: Thomas C. Smyrk, Mayo Clinic College of Medicine, Rochester, MN Background: BRAF encodes a serine-threonine kinase that is a downstream effector of activated RAS. A point mutation (V600E) in BRAF occurs in a subset of colorectal cancers (CRCs) and is associated with adverse outcome and may predict non response to anti-EGFR antibodies. Detection of a BRAFV600E mutation in a CRC with microsatellite instability indicates a sporadic origin and excludes Lynch Syndrome. While BRAFV600E mutation status is determined using a DNA-based assay, antibodies against the BRAFV600E protein have recently been developed. We examined mutant BRAFV600E protein expression and its concordance with mutation status. Methods: Primary stage III colon carcinomas (50 BRAFV600E mutation carriers and 25 wild-type cases) were studied from a completed phase III adjuvant trial comparing FOLFOX ⫹/- cetuximab (NCCTG N0147). In archival resection specimens, immunohistochemistry (IHC) was performed using a pan-BRAF antibody and a V600E mutation-specific antibody raised against an immunogenic synthetic peptide derived from the internal region of the BRAFV600E protein. BRAFV600E mutations in codon 15 were analyzed in extracted DNA using a multiplex, allele specific PCR– based assay. BRAF staining was scored independently by two pathologists blinded to mutation status. Results: In primary colon carcinomas stained with a pan-BRAF antibody, diffuse cytoplasmic staining for BRAF proteins was detected in 74 of 75 carcinomas with one case deemed non-evaluable. Using the mutation-specific BRAFV600E antibody, diffuse cytoplasmic staining was detected in 49 of 74 tumors without appreciable heterogeneity of expression. Among these 49 tumors expressing mutant BRAFV600E proteins, all (100%) were found to carry a BRAFV600E mutation according to a DNA-based assay. In contrast, absent BRAFV600E staining was observed in all 25 tumors that were found to have wild-type copies of BRAFV600E detected using a PCR-based assay. Conclusions: For the detection of mutant BRAFV600E, complete concordance was found between IHC and a DNA-based method in colon carcinomas. This finding supports the use of IHC as a simplified strategy to screen CRCs for mutant BRAFV600E proteins in routine clinical practice to inform clinical decision-making.


224s 3577

Gastrointestinal (Colorectal) Cancer General Poster Session (Board #6C), Sun, 8:00 AM-11:45 AM

Thymidylate synthase (TS) expression as a prognostic molecular marker in stage II/III colon cancer. Presenting Author: Dirk Klingbiel, SAKK - Swiss Group for Clinical Cancer Research, Coordinating Center, Berne, Switzerland Background: Studies on the association between colorectal cancer (CC) outcome and thymidylate synthase expression have provided inconsistent results. In this study we attempted to resolve the issue by assessing the associations between TS expression and outcome in a population of primary CC patients (pts), who after resection were randomized to 5-FU/FA vs. FOLFIRI adjuvant therapy. Methods: Immunohistochemical staining for TS protein was successfully performed for 1211 pts in the PETACC3 trial. TS immunoreactivity was scored as high expression (ⱖ75% positive) and low expression (⬍75% positive). Gene expression respectively copy number data were available for 853 respectively 306 of these samples. Twelve single nucleotide polymorphisms (SNPs) close to the TYMS gene were assessed in 923 pts. Association of variables with relapse-free (RFS) and overall survival (OS) was assessed using Cox regression models. Results: High TS expression and RNA level were strongly associated (log fold change 0.65, p⬍0.001). Both were significantly higher in proximal CC. As expected, both were associated with other characteristics of proximal CC: MSI, BRAF mutation, high tumor grade. RNA was significantly correlated with gene copy number, distal CC showing more frequent allelic loss. Three SNPs were associated with gene expression which was validated in data from the 1000 genomes project, but none with survival. High TS expression was more strongly associated with better OS in pts receiving FOLFIRI (HR 0.4, 95% CI 0.3– 0.6, p⬍0.001), than 5-FU/FA (HR 0.8, 95% CI 0.5–1.1, p⫽0.13), with a significant interaction (p⫽0.05). Similar results were observed for RFS (HR 0.5, p⬍0.001 vs. HR 0.7, p⫽0.07; interaction p⫽0.11). TS expression is still highly prognostic in multivariate models adjusting for factors associated with risk or proximal tumors in FOLFIRI treated pts (OS: HR 0.5, p⫽0.008; RFS: HR 0.6, p⫽0.02), but not in F-FU/FA treated pts (OS and RFS: HR⫽1, p⫽1). Conclusions: TS expression is lower in distal CC, partly due to deletion of the TYMS locus. Pts with high TS expression have longer RFS and OS, notably when treated with FOLFIRI. For these pts addition of irinotecan to 5-FU/FA adjuvant chemotherapy might be considered. Clinical trial information: NCT00026273.

3579


Influence of sex and anthropometric factors on tumor biologic characteristics of colorectal cancer: A cohort study. Presenting Author: Jenny Brandstedt, Department of Clinical Sciences, Division of Pathology, Lund University, Lund, Sweden Background: How body size influences risk of molecular subtypes of colorectal cancer (CRC) remains unclear. In this study, we investigated the relationship between height, weight, BMI, WHR and risk of CRC according to expression of beta-catenin, cyclin D1, p53 and microsatellite instability (MSI) status. Methods: Immunohistochemical expression of beta-catenin, cyclin D1, p53 and MSI-screening status was assessed in tissue microarrays with tumours from 584 cases of incident colorectal cancer in the Malmö Diet and Cancer Study. Four anthropometric factors: height, weight, body mass index (BMI), waist- hip ratio (WHR) were categorized by quartiles of baseline anthropometric measurements, and relative risks of CRC according to expression of betacatenin, cyclin D1, p53 and MSI screening status were calculated using multivariate Cox regression models. Results: Expression of cytoplasmatic and nuclear betacatenin, cyclin D1, p53 and MSS all revealed a positive association with increased weight and BMI in the overall analysis. Negative expression of the above mentioned factors was more frequently associated with increased height. MSI was not associated with any of the anthropometric factors in overall analysis and according to gender.Gender specific analysis revealed no association between any anthropometric factors and positive and negative cytoplasmatic beta-catenin expression, beta-catenin nuclear negativity, cyclin D1 negativity and p53 positivity. Nuclear beta-catenin positivity, cyclin D1 positivity, p53 negativity and MSS were all associated with increased weight in women. In men, positive expression of cytoplasmatic and nuclear beta-catenin, cyclin D1 positivity and p53 positivity were all associated with increased WHR. Negative expression of betacatenin was associated with increased weight, while there were no associations between any anthropometric factors and cyclin D1 negativity, MSS or MSI status in men. Conclusions: Findings from this large prospective cohort study demonstrate an association between obesity, measured as weight and BMI, and risk of CRC according to the expression of beta-catenin, cyclin D1, p53 and MSI status.

3578


Risk of second primary cancers after treatment for locoregional rectal cancer. Presenting Author: Chaitali Singh Nangia, Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, CA Background: The risk of second primary colorectal cancers among rectal cancer patients has been described, but little is known about the risk of non-colorectal malignancies that may occur in the field of radiation. We attempted to quantify the risk, using data from the large population-based California Cancer Registry (CCR). Methods: We analyzed the CCR data for surgically-treated locoregional rectal cancer cases, diagnosed during the period 1988 –2009. We excluded cases with second primary tumor (SPT) diagnosed within 12 months of initial diagnosis . Radiation treatment used was external beam radiation therapy. Standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated to evaluate risk as compared to the underlying population after matching for age, sex, ethnicity, and time. Results: Of the study cohort of 13,418 rectal cancer cases, 1572 cases of SPTs were observed . The SIR was increased for small intestine cancer among cases receiving radiation treatment (4 cases observed vs. 1.01 cases expected; SIR⫽3.94, 95% CI 1.07-10.10) but not among cases lacking radiation treatment (4 observed vs. 4.45 expected; SIR⫽0.90, 5% CI 0.24-2.30). Among females treated with radiation, the SIR was increased for uterine cancer (12 observed vs. 5.59 expected; SIR⫽2.15, 95% CI 1.11 to 3.75) but not among cases lacking radiation therapy (23 observed vs. 26.17 expected; SIR⫽0.88, 95% CI 0.56-1.32). Among males receiving radiation treatment, the SIR for prostate cancer was decreased (23 observed vs. 69.78 expected; SIR⫽0.33; 95% CI 0.21 to 0.49) but of borderline significance among males lacking radiation therapy (243 observed vs. 276.97 expected; SIR⫽0.88, 95% CI 0.77-0.99). No significant differences were observed for cancers of the vagina, cervix, ovary, kidney, bladder, penis, testes, or leukemia based on prior radiation treatment for rectal cancer. Conclusions: Patients receiving pelvic radiation for treatment of rectal cancer have a subsequently higher than expected incidence of small intestine and uterine cancer. The incidence of prostate cancer appears to fall after pelvic radiation. These unexpected findings suggest complex relationships associated with radiation treatment for rectal cancer and SPT risk.

3580


Survival benefit and complications of primary tumor resection (PTR) in patients with stage IV colorectal cancer (CRC) in the era of modern chemotherapy: A systematic review and meta-analysis. Presenting Author: Shahid Ahmed, Department of Medical Oncology, Saskatoon Cancer Centre, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada Background: Although there is evidences that PTR in advanced CRC may improve outcome, most studies were conducted during the period of monotherapy with 5-fluorouracil. Limited data is available regarding potential benefits and risk of PTR in patients with stage IV CRC treated with modern chemotherapy (MC). A recent phase II study suggested that outcomes are not compromised by leaving the primary colon tumor intact in such patients (JCO.2012;30:3223). Purpose:To compare survival of patients with advanced CRC who underwent PTR with patients without resection in the era of MC. The review also aims to determine post-operative mortality and non-fatal complications rates, primary tumor complications rate (PTCR), non-resection surgical procedures rate (NSPR) and quality of life (QOL). Methods: A literature search was conducted by using CENTRAL (2012), Medline (1946-2012), and EMBASE (1947-2012). Studies involving patients with stage IV CRC who underwent PTR were selected with restriction to publication dates from 2000, English language and human studies. Screening, evaluation of relevant articles and data abstraction was done in duplication and agreement was assessed. Articles that met the inclusion criteria were assessed for quality by using Ottawa-Newcastle score. Data was collected and synthesized as per protocol. Results: Of total of 3,379 reports, 10 retrospective studies were selected with patients population of 2,655. Among 2,655 patients, 1616 (61%) underwent PTR with a median overall survival of 18.7 months (range: 11-30.7) compared with 12.9 months (range: 5.8-22) in the control. The HR for survival was in 0.68 (95% CI: 0.56-0.83) favoring the PTR. Mean 30 days post-operative mortality rate in the PTR group was 3.9% (95% CI: 0-11). Mean PTCR and NSPR in the control group were 27.4% (95% CI: 16.4-38.5) and 27% (95% CI: 12.5-41.6) respectively. No study provided QOL. Conclusions: The retrospective data favors PTR in advanced CRC in the era of modern chemotherapy. Future prospective randomized trials are warranted to confirm the findings.




Phase II study of dacarbazine for metastatic colorectal cancer: Final results with MGMT analysis. Presenting Author: Alessio Amatu, Dipartimento Oncologico, Ospedale Niguarda Ca’ Granda, Milano, Italy Background: O6-methylguanine-DNA-methyltransferase (MGMT) is a DNA repair protein removing mutagenic and cytotoxic adducts from O6-guanine in DNA. Approximately 40% of colorectal cancers (CRCs) display MGMT deficiency due to promoter hypermethylation leading to silencing of the gene. Alkylating agents, such as dacarbazine, exert their antitumor activity by DNA methylation at the O6– guanine site, inducing base pair mismatch, therefore activity of dacarbazine could be enhanced in CRCs lacking MGMT. We conducted a phase II study with dacarbazine in CRCs who had failed standard therapies (oxaliplatin, irinotecan, fluoropyrimidines, and cetuximab or panitumumab if KRAS wild type). Methods: All patients had tumor tissue assessed for MGMT as promoter hypermethylation in doubleblind for treatment outcome. Patients received dacarbazine 250 mg/m2 i.v. qd for 4 consecutive days q21 until PD or intolerable toxicity. We employed a Simon two-stage design to determinate if the ORR would be ⱖ 10%. Secondary endpoints included association of response, PFS and disease control rate with MGMT status. Results: Sixty-eight patients were enrolled from May 2011 to March 2012. Patients received a median of 3 cycles of dacarbazine [range 1-12]. Grade 3-4 toxicities included: fatigue (41%), nausea/vomiting (29%), constipation (25%), platelet count decrease (19%), anemia (18%). Overall, 2 patients (3%) achieved partial response (PR) and 8 patients (12%) had stable disease (SD). Disease control rate (PR⫹SD) was significantly associated with MGMT promoter hypermethylation in the corresponding tumors. Conclusions: Objective clinical responses to dacarbazine in metastatic CRC patients are confined to those tumors harbouring epigenetic inactivation of the DNA repair enzyme MGMT. Clinical trial information: 2011-002080-21.

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Impact of nodal metastasis on survival of stage IV colon cancer: Analysis of National Cancer Data Base (NCDB). Presenting Author: Mohammed Shaik, Hurley Medical Center, Michigan State University, Flint, MI Background: Nodal metastasis (mets) is an important prognostic factor in the staging of colon cancer (CCa). However, the significance of nodal mets in stage IV CCa remains undetermined. Therefore, we investigated the impact of nodal mets on 5 year overall survival (5-yr OS) in stage IV CCa. Methods: Patients (pts) from the NCDB who had been diagnosed with histologically confirmed Stage IVCCa from 1998-2010 were divided into two groups: with(⫹ve) or without(-ve) nodal mets and the 5 yr OS was compared using the Kaplan Meier Curves. Multivariate analysis was performed using CoxProportional regression model. An adjusted hazard ratio(aHR) was calculated for pts with nodal mets compared to those without nodal mets after adjusting for age, grade and tumor size. Results: 70,387 pts from the NCDB with stage IV CCa were included in our analysis. Of these, 12,363(17.5%) had no nodal mets (TN0M1), 23,052(32.7%) had 1-3 nodal mets (TN1M1), and 34,972 (49.69%) had 4 or more nodal mets (TN2M1) involved at the time of diagnosis (Table 1a).The overall nodal positivity was 82.4%. The 5-yrOS of all stage IV pts was 10.7% (Table 1b); 5 yr OS for node -ve pts was 18.4% versus 9.2% for node ⫹ve pts (p⬍0.0001)(Table1b). The 5 yr OS of N1 and N2 was 12% and 7.2%, respectively. The aHR of pts with nodal mets versus without nodal mets was 1.8 (95% CI of 1.7-1.9), after adjusting other prognostic covariates. Conclusions: Stage IV CCa with nodal mets is associated with an increased risk of death compared to node-negative disease. The number of positive lymph nodes at the time of diagnosis is also an important risk factor. 1a. Distribution of nodal status in stage IV. Nodal status Node negative Node positive Total

Number of patients

Nodal positivity

12,363 58,024 70,387

17.6% 82.4% 100%

1b. Five-year overall survival analysis of stage IV*. Overall 5yr OS Survival for node-negative pts Survival for node ⴙve pts Survival for 1-3 LN ⴙ pts Survival for 4 and above LN ⴙ pts

10.76% 18.4% 9.2% 12.1% 7.2%

* p value⬍0.0001.

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Use of tumor size to predict long-term survival in colon cancer patients: Analysis of National Cancer Data Base (NCDB). Presenting Author: Sukamal Saha, McLaren Regional Medical Center, Michigan State University, Flint, MI Background: Tumor size (TS) is a known prognostic factor in breast, renal, and lung cancers, however, not in colon cancer (CCa). Tumor (T) depth, nodal status (N), and metastasis (M) are used in the TNM staging. Hence, we studied if TS is an independent risk factor for death in CCa. Methods: Data included TS, grade, T-stage, N, and M-status from the NCDB for 298,021 CCa pts (1998-2010). We divided pts into 4 groups by TS (⬍2cm;2-4cm;4-6cm;⬎6cm). Data was analyzed using Spearman’s rho correlation (r) and Kaplan-Meier for overall 5-yr survival (5yrOS). Hazard ratios (HR) were calculated using a Cox model adjusting for age, sex, grade, T, N-status and TNM stage. Results: Proportion of pts with TS 0-2, 2-4, 4-6 and ⬎6cm were 13.25%, 38.95%, 29.54%, and 18.26% respectively. Median TS was 4cm. TS was positively correlated with grade, T, N-status and TNM stage (p⫽0.0001) and negatively correlated with 5yrOS (65.5%, 52.4%, 45.5%, and 41.2% for four sizes respectively) (Table). Cox modeling demonstrated TS of 4-6cm and ⬎6cm had HRs of 1.23 (95%CI 1.14-1.34) and 1.7 (95%CI 1.5-1.8) respectively. Conclusions: A primary TS of 4-6cm and ⬎6cm is associated with a 23% and 70% increased risk of death, respectively, over 5-yrs in CCa. Prospective studies are needed to evaluate the role of primary TS in CCa prognosis. Association of tumor size with other variables. Variable T stage

Nodal status TNM staging

5-yr OS

0-2cm (Col%) T1 T2 T3 T4 N0 I II III IV

2-4cm (Col%)

4-6cm (Col%)

>6cm (Col%)

Median size (cm)

16,288(41.3) 8,169(7.0) 1,701(1.9) 798(1.4) 1.9 13,214(33.5) 36,172(31.0) 15,364(17.4) 5,185(9.5) 3.3 8,563(21.7) 62,274(53.5) 58,260(66.1) 34,814(64.2) 4.5 1,329(3.3) 9,757(8.3) 12,772(14.5) 13,361(24.6) 5.5 32,732(83.1) 71,773(61.6) 45,657(51.8) 26,557(49.0) 3.5 N1/N2 6,657(16.9) 44,594(38.3) 42,438(48.1) 27,599(50.9) 2,751(70.0) 39,811(34.2) 14,845(16.8) 5,117(9.4) 3 4,629(11.7) 27,974(24.0) 26,242(29.7) 18,026(33.2) 4.5 4,505(11.4) 25,513(21.9) 20,565(23.3) 12,895(23.8) 4.5 2,748(7 .0) 23,074(19.8) 26,445(30.0) 18,120(33.4) 5 All

65.5%

52.4%

45.5%

41.2%

* Chi-square test with p ⬍ 0.0001; ASE-asymptotic standard error; Col%- column%.

r(ASE)* 0.42(0.0016)

0.18(0.0018) 4.6 0.33(0.0017)

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Primary tumor resection in metastatic colorectal cancer (mCRC): A prospective cohort study. Presenting Author: Shu Fen Wong, Royal Melbourne Hospital, Melbourne, Australia Background: The role of primary tumor resection in patients presenting with mCRC remains controversial. Previously reported survival benefits associated with primary tumor resection may not translate in the modern era of systemic therapies. We examined the impact of primary tumor resection on survival in a modern cohort of mCRC patients. Methods: Patients were identified using a clinician-designed mCRC registry involving 15 participating Australian sites from mid 2009. Patients were excluded if planned for curative metastasectomy or had incomplete data. Univariate logistic regression and multivariate cox regression was utilized to identify significant associations between resection, clinical variables and survival outcomes. Results: We identified 682 mCRC patients with median follow up 20 months. 40% (n ⫽ 275) had their primary in-situ. Rates of primary resection were higher for age ⬎ 70 years (OR 1.66 95% CI [1.22 – 2.26], p ⫽ 0.001) and Charlson score ⱖ3 (OR 1.50 [1.10 – 2.06], p ⫽ 0.011). Lower resection rates were observed for rectal v colon primary (OR 0.39 [0.28 – 0.55], p ⬍ 0.001), liver metastases (OR 0.59 [0.42 – 0.82], p ⫽ 0.002) and ECOG 2 - 4 (OR 0.64 [0.45 – 0.92], p ⫽ 0.015). There was a significant survival advantage for pts with primary tumor resection (median OS 21.3 vs 16.8 months; HR 0.63, p ⬍ 0.001), even when adjusting for known prognostic factors in a multivariate analysis (HR 0.56 [0.44 – 0.72], p ⬍ 0.001). Multivariate analyses also demonstrated that age ⬎ 70 years (HR 1.32 [1.03 – 1.71], p ⫽ 0.031) and ECOG ⱖ 2 (HR 3.17 [2.43 – 4.15], p ⬍ 0.001) were significantly associated with poorer outcomes; whereas chemotherapy use (HR 0.61 [0.45 – 0.84], p ⫽ 0.002), bevacizumab use (HR 0.68 [0.52 – 0.89], p ⫽ 0.005) and rectal primary (HR 0.69 [0.53 – 0.91], p ⫽ 0.009) predicted improved survival. Conclusions: Our study suggests that primary tumor resection is associated with significant survival advantages for mCRC patients in the modern era of systemic therapies. The 40% of primary cancers in-situ is higher than previous mCRC studies and suggests a tendency for non-operative intervention in Australia. Further analysis aimed at examining the impact of other confounding variables such as tumor burden is ongoing and will be presented.


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Small bowel adenocarcinoma phenotyping and prognostic factors. Presenting Author: Thomas Aparicio, Hôpital Avicenne, APHP, Bobigny, France Background: SBA is a rare tumor with poor prognosis. Data regarding SBA molecular alterations are lacking. Methods: We searched for several candidate oncogenic alterations and characterised the immunophenotype according to the primary tumour location in pts with SBA (all stages; ampullary tumours excluded) treated in 11 centres from 1996 to 2008. Tissue microarrays were constructed from tumour samples, and DNA was extracted from formalin-fixed, paraffin-embedded samples. HER2, ␤-catenin, TP53, and mismatch repair (MMR) protein expression was assessed by immunohistochemistry. A molecular analysis assessed microsatellite instability, KRAS mutation and BRAFV600E mutation. Results: We obtained samples from 63 SBA pts (median age, 58 years; tumour stage: I-II, n⫽19 (30%); III, n⫽22 (35%); IV, n⫽20 (32%); locally advanced, n⫽2 (3%)). HER2 overexpression (3⫹) was observed in 2/62 (3%) pts. Overexpression of TP53 was observed in 26/62 (42%) pts. Abnormal expression of ␤-catenin was observed in 12/62 (19%) pts. MMR deficiency (dMMR) was observed in 14/61 (23%) pts, consistent with Lynch syndrome in 7/14 (50%) pts. All of the dMMR tumours were in duodenum or jejunum. Only one of dMMR tumour was stage IV. A KRAS mutation was observed in 21/49 (43%) pts. BRAFV600E mutation was observed in only 1/40 pt. Median overall survival (OS) was 36.6 months (95% confidence interval [CI], 26.9-72.2). In univariate analysis, stage I-II (p⬍0.001) and dMMR phenotype (p⫽0.02) were significantly associated with longer OS. In multivariate analysis, only disease stage independently predicted longer OS (p⬍0.001). For stage IV pts, median OS was 17.9 months (CI, 12.6-36.6). For stage I-III pts median recurrence-free survival (RFS) was 26.7 months (CI: 14.6-42.4). A trend for a better RFS was observed if tumour was dMMR HR: 0.39 (CI, 0.10-1.44], p⫽0.15. Conclusions: This large study suggests that molecular alterations in SBA are closer to those in colorectal cancer (CRC) than those in gastric cancer, with low levels of HER 2 overexpression and high rates of KRAS mutations. The seemingly higher rate of dMMR than in CRC may be explained by the higher frequency of Lynch syndrome in SBA in pts. A trend for good prognosis was associated with dMMR.

3587


The MEK inhibitor selumetinib ([SEL], AZD6244, ARRY-142886) plus irinotecan (IRI) as second-line therapy for KRAS-mutated (KRASm) metastatic colorectal cancer (CRC). Presenting Author: Howard S. Hochster, Yale School of Medicine, New Haven, CT Background: There are fewtherapies for second-line KRASm CRC. Inhibiting downstream signal transduction may offer therapeutic options. Use of selumetinib (MEK 1/2 inhibitor; AstraZeneca) is supported by preclinical and clinical evidence. We designed a dose-finding/phase II study of IRI ⫹ SEL in KRASm CRC. Methods: Eligibility included: KRASm or BRAFm CRC with measurable disease progressing after 1st-line therapy with an oxalipatin ⫹ bevacizumab regimen; PS 0-1; acceptable organ function. Patients (Pts) were treated with IRI 180 mg/m2 iv q2w and SEL 50 or 75 mg po bid. Dose escalation was traditional 3⫹3 (50 mg bid SEL, then 75 mg bid). In Part B/phase II, primary endpoint was PI-determined response rate (RR) by RECIST. A Simon 2-stage design allowed expansion to 45 pts if ⱖ1 responses in 20 pts was seen; ⱖ4/45 responses would be encouraging, when compared to historical RR of 4% (and median PFS 2.5 mo) [EPIC, Sobrero 2008], with approximately 90% power to detect an ORR of 15% at the 10% alpha level (one-sided). Results: N ⫽32 pts entered; 31 treated. Median age was 54 (27-75) yrs; 18 male and 24 Caucasian. The first 3 pts tolerated SEL 50 mg bid without DLT and the remaining 28 were treated at 75 bid. Median number of cycles on study was 3.5 and median PFS was 3.4 mo. Grade 3 AEs included (N): diarrhea 3, fatigue 2, neutropenia 2, and 1 each thrombocytopenia, enteritis, GI bleed, rash. There was one Grade 4 neutropenia. The best PI-reported response included 3 (10%) confirmed PR and 16 (52%) SD [including 1 unconfirmed PR]. 6 patients were on study for more than 6 (up to 22) months. The study was terminated early due to non-protocol considerations. Conclusions: In this small study, the RR of 10% and med PFS of 3.4 mo in pts with KRASm CRC treated with IRI ⫹ SEL in 2nd line are promising compared with prior studies in non-selected patients. MEK inhibition in KRASm CRC should be explored further. Supported in part by AstraZeneca.

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Final results of the AIO 0307 study: A controlled, randomized, doubleblind phase II study of FOLFOX6 or FOLFIRI combined with sorafenib (S) versus placebo (P) in second-line metastatic colorectal carcinoma (mCRC) treatment. Presenting Author: Thomas Hoehler, Department of Medicine I, Prosper Hospital Recklinghausen, Recklinghausen, Germany Background: The oral multikinase inhibitor Sorafenib (S) inhibits angiogenesis and tumor growth in preclinical models of CRC. This study investigated the addition of S to standard 2nd line chemotherapy (CTX). Methods: Patients (pts) with mCRC and progression after first-line therapy with an oxaliplatin- or irinotecan based fluoropyrimidine containing regimen ⫾ Bevacizumab (Bev), were randomized to receive chemotherapy (CTX) (FOLFOX6 or FOLFIRI) ⫹ S (400 mg bid) or CTX ⫹ placebo (P). 240 pts were planned to be enrolled to ensure a power of 80% if median progression-free survival (PFS) with S is increased by 2 months compared to P. Results: Between 04/09 and 10/11, 101 pts were enrolled. Recruitment was stopped prematurely due to slow accrual. 97 pts were evaluable in the full analysis set. Median age was 65 years, 60 pts were male, 97% with ECOG 0 or 1. Median PFS was 5.2 months (mths) in S and 5.6 mths in P (HR 0.84, 90% CI 0.58, 1.22, p⫽0.439). Best response rate was 25.6% and 12.2% (p⫽0.106), respectively. Disease control rates were comparable. Median overall survival (OS) was 9.6 mths with S compared to 12.7 mths with P (HR 1.57, 90% CI 1.03, 2.41, p ⫽ 0.076). Difference in OS was even more pronounced in subgroup (n⫽41) with FOLFOX6 backbone (9.6 vs. 13.8 mths, HR 2.37, 90% CI 1.22, 4.60, p⫽0.026). In 69 Bev-pretreated pts OS was 8.4 vs. 14.9 mths (HR 2.30; 90% CI 1.36, 3.88, p⫽0.007) compared to 13.1 vs. 7.4 mths (HR⫽0.61; 90% CI 0.28, 1.36, p⫽0.308) in 28 pts without Bev pretreatment. Adverse events (AEs) were consistent with the known safety profiles. Most frequent grade 3/4 AEs affected the gastrointestinal tract (diarrhea, mucositis/stomatitis, nausea); other frequent severe AEs included neutropenia and leukopenia, fatigue, fever, sensory neuropathy, and thrombosis. Conclusions: No unexpected safety concerns occurred during the course of the study. S did not lead to improved PFS. There was a detrimental effect of S on OS in patients with Bev pretreatment. Clinical trial information: 2008-000803-26.

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Peripheral blood monocytes as biomarkers for colorectal cancer. Presenting Author: Hans Prenen, Digestive Oncology Unit, University Hospitals Leuven, Department of Oncology, KU Leuven, Leuven, Belgium Background: Peripheral blood monocytes (PBM) represent a reservoir of inflammatory cells that contribute to cancer progression. When recruited into tumors, monocytes give rise to either macrophages or dendritic cells. Tumor-derived soluble factors can influence the differentiation of tumorassociated macrophages (TAMs) and drive their phenotype to either tumoricidal (M1) or pro-tumorigenic macrophages (M2). We hypothesized that PBM might change their phenotype already when in circulation and can be used as potential markers for early diagnosis of colorectal cancer (CRC) and its progression to metastatic disease. Methods: Monocytes were isolated by using magnetic microbeads conjugated to antibodies against CD14. In a monocentric training set we included 55 (27 non metastatic (NM), 38 metastatic (M)) untreated CRC patients. The third group included age and gender matched healthy volunteers (HV). Following RNA extraction, gene expression profiles of PBM were investigated by high throughput screening using Illumina. Statistical analysis was done on the microarray expression data to delineate a disease specific signature. A cut off was set to select the genes showing a minimum fold change of 1,5. A validation study was performed in three additional major oncological centers throughout Europe. Results: There was a broad overlap in the gene signature of PBM from NM and M patients, indicating that this signature already exists in an early stage. Then we assessed the performance of the gene signature of cancer versus HV as diagnostic tool, in particular the sensitivity and specificity, which were remarkably high in the ROC analysis. Out of 40 differentially expressed genes, 21 genes were confirmed by qRT-PCR analysis on samples processed independently. In the validation study the number of genes was downsized to a 12 gene signature without loss of specificity and sensitivity. Conclusions: This first biomarker study of PBM in CRC suggests an ‘imprinting’ of PBM by the tumor in CRC patients. Since the imprinting profile might also be reversed, the PBM signature might not only be useful in CRC diagnosis, but also for the follow-up of treated CRC patients. Overall, our data offer new opportunities to develop a non-invasive test for CRC detection and monitoring.




Correlation of hypertension and proteinuria with outcomes in elderly bevacizumab (BEV)-treated patients with metastatic colorectal cancer (mCRC): Analysis of the BECOX and BECA studies. Presenting Author: Antonieta Salud Salvia, Hospital Arnau de Vilanova, Lleida, Spain Background: Studies suggest a relationship between hypertension, which is common in older patients, and outcome in BEV-treated patients with mCRC. We performed a retrospective analysis of two studies – BECA [Feliu et al BJC 2010; EudraCT 2005-002808-42] and BECOX [NCT01067053] – to determine if hypertension and proteinuria predict outcome in elderly BEV-treated patients. Methods: Patients ⱖ70 years received capecitabine 1250 mg/m2 bid po on days 1–14 ⫹ BEV 7.5 mg/kg on day 1 every 21 days in the BECA study; BECOX patients received capecitabine 1000 mg/m2 bid po on days 1–14 with BEV 7.5 mg/kg and oxaliplatin 130 mg/m2 on day 1 (oxaliplatin discontinued after cycle 6). Primary endpoints were overall response rate (ORR) in BECA and time to progression (TTP) in BECOX. Correlations were investigated for hypertension and proteinuria with ORR, disease control rate (DCR), overall survival (OS) and TTP. Logistic regression was performed to identify factors associated with hypertension and proteinuria. Results: 127 patients were included (BECA n⫽59; BECOX n⫽68; 61% male, median age 76 years; ECOG PS 0/1/2 45%/52%/2%). During the study 16% of patients had hypertension and 61% had proteinuria as an adverse event. Hypertension correlated with DCR, OS and TTP but not ORR; proteinuria correlated with ORR and DCR (Table). Development of proteinuria or hypertension in the first 2 cycles did not correlate with efficacy. Risk factors associated with development of hypertension were female gender (odds ratio [OR] 0.241; p⫽0.011) and greater no. of BEV cycles (OR 1.112; p⫽0.002); factors associated with proteinuria were diabetes (OR 3.869; p⫽0.006) and greater no. of BEV cycles (OR 1.181; p⬍0.0001). Conclusions: This analysis of the BECOX and BECA studies suggests that hypertension and proteinuria are associated with outcome in BEV-treated elderly patients with mCRC. Clinical trial information: NCT01067053. Hypertension

Proteinuria

Outcome

Yes (nⴝ20)

No (nⴝ107)

p

Yes (nⴝ77)

No (nⴝ50)

p

Median OS, mo Median TTP, mo ORR, % DCR, %

NR 14.0 50 95

16.9 10.6 37 71

0.012a 0.174a 0.325b 0.024b

22.0 13.0 47 86

20.1 7.4 28 58

0.211a 0.063a 0.042b 0.001b

aLog-rank

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Impact of M1a and M1b staging in patients (pts) with metastatic colorectal cancer. Presenting Author: Hagen F. Kennecke, British Columbia Cancer Agency, Vancouver, BC, Canada Background: In 2009, pts with M1 colorectal cancer were divided into two subsets for the American Joint Committee on Cancer (AJCC) 7th edition. Pts with metastases (mets) confined to one organ or site at initial diagnosis became stage M1a while multiple sites or peritoneal mets became M1b. The objectives of the study are to evaluate the impact of site of mets and M1a/b staging among pts with M1 colorectal cancer. Methods: All pts referred to the BC Cancer Agency from 1999-2007 with newly diagnosed M1 colon or rectal cancer were included. Demographic, treatment, and outcome data were prospectively collected. The prognostic impact of individual sites of mets was assessed by hazard ratio estimates from univariate Cox models. Multivariable Cox proportional-hazards models were used to determine variables associated with overall survival in the entire cohort and in those undergoing resection of their primary tumor. Results: 2,049 pts with M1 disease were included. Median age was 66 years; 71% had colonic origin; 70% had their primary tumor resected; and 69% received chemotherapy. In univariate analysis, solitary mets were associated with improved survival. In multivariable analysis, M1a/b status still had significant prognostic effect. The effect remained significant in the subgroup analysis of pts with resected primary tumors when histology, T and N stage were included. Conclusions: Pts with solitary mets, including peritoneum, have superior overall survival as compared to those with multiple sites of mets. AJCC 7th edition staging that includes M1a/b provides significant prognostic information and should be considered in clinical practice and trials of pts with M1 disease who otherwise have few prognostic factors. Univariate analysis: Site of mets

Multivariate analysis: M1a/b status and standard prognostic variables

Site of mets Multiple

HR [95% CI] 1.0 Referent

Solitary liver Solitary lung

HR⫽0.62 [0.56, 0.69] HR⫽0.50 [0.40, 0.62]

Solitary peritoneal

HR⫽0.70 [0.54, 0.91]

Solitary other

HR⫽0.70 [0.57, 0.86]

Variable Resected yes vs no M1b vs M1a Age: ⬎70 vs ⬍⫽70 ECOG 2 vs 0-1 ECOG 3-4 vs 0-1

P value ⬍0.0001

HR [95% CI] 0.46 [0.41,0.52]

⬍0.0001 ⬍0.0001

1.38 [1.22,1.55] 1.32 [1.18,1.47]

⬍0.0001

1.64 [1.43,1.88]

⬍0.0001

3.49 [3.02,4.02]

test. bFisher’s exact test. NR, not reached.


Prognostic stratification of k-RAS wild type colorectal cancer patients receiving irinotecan-cetuximab treatment: Preliminary results of a prospective study. Presenting Author: Mario Scartozzi, Medical Oncology, AO Ospedali Riuniti-UNIVPM, Ancona, Italy Background: Translational research identified numerous putative markers for a “beyond-k-RAS” selection of colorectal cancer patients receiving cetuximab, but none of these entered clinical practice mainly because prospective validation is lacking. The aim of our study was to evaluate whether a panel of biomarkers, prospectively analysed may be able to predict patients’ clinical outcome more accurately than k-RAS status alone. Methods: Metastatic, K-RAS wild type colorectal cancer patients, candidate to receive second/third-line cetuximab with chemotherapy have been prospectively allocated, after informed consent, into 2 groups on the basis of their genetic profile: favourable (BRAF and PIK3CA exon 20 wild type, EGFR GCN ⱖ 2.6, HER-3 Rajkumar score ⱕ 8, IGF-1 immunostaining ⬍ 2) and unfavourable (any of the previous markers altered or mutated). All patients received cetuximab treatment as planned by treating physician who was unaware of biomarkers results. To detect a difference in terms of response rate (RR) among patients with an unfavourable profile (estimated around 25%) and patients with a favourable profile (estimated around 60%), assuming a probability alpha of 0.05 and beta of 0.05, required sample size will be 46 patients. Results: 31 patients have been enrolled, most patients (27, 86%) received cetuximab as third-line. Eleven patients (35%) were allocated to the favourable profile and 20 patients (75%) to the unfavourable profile. Patients with the unfavourable profile showed 1 BRAF mutation, 2 PIK3CA exon 20 mutations, 12 cases of EGFR GCN ⬍ 2.6, 13 cases of HER-3 and 11 cases of IGF-1 overexpression respectively. RR in the favourable and unfavourable group was 7/11 (64%) and 1/20 (5%) (p⫽ 0.008) respectively. The favourable group also showed an improved median TTP (8 months vs. 2.6 months, p ⫽ 0.0007) and OS (16 months vs. 6 months, p ⫽ 0.0002). Conclusions: Our results suggest that prospective selection of candidates for cetuximab may be able to improve clinical outcome in patients with a favourable profile. This approach, if confirmed, may also allow an early switch to alternative treatment in patients with an unfavourable profile.

3592


Association of body mass index (BMI) with overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) who received targeted therapies (TT). Presenting Author: Gargi Surendra Patel, Deptartment of Medical Oncology, Flinders Centre for Innovation in Cancer, Flinders Medical Centre, Adelaide, Australia Background: Preclinical data suggest that adiposity activates pro-inflammatory and insulin-dependent pathways which may lead to resistance to TT, e.g., bevacizumab (Bev) or cetuximab (Cet). Only two retrospective trials have studied the relationship between BMI and outcome for mCRC pts who received TT, with conflicting results. Our aim was to compare OS across BMI groups for mCRC pts treated with TT. Methods: Retrospective data, pertaining to clinical characteristics and outcome, were obtained from the South Australian Registry for mCRC from Feb 2006-Oct 2012. The BMI at first treatment was grouped as Normal (N) ⫽ 18.5- ⬍25, Overweight (OW) ⫽ 25- ⬍30, Obese I(Ob1) ⫽ 30- ⬍35, Obese II (Ob2)ⱖ35. Results: Of 1,174 pts, 39% were OW, 15% Ob1 and 7% Ob2. 352 pts received chemo⫹TT (Bev, Cet, panitumumab (Pan) and/or regorafenib) and 814 chemo alone. Baseline characteristics were similar across all BMI groups except for type of mCRC: N pts were more likely than obese pts to have synchronous CRC (77.9% vs 56-69.7% for obese). On adjustment for age, sex, synchronous disease, metastatic sites, number of lines of chemo and TT, median OS was longer for N versus OW or Ob1 pts with chemo⫹TT (35.4 vs 24.9 or 22.7 mons, Table) with no difference in OS for chemo alone. Only N gp pts had an improvement in OS on the addition of TT to chemo. On breakdown by type of TT, OW and Ob1 pts had a poorer outcome with Bev but not with EGFR TT. Conclusions: The BMI is an independent predictor for a poorer outcome for OW and OB1 pts with chemo⫹TT, specifically for pts receiving Bev. The OW and OB1 patients may be a target group for lifestyle and nutrition advice to improve OS with TT. Prospective studies are required to validate this finding. Hazard ratios and median OS. All TT (nⴝ352) N OW Ob1 Ob2 VEGF TT (nⴝ200) N OW Ob1 Ob2 EGFR TT (nⴝ106) N OW Ob1 Ob2

HR

P value

95% CI

Median OS (months)

R 1.86 1.85 1.28

0.001 0.011 0.435

1.29-2.69 1.15-2.96 0.69-2.35

35.4 24.9 22.7 30.6

R 2.08 2.67 0.81

0.001 0.004 0.677

1.35-3.21 1.37-5.20 0.30-2.21

36.1 17.5 16.0 63.5

R 1.33 0.95 1.90

0.356 0.900 0.230

0.72-2.47 0.39-2.27 0.67-5.38

40.8 30.3 41.6 31.8


228s 3593


3594


Natural history and outcomes of synchronous and metachronous colorectal cancers (CRC): A population-based analysis. Presenting Author: Jackson Chu, University of British Columbia, Vancouver, BC, Canada

Estrogen and colorectal cancer incidence and mortality in the Women’s Health Initiative clinical trial. Presenting Author: Sayeh Moazami Lavasani, Karmanos Cancer Institute, Wayne State University, Detroit, MI

Background: Early data suggest that synchronous and metachronous CRC portend a worse prognosis when compared to solitary CRC. Our aims were to 1) characterize the clinical features and treatment patterns of synchronous and metachronous CRC and 2) compare their survival outcomes with those of solitary CRC. Methods: All patients diagnosed with non-metastatic CRC between 1999 and 2008 and referred to any 1 of 5 regional cancer centers in British Columbia, Canada were reviewed. Synchronous and metachronous CRC were defined as multiple (2 or more) distinct tumors that were diagnosed within and beyond 6 months of the date of index CRC diagnosis, respectively, during the study period. Patients with liver metastases at initial diagnosis were excluded. Kaplan-Meier and Cox regression analyses were used to estimate survival among the different CRC groups. Results: A total of 6360 patients were identified: 6147 (96%) solitary, 178 (3%) synchronous and 35 (1%) metachronous tumors; median age was 68 years (IQR 59-76); 57% were men; and 75% were ECOG 0/1 at the time of index cancer diagnosis. Baseline demographic characteristics were comparable across patients (all p⬎0.05). Compared with solitary CRC, synchronous and metachronous CRC more commonly affected the colon rather than the rectum (84 vs 85 vs 59%, respectively, p⬍0.001), but presenting symptoms, treatment approaches, and use of chemotherapy, radiation and surgery were similar among the different tumor groups (all p⬎0.05). In terms of survival, no differences were observed in 3-year relapse free survival (66 vs 66 vs 56%, p⫽0.20), 5-year cancer specific survival (69 vs 69 vs 53%, p⫽0.34) and 5-year overall survival (62 vs 59 vs 49%, p⫽0.74) for solitary, synchronous and metachronous CRC, respectively. These findings persisted after controlling for known prognostic factors, such as age and ECOG. Conclusions: In this large population-based cohort, there were no differences in survival outcomes among solitary, synchronous and metachronous CRC. Patients who present with multiple tumors in the colon or the rectum should be managed similarly to those who present with an isolated tumor.

Background: The preponderance of observational studies associate estrogen alone use with lower colorectal cancer incidence. In contrast, no difference in colorectal cancer incidence was seen in the Women’s Health Initiative (WHI) randomized, controlled trial (RCT) of estrogen versus placebo after 7.1 years mean intervention. We now assess the influence of estrogen alone use on longer-term colorectal cancer incidence and mortality after an additional 5.6 years post-intervention follow-up. Methods: The WHI study was a randomized, double-blind, placebo-controlled clinical trial involving 10,739 postmenopausal women who had undergone prior hysterectomy and who were randomly assigned to receive daily 0.625 conjugated equine estrogen (n ⫽ 5279) or matching placebo (n ⫽ 5409). Colorectal cancer diagnosis rates and mortality were assessed after a mean of 7.1 years (standard deviation [SD] 1.1) of intervention and 12.7 years follow-up. Results: Colorectal cancer incidence in the treatment and control groups were almost equivalent, 0.15% diagnoses/year v 0.13% in the estrogen therapy arm and the placebo group, respectively (Hazard ratio [HR], 1.12; 95% Confidence Interval [CI], 0.83-1.52; P ⫽ 0.46). Bowel screening examinations were comparable in both groups throughout. For women age 70-79 at study entry, hormone therapy was associated with an increased risk of colorectal cancer, HR 1.71; 95% CI, (1.02-2.86). For women age 50-59 and 60-69, the respective HR’s and 95% CI were 0.86 (0.43-1.71) and 0.98 (0.64-1.49), p-interaction 0.165. For women with a waist circumference of ⬎ 88 cm, there was an increased risk of colorectal cancer, HR 1.53; 95% CI, 0.95-2.45 compared to 0.95 (0.66-1.39) for waist circumference of ⬍ 88 cm, p-interaction 0.124. Although not statistically significant, there was a higher number of colorectal cancer deaths in the hormone therapy arm (33 v 24 deaths; 0.05% v 0.04%; HR, 1.42; 95% CI, 0.84-2.41; P ⫽ 0.19). Conclusions: There were no significant differences in colorectal cancer incidence or mortality after long-term follow-up in the WHI RCT of conjugated equine estrogen. There was a suggestion of an elevation in colorectal cancer risk among older women randomized to estrogen. Clinical trial information: NCT00000611.

3595

3596



A phase II trial of salvage treatment with gemcitabine and S-1 combination in heavily pretreated patients with metastatic colorectal cancer. Presenting Author: Sun Jin Sym, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, South Korea

A French multifactorial prospective study of tumor protein and genetic markers in stage I-III colorectal cancer (CRC): Highlight on molecular characteristics related to mismatch repair (MMR) status. Presenting Author: Gerard Milano, Centre Antoine Lacassagne, Nice, France

Background: We conducted a phase II trial of gemcitabine with S-1 to evaluate the activity and toxicity of such a combination in heavily pre-treated patients (pts) with metastatic colorectal cancer (mCRC) who have progressed after treatment with fluoropyrimidines-, oxaliplatin- and irinotecan-containing regimens. Methods: 36 pts were enrolled, with the following characteristics: 19 females (53%), median age 57 (28-72), 30 EOGO PS 0-1 (83%). S-1 was given orally (30 mg/m2) b.i.d for 14 consecutive days and gemcitabine (1000 mg/m2) was given on days 1 and 8, every 21 days, until disease progression and for a maximum of 9 cycles. The primary endpoint was objective response rate (ORR). Results: The median number of cycles was 5 (range 1-9), ORR was 16.7% (95% confidence interval [CI] 4.5-28.9%) and disease control rate was 61.1% (95% CI 45.2-77.0%) with 6 partial responses and 16 stable diseases. Median duration of disease control was 5.8 months (95% CI 4.1-7.5 months). Median progression-free survival was 3.7 months (95% CI 2.2-5.2 months) and median overall survival was 10.0 months (95% CI 7.4-12.7 months). Grade 3-4 toxicities were rare (neutropenia 12%, anemia 11%, leucopenia 6%, thrombocytopenia 3% and diarrhea 3%). Conclusions: Combination chemotherapy with gemcitabine and S-1 was a convenient, well tolerated and efficacious for heavily pre-treated pts with mCRC. This regimen warrants further evaluation in pts with good PS but no further treatment options.

Background: There is still a need to identify prognostic markers in stage II CRC for setting up adjuvant treatment. The prognostic value of tumor genetic and protein markers was analyzed in CRC patients, as well as relationships between markers. Given the strong prognostic and predictive value of deficient MMR (dMMR), we examined whether dMMR tumors had a distinct protein profile as compared to proficient (pMMR) tumors. Methods: This prospective multicentric study involved 251 stage I-II-III CRC patients with complete surgical resection. Primary end-point was disease free survival (DFS, 60 events, median follow-up 88 months). Biomarkers analyzed on frozen primary tumors were: MMR status (bat 25, bat 26), mutations of KRAS (codons 12-13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4-9), CIMP status, ploidy, S-phase fraction, LOH (8p, 17p, 18q), EGFR (ligand-binding assay), VEGFA expression (Elisa), thymidylate synthase (TS) enzyme activity and expression (RT-PCR), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions (RT-PCR). Results: 30 stages I, 116 stages II and 105 stages III were included (FUFOL adjuvant treatment in 30 stages II and 61 stages III). 14% were dMMR. Multivariate Cox analyses showed that tumor staging was the only significant predictor of DFS. Log Rank analyses restricted to stage III showed tendencies for a shorter DFS in KRAS-mutated (p⫽0.005), BRAF wt (p⫽0.009) and pMMR tumors (p⫽0.036). dMMR tumors significantly expressed elevated TS (median 3.1 vs 1.4) and TP (median 5.8 vs 3.5) expression relative to pMMR (p⬍0.001) and tended to express higher DPD expression (median 14.9 vs 7.9, p⫽0.027) and EGFR content (median 69 vs 38, p⫽0.037) relative to pMMR. Conclusions: The present data, suggesting for the first time that both TS (5FU target) and DPD (FU catabolism enzyme) are overexpressed in dMMR tumors, bring strong arguments to explain the resistance of dMMR CRC tumors to FU-based therapy. The fact that dMMR tumors tend to express elevated EGFR levels and are prone to be KRAS wt suggests that anti-EGFR may be a relevant therapy in these patients. Clinical trial information: 1997.CHUNice-948.




Prognostic significance of tumor stromal and epithelial claudin 2 in metastatic colorectal cancer. Presenting Author: Artur Mezheyeuski, 1)Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden 2)Department of Pathology, Belarusian State Medical University, Minsk, Belarus, Stockholm, Sweden Background: Tight junctions (TJ) are the most apical epithelial cell– cell adhesions. Claudin super-family trans-membrane proteins, including claudin 2 (cl2), are important components of TJs. Expression of cl2 has been reported to be elevated in colorectal cancer (CRC) and its up-regulation increases tumorigenicity of CRC cells in vitro. The aim of this study was to analyze the prognostic significance of cl2 in CRC. Methods: A tissue microarray (TMA) from the stage IV CRC patients of the phase III NORDIC-VII study was used. Cl2 IHC staining was evaluated in a semiquantitative manner in cancer cells (cl2-C) and in the tumor stroma (cl2-S). Primary fibroblasts were established from human CRC tumor tissue and non-tumor colon tissue, and evaluated by immunoblotting. Results: Analyses of the TMA derived from the NORDIC-VII cohort revealed that cancer cell expression and tumor stroma expression of cl2 was associated with shorter OS in a Log-Rank test for trend (cl2-C, n⫽315, p⫽0.018; cl2-S, n⫽319, p⫽0.020). Expression of cl2-S, but not cl2-C was prognostic in multivariate analysis including WHO performance status, alkaline phosphatase level and BRAF mutation status (HR⫽1.30; 95% CI 1.08-1.56; p⫽0.006). When cl2-C and cl2-S expression was combined the prognostic significance was increased. The group with high cl2-C and high cl2-S (N⫽182), when compared with the rest of the cases (n⫽129), displayed a worse prognosis in terms of OS (19.1 mo vs 27.2 mo; p⫽0.003) in univariate analyses (HR⫽1.55, 95% CI 1.16-2.08, p⫽0.003) and in multivariate analyses (HR⫽1.52, 95% CI 1.13-2.05, p⫽0.006). Immunoblotting analysis of primary cultures of fibroblasts confirmed cl2 expression in fibroblasts from CRC tissue and from non-tumor tissue, with higher expression observed in the tumor fibroblasts. Conclusions: CRC display a previously un-reported stromal expression of cl2 of prognostic significance. High cl2-S is associated with worse prognosis in patients with metastatic CRC, in a manner independent of WHO status, alkaline phosphatase levels and BRAF status. Furthermore, high expression of cl2 in both cancer cells and the tumor stroma is also associated with poor prognosis.

3599


Hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil, and oxaliplatin plus intravenous cetuximab (Cet) (Optiliv) after failure on one versus two or three chemotherapy protocols in patients (pts) with unresectable liver metastases from wt KRAS colorectal cancer (LM-CRC) (European phase II clinical trial NCT00852228). Presenting Author: Michel Ducreux, Institut Gustave Roussy, Villejuif, France Background: Optiliv allowed complete macroscopic resection (R0-R1) of previously unresectable LM-CRC in 28% of the pts, despite failure of 1-3 prior chemotherapy protocols (Lévi et al. Proc ASCO GI 2013). Purpose: To assess tolerability and efficacy of Optiliv according to previous chemotherapy exposure. Methods: Pts received iv Cet (500 mg/m²) and chronomodulated or conventional HAI of Irinotecan (180 mg/m²), 5-Fluorouracil (2800 mg/m²), and Oxaliplatin (85 mg/m²) q2 wks. Liver surgery was performed according to q6wks multidisciplinary reviews. Pts were categorized according to Optiliv as 2nd (N⫽29 pts) vs 3rd-4th chemotherapy line (N⫽35 pts). Results: Pt characteristics were similar in both groups. Overall, there were 22F and 42 M, aged 33-76 years, with good PS (0/1/2: 40/22/2) and predominantly liver lesions. LM-CRC were bilateral in 51 pts (79.7%), with a median of 10 metastases (1-50), 6 segments involved (1-8), and largest diameter of 52 mm (15-172). 61 pts (2nd line, 27; 3rd-4th line, 34) received a median of 6 courses (1-15). Grade 3-4 toxicities per pt were similar in both groups except for abdominal pain (2nd line, 15% vs 3rd-4th line, 35%, p⫽0.07), diarrhea (7% vs 24%, p⫽0.09), thrombocytopenia and febrile neutropenia (0 vs 9%, p⫽0.25). Four CR were achieved in 2nd line (15%) vs none in 3rd-4th line. Respective objective response rates were 63% and 38% (p⫽0.05). R0-R1 resections were performed in 11/27 pts (41%) on 2nd line vs 6/34 pts (18%) on 3rd-4th line (p⫽0.06), resulting in respective median progression-free survival (PFS) of 14.2 months [7.8 - 20.7] vs 7.3 [5.5 - 9.1] (p⫽0.002). Median overall survival (OS) was not reached at 3 years in the pts on Optiliv as 2nd line vs 15.2 months in the more heavily pretreated pts (p⬍0.001). Conclusions: Intravenous Cet and triplet hepatic artery infusion resulted in the doubling of secondary surgical resection rate of LM-CRC, PFS and OS in 2nd lineas compared to 3rd-4th line. Optiliv now deserves upfront testing. Clinical trial information: NCT00852228.

3598

229s


Aspirin use and survival outcomes in patients (pts) with PIK3CA mutant colorectal cancer (CRC). Presenting Author: Ben Tran, Royal Melbourne Hospital, Melbourne, Australia Background: Aspirin has an established role in preventing CRC. Recent data suggests aspirin use may also benefit a subset of pts diagnosed with CRC. In one series, the authors identified PIK3CA mutations as a potential predictive biomarker for aspirin use, reporting that PIK3CA mutant CRC pts receiving aspirin had superior cancer specific survival (CSS) compared to those not receiving aspirin (HR 0.18, p⬍0.001), whereas in pts with wildtype PIK3CA, aspirin had no survival impact. Our study aims to confirm the survival benefit associated with aspirin use in pts with PIK3CA mutant CRC. Methods: A cohort of CRC pts with PIK3CA mutations (Sanger sequencing) was identified. Prospectively collected clinicopathological, treatment and outcome data was available. Aspirin use was confirmed by chart review. CSS and overall survival (OS) analyses were conducted using Cox proportional hazards in univariate and multivariate settings. Recurrence free survival (RFS) analyses were limited to early stage CRC pts (Stage A-C). Statistical differences in 5-year CSS (5YS) rates were calculated using Fisher’s exact test. Results: From a cohort of 1,019 CRC pts with known PIK3CA mutation status, 121 (12%) harbored PIK3CA mutations. Of these, 112 (92%) had aspirin usage data available: 27 (24%) pts used aspirin, 85 (76%) did not. In the aspirin group, there were 22 (81%) early stage and 5 (19%) metastatic CRC pts; in the no-aspirin group, there were 59 (69%) early stage and 26 (31%) metastatic CRC pts. In univariate analyses, aspirin use was not associated with superior CSS (HR 0.57, p⫽0.21), OS (HR 0.83, p⫽0.57), or RFS (HR 0.72, p⫽0.57). In multivariate analyses, aspirin use was not associated with improved OS (HR 1.07, p⫽0.86), CSS (HR 1.04, p⫽0.94) or RFS (HR 0.54, p⫽0.34). In 69 (62%) pts with mature follow-up, there was a trend towards superior 5YS for aspirin users (69% v 42%, p⫽0.09), but this may reflect imbalances in stage at diagnosis. Conclusions: Our study was unable to confirm the recently reported survival benefit associated with aspirin use in pts with PIK3CA mutant CRC. Given the small numbers of pts, a modest survival benefit associated with aspirin use cannot be excluded. Analyses in an expanded cohort of early stage pts are underway.

3600


A phase II, randomized, double blind comparison of calcium aluminosilicate clay (CASAD) versus placebo (dibasic calcium carbonate) for the prevention of diarrhea in patients (pts) with metastatic colorectal cancer (mCRC) treated with irinotecan (I). Presenting Author: Bryan K. Kee, The University of Texas MD Anderson Cancer Center, Houston, TX Background: CASAD is a naturally occurring calcium montmorrilonite clay that serves as a cation exchange absorbent. One of the active metabolites of Irinotecan is SN-38, which is adsorbed by CASAD in vitro. The study hypothesis was that oral CASAD would reduce the rate of grade 3/4 diarrhea in mCRC patients treated with irinotecan. Methods: The study is a multicenter, prospective, randomized, double blinded placebo-controlled phase II trial. One hundred patients receiving I-based chemotherapy were randomized equally between CASAD (1000 mg po 4x daily) and placebo in order to have 75% power to detect a difference in the proportions of patients with grade 3/4 diarrhea within 6 weeks at a 1-sided 5% significance level. We also compared symptom burden using the MDASI questionnaire summed over the 13 symptom items for weeks 0, 3, 5, and 6. Results: Between 5/2009 and 5/2012, 100 patients were randomized in a 1:1 ratio between study arms. Median age 57 yrs, 54% male, 74% Non-Hispanic White, 93% performance status 0 or 1. Serious diarrhea was less frequent than expected based upon prior studies with Irinotecan. In evaluable patients, no significant difference in the rate of G3/4 diarrhea was seen (the primary endpoint): CASAD arm: 7/43 pts (16%), Placebo arm: 3/32 pts (9%), p⫽0.70. The rate of any diarrhea among all pts was also similar: CASAD arm 64% vs. Placebo arm 70%. The rate of study dropout was 14% in CASAD and 38% for placebo (p⫽0.01; 2-sided). No differences were found in symptom burden or individual symptom items or serious adverse events. Conclusions: Compared with placebo, CASAD use was safe but ineffective in preventing diarrhea in mCRC patients treated with irinotecan-containing chemotherapy regimens. There were no favorable or unfavorable signals in terms of the patient experience related to symptoms, but there were significantly more dropouts in the placebo arm. Future CASAD trials are focused on active treatment of diarrhea. Clinical trial information: NCT00748215.


230s 3601


3602


Prevention of 5-FU-induced health-threatening toxicity by pretherapeutic DPD deficiency screening: Medical and economic assessment of a multiparametric approach. Presenting Author: Michele Boisdron-Celle, Institut de Cancérologie de l’Ouest Paul Papin, Département d’Oncopharmacologie, INSERM U892, Angers, France

Prospective analysis of the early modulation of plasma amphiregulin (AR) during treatment with cetuximab and irinotecan in irinotecan-refractory metastatic colorectal cancer (mCRC) patients (pts). Presenting Author: Chiara Cremolini, U.O. Oncologia Medica 2, Azienda OspedalieroUniversitaria Pisana, Istituto Toscano Tumori, Pisa, Italy

Background: While 5-FU is the foundation of many in GI oncology treatments, pts with DPD deficiency can experience early-onset severe (5%) even fatal (0.3%) toxicities. This study aimed to confirm the pharmaco-economic benefits of pre-therapeutic screening for DPD deficiency using a multiparametric approach in a multicenter prospective cohort study (NCT01547923). Methods: Two parallel cohorts of pts treated with 5-FU-based chemotherapy for colorectal carcinoma were compared: Group A: initial DPD deficiency screening; Group B: no evaluation. Enrollment was based on 5-FU administration guidelines of each institution. DPD deficiency screening combined genotyping and phenotyping (ODPM Tox) (1,2,3). The 2 groups were to be compared in terms of early 5-FU-induced toxicity grade, toxicity cost and DPD screening cost. The enrollment was to be immediately closed in the case of proven 5-FU-related toxic death. Results: 1,130 pts were included from 06/01/2008 to 07/31/2012. Group A: no severe toxicity despite 1 pt with complete deficiency (pt not treated with 5-FU), 20 pts with partial deficiency had safe PK-monitored 5-FU (ODPM Protocol) with only one hospitalization due to toxicity. Group B: One death due to complete DPD deficiency, confirmed retrospectively. Enrollment prematurely closed after experts’ unanimous decision citing ethical concerns. 21 pts with partial DPD deficiency. 5 reported toxicity-related hospitalizations. Data treatment is ongoing. Conclusions: One complete deficiency occurred in both groups: Group A pt had safe treatment whereas Group B pt died due to 5-FU toxicity. Pre-therapeutic DPD deficiency screening using this multi-parametric approach should be performed before 5-FU-based treatment and PKguided dose adaptation allows for safe treatment of even partially DPD deficient patients. Clinical trial information: NCT01547923.

Background: The potential role of AR tissue levels in the prediction of benefit from anti-EGFRs in mCRC pts was suggested by retrospective series. Preclinical and preliminary clinical experiences showed a modulation of plasma EGFR ligands during the treatment with cetuximab. Previous data by our group evidenced that a significant increase of plasma AR occurred one hour after the administration of cetuximab and higher increases were associated with worse clinical outcome in KRAS and BRAFwt irinotecan-refractory mCRC pts receiving cetuximab and irinotecan. Methods: We designed a prospective confirmatory study in the same setting of mCRC pts. To detect a HR for PFS of 2.3 for pts with high AR levels one hour after the administration of cetuximab (1hr-AR) compared to those with low levels, with two-sided a⫽0.05 and b⫽0.2, 45 events were required. The median value was adopted as cut-off. Plasma AR levels were assessed by means of validated ELISA kits. Results: Forty-nine KRAS and BRAFwt pts were included. A significant early increase of AR levels was observed (median increase ⫹24.7%; median levels of baseline AR and 1hr-AR: 18.06 and 24.06 pg/mL, respectively; Wilcoxon signed rank test, p⬍0.0001). At a median follow-up of 20.4 mos, median PFS and OS were 4.6 and 12.1 mos, respectively. No differences in PFS or OS were observed according to 1hr-AR levels (median PFS 5.5 vs 4.6 mos, HR: 0.76 [95%CI:0.40-1.32], p⫽0.322; median OS: 15.6 vs 13.4 mos, HR:0.77 [95%CI:0.36-1.62], p⫽0.485). Conclusions: This prospective experience confirms that AR early increases one hour after the administration of cetuximab. Underlying biological mechanisms should be investigated. Nevertheless, this modulation of AR does not predict clinical outcome. Our work underlines the need to prospectively validate retrospective findings in independent series, to assess their reliability. Clinical trial information: 2008-003160-19.

Group A Group B

3603

DPD screening

No. of patients

Partial deficiency

Complete deficiency

5-FU induced toxic death

Yes No

720 410

20 21

1 1

0 1


3604


Circulating angiogenic factors as predictors of benefit from bevacizumab (bev) beyond progression in metastatic colorectal cancer (mCRC): Traslational analyses from the phase III BEBYP trial. Presenting Author: Carlotta Antoniotti, U.O. Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy

Bevacizumab plus chemotherapy continued beyond first disease progression in patients with metastatic colorectal cancer previously treated with bevacizumab-based therapy: Patterns of disease progression and outcomes based on extent of disease in the ML18147 study. Presenting Author: Richard Greil, Universitätsklinikum der PMU, Salzburg, Austria

Background: TML and BEBYP trials demonstrated that the strategy of prosecuting bev beyond progression is effective in mCRC. Previous analyses from phase II studies showed that a modulation of plasma angiogenic factors occurs during 1st-line treatment with chemotherapy (CT) ⫹ bev and a wide variability in soluble Vascular Endothelial Growth Factor Receptor-2 (sVEGFR-2) levels was observed at the time of progression. Moving from preliminary analyses in murine models we selected a pool of candidate ligands to be tested in the clinical setting. Methods: sVEGFR2, Placental Growth Factor (PlGF), Platelet-Derived Growth Factor-C, basic Fibroblast Growth Factor, Angiopoietin-2 and soluble Tie-2 were assessed by ELISA on plasma samples collected at baseline in a cohort of 59 patients enrolled in phase III BEBYP trial of 2nd-line CT ⫾ bev beyond progression to a bev-containing first-line regimen. Plasma levels were defined high or low adopting the median values as cut-off. Results: A significant interaction between treatment arm and baseline sVEGFR-2 levels was observed (p⫽0.036). Among 30 patients with high sVEGFR-2 levels, the prosecution of bev was associated with a significant benefit in terms of PFS (median: 10.4 vs 3.4 months, HR 0.37 [95%CI 0.10-0.58], p⫽0.0015), that was not evident among 29 patients with low sVEGFR-2 levels (5.4 vs 5.0 months, HR 0.98 [95%CI 0.45-2.11], p⫽0.956). Despite a trend towards a greater benefit from bev among 30 patients with high PlGF levels (HR 0.45 [95%CI 0.13-0.86]), no interaction between treatment arm and baseline PlGF levels was observed (p⫽0.210). Combined analysis of sVEGFR-2 and PlGF showed that prosecuting bev provided a substantial benefit in PFS in the subgroup with high levels of both ligands (10.5 vs 2.3 months, HR 0.25 [95%CI 0.01-0.45], p⫽0.043). Conclusions: sVEGFR-2 levels at the time of first progression may predict benefit from prosecuting bev. Interesting results from simultaneous analysis of sVEGFR-2 and PlGF may be affected by a pronounced subgrouping and should be considered cautiously. Given their potential clinical value, these data need prospective confirmation. Clinical trial information: NCT00720512.

Background: ML18147 demonstrated that bevacizumab (BEV) ⫹ chemotherapy (CT) continued beyond first disease progression (PD) significantly prolongs overall survival (OS) and progression-free survival (PFS) as second-line treatment for metastatic colorectal cancer (mCRC) [Bennouna et al. Lancet Oncol 2012]. Here we report exploratory analyses of patterns of PD and outcomes based on extent of disease. Methods: In ML18147, patients (pts) with unresectable, histologically confirmed mCRC who progressed ⱕ3 months after discontinuation of first-line BEV were randomised to second-line CT⫾BEV. This exploratory analysis evaluated PD patterns, time from discontinuation of study medications to PD, and survival outcome (OS, PFS) based on liver-limited vs extensive disease. Results: Details on patterns of PD and outcome by extent of disease are shown in the table. Conclusions: These exploratory analyses suggest that pts with liver-limited or extensive disease seem to benefit equally from BEV⫹CT continued beyond PD. Our findings indicate that the pattern of PD does not appear to differ between the two treatment arms following cessation of BEV treatment in this setting. Clinical trial information: NCT00700102. Patterns of PD, n (%) No. of pts with PD No. of pts with PD due to new lesion Site of baseline lesion (in pts with PD due to new lesion) Lung Liver Site of new lesion Lung Liver Peritoneum Local lymph nodes Other

Time from discontinuation of study medication to PD Median Liver-limited disease OS Median PFS Median Extensive disease OS Median PFS Median

CT alone (nⴝ410)

BEVⴙCT (nⴝ409)

321 (78.3%) 163 (50.8%)

302 (73.8%) 132 (43.7%)

87 (53.4%) 132 (81.0%)

59 (44.7%) 118 (89.4%)

74 (45.4%) 53 (32.5%) 10 51 (38.6%) 55 (41.7%) 13 (6.1%) 7 (4.3%) 48 (29.4%) (9.8%) 8 (6.1%) 26 (19.7%) n⫽345 (84.1%) n⫽329 (80.4%) HR⫽0.82 (95% CI 0.69–0.98; p⫽0.02) 0.4 months 0.5 months n⫽117 (28.5%) n⫽109 (26.7%) HR⫽0.79 (95% CI 0.59–1.06) 9.3 months 11.6 months HR⫽0.68 (95% CI 0.52–0.89) 4.1 months 5.7 months n⫽292 (71.2%) n⫽300 (73.3%) HR⫽0.81 (95% CI 0.67–0.97) 10.0 months 11.0 months HR⫽0.68 (95% CI 0.57–0.80) 4.1 months 5.6 months




Chemotherapy first, followed by chemoradiation (CRT) and then surgery, in the management of locally advanced rectal cancer (LARC). Presenting Author: Andrea Cercek, Memorial Sloan-Kettering Cancer Center; Department of Medicine, New York, NY Background: Standard pre-op CRT and post-op chemo for LARC delays the start of optimal systemic therapy by 18-22 weeks. To more promptly address micrometastases that could lead to distant failure, and supported by evidence of excellent primary tumor response to FOLFOX, we began offering FOLFOX as initial treatment for patients (pts) with high-risk LARC. More recently, we have begun offering all planned FOLFOX prior to CRT and surgery. Methods: We obtained an IRB waiver to review records of all clinical stage II/III RC pts treated with initial FOLFOX followed by CRT and total mesorectal excision (TME) at our institution between 2007 and 2012. Of approximately 300 rectal pts treated with CMT, 61 received some or all of their planned FOLFOX as initial therapy. Results: The median age of these 61 pts was 52 years, 54% male. At diagnosis, 84% had T3N1-2 or T4N0-1 tumors and 16% had T3N0 tumors. Of these, 57 received induction FOLFOX (median 7 cycles) then received pre-op CRT, while 4 pts achieved an excellent response to chemotherapy alone, declined CRT, and went directly to TME. Twelve pts did not undergo surgery; 9 had a complete clinical response and elected to be managed non-operatively; 1 refused recommended surgery despite incomplete tumor regression, 1 had surgery deferred due to comorbidities, and 1 developed distant metastatic disease prior to planned surgery. Of the 61 patients, 19 (31%) had either a pathCR (14) or a complete clinical response (5) leading to non-operative management. Of the 49 pts who underwent TME, all had R0 resections and 23 (47%) had tumor response ⬎90%, including 13 (27%) with pathCR. Of the 28 patients who received all 8 cycles of initial FOLFOX, 8 achieved a pathCR (29%) and 3 achieved a complete clinical responses (11%), managed non-operatively. All patients completed therapy as planned. There were no SAEs requiring delay in treatment during either FOLFOX or CMT. Conclusions: FOLFOX before CRT results in substantial tumor regression, a high rate of delivery of all planned therapy, and a substantial rate of pathCRs. Chemo and CMT before planned TME provides a favorable opportunity for consideration of non-operative management.

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The distribution of chromosomal and microsatellite instability in colorectal cancers related to inflammatory bowel disease. Presenting Author: Stephan Brackmann, Akershus University Hospital, Nordbyhagen, Norway Background: Surveillance for colorectal cancer (CRC) in inflammatory bowel disease (IBD) has so far not been effective. Mucosal or fecal biomarkers may be useful in the selection of high risk patients. The yield may depend on the underlying carcinogenic pathway. In IBD associated CRC (IBD-CRC) the distribution of chromosomal instability (CIN) and microsatellite instability (MSI) is not well documented. Our objective was to determine the distribution of CIN and MSI and the association to clinico-histological factors in a cohort of patients with IBD-CRC. Methods: Ploidy was measured by high-resolution image cytometry and MSI by using two markers (BAT 25 and BAT26) in 62 patients with 72 CRC-IBD selected by matching the Norwegian Cancer Registry with IBD cohorts of three university hospitals in Oslo. The association between ploidy/MSI status and clinicohistological factors were analyzed by non-parametric tests. Results: Ploidy status was analyzed in 67 (93%), microsatellite stability in 68 (94%) tumors. Fourty-nine (73.1%) were non-diploid (43 aneuploid, 1 polyploid, 5 tetraploid), 13 (19.4 %) diploid, five (7.5%) indeterminate. Forty-three (63.2%) were microsatellite stable (MSS), four (5.8%) microsatellite instable (MSI). One tumor was MSI in BAT25 but MSS in BAT26. Twenty (29.5%) tumors showed no PCR-product in at least one of the markers. In 46 tumors, both ploidy and MSI status were available. All non-diploid tumours (36, 78.3%) were MSS and all MSI tumors (4, 8.7%) were diploid. Six (13%) tumors were diploid and MSS. Four patients were treated with 5-ASA prior to diagnosis of CRC. Three developed diploid, one aneuploid cancers. Of the untreated patients, 31 developed aneuploid, 7 diploid cancers (p⫽0.036). We did not find an association between age, gender, type of IBD, duration of IBD, localisation of CRC,TNM-stage and CIN or MSI. Conclusions: The majority of CRC-IBD in our cohort seem to present CIN and only a minority MSI. Some CRC-IBD patients present neither CIN nor MSI. Future studies should determine whether these display the CpG island methylator phenotype. Biomarkers for CRC-IBD should be derived from all three pathways.

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Chronomodulated hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil (5-FU), and oxaliplatin (l-OHP) plus intravenous (iv) cetuximab (Cet) (Chrono-Optiliv) in patients with unresectable liver metastases from wt KRAS colorectal cancer (LM-CRC) after treatment failure (European Phase II trial NCT 00852228). Presenting Author: Mohamed Bouchahda, Medical Oncology Department, INSERM U776, Paul Brousse Hospital, Villejuif, France Background: Hepatic artery triplet chronotherapy is an effective salvage therapy for pretreated LM-CRC (Bouchahda et al. Cancer 2009). The combination of iv Cet with chrono or conventional triplet HAI allowed complete macroscopic resection (R0-R1) of previously unresectable LMCRC in 28% of the pts, and median progression-free (PFS) and overall survival (OS) of 8.7 and 25.7 months respectively, despite prior chemotherapy (Lévi et al. ASCO-GI 2013). Purpose: To relate tolerability and efficacy of Chrono-Optiliv to pharmacokinetics (PK). Methods: 18/64 registered patients received iv Cet (500 mg/m²) and chrono HAI of Irinotecan (180 mg/m²), 5-FU (2800 mg/m²), and l-OHP (85 mg/m²) q2 weeks. Liver surgery was performed according to q6wks reviews. The systemic exposure to the 4 drugs was determined on 1st course in 11 pts, through 16 samples over 56h. Results: 8F, 10M, aged 33-72 years had good PS (0/1: 83%/17%), a median of 7 LM-CRC (2-50) in 6 segments (1-8) with median largest diameter of 47 mm (15-130). LM-CRC were bilateral in 13 pts (72%); 10 pts (56%) got Chrono-Optiliv as 3rd-4th line. Main grade 3-4 toxicities were neutropenia (56%), abdominal pain (44%), diarrhea and fatigue (22%). The rate of objective responses was 50% [26.9-73.1], and that of R0-R1 33.3% [11.5 -55.1], resulting in median PFS and OS (months) of 12.6 [8.8 -16.1] and 21.9 [7.4-36.4] respectively. Plasma PK revealed the expected Cet levels and a relevant systemic exposure to the HAI drugs, with median trapezoidal AUC’s of 12.4 ␮g*mn/mL (2.6-38.5) for SN-38, 142 ␮g*mn/mL (96- 434) for 5-FU and 100 ␮g*mn/mL (37-189) for free l-OHP. A significant correlation was found between free l-OHP AUC and abdominal pain (p⫽0.016) and between SN38 AUC and both neutropenia (p⫽0.018) and response (p⫽0.028). Conclusions: The significant systemic exposure to the HAI drugs together with iv Cet could explain efficacy and lack of early progression on Chrono-Optiliv. The results call for upfront testing of optimized Chrono-Optiliv. Clinical trial information: NCT 00852228.

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Phase Ib dose-escalation study of Pexa-Vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia virus, administered by intravenous (IV) infusions in patients with metastatic colorectal carcinoma (mCRC). Presenting Author: Jeeyun Lee, Sungkyunkwan University School of Medicine, Samsung University, Seoul, South Korea Background: Pexa-Vec is an EGFR-targeted vaccinia virus engineered to express granulocyte-macrophage colony stimulating factor (GM-CSF), thereby stimulating direct oncolysis, tumor vascular disruption and antitumor immunity (Nat Rev Cancer 2009). Dose-dependent IV Pexa-Vec delivery was defined previously (Nature2011). This study was designed to assess the safety, maximal tolerated dose and anti-tumor activity of Pexa-Vec administered IV in patients with mCRC after failure of standard therapies. Methods: Nine patients were treated at 1 of 3 dose levels (106, 107 or 3x107pfu/kg IV every 2 weeks x 4) in a standard 3⫹3 doseescalation design; 6 additional patients were enrolled at the MFD. Anti-tumor activity according to RECIST was determined using serial CT scans. Pharmacokinetic studies were also performed. Data summarized prior to database lock. Results: 15 patients with mCRC refractory to irinotecan, oxaliplatin, and 5-FU were treated (median lines of therapy 5; range 2-7); 13 of 15 received prior anti-angiogenic agents, and 11 of 12 KRAS WT tumors failed cetuximab. Adverse events were generally grade 1/2 and included: fever (93%), chills (93%), headache (60%), nausea (60%), and hypotension (40%). No dose-limiting toxicities or grade 3/4 events were reported. Only patients treated at high-dose (Cohort 3 & Expansion) exhibited a pustular rash (n⫽9; 78%). Pexa-Vec genomes detected in blood acutely were above the dose threshold for systemic delivery. Notably, clearance was not more rapid with repeated IV treatments despite the induction of humoral immunity. Furthermore, patients at the top dose level exhibited increased disease stabilization at Week 4 (89% high-dose (n⫽ 9) versus 33% low-dose (n⫽6)). A trend (p⫽0.16) towards increased overall survival at high vs low-dose Pexa-Vec was observed with 78% high-dose patients still alive between 5 and 13 mos. Conclusions: Repeat IV Pexa-Vec was well-tolerated with transient flu-like symptoms. Dose-dependent safety, pharmacokinetics and anti-tumor activity were described in treatment-refractory mCRC patients. Clinical trial information: NCT01380600.


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Association of KRAS mutation with worse recurrence-free survival and site of metastatic progression after resection of hepatic colorectal metastases. Presenting Author: Nancy E. Kemeny, Memorial Sloan-Kettering Cancer Center, New York, NY Background: There are conflicting results regarding the influence of KRAS mutation status and outcome in patients (pts) with colorectal cancer. A recent report suggested worse outcome in KRAS mutated (MUT) pts who underwent resection of hepatic metastases (Karagkounis et al, ASCO 2012). Methods: Recurrence patterns and survival were evaluated in 169 patients who had undergone resection of liver metastases, then received adjuvant hepatic arterial infusion and systemic chemotherapy, and for whom KRAS data were available. Kaplan-Meier methods were used to estimate recurrence free survival (RFS) and overall survival (OS). Log-rank test was used to determine whether survival functions differed by KRAS mutation status. Cumulative incidence function was used to estimate the probability of time from adjuvant therapy to bone, brain, lung and liver metastases separately. Mutations in KRAS (codons 12, 13) were detected using the iPLEX assay (Sequenom, Inc). Results: Median follow-up for the entire cohort was 38.8 months. 118 were KRAS wildtype (WT), and 51 were KRAS MUT (45 G12, 5 G13, 1 K117N). The 3 year RFS was 48% [95%CI: 37-58%] for KRAS WT pts and 30% [15-44%] for MUT pts (p⬍0.01). OS at 3 years was 96% [88-98%] for KRAS WT and 80% [61-90%] for MUT pts (p⫽0.08). Cumulative incidence of developing bone, brain, lung, and liver metastases by 2 years is presented in Table 1. The cumulative incidence of metastases to bone at 2 years was 0% and 13.7% in KRAS WT versus MUT pts (p⬍0.01), to brain 0% versus 4.6% for KRAS WT versus MUT (p⫽0.05), and to lung 27% versus 47.5% in KRAS WT versus MUT pts (p⬍0.01). Conclusions: In pts who have had liver resection followed by adjuvant therapy, those with KRAS MUT have a worse RFS and seemingly worse OS than those who are KRAS WT. Also, patients with KRAS MUT appear more likely to develop bone, brain, and lung metastases. Further investigation of a larger number of patients is warranted. Cumulative incidence of development of metastases at 2 years. Site Bone Brain Lung Liver

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Nⴝ118 KRAS WT [95%CI]

Nⴝ51 KRAS MUT [95%CI]

P value

0 0 27% [17.5-36.5%] 18% [8-25.8%]

13.7% [0.3-27.2%] 4.6% [0-13.5%] 47.5% [32.4-68.4%] 37% [19.3-54.6%]

⬍0.01 0.05 ⬍0.01 0.08


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Impact of early tumor shrinkage on clinical outcome in KRAS wild-type colorectal liver-limited metastases treated with cetuximab plus chemotherapy: Lessons from a randomized controlled trial. Presenting Author: Le-chi Ye, Department of General Surgery, Zhongshan Hospital, Fudan, Shanghai, China Background: Recently, early tumor shrinkage (ETS) was reported to predict outcome in metastatic colorectal cancer treated with cetuximab (cet). This study was to evaluate the impact of ETS on long-term outcome in patients (pts) with wild-type-KRAS unresectable CLLM receiving cet plus chemotherapy (CT, FOLFIRI or mFOLFOX6). Methods: 138 pts treated in a randomized controlled trial (70 in armA received CT plus cet and 68 in armB received CT alone) previously reported (Jianmin et al, ESMO 2012, abstract-557, ClinicalTrials.gov, number NCT01564810) were included into this analysis. ETS was defined as a reduction of ⱖ20% in the sum of the longest diameters of target lesions compared to baseline at the first evaluation (8 weeks). Outcome measures were progression-free survival (PFS) and overall survival (OS). Results: 132 pts were available for evaluation, and ETS occurred more frequently in armA than that in armB (45/68 vs. 26/64, p⫽ .003). Irrespective of treatment arm, pts achieved ETS were associated with longer OS (armA: 38.0 vs. 18.7months, p⬍ .001; armB 30.6 vs.17.7months, p⫽ .003) and PFS (armA: 11.8 vs. 4.8months, p⬍ .001; armB 8.0 vs.4.6months, p⫽ .001) when compared to pts with no-ETS. Among pts with ETS, there were statistic difference between armA and armB in terms of PFS (11.8 vs. 8.0months, p⫽ .041) but not of OS (38.0 vs. 30.6months, p⫽ .30); the converted resection rates for liver metastases were 40.0% (18/45) in armA and 19.2% (5/26) in armB, which were no significantly different (p⫽ .072). For pts without liver surgery, pts observed ETS also gained an increased survival benefit over those no-ETS in armA with regards to OS (p⫽ .01) and PFS (p⬍ .001) though it was not full certified in armB (OS: p⫽ .054; PFS: p⫽ .041). For pts in armA, cet-induced skin toxicity correlated with the occurrence of ETS (p⫽ .048). In addition, cox regression for OS using indicated a hazard ratio of 0.39 (95%CI 0.21– 0.72, p ⫽ .003). Conclusions: ETS ⱖ20% at 8 weeks may serve as a predictor of favorable outcome in pts with wild-typeKRAS CLLM receiving cet plus CT.

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Quality of life (QOL) and toxicity among patients in CALGB 80405. Presenting Author: Michelle Joy Naughton, Wake Forest University, School of Medicine, Winston-Salem, NC

Genomic classifier (ColoPrint) to predict outcome and chemotherapy benefit in stage II and III colon cancer patients. Presenting Author: Scott Kopetz, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: CALGB 80405, a phase III trial, was originally designed to compare toxicity and overall survival of metastatic colorectal patients treated with standard chemotherapy (choice of FOLFOX or FOLFIRI) and either: 1) Bevacizumab; 2) Cetuximab; or 3) both Bevacizumab and Cetuximab. Because Cetuximab causes a prominent acneiform skin rash, adverse effects on QOL were anticipated and assessed in a QOL companion. Methods: The QOL companion enrolled the first 518 consenting patients randomized to CALGB 80405 between 10/2005-9/2007, the majority prior to amendments that eliminated the dual biologic arm and restricted participation to patients with KRAS wttumors. QOL was assessed at baseline, 6 weeks, and 3, 6 and 9 months post-randomization, using the EORTC QLQ-30 and the Dermatology-Specific Quality of Life (DSQL) Scale. We hypothesized that patients receiving Cetuximab would have lower satisfaction with appearance, reduced social functioning and lower overall QOL at 3 months, (a primary assessment point). Results: Patients had a mean age of 59, were predominantly male (58%), performance status 0 (62%), and non-Hispanic White (85%). 83% completed a 3 month assessment. There were no differences in global health functioning (p⫽0.164) or other items/subscales of the EORTC at 3 months by treatment arm. However, significant differences were found across arms in skin symptoms (p⬍.0001), limitations in social activities due to skin condition (p⫽0.008), and concerns about appearance (p⬍.0001), as measured by the DSQL. Patients randomized to Bevacizumab reported fewer skin symptoms, fewer social limitations and appearance concerns than patients receiving Cetuximab alone or Cetuximab ⫹ Bevacizumab. The choice of chemotherapy (FOLFOX or FOLFIRI) had no bearing on these results. Conclusions: Global QOL, as well as physical, role, social and emotional functioning, were not significantly different across treatment arms. However, Cetuximab recipients reported greater symptoms and QOL concerns relating to their skin than those receiving Bevacizumab alone. Interventions to more adequately address skin problems from Cetuximab treatment are warranted. Participants are still being followed to determine survival differences between the biologics. Clinical trial information: NCT00265850.

Background: Although benefit of chemotherapy in stage II and III colorectal cancer patients is significant, many patients might not need adjuvant chemotherapy because they have a good prognosis even without additional treatment. ColoPrint is a gene expression classifier that distinguish patients with low or high risk of disease relapse. It was developed using whole genome expression data and validated in independent validation studies (JCO 2011, Ann Surg 2013). Methods: In this study, ColoPrint was validated in stage II (n⫽96) and III patients (n⫽95) treated at the MD Anderson Cancer Center. Frozen tissue specimen, clinical parameters and follow-up data (median follow-up 64 months) were available. Stage II patients from this study were pooled with patients from previous studies (n⫽416) and ColoPrint performance was compared to clinical risk factors described in the NCCN Guidelines 2013. Results: In the MDACC patient cohort, ColoPrint classified 56% of stage II and III patients as being at Low Risk. The 3-year Relapse-Free-Survival (RFS) was 90.5% for Low Risk and 78.1% for High Risk patients with a HR of 2.42 (p⫽0.025). In uni-and multivariate analysis, ColoPrint and stage were the only significant factors to predict outcome. Low Risk ColoPrint patients had a good outcome independent of stage or chemotherapy treatment (91% 3-year RFS for treated patients, 90% for untreated patients) while ColoPrint High Risk patients treated with adjuvant chemotherapy had 3-year RFS of 84%, compared to 70% 3-year RFS in untreated patients (p⫽0.037). In the pooled stage II dataset, ColoPrint identified 63% of patients as Low Risk with a 3-year RFS of 93% while High Risk patients had a 3-year RFS of 82.3% with a HR of 2.7 (p⫽0.001). In the univariate analysis, no clinical factor reached statistical significance. Using clinical high risk factors as described in the NCCN guidelines as classification, 56% of patients were classified as low risk with a 3-year RFS of 90.3% while high risk patients had a 3-year RFS of 87.7% with a HR of 0.6 (p⫽0.63). Conclusions: ColoPrint significantly improves prognostic accuracy, thereby facilitating the identification of patients at higher risk who might be considered for additional treatment.




Analysis of NRAS mutation as poor prognostic indicator and predictor of resistance to anti-EGFR monoclonal antibodies (anti-EGFRs) in metastatic colorectal cancer (mCRC) patients (pts). Presenting Author: Marta Schirripa, U.O. Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy Background: NRAS belongs to RAS family. NRAS mutations are mutually exclusive with KRAS and BRAF mutations and contribute to the activation of Ras/Raf/MAPK pathway. Previous experiences evaluated the prognostic/ predictive role of NRAS mutations suggesting a poorer prognosis and resistance to anti-EGFRs for NRASmutant (mut) mCRC pts. The aim of the present study was to confirm such preliminary findings in a large cohort of mCRC pts. Methods: Data on KRAS (codons 12, 13 and 61) and BRAFV600E mutational status of mCRC pts referred to our pathology from ’09 to ’12 were collected. NRAS mutational status (codons 12, 13 and 61) was evaluated in KRAS and BRAF wt pts. OS was calculated from date of diagnosis of metastatic disease. Data on response and PFS according to RECIST were collected for NRASmut irinotecan-refractory pts treated with anti-EGFRs ⫹/- irinotecan. Results: 774 mCRC pts were included. KRAS/ BRAF mutations were found in 384 (50%)/69 (9%) cases. NRAS was mut in 47 (15%) out of 318 KRAS and BRAF wt pts. NRAS mut pts had significantly shorter OS in comparison to KRAS-BRAF-NRAS wt pts (HR⫽0.60 [0.29-0.99] p⫽0.045). BRAF mut pts had significantly worse OS in comparison to NRAS mut pts (HR⫽1.75 [1.073-2.87] p⫽0.03). No difference was observed between NRAS mut and KRAS mut pts (HR⫽0.86 [0.51-1.43] p⫽0.61). 18 pts out of 47 NRAS mut pts received anti-EGFRs in advanced lines. 8 pts (7 cetuximab-based, 1 panitumumab monotherapy) were evaluable according to RECIST criteria and therefore eligible for the present analysis. None of them responded and only 1 SD was observed. Pooling our results with available data on anti-EGFRs’ activity in NRASmut pts in advanced lines of treatment (De Roock, 2010; Peeters, 2013; Andrè, 2012), only 1 response is described out of 35 treated pts (2,9%). Conclusions: Our data demonstrate that NRAS mutations have a relevant incidence in KRAS and BRAF wt mCRC pts. Present results are consistent with previous experiences and confirm that NRAS mutations affect prognosis of mCRC patients and predict lack of response to anti-EGFRs. Further insights into NRAS mut mCRC biology and prospective validation are warranted.

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Second-line chemotherapy (CT) with or without bevacizumab (BV) in metastatic colorectal cancer (mCRC) patients (pts) who progressed to a first-line treatment containing BV: Updated results of the phase III “BEBYP” trial by the Gruppo Oncologico Nord Ovest (GONO). Presenting Author: Gianluca Masi, U.O. Oncologia Medica 2, Azienda OspedalieroUniversitaria Pisana, Istituto Toscano Tumori, Pisa, Italy Background: Retrospective data suggested that the continuation of BV with second-line CT beyond progression (PD) in pts who received BV in first-line can improve the outcome. Recently, results of the AIO/AMG ML18147 study demonstrated an improved overall survival (OS) by continuing BV beyond PD. Methods: This phase III study randomized pts with measurable mCRC treated in first-line with BV plus fluoropyrimidine, FOLFIRI, FOLFOX or FOLFOXIRI, to receive in second-line mFOLFOX6 or FOLFIRI (depending on first-line CT) with or without BV. The primary end-point was progression free survival (PFS).To detect a HR for PFS of 0.70 with an ␣ and ␤ error of 0.05 and 0.20 respectively, the study required 249 events. Assuming an accrual time of 24 months (mos) and a follow up of 12 mos we planned to randomize 262 pts. Results: Considering the results of the AIO/AMG ML18147 trial, the study accrual was stopped prematurely. A total of 185 pts were randomized and 184 pts were included in the ITT analysis (1 pt randomized in error). Pts characteristics were (arm A/arm B): number 92/92, gender M75%-F25%/M57%-F43%, median age 66 (38-75)/62 (38-75) years, PS⫽0 82%/82%, multiple site of disease 76%/77%. At a median follow up of 18 mos the study met its primary endpoint by improving PFS in the BV arm. We updated results and at a median follow up of 22 mos the improvement in PFS for the experimental arm was confirmed with a median PFS of 5.2 mos for arm A and 6.7 mos for arm B (HR⫽0.66; 95% CI 0.49 – 0.90; unstratified p⫽0.0072). Subgroup analyses showed a consistent benefit in all subgroups including gender (F: HR⫽0.63; M: HR⫽0.72) and first-line PFS (ⱕ10 mos: HR⫽0.57; ⬎10 mos: HR⫽0.71). Response rates (RECIST) were 18% and 21% (p⫽0.71). Toxicity profile was consistent with previously reported data. The OS data are still immature, with 56 events in arm A and 54 in arm B and the median OS is 16.0 mos and 16.5 mos respectively (HR⫽0.83; 95% CI 0.57-1.22; unstratified p⫽0.34). Conclusions: This study demonstrates an improvement in PFS by continuing BV in second-line in pts who had received CT⫹BV in first-line. Clinical trial information: NCT00720512.

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Primary prophylactic granulocyte colony-stimulating factor (GCSF) in Gilbert’s disease patients treated with FOLFIRI first line for metastatic colorectal cancer (mCRC): Final results of the FFCD 0604 study. Presenting Author: Thierry Lecomte, Francois Rabelais University, Tours, France Background: Gilbert’s disease patients (pts) (homozygotous for the UGT1A1*28 allele) have a major risk (⬎30%) of severe, life-threatening, neutropenia when treated with Irinotecan (IRI). The aim of this study was to demonstrate that, in these pts, treated with IRI 1st line for mCRC, primary prevention with GCSF (lenograstim) reduces under 10% the risk of grade 4 or febrile neutropenia. Methods: This is a prospective, multicenter, phase II study of FOLFIRI ⫹ bevacizumab 1st line (IRI 180 mg/m² every 2 weeks) and primary prophylactic GCSF (D5 to D11 each course) in mCRC pts with Gilbert’s disease. Pre-chemotherapy UGT1A1 genotyping was centralized and standardized using a biological molecular technique applied on DNA blood-extracted lymphocytes. Using a 2-step Fleming design, (␣⫽5% and ␤⫽90%), 30 pts had to be included with an interim analysis (IA) planned after 20 pts and 4 months of follow-up. Results: Twenty pts from 7 centers were included between 10/2007 and 02/2012 and 19 analysed for the IA. Median pts age was 63 years (range: 45-73), 60% were females, 90% were PS 0 or 1, 80% had a colic primary site and 73% hepatic metastases. The primary site was non- resected in 1/3 of pts. The total number of administered courses of chemotherapy was 229 with a median of 12 per pt (range: 1-40). Among all these courses, 213 were administered with GCSF. IRI was administered as defined by the protocol with a nearly 100% rate of received /theoretical dose. Grade 3 neutropenia rate was 10.5%. No grade 3-4 diarrhea, no grade 4 or febrile neutropenia and no toxic death were observed. No declared SAEs were related to GCSF. In term of best response at 6 months, 7 pts were in complete or partial response and 9 had stable disease. Median progression free survival and overall survival were respectively 8.7 months (4.9; 13.4) and 24.4 months (12.6; ND). Conclusions: This study is the first to demonstrate that a pharmacogenetic approach based on a simple genetic test easy to perform can achieve a high rate of safe and performant administration of IRI in high risk mCRC pts. Clinical trial information: NCT00541125.

3616


SPIRITT (study 20060141): A randomized phase II study of FOLFIRI with either panitumumab (pmab) or bevacizumab (bev) as second-line treatment (tx) in patients (pts) with wild-type (WT) KRAS metastatic colorectal cancer (mCRC). Presenting Author: Allen Lee Cohn, Rocky Mountain Cancer Centers, Denver, CO Background: Pmab has demonstrated significant improvement in progression-free survival (PFS) in pts with WT KRAS mCRC as 2nd-line tx in a phase III trial comparing pmab ⫹ FOLFIRI vs FOLFIRI alone. Here, we describe the results of SPIRITT, a multicenter, randomized phase II study evaluating pmab ⫹ FOLFIRI and bev ⫹ FOLFIRI in pts with WT KRAS mCRC previously treated with a 1st-line bev ⫹ oxaliplatin (Ox)-based chemotherapy regimen. Methods: Pts were randomized 1:1 to pmab 6.0 mg/kg ⫹ FOLFIRI Q2W or to bev 5.0 or 10.0 mg/kg ⫹ FOLFIRI Q2W. Eligibility criteria included: WT KRAS mCRC, ECOG ⱕ 1, no prior irinotecan or anti-EGFR tx, and tx failure of prior 1st-line bev ⫹ Ox-based therapy (ⱖ 4 cycles). The primary endpoint was PFS; secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. No formal hypothesis was tested. Results: 182 pts with WT KRAS mCRC were randomized. All pts received tx. Efficacy results are shown (Table). Worst grade of 3/4 adverse events (AE) occurred in 78% of pts in the pmab ⫹ FOLFIRI arm and 65% in the bev ⫹ FOLFIRI arm. Grade 5 AEs occurred in 7% of pts in the pmab ⫹ FOLFIRI arm and 7% in the bev ⫹ FOLFIRI arm. Tx discontinuation due to any AE was 29% in the pmab ⫹ FOLFIRI arm and 25% in the bev ⫹ FOLFIRI arm. Conclusions: In this estimation study of pts with WT KRAS mCRC that previously received bev ⫹ Ox-based tx, the PFS hazard ratio (HR) was 1.01 (95% CI: 0.68 - 1.50). The OS HR was 1.06 (95% CI: 0.75 - 1.49). The observed ORR was higher in the pmab ⫹ FOLFIRI arm. 54% of bev ⫹ FOLFIRI pts received subsequent anti-EGFR tx. The safety profile for both arms was similar to previously reported studies. Tx discontinuation rates due to AEs were similar between the arms. Clinical trial information: NCT00418938. N Median PFS,* mos (95% CI) Median OS, mos (95% CI) N ORR,* n (% [95% CI]) Pts receiving therapy after tx phase, n (%) Anti-EGFR Anti-VEGF

Pmab ⴙ FOLFIRI

Bev ⴙ FOLFIRI

91 7.7 (5.7 - 11.8) 18.0 (13.5 - 21.7) 87 28 (32 [23 - 43])

91 9.2 (7.8 - 10.6) 21.4 (16.5 - 24.6) 83 16 (19 [11 - 29])

24 (26) 18 (20)

49 (54) 22 (24)

HR (95% CI)

1.01 (0.68 - 1.50) 1.06 (0.75 - 1.49)

*Assessments based on blinded central radiology review per modified RECIST 1.0.


234s 3617


Comprehensive analysis of KRAS and NRAS mutations as predictive biomarkers for single agent panitumumab (pmab) response in a randomized, phase III metastatic colorectal cancer (mCRC) study (20020408). Presenting Author: Scott D. Patterson, Amgen, Inc., Thousand Oaks, CA Background: An exploratory biomarker analysis of the randomized, phase 3 monotherapy 20020408 study of pmab vs best supportive care (BSC) demonstrated that mutations in KRAS exon 3 and NRAS exons 2 and 3 appeared to be predictive of pmab response (Peeters et al, 2013). We expanded these results to determine whether mutations in exon 4 of the KRAS and NRAS genes are predictive for pmab treatment and to determine the treatment effect in the overall wild-type (WT) KRAS and NRAS population. Methods: Using a combination of Next Generation Sequencing, Sanger Sequencing, and WAVE-based SURVEYOR Scan Kits from Transgenomic, archival patient tumors were examined for mutations in KRAS and NRAS exon 4. These data were combined with previously presented data from KRAS and NRAS exon 2 and 3 analyses for evaluation of the comprehensive WT KRAS and NRAS subgroup. Results: 9/243 (3.7%) and 2/243 (0.8%) patient tumors with WT KRAS exon 2 status harbored a mutation in KRAS or NRAS exon 4, respectively. One tumor had mutations in both KRAS and NRAS exon 4. In the pmab arm, patients with WT KRAS and WT NRAS tumor status had an objective response rate (ORR) of 15% (11/72) whereas patients with mutant (MT) KRAS or MT NRAS tumor status had an ORR of 1% (1/95; 1 patient with MT KRAS exon 4 had a partial response). There were no responses in the BSC arm regardless of the tumor status. In this analysis set, the treatment hazard ratio (HR; pmab:BSC) for progression-free survival (PFS) in the WT KRAS and WT NRAS subgroup was 0.38 (95% CI: 0.27 - 0.56), and in the MT KRAS or MT NRAS subgroup was 0.98 (95% CI: 0.73 - 1.31). The original WT KRAS exon 2 subgroup PFS HR was 0.45 (95% CI: 0.34 - 0.59) (Amado et al, 2007). Conclusions: This exploratory analysis suggests that mutations in KRAS and NRAS exon 4 occur in a small, but meaningful percentage of patients with mCRC. Extending previous findings from this study in patients with MT KRAS and/or MT NRAS exon 2 and/or 3 tumors, patients with MT KRAS and/or MT NRAS exon 4 tumors do not appear to benefit from pmab therapy. Clinical trial information: NCT00113763.

3619^


3618


Accent-based nomograms (NGs) to predict time to recurrence (TTR) and overall survival (OS) in stage III colon cancer (CC). Presenting Author: Lindsay A. Renfro, Mayo Clinic, Rochester, MN Background: Current prognostic tools and staging systems in CC use relatively few patient (pt) characteristics; including additional covariates may improve prediction. Using the large ACCENT database, we constructed clinically based NGs for OS and TTR in stage III CC that better separate pts into risk groups compared to AJCC v7 staging. Methods: 15,936 stage III pts accrued to phase III clinical trials since 1989 were used to construct Cox models for TTR and OS. Variables included age, sex, race, BMI, performance status, tumor grade, tumor stage, ratio of positive lymph nodes to nodes examined, number/location of primary tumors (any multiple versus single left, right, or transverse), and treatment (5FU variations vs. 5FU with oxaliplatin or irinotecan). Missing data (⬍18%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions included if p ⬍ 0.001. Final models were internally validated via bootstrapping for corrected calibration and C-indices for survival data. NG-defined risk tertiles were compared to AJCC v7 stage III for observed 3-year (yr) TTR and 5-yr OS for a subset of 7400 pts with complete data. Results: All variables were statistically and clinically significant for OS; age and race did not predict TTR. No meaningful interactions existed. NGs for OS and TTR were well calibrated and associated with C-indices of 0.66 and 0.65, respectively, vs. 0.58 and 0.59 for AJCC. NG risk tertiles were better separated than AJCC groups, (3-yr TTR, 5-yr OS below), with fewer mid-risk NG pts. Removing treatment from NGs did not affect performance (C⫽0.66 for OS and 0.65 for TTR). Conclusions: The proposed ACCENT NGs are internally valid and have the potential to aid prognostication, decisionmaking, and patient/physician communication in pts with stage III CC. 3Y TTR (95% CI)

AJCC Nomo

3620

5Y OS (95% CI)

IIIA / Low

IIIB / Mid

IIIC / High

IIIA / Low

IIIB / Mid

IIIC / High

0.82 (0.80, 0.84) N ⫽ 1336 0.82 (0.80, 0.83) N ⫽ 2,891

0.72 (0.70, 0.73) N ⫽ 4575 0.71 (0.67, 0.73) N ⫽ 2,184

0.47 (0.44, 0.50) N ⫽ 1012 0.51 (0.49, 0.53) N ⫽ 1,848

0.80 (0.78, 0.83) N ⫽ 1336 0.85 (0.84, 0.86) N ⫽ 2,863

0.75 (0.74, 0.76) N ⫽ 4575 0.74 (0.72, 0.76) N ⫽ 2,185

0.51 (0.48, 0.54) N ⫽ 1012 0.53 (0.51, 0.56) N ⫽ 1,875


Randomized, phase II study of bevacizumab with mFOLFOX6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: Resectability and safety in OLIVIA. Presenting Author: Thomas Gruenberger, Medical University Hospital, Vienna, Austria

Overall survival (OS) analysis from PRIME: Randomized phase III study of panitumumab (pmab) with FOLFOX4 for first-line metastatic colorectal cancer (mCRC). Presenting Author: Jean-Yves Douillard, Centre René Gauducheau, Nantes, France

Background: Patients (pts) with unresectable colorectal cancer liver-only metastases (CLMs) may become resectable after downsizing by chemotherapy (CT) and biologic therapy. Although biologics are thought to improve overall response rate (ORR), the optimal combination of a biologic and CT for resectability remains uncertain. Methods: This open-label, multinational study randomized pts with unresectable CLMs to bevacizumab (BEV) plus mFOLFOX6 or FOLFOXIRI q2w. Resectability was assessed by interdisciplinary review. Unresectability was defined as ⱖ1 of the following: no possibility of upfront R0/R1 resection of all hepatic lesions, ⬍30% estimated residual liver after resection, or disease in contact with major vessels of the remnant liver. The primary end point was overall resection rate (R0/R1/R2). Results: From 10/2008 to 12/2011, 80 pts were randomized to mFOLFOX6-BEV (n⫽39) or FOLFOXIRI-BEV (n⫽41). Pt characteristics were male (46% vs 71%), aged ⱖ60 y (36% vs 63%), ECOG PS of 1 (23% vs 37%), and ⱖ5 target CLMs (49% vs 49%) in the mFOLFOX6-BEV and FOLFOXIRI-BEV arms, respectively. Resection rate, ORR, and progression-free survival (PFS) data are shown (Table). Grade ⱖ3 adverse events (AEs) occurred in 84% and 95% of pts receiving mFOLFOX6-BEV and FOLFOXIRI-BEV, respectively, and included neutropenia (35% vs 48%; febrile, 8% vs 13%) and diarrhea (14% vs 28%). Conclusions: The results suggest that FOLFOXIRI-BEV improves resection rates, ORR, and long-term outcomes vs mFOLFOX6-BEV in pts with initially unresectable CLMs. CT- and BEV-related AEs occurred with the expected incidence and were manageable. FOLFOXIRI-BEV should be evaluated further as an effective regimen to downsize CLMs. Clinical trial information: NCT00778102.

Background: The primary and final analyses of PRIME demonstrated that pmab ⫹ FOLFOX4 significantly improved progression-free survival (PFS) vs FOLFOX4 alone for first-line treatment of patients (pts) with wild-type (WT) KRAS exon 2 mCRC. Methods: Pts were randomized 1:1 to pmab 6.0 mg/kg every 2 weeks ⫹ FOLFOX4 or FOLFOX4 alone and had no prior chemotherapy for mCRC, ECOG performance status ⱕ 2, and tumor tissue for biomarker testing. The primary endpoint was PFS by central assessment. Secondary endpoints included OS, objective response rate, and safety. KRAS exon 2 tumor status was determined by a blinded central lab prior to the primary analysis. This exploratory analysis of updated survival (⬎80% OS events) estimated the treatment effect of pmab ⫹ FOLFOX4 compared with FOLFOX4 alone on OS by KRAS exon 2 status. Previous analyses in pts with WT KRAS exon 2 tumor status reported OS with an event rate of 54% of pts in the primary analysis and 68% of pts in the final analysis. Results: 1183 pts were randomized and received treatment: 593 pts in the pmab ⫹ FOLFOX4 arm and 590 pts in the FOLFOX4 alone arm. The KRAS exon 2 ascertainment rate was 93%, consistent with the primary analysis. 535/ 656 pts (82%) with WT KRAS exon 2 mCRC had an OS event at the time of this analysis. Results are shown (Table). Conclusions: In this updated analysis, an improvement in OS was observed in pts with WT KRAS exon 2 mCRC treated with pmab ⫹ FOLFOX4 vs FOLFOX4 alone (p ⫽ 0.03). Median OS was reduced in pts with mutant (MT) KRAS mCRC (p ⫽ 0.16) and is consistent with previous analyses. Updated efficacy and safety results will be presented. KRAS testing is critical to select appropriate pts with mCRC for treatment with pmab. Clinical trial information: NCT00364013.

Pts, % (95% CI) Resection rate (R0/1/2) Resection rate (R0/1) Resection rate (R0) ORR Median PFS (immature), mo (95% CI)

mFOLFOX6-BEV nⴝ39

FOLFOXIRI-BEV nⴝ41

Difference

P

48.7 (32.4–65.2) 33.3 (19.1–50.2) 23.1 (11.1–39.3) 61.5 (44.6–76.6) 11.6 (8.1–14.2)

61.0 (44.5–75.8) 51.2 (35.1–67.1) 48.8 (32.9–64.9) 80.5 (65.1–91.2) 21.0 (18.6–31.8)

12.3 (⫺11.0–35.5) 17.9 (⫺5.0–40.7) 25.7 (3.9–47.5) 18.9 (⫺2.1–40.0) –

.271 .106 .017 .061 –

Pmab ⴙ FOLFOX4 (n ⴝ 325)

FOLFOX4 alone (n ⴝ 331)

Pts who have died (any cause) - n (%) Median OS - mos (95% CI)

256 (79) 23.8 (20.0 – 27.7)

279 (84) 19.4 (17.4 – 22.6)

MT KRAS mCRC (n ⴝ 440) Pts who have died (any cause) - n (%) Median OS - mos (95% CI)

Pmab ⫹ FOLFOX4 (n ⫽ 221) 193 (87) 15.5 (13.1 – 17.6)

FOLFOX4 alone (n ⫽ 219) 195 (89) 19.2 (16.2 – 21.5)

WT KRAS mCRC (n ⴝ 656)

Hazard ratio (95% CI)

Descriptive p value

0.83 (0.70 – 0.98)

0.03

1.16 (0.94 – 1.41)

0.16




3622

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Phase II clinical activity and tolerability of the SMAC-mimetic birinapant (TL32711) plus irinotecan in irinotecan-relapsed/refractory metastatic colorectal cancer. Presenting Author: Neil N. Senzer, Mary Crowley Cancer Research Center, Dallas, TX

Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic CRC, gastric cancer (GC), SCCHN, or other tumors. Presenting Author: Josep Tabernero, Vall d’Hebron University Hospital, Barcelona, Spain

Background: Birinapant (B) is a SMAC-mimetic that inhibits IAPs and has potent preclinical anti-tumor synergy combined with TNFa-inducing chemotherapies [i.e irinotecan (I)]. B and I combination is well-tolerated and has encouraging activity in a phase 1 study. This study tested B⫹I with an ascending dose strategy (ADS) of B to mitigate Bell’s palsy (BP) risk, an unusual and reversible side effect of SMAC mimetics. Methods: I at 350mg/m2 IV q3weeks was administered with B weekly (2 of 3 weeks). The dose of B was titrated incrementally during Cycle 1: C1D1 at 5.6mg/m2 and C1D8 at 11mg/m2 for ADS. For Cycle 2 (C2) and ongoing treatment, the B dose was 22mg/m2 or 35mg/m2, which were the MTD and DLT (BP) dose levels when combined with I from the Ph 1 study. Safety and clinical activity for KRAS mutant (KRAS-MT) and wild-type (KRAS-WT) were assessed in 3 cohorts: (1) at 22mg/m2 for CRC KRAS MT; (2) 22mg/m2 for CRC KRAS WT; (3) 35mg/m2 for CRC KRAS MT. Results: 51 patients (pts) with CRC had a median number of 4 prior regimens with 47 refractory/ relapsed to irinotecan (92%). Tolerability was comparable to I alone. There were 2 PRs (4%), 27 SD (⬎2 cycles; 53%, median 4.7 mo), 17 PD (33%), and 5 non- evaluable pts (9%) for an overall clinical benefit (CR⫹PR⫹SD) rate of 57%. Median progression-free survival (PFS) was 2.1 months, and 6 mo PFS was 20%. KRAS MT CRC with prior I had a median PFS of 2.9 mo and 6 mo PFS of 25% (n⫽20). KRAS WT CRC with prior I had a median PFS of 1.4 mo and 6 mo PFS of 17% (n⫽18). The ADS seemed to reduce BP risk. No BP events occurred among 40 pts (22mg/m2 with ADS), compared to 1 of 7 pts (22mg/m2 without ADS). In the 35mg/m2 cohort, 1 BP event occurred among 12 pts (with ADS), compared to 3 of 6 (35mg/m2 without ADS). Conclusions: B ⫹ I demonstrated clinical benefit in pts refractory/relapsed to irinotecan, with greatest benefit in KRAS MT CRC. The ADS may provide a mitigation strategy for BP risk. Prior studies with I retreatment have showed no benefit in KRAS MT CRC. Comparable CRC pts with best supportive care have 6 mo PFS of 2%. Clinical activity supports the hypothesis for therapeutic synergy of B ⫹ I, with I as a TNFa-inducing agent. Further study of this combination is warranted. Clinical trial information: NCT01188499.

Background: PD-L1 has been reported to be expressed broadly in human cancer and can lead to inhibition of anti-tumor T-cell responses. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Pts with a broad range of tumors were examined in an expansion study with MPDL3280A. Methods: Pts with locally advanced or metastatic tumors received MPDL3280A administered IV q3w. Pts were treated for up to 1 y. Response was assessed by RECIST v1.1. Results: As of Jan 10, 2013, 20 pts with tumor types other than NSCLC, RCC and mM were evaluable for safety and treated at doses of 0.01-20 mg/kg (ⱕ1 [n⫽3], 3 [n⫽1], 10 [n⫽3] and 20 mg/kg [n⫽13]). Median pt age was 67 y (range 26-80 y), 100% were PS 0-1, 90% had prior surgery and 45% had prior radiotherapy. 95% of pts received prior systemic therapy. Pts received MPDL3280A treatment for a median of 96 days (range 22-330). The incidence of all G3/4 AEs, regardless of attribution, was 50%. No G3-5 pneumonitis or diarrhea was reported. Confirmed RECIST responses were observed in several tumor types, including CRC, GC and SCCHN. Additionally, antitumor activity (tumor shrinkage that has not yet met criteria for a RECIST response) has been observed in sarcoma and lymphoma. Analysis of biomarker data from archival tumors revealed that all pts reported to have RECIST response had baseline tumors that were PD-L1 positive. Updated data will be presented. Conclusions: Treatment with MPDL3280A was well tolerated, with no pneumonitis-related deaths. Rapid responses were observed in pts with CRC, GC and SCCHN. PD-L1 tumor status appears to correlate with responses to MPDL3280A. These data suggest that PD-L1 is a conserved mechanism for mediating tumor immune escape across a range of tumor types. MPDL3280A may be broadly active as anti-cancer therapy in PD-L1– expressing tumors, supporting further investigation. Clinical trial information: NCT01375842.

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Discovering new targeted therapies for BRAF mutant-like colorectal cancers. Presenting Author: F. Anthony San Lucas, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Approximately 10% of colorectal cancers (CRCs) harbor a BRAF mutation (BRAFm). Patients with BRAFm tumors have poor prognosis and are a therapeutic challenge. A BRAFm gene expression signature has been communicated (Popovici et al, JCO 2012), which can identify BRAFm tumors as well as BRAF wild-type tumors that display a similar expression pattern. Collectively, these tumors are termed BRAFm-like. Our goal was to validate this signature using next-generation sequencing and to discover novel therapies for BRAFm-like CRCs using a systems biology approach. Methods: We developed a semi-automated workflow that integrates publicly available tools named the Cancer In-silico Drug Discovery (CIDD). To validate the BRAFm-like signature, we used CIDD to analyze the CRC dataset from the The Cancer Genome Atlas Network (TCGA). Samples were stratified on BRAFm status using exome-sequencing, and expression profiles were inferred from RNA-sequencing. We matched expression profiles with drug-induced signatures inferred from the Connectivity Map (CMap) – a systems biology tool that contains expression data of cell lines treated with 1,500 compounds. CIDD statistically ranks candidate compounds and annotates them to pathways using public databases. Results: When applied to TCGA RNA-sequencing data, a classifier based on the BRAFm-like signature resulted in 93.3% sensitivity and 83.5% specificity for detecting BRAFm samples. When applied to Agilent gene expression data, this resulted in 80% sensitivity and 91.1% specificity. 41% of KRAS-mutated samples and 14% of double wild-type samples were predicted to be BRAFm-like. 100% of MSI-high and 18% of MSS samples were predicted to be BRAFm-like. Compounds near the top of our drug rankings include Gefitinib and MG-262 a proteasome inhibitor. Conclusions: We have validated the BRAFm-like signature using RNA-sequencing and Agilent expression data from the TCGA, and showed a high degree of robustness across technologies. We have identified EGFR and proteasome inhibitors as potential compounds to target BRAFm-like CRCs.


Predicting overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) treated with chemotherapy (CT): The British Columbia Cancer Agency (BCCA) mCRC score. Presenting Author: Leo Chen, University of British Columbia, Vancouver, BC, Canada Background: The prognosis of individual pts with mCRC can be highly variable. Our objective was to develop a scoring system to improve the prognostication of mCRC pts at baseline assessment. We also further explored the impact of palliative resection (PR) of the primary tumor on OS. Methods: Pts diagnosed with mCRC from 2006 to 2008, referred to 1 of 5 regional cancer centers in British Columbia were retrospectively reviewed. Pts with prior early stage CRC who relapsed with mCRC were excluded. Multivariate stepwise selection was performed using significant variables from univariate analysis. Patients were assigned a composite risk score (range 0-15) based on their baseline variables, and then separated into quartiles for OS using cut-point analysis and Kaplan Meier methods. A secondary propensity score matched analysis was performed to obtain hazard ratios (HR) for death in order to control for baseline differences between pts who underwent PR and those who did not. Results: A total of 505 mCRC pts were included: median age 63 (range 22-86), 58% male, 75% ECOG 0-1, 58% colon primary, 34% ⬎1 metastatic site, and 46% smokers. In this cohort, 81% of the population underwent PR. ECOG 2-3, no primary resection, colon primary, ⬎1 metastatic site, CEA level ⬎4 ng/ml, male gender, and smoker were significant in the multivariate model and subsequently assigned a score. Median OS varied significantly depending on the composite risk score (table). After ECOG PS, PR of the primary was the second strongest prognostic factor (HR 2.3, 95%CI 1.6-3.3). To further explore this, a propensity score matched analysis was performed adjusting for age, gender, ECOG and receipt of chemotherapy. Prognosis continued to be more favorable in the PR group with a median OS of 17 vs. 7.9 months (HR 0.66, 95% CI 0.50-0.86, p⫽0.0019). Conclusions: In this population based analysis, the BCCA mCRC score was a simple and effective method to improve prognostication for mCRC pts. PR of the primary was associated with significantly longer OS. Score 0-3 4-5 6-8 9-15 P value

N

Median OS (months)

HR [95% CI]

181 136 117 71

33.6 25.9 17.1 10.4

1.0 1.47 [1.03-2.11] 2.31 [1.64-3.25] 5.92 [4.0-8.7] ⬍0.01


236s 3625


Phase I dose escalation of the oral histone deacetylase inhibitor (HDACi) resminostat in combination with FOLFIRI in colorectal cancer (CRC) patients: The SHORE trial. Presenting Author: Henning Schulze-Bergkamen, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany

3626


Effect of EGFR inhibition on HER3/PI3K activation by feedback induction of ErbB heterodimers in cetuximab-sensitive colon cancer cells. Presenting Author: Bart Jacobs, Laboratory of Molecular Digestive Oncology, KU Leuven, Leuven, Belgium

Background: Resminostat is a novel oral HDAC inhibitor with broad activity in various cancer models. In CRC models, resminostat revealed synergistic effects with 5-FU and irinotecan/SN-38, indicating its (re-)sensitization potential when applied in combination therapy. Furthermore, resminostat downregulates thymidylate synthase, involved in drug resistance to 5-FU and effectively inhibits HDAC2, one of the target enzymes believed to critically support development of CRC. The phase I/II SHORE trial investigates resminostat in combination with FOLFIRI in patients previously treated with 5-FU. Methods: Patients (pts) with advanced CRC having previously received 5-FU alone or in combination with other agents who were scheduled for FOLFIRI in second or later treatment lines were included. The phase I comprised an open-label, inter-patient, ‘3⫹3’ dose escalation design with increasing doses of resminostat combined with standard FOLFIRI. Pts received resminostat on 5 consecutive days, followed by a 9-day drug free period (‘5⫹9’ scheme, i.e. 14-day cycles). On days 3 and 4 of each cycle (C), FOLFIRI was administered. Primary objective of the Phase I part was to determine safety and tolerability, the maximum tolerated dose and pharmacokinetics of the combination. Results: 17 pts (median age 61 yrs; 12 males; 11 ECOG 0; 6 ECOG 1; median therapy line 2 [2-6]) were enrolled in 4 dose levels of resminostat 200, 400, 600 mg QD (3 pts each) and 400 mg BID (6 pts) plus FOLFIRI. Two pts discontinued in C1 and were replaced. No DLT occurred. AEs consisted mainly of GI symptoms of mild and moderate intensity (nausea, vomiting and diarrhea) leading to decreased electrolyte plasma levels in some pts. In the highest dose level tested (400 mg BID) hematological toxicity, mainly neutropenia up to grade 4, was observed leading to dose reductions in 3 pts in C3 and C7. No objective responses were reported, however some pts showed SD for prolonged time (up to 32 w). Results of the completed phase I part will be reported. Conclusions: The combination of resminostat with standard FOLFIRI was safe and well tolerated warranting continuation into the Phase II part of the study. Clinical trial information: NCT01277406.

Background: Although cetuximab treatment has been successful for the treatment of KRAS wild-type colorectal cancers, complete remissions are rarely seen in patients, leading ultimately to resistance. We hypothesized that in cetuximab-sensitive patients, the ErbB network is insufficiently targeted since network plasticity may occur. Methods: We have used EGFR-sensitive colorectal cancer cells and investigated ErbB network activity and adaptations by RTK arrays, western blot, and Collaborative Enzyme Enhance Reactive immunoassay (CEER). These were complemented by ErbB heterodimerization (HER2:3, HER1:2, HER1:3, HER3: PI3K) assays using CEER. Effects on cell survival were measured using colony formation assay. In addition to the EGFR sensitive cell line, 200 clinical colorectal cancer (CRC) samples were profiled utilizing CEER for RTKs, downstream signaling, and heterodimerization. Results: EGFR and downstream signaling proteins AKT, ERK, and RSK were potently inhibited by cetuximab or gefitinib at 24h of treatment in EGFR sensitive colorectal cancer cell line. At 24h of treatment, we observed approximately 2 folds increase in total HER2 and HER3 protein levels, 2.7 folds in phosphorylated HER3, and 5.4 folds in HER2:HER3 heterodimer formation. Concurrently, increased in ErbB heterodimer formation was accompanied by 5 folds increase in PI3K binding to HER3, resulting in enhanced HER3 signaling, with increase in AKT, ERK, and RSK. Co-treatment of these cells with cetuximab and HER2 inhibitor Trastuzumab or by treatment with lapatinib blocked the induction of HER2:HER3 heterodimer, HER3 phosphorylation, and PI3K binding to HER3. In 30% of the 200 clinical colorectal cancer samples profiled, we observed an increased in phosphorylated HER3, formation of HER2:HER3 and HER3:PI3K heterodimers along with HER1 activation (KRAS WT). Conclusions: Combination of HER2 inhibitor with an EGFR inhibitor could potentially increase the therapeutic index in cetuximab sensitive patients, and suppress activation of feedback mechanisms upon EGFR inhibition. Current findings suggest that CRC patients with similar profile would benefit from these combination therapies.

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Cost implications of reactive versus prospective testing for dihydropyrimidine dehydrogenase (DPD) deficiency in patients with colorectal cancer. Presenting Author: Gul Ahmed, Bon Secours Hospital, Cork, Ireland Background: DPD is an enzyme encoded by the DPYD gene involved in the metabolism of the chemotherapy drug 5-fluorouracil (5FU) and the oral 5FU prodrug capecitabine. Patients (pts) with DPYD mutations are at risk of severe toxicities from standard dose 5FU, although they may safely receive lower dose therapy with careful monitoring and dose escalation. Methods: In this retrospective study we identified all pts starting 5FU-based chemotherapy for colorectal cancer (CRC) at our institution between Jan 1 2010 and Dec 31 2012. During this time DPD testing was usually performed in a reactive manner, typically for pts experiencing severe toxicities. We reviewed the charts of pts who tested positive for DPYD mutations and assessed the financial implications of their hospitalizations with toxicity. These costs were compared to the costs which would have incurred if all pts starting such therapy had been proactively tested. Results: A total of 134 pts started first-line 5FU-based chemotherapy for CRC over the study period, 66 in the adjuvant setting and 68 for metastatic disease. 31 pts had DPYD mutation testing performed. 6 tests (19% of those tested, 4.5% of the total population) revealed heterozygote DPYD mutations. 5 pts had already experienced severe treatment-related toxicity resulting in cessation of therapy, while one was tested prospectively and received chemotherapy with dose reduction ab initio. The total cost related to hospitalization with toxicity for these 5 pts was €155,083. At €177 per test, the cost to prospectively test all pts starting first-line 5FU-based therapy over the time period would have been €23,718 representing a saving of €131,365 through avoiding these admissions alone. 4 pts who tested positive for DPYD mutations were receiving adjuvant therapy and none restarted therapy following severe toxicity early in their therapy. 2 pts subsequently relapsed with metastatic disease. Conclusions: Prospective testing for DPYD mutations in pts with CRC starting 5FU-based therapy for the first time represents a considerable cost-saving opportunity, in addition to potentially avoiding prolonged hospitalization and morbidity for a sizeable minority of pts.


TFAP2E methylation status and prognosis of patients with radically resected colorectal cancer. Presenting Author: Seong Joon Park, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea Background: Transcription factor AP-2␧, a member of the AP-2 family has extensively studied in many cancers. Recently, it has been suggested that the gene encoding AP-2␧ (TFAP2E) is involved in the development of colorectal cancer (CRC) and is also associated with clinical outcomes of the patients with CRCs. Therefore, we have investigated the clinical significance of TFAP2E in CRC patients who underwent curative resections. Methods: A single-institution cohort of 248 patients with curatively resected, stage I/II/III CRCs between March and December, 2004 were included, and the analyses were performed in 193 patients whose tumors were available for TFAP2E methylation status Results: One hundred twelve patients (58%) showed TFAP2E hypermethylation, which was significantly more common in CRCs with distal location, low pathologic T stage (T1/T2) and stage I. After a median follow-up duration of 86.3 months, the patients with TFAP2E hypermethylation had a trend for better survival outcome in terms of relapse-free survival (RFS) and overall survival (OS) (TFAP2E hypermethylation vs. hypomethylation; 5-year RFS rate 90% vs. 80%, p⫽0.063; 6-year OS rate 88% vs. 80%, p⫽0.083). Multivariate analysis showed pathologic nodal stage and TFAP2E methylation status were independent prognostic factors affecting both RFS and OS, which also remained significant factors in the subgroup analysis including 154 patients with stage II/III CRCs who had received adjuvant chemotherapy. Conclusions: TFAP2E hypermethylation was associated with better clinical outcome and may be considered as an independent prognostic factor in the patients with curatively resected CRC.




Prognostic biomarkers in a series of stage II colon cancer. Presenting Author: Cristina Santos, Department of Medical Oncology, Institut Català d’Oncologia-IDIBELL, L’Hospitalet de LLobregat, Spain Background: Different clinico-pathological factors are used to define a group of patients with high-risk stage II colon cancer (CC) that may benefit of adjuvant treatment. Moreover, several molecular markers, such as microsatellite instability (MSI) and BRAF, have been widely investigated as prognostic factors. Recently a high stroma component (EMT⫹ subtypes) has also been associated with poor outcome. The aim of the study is to analyze the prognostic value of MSI, BRAF and tumor-stroma ratio in a prospective series of stage II CC patients. Methods: FFPE tissue from 432 stage II CC patients operated at Hospital Universitari de Bellvitge (1996 2006) were included in the study. MSI status was assessed by the analysis of 5 mononucleotide repeat markers (BAT-25, BAT-26, NR-21, NR-24 and MONO-27). BRAF V600E mutation was analyzed by single strand conformation polymorphism technique. Tumor-stroma ratio was analyzed by immunohistochemistry. Associations between molecular factors and clinical features were assessed by Chi-Squared (X2) tests. A Cox regression model was used to evaluate the Relapse Free (RFS) and the Colon Cancer specific Survival. Results: MSI status could be determined in 350 patients. 48 (14%) had MSI high (MSI-H) tumor. BRAF status could be assessed in 380 cases. 58 (15%) cases were BRAF mutated. Tumor-stroma ratio was analyzed in 407 tumor samples. 176 (43%) tumors had more than 50% intra-tumor stroma and were classified as stroma-high. MSI-H tumors were significantly located in right colon (X2 p-value ⫽ 1.03e-5), were poorly differentiated (X2 p-value ⫽ 0.003) and had more than 12 lymph nodes resected (X2 p-value ⫽ 0.037). MSI-H tumors were associated with BRAF mutation (X2 p-value ⫽ 0.02) and stroma-low (X2 p-value ⫽ 0.0005). When a molecular prognostic risk classification was performed, patients with MSI-H /stroma-low suggested a low risk of relapse comparing to MSI-H/ stroma-high, microsatellite stable (MSS)/stroma-low and MSS/stroma-high patients (HR ⫽ 3.15; 95 CI, 0.76 – 13.1, p-value ⫽ 0.0602). Conclusions: MSI-H tumors have BRAF mutation as well as low intra-tumor stroma. Our results suggest that tumor-stroma ratio can explain differential prognosis in MSI-H stage II tumors.

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Analysis of KRAS/NRAS mutations in PEAK: A randomized phase II study of FOLFOX6 plus panitumumab (pmab) or bevacizumab (bev) as first-line treatment (tx) for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC). Presenting Author: Lee Steven Schwartzberg, The West Clinic, Memphis, TN Background: PEAK estimated the tx effect of FOLFOX6 with pmab or bev in 1st-line WT KRAS mCRC. The PRIME study showed significantly improved progression free survival (PFS) and overall survival (OS) with pmab ⫹ FOLFOX vs FOLFOX in pts with WT RAS (KRAS/NRAS exons 2, 3, 4) mCRC in a prospective-retrospective analysis (unpublished data). Methods: This prospectiveretrospective analysis of PEAK was designed to assess the effect of pmab ⫹ FOLFOX6 or bev ⫹ FOLFOX6 on PFS (primary endpoint) and OS in WT RAS (KRAS/NRAS exons 2, 3, 4) mCRC. Pts were required to have WT KRAS exon 2 tumors. Bidirectional Sanger sequencing and Transgenomic SURVEYOR/WAVE analysis were independently conducted to detect mutations in KRAS exon 3 (codons 59/61), exon 4 (codons 117/146); NRAS exon 2 (codons 12/13), exon 3 (codons 59/61), exon 4 (codons 117/146); BRAF exon 15 (codon 600) in banked specimens. Results: 285 WT KRAS (exon 2) mCRC patients (pts) were randomized, 278 received tx. The current RAS ascertainment rate is 75%. Tx HRs (pmab:bev) for pts with WT RAS were 0.63 (95% CI, 0.43-0.94; p ⫽ 0.02) for PFS and 0.55 (95% CI, 0.30-1.01; p ⫽ 0.06) for OS (Table). The incidence of worst grade 3-5 adverse events was consistent with the primary analysis. Updated OS and BRAF results will be presented. Conclusions: In this 1st-line estimation study in WT RAS mCRC, PFS and OS HR favored pmab ⫹ FOLFOX6 relative to bev ⫹ FOLFOX6, suggesting that activating RAS mutations appear to be predictive for pmab tx effect. The safety profile for both arms was consistent with previously reported studies. Clinical trial information: NCT00819780. WT RASa, n Median PFS - mos (95% CI) Median OS - mos (95% CI) WT KRAS-2, Mutant RASb, n Median PFS - mos (95% CI) Median OS - mos (95% CI) a

Pmab ⴙ FOLFOX6

Bev ⴙ FOLFOX6

80 13.1 (10.7 - 15.1) NRd (28.8 - NRd) 24 7.8 (6.5 - 9.8) NRd (13.0 - NRd)

80 9.5 (7.9 - 12.7) 29.0 (24.3 - NRd) 23 8.9 (7.3 - 12.0) 21.6 (13.9 - 25.4)

HRc (95% CI)

Descriptive p value

0.63 (0.43 - 0.94) 0.55 (0.30 - 1.01)

0.02

1.31 (0.66 - 2.59) 0.72 (0.28 - 1.83)

0.06

0.44 0.50

WT in KRAS and NRAS (exons 2, 3, 4). bWT KRAS (exon 2) and Mutant KRAS (exons 3 or 4) or Mutant NRAS (exons 2, 3, or 4). cStratified Cox proportional hazards model. dNot reached.

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Quantitative analysis of the impact of deepness of response on postprogression survival time following first-line treatment in patients with mCRC. Presenting Author: Ulrich Robert Mansmann, Institute for Medical Informatics, Biometry and Epidemiology, University of Munich, Munich, Germany Background: The extent of tumor shrinkage in patients (pts) receiving chemotherapy with or without monoclonal antibodies is prognostic for PFS and OS. The ‘Deepness of response (DpR)’ concept aims to relate tumor shrinkage to post-progression survival (PPS). If tumor shrinkage occurs, DpR is the percentage of shrinkage observed at the nadir compared with baseline. DpR is 0 for no change and negative if the tumor load increases. Longest diameter (LD) based on RECIST or a calculated tumor volume (ASCO GI 2012 #635) can be used to quantify the tumor load. A joint model was presented (ASCO GI 2012 #580, ASCO 2012 #3603) which allows the prediction of a pt PPS time based on DpR. Methods: Based on data from the randomized CRYSTAL and OPUS trials, 4 treatment regimens (FOLFIRI ⫹/- cetuximab and FOLFOX4 ⫹/- cetuximab) were studied. A joint model was used to quantify individual changes in tumor size over time and to relate these changes to PFS and OS. Relationships between baseline tumor load and DpR and PPS were studied. A Spearman correlation was used to study the relationship between DpR and PPS for KRAS wild-type (wt) pts with progressive disease. Results: Results are reported using LD-based measures for 841 pts with KRAS wt tumors and imaging data. The 348 pts treated with FOLFIRI alone had a median DpR of 33.3% (interquartile range [IR]: 8.0%, 58.0%) while the 315 pts treated with FOLFIRI ⫹ cetuximab had a significantly higher median DpR of 50.9% (IR: 18.4%, 78.6%), p⬍0.0001. The 96 pts treated with FOLFOX4 alone had a median DpR of 30.7% (IR: 4.0%, 55.9%) and the 82 pts treated with FOLFOX4 ⫹ cetuximab had a significantly higher median DpR of 57.9% (IR: 24.0%, 92.9%), p⫽0.0008. Correlation between DpR and PPS for pts with documented progression is statistically significant in each treatment group for both LD-based and volume-based measurements (p⬍0.0001 for the CRYSTAL study and p⬍0.005 for the OPUS study). Conclusions: Our results emphasize the value of DpR as a new efficacy outcome measure for clinical trials. The tumor-shrinking capacity of cetuximab was shown to be associated with its ability to prolong PPS.

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Clinicopathologic features of KRAS-mutated colorectal tumors vary by site of mutation. Presenting Author: Van Karlyle Morris, The University of Texas MD Anderson Cancer Center, Houston, TX Background: KRAS mutations in codons 12 and 13 are present in approximately 40% of all colon cancers and predict a lack of response to monoclonal antibodies to the EGFR among patients with metastatic disease. Activating mutations in codons 61 and 146 occur less frequently, and the clinicopathologic features of this subpopulation of KRAS-mutant colorectal tumors have not been clearly defined. Methods: Records of patients treated at MD Anderson Cancer Center between December 2000 and August 2012 for metastatic colorectal cancer whose tumors underwent testing for a KRAS mutation were reviewed for clinical characteristics, concurrent mutations, and survival outcomes. Associations between mutation status and clinic features were measured by calculation of odds ratios, and survival was estimated according to the Kaplan-Meier method. Results: Among the 487 records reviewed, 225 KRAS 12/13 mutations (47.2%) and 14 KRAS 61/146 mutations (2.9%) were detected. Liver metastases were less common for patients with KRAS 61/146 mutations than for patients with KRAS 12/13 mutations (OR 0.26, p-value⫽0.02). No difference in lung metastases was identified for KRAS 61/146 mutated patients when compared to those with KRAS wild-type tumors (OR⫽2.1, p-value⫽0.26), even though lung metastases were more common for patients with KRAS 12/13 mutations (OR 2.86, p-value⫽0.001). There was no association between the presence of a KRAS 61/146 mutation and gender, stage at presentation, site of primary tumor, body mass index, tobacco history, or concurrent PIK3CA mutation. Whereas a worse survival difference from the time of metastasis detection was noted for KRAS 12/13 patients when compared to those with KRAS wild-type tumors (HR 1.74, p-value⫽ 0.002), patients with KRAS 61/146 mutations demonstrated no change in survival outcome (HR 1.10, p-value⫽0.87). Conclusions: Patients with KRAS 61/146 mutations have different patterns of metastases compared to KRAS 12/13, but do not appear to share the poor prognosis associated with the more common KRAS 12/13. These results suggest that clinical phenotypes for patients afflicted with colorectal cancer may differ based on the specific codon mutated within the KRAS oncogene.


238s 3633


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A phase I study of sorafenib with FOLFIRI as first-line therapy for metastatic colorectal cancer (mCRC): Safety and efficacy results. Presenting Author: Jean Alfred Maroun, The Ottawa Hospital Cancer Center, Ottawa, ON, Canada

Ultra-deep amplicon sequencing to identify actionable mutations in matched plasma/tumor specimens from 44 patients with colorectal cancer of UICC stage III and IV. Presenting Author: Paulina Pechanska, Signature Diagnostics AG, Potsdam, Germany

Background: Phase I dose escalation to a maximum planned dose (MPD) o determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended-phase-II-dose (RP2D) and preliminary efficacy of sorafenib and FOLFIRI (irinotecan reduced-dose) in metastatic colorectal cancer (mCRC) patients. Methods: Starting doses: irinotecan 80 mg/m2 iv d1, sorafenib 400 mg po twice daily (bid, continuous), starting day 2. Escalations based on toxicity observed at the previous dose level (DL) up to: irinotecan 100 mg/m2 and sorafenib 800 mg bid. DLT was evaluated within the 1st study cycle (1 cycle ⫽ 2 FOLFIRI treatments). Results: 5 cohorts were concluded. All 16 ECOG PS 0-1 patients (9/7 men/women; 2/14 rectal/colon) with median age of 64, discontinued study: 10 (62%) disease progression, 4 (25%) toxicity, 1 curative surgery, 1 comorbidities. The dose levels of irinotecan (mg/m2, day1) and sorafenib (mg/day, bid, day 2-28) studied were DL1-80/400, DL2-80/600, DL3-90/600, DL4-100/600 and DL5-100/800, repeated every 4 weeks, 3 patients/DL. No DLT was observed. The MTD was not reached at the MPD (DL5). The most common ⱖGr2 treatment related adverse events (AEs) were: neutropenia 81%, HFS 69%, leucopenia 50%, fatigue 38%, anemia 31%, constipation 31%, nausea/vomiting 31%, mucositis 31%, diarrhea 25%, hypophosphatemia 25%. The most severe treatment related AEs were: Gr4: neutropenia 2 (12.5%); pulmonary embolism 1 (6%); Gr3: HFS 9 (56%), neutropenia 3 (19%), leucopenia 3 (19%), hypophosphatemia 3 (19%). Objective response rate was 56% (9 of 16 patients, 95%CI; 33-77%). Response duration was 13 months (95%CI; 5-17). Median progression-free survival and overall survival were 11 months (95%CI; 6-17) and 25 months (95%CI; 15-34), respectively. Conclusions: Combination therapy with S and modified FOLFIRI in these patients is well tolerated and demonstrates clinical efficacy at the MPD. The MTD was not reached at the MPD. Future research of this combination is warranted. Supported by Bayer Healthcare Pharmaceuticals. Clinical trial information: NCT00780169.

Background: Circulating cell-free DNA (cf-DNA) isolated from plasma samples of cancer patients (pts) is a promising source for noninvasive examination of tumor-specific mutation patterns. We examined the efficiency of ultra-deep amplicon sequencing (UDAS) of cf-DNA isolated from plasma and tumor DNA isolated from matched primary tumor tissue of pts with colorectal cancer (CRC). Methods: Blood was drawn prior to surgery from 44 pts: 20 male, 24 female; 44-79 years of age (median: 67.5); 11 stage III, 33 stage IV; 36 colon, 8 rectum tumors; no neo-adjuvant therapy. Cf-DNA was isolated from 2 ml of EDTA plasma. UDAS was applied to 72 DNA samples (44 plasma, 28 matched snap-frozen primary tumors) using the MiSeq platform (Illumina). A panel of 49 highly multiplexed amplicons was designed (Life Technologies) representing 9 cancer genes frequently mutated in CRC. For 16 primary tumors the mutation profile was determined using the TruSeq Amplicon Cancer Panel (Illumina). Results: Median cf-DNA yield was 310 ng / 2 ml plasma (1ng – 6.600 ng). There was no significant relation between cf-DNA yield and any clinical characteristic. Median amplicon coverage was 20.162 reads per bp (2.913 - 115.782). 33/49 amplicons (67%) had a coverage of ⬎ 10.000 reads. Altogether 61 high quality COSMIC-cited mutations were confirmed in plasma of 29/44 (66%) pts: 24/33 (73%) pts in stage IV, 5/11 (45%) pts in stage III. Confirmed mutations are: APC-17; BRAF-2, FBXW7-1, KRAS-15, NRAS-1, PIK3CA-4, SMAD4-2, and TP53-19 mutations. No high quality mutations were found in CTNNB1 and HRAS. Moreover two pts exhibited four high quality plasma mutations which were not detected in the matched primary tumor: APC (R216X), KRAS (Q61K), and SMAD4 (D355E); PIK3CA (E545K). Conclusions: Ultra deep amplicon sequencing is suitable to detect mutations in plasma samples of CRC pts with a high concordance to matched primary tumors. The concordance rate can be further increased by extending the spectrum of analyzed mutations or by the enrichment of cf-DNA tumor copies. This method could be applied to detect and monitor metastasis thus opening a new paradigm for the selection of pts for targeted therapies.

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Minor response rate to predict patient survival. Presenting Author: Binsheng Zhao, Department of Radiology, Columbia University Medical Center, New York, NY Background: RECIST is widely used to evaluate anticancer therapy efficacy, yet its response cutoff values have not been proven biologically or measurement-error relevant. Our previous study showed that the variability in measuring relative change in total tumor burden (TTB%) was ⫹/-10% in metastatic colorectal cancer (mCRC). Our study investigated the impact of a finer gradation of response categories in predicting survival. Methods: 468 patients enrolled in a phase II/III clinical trial evaluating a systemic therapy in mCRC were analyzed. TTB on baseline and 6-week (⫹/- 3-wk) scans were obtained per RECIST 1.0. Overall survival (OS) was defined from the start of treatment and the date of the scan using the landmark method. The TTB% was summarized using RECIST category and a finer gradation that included cut-offs established in our variability study (⬍-30%, -30% - -10%, -10% 10%, 10% - 20%, ⬎20%). The OS and TTB% correlation was evaluated by the Kaplan Meier method and Cox regression. The discriminatory powers of the response summaries were examined using Harrel’s c statistics and concordance probability. Results: Out of the 468 patients, 141 died. The median survival time for patients with a TTB% at 6 weeks of [-30%, -10%] (n⫽116), [-10%, 10%] (n⫽171), [10%, 20%] (n⫽43), ⬎20% (n⫽62) were 417, 287, 223 and 172 days, respectively. Among those with a change of ⬍ -30% (n⫽76), over half of patients were still alive. The hazard ratio for OS compared to those with a change of ⬍-30% are listed in the Table. The inclusion of additional categories increased both Harrel’s c-statistic (0.69 vs 0.73) and concordance probability (0.63 vs 0.69). Combining the [-10%, 10%] and the [10%, 20%] categories yielded very similar statistics compared to having all 5 categories. Both definitions of OS yielded consistent results. Conclusions: Evidence suggests that, in the context of this study, the minor change category of [-30%, -10%] at 6-wk correlates with longer survival compared to the change category of [-10%, 20%], suggesting a possible re-evaluation of conventional response cut-off values. Relative change at 6 week -30% to -10% -10% to 10% 10% to 20% >20%

Hazard ratio

95% Confidence interval

P

1.91 5.37 4.69 12.60

(0.98, 3.74) (2.91, 9.92) (2.04, 10.74) (6.57, 24.15)

0.057 ⬍0.001 ⬍0.001 ⬍0.001


Regorafenib (REG) in progressive metastatic colorectal cancer (mCRC): Analysis of age subgroups in the phase III CORRECT trial. Presenting Author: Eric van Cutsem, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium Background: In the CORRECT phase III trial, the multikinase inhibitor REG demonstrated significant improvement in overall survival (OS) and progressionfree survival vs placebo (Pla) in patients (pts) with mCRC whose disease progressed on other standard therapies. The most frequent REG-related grade ⱖ3 adverse events (AEs) of interest were hand–foot skin reaction (HFSR), fatigue, diarrhea, hypertension, and rash/desquamation. We explored whether the impact of REG in pts aged ⱖ65 years differed from that in younger patients. Methods: Pts with mCRC progressing following all other available therapies were randomized 2:1 to receive REG 160 mg once daily (n⫽505) or Pla (n⫽255) for the first 3 weeks of each 4-week cycle. The dose could be modified to manage AEs. The primary endpoint was OS. We report efficacy, safety, and dosing data from REG recipients by age. Results: The REG treatment group included 309 pts ⬍65 years (307 evaluable for safety) and 196 pts ⱖ65 years (193 evaluable for safety). The OS hazard ratio (REG/Pla) was 0.72 (95% confidence interval [CI] 0.56 – 0.91) in pts ⬍65 years and 0.86 (95% CI 0.61–1.19) in pts ⱖ65 years (interaction p-value ⫽ 0.405). Median OS was 6.7 vs 5 months for REG vs Pla in pts ⬍65 years, and 6.0 vs 5.6 months, respectively, in pts ⱖ65 years. Most pts experienced drug-related AEs (⬍65 years: 93.8%; ⱖ65 years: 91.7%). The rates of grade ⱖ3 REG-related AEs of interest and dose modifications are shown in the Table. In pts ⬍65 years vs ⱖ65 years, median (interquartile range [IQR]) duration of REG was 7.6 weeks (6.6 –15.4) vs 7.1 weeks (5.1–17.2), median (IQR) daily REG dose was 160.0 mg (134.6 –160.0) vs 160.0 mg (137.5– 160.0), and median (IQR) proportion of planned REG dose was 83.3% (65.7–100.0) vs 78.6% (66.7–100.0), respectively. Conclusions: In the CORRECT trial, REG demonstrated an OS benefit in pts ⬍65 years and ⱖ65 years. Safety and tolerability of REG appeared to be similar in both age subgroups. Clinical trial information: NCT01103323. Grade >3 AEs, % Any HFSR Fatigue Hypertension Diarrhea Rash/desquamation Pts with dose modifications, % Any Reduction Interruption

75 years (nⴝ38)

52 19 9 5 7 5

57 12 8 12 7 8

66 18 16 11 11 3

76 27 94

73 31 100

84 9 100




Time profile of adverse events (AEs) from regorafenib (REG) treatment for metastatic colorectal cancer (mCRC) in the phase III CORRECT study. Presenting Author: Axel Grothey, Mayo Clinic, Rochester, MN Background: In the CORRECT phase III trial, the multikinase inhibitor REG demonstrated significant improvement in overall survival and progressionfree survival vs placebo (P) in patients with mCRC whose disease had progressed on other standard therapies. The most frequent grade 3 AEs were hand–foot skin reaction (HFSR), fatigue, diarrhea, hypertension, and rash. We examined when these AEs first occurred and what impact they had on REG dosing. Methods: Adults with mCRC progressing after all standard therapies were randomized to receive REG 160 mg (n⫽505) or P (n⫽255) orally once daily for the first 3 weeks of each 4-week cycle. AEs were managed with dose modifications (reduction and interruption) according to the protocol. Results: The safety population comprised 753 pts (REG n⫽500, P n⫽253). The mean ⫾ SD treatment duration was 12.1 ⫾ 9.7 weeks for REG and 7.8 ⫾ 5.2 weeks for P. Treatment-emergent AEs occurred in 99.6% of REG pts and 96.8% of P pts. AEs occurring in ⱖ10% more REG than P pts were fatigue, HFSR, anorexia, diarrhea, weight loss, voice changes, hypertension, rash/desquamation, oral mucositis, fever, hyperbilirubinemia, and low platelet count. The incidence of grade ⱖ3 HFSR, fatigue, hypertension, and rash/desquamation typically peaked in cycle 1 and tapered to a relatively stable lower incidence over later cycles, while the incidence of diarrhea remained relatively constant throughout the study; median time to first occurrence and worst grade of these AEs is shown in the table. AEs led to dose modifications in 66.6% of REG pts and 22.5% of P pts. Conclusions: The most common AEs in the REG group typically occurred early during treatment. Close early monitoring of AEs and proper management by dose modification is recommended. Clinical trial information: NCT01103323.

AE Diarrhea

REG (nⴝ500) Time to AE, days* Pts affected, First Worst % occurrence grade 43

Fatigue

63

HFSR

47

Hypertension

30

Rash

29

23.5 (12–50) 15 (8–29) 15 (11–35) 14 (8–29) 15 (11–21)

31.5 (15–71) 20 (11.5–56) 22 (13–51) 15 (8–34) 15 (11–23)

P (nⴝ253) Time to AE, days* Pts affected, First Worst % occurrence grade 17 46 8 8 5

29 (11–50) 18 (11–29) 16 (8–42) 20 (14.5–33) 15 (12–27)

29 (13–50) 29 (15–43) 16 (8–42) 20 (14.5–33) 15 (12–27)

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Randomized phase III clinical study comparing postoperative UFT/ LV,UFTⴙLV/UFT and UFTⴙLVⴙPSK/UFTⴙPSK as adjuvant therapy for curatively resected stage III colorectal cancer HGCSG-CAD study. Presenting Author: Toshiaki Shichinohe, Devision of Surgical Oncology, Hokkaido University Hospital, Sapporo, Japan Background: Study showed that the oral anticancer agent UFT/LV is useful as postoperative adjuvant chemotherapy for stage III colorectal cancer. PSK, a protein-bound polysaccharide extracted from the mycelia of Coriolus versicolor, is an immunomodulator widely used in gastric, colorectal and lung cancers. Methods: Patients aged 20-80 years with stage III colorectal cancer registered in 35 facilities were randomized to: group A (UFT/LV 28 days/5 weeks for 6 months); group B (UFT⫹LV 28 days/5 weeks for 6 months, then UFT for 12 months); and group C (UFT⫹LV⫹PSK 28 days/5 weeks for 6 months, then UFT⫹PSK for 12 months). Treatment was started within 6 months after curative resection. Outcome measures were relapse-free survival (RFS), overall survival (OS), incidence and severity of adverse events, and QOL. Results: Of 342 patients registered, 340 eligible patients were analyzed (84 in group A, 85 in group B, and 171 in group C). At baseline, variation in QOL score was observed but histopathological parameters were not different among 3 groups. Median observation period was 36 months. 3-year RFS was 73.8%, 77.6% and 73.9% in groups A, B, and C [A vs C: hazard ratio (HR) 0.960, 95% confidence interval (CI) 0.575-1.601; B vs C: HR 0.837, CI 0.488-1.433; A vs B: HR 1.151, CI 0.623-2.126]. 3-year OS was 95.2%, 91.8% and 89.9% in groups A, B, and C (A vs C: HR 0.460, CI 0.155-1.367; B vs C: HR 0.814, CI 0.338-1.963 A vs B: HR 0.570, CI 0.167-1.947). Adverse events ⱖgrade 3 included gastrointestinal symptoms and general status. There was no treatment-related death. Excluding high fatigue score in QOL scale that showed pretreatment variation, stratification analysis showed interaction between family score and group, and efficacy was suggested especially in group C with high score (3-yesr RFS: 66.7%, 68.2% and 88.1% in groups A, B, and C. A vs C: HR 3.289, CI 0.951-11.375, B vs C: HR 3.070, CI 0.973-9.685, A vs B: HR 1.084, CI 0.344-3.417). Conclusions: A significant difference in primary endpoint was not detected. Variation in QOL at treatment initiation probably greatly affected outcome. Clinical trial information: NCT00209742.

* Median (interquartile range).

3639


3640


Guanylyl cyclase C (GCC) expression in lymph nodes (LNs) as a determinant of recurrence in stage II colon cancer (CC) patients (pts). Presenting Author: Daniel J. Sargent, Mayo Clinic, Rochester, MN

Real-world comparative economics of a 12-gene assay for prognosis in stage II colon cancer. Presenting Author: Tiffany Yu, Cedar Associates, LLC, Menlo Park, CA

Background: The first phase of the multi-center prospectively specified retrospective study Validating Indicators To Associate Recurrence (VITAR), assessing the relationship between GCC gene expression in formalin fixed (FFPE) LNs and time to recurrence (TTR) in stage II CC pts not treated with adjuvant chemotherapy (Sargent, Annals Surg Onc 2011), showed promising initial results. Here we report a validation set of 463 new stage II CC pts. Methods: GCC mRNA was quantified by RT-qPCR using FFPE LNs from untreated T3N0 CC pts diagnosed from 1999-2008 with at least 12 LNs examined , blinded to clinical outcomes. Patients were classified by GCC LN ratio (LNR) (high risk: LNR ⬎ 0.1; low risk: LNR ⱕ 0.1), with LNR defined as ratio of GCC positive to GCC informative LNs. Cox regression models tested the relationship between GCC and the primary endpoint of TTR, adjusted for age, tumor grade, number of LN examined pathologically, and lymphovascular invasion. Mismatch repair (MMR) status was also assessed. All primary analyses and cut-points were pre-specified. Results: 46pts (10%) recurred (rec), median follow-up was 65 months, median LNs examined was 20, and 42% (195/463) were classified high risk. Overall, TTR was not significantly associated with binary GCC LNR risk class (HR⫽1.47, p⫽.208) or DFS (HR⫽ 1.39, p⫽.097). One site’s (n⫽97) tissue grossing method precluded appropriate LN assessment with existing GCC qualification methods. Excluding this site resulted in a TTR HR⫽1.91, p⫽0.051 (multivariate). In a post-hocanalysis excluding this site and using a 3-level GCC risk group of high (LNR ⬎ 0.20), intermediate (0.10 ⬍ LNR ⬍ 0.20) and low (LNR ⬍ 0.10), high risk group pts had a 5-yr rec risk of 22% versus 8% in low risk (HR 2.72, p⫽0.006). MMR status was not significantly associated with TTR (multivariate p⫽0.30). Conclusions: GCC status is a promising prognostic factor in appropriately staged stage II CC pts not treated with adjuvant therapy independent of traditional histopathology risk factors, but GCC determination must be performed with methodology adapted to the tissue procurement and fixation technique. Outcome associations were strengthened when considering a 3-level GCC categorization.

Background: Prior economic analysis of a 12-gene assay (Oncotype DX), compared with patterns of care reported in the NCCN database of patients with stage II, T3, DNA mismatch repair proficient (MMR-P) colon cancer, predicted that the assay would save medical costs and improve patient well-being (Hornberger et al. Value Health 2012). This study assessed the validity of those findings with actual adjuvant chemotherapy (aCT) recommendations. Methods: Outcomes and costs were estimated for patients with stage II, T3, MMR-P colon cancer using a Markov model. A study of 141 patients from 17 sites in the Mayo Clinic Cancer Research Consortium collected data on aCT recommended before and after knowledge of the 12-gene assay results (Srivastava et al. abstract). Quality-adjusted life years (QALY) and medical resource use after recurrence were computed using guideline-validated state-transition probability estimation methods. Risk of progression and incidence of adverse events with different aCT regimens were based on published literature. Drug and administration costs for aCT were obtained from 2012 Medicare fee schedules. One-way sensitivity analyses were conducted to evaluate parameter influence on economic impact. Results: After receiving the 12-gene assay results, physician recommendations in favor of aCT decreased 22% (95% CI 11%-32%; McNemar test p⬍0.001) from 73 (52%) to 42 (30%) patients. Oxaliplatin aCT and 5-FU monotherapy recommendations each declined 11%. Average aCT costs decreased $3,228 for drugs, $750 for administration, and $3,168 for adverse events management. Overall, average total direct medical costs decreased $1,683. The net effect on average patient well-being was a gain of 0.102 QALYs. Total change in medical costs is most influenced by the cost of death due to colon cancer, time-preference discount rate, and the change in aCT recommendations. Savings are expected to persist even if the cost of oxaliplatin dropped by ⬎75% due to generic substitution. Conclusions: The 12-gene assayhas been shown to alter aCT recommendations for patients with stage II, T3, MMR-P colon cancer. This study provides real-world confirmation that these aCT changes reduce direct medical costs and improve patient well-being.


240s 3641


Gain of ALK gene copy number to predict lack of response to anti-EGFR treatment in advanced chemorefractory colorectal cancer (CRC) with KRAS/NRAS/BRAF/PI3KCA wild-type status. Presenting Author: Filippo Pietrantonio, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

3642


Bevacizumab before cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis of colorectal origin: Analysis of early postoperative complication rate and long term follow-up. Presenting Author: Clarisse Eveno, Hopital Lariboisiere, Paris, France

Background: KRAS, BRAF, NRAS and exon 20 PIK3CA quadruple wild-type CRC is associated with 41.2% response rate to anti-EGFR treatments. Even in molecular characterized patients, there is still a subset of non responders. The identification of additional predictive biomarkers is an unmet clinical need for treatment personalization. Alterations of ALK oncoprotein may interfere with the biological activity of EGFR through cross-talk of downstream signalling pathways. Methods: This retrospective analysis aimed to investigate the correlation between ALK gene copy number (GCN), assessed by fluorescence in situ hybridization (FISH), and clinical outcome in KRAS/NRAS/BRAF/PI3KCA wild-type chemorefractory advanced CRC patients receiving cetuximab or panitumumab. FISH was perfomed with break-apart ALK (2p23) probes and gain of ALK GCN was defined as a mean of 3 to 5 signals in ⱖ10% of cells and amplification as ⱖ6 signals. Association of ALK status with RECIST response was performed by Fisher’s exact test. Results: Forty-one patients were identified, of whom 17 (41%) were ALK GCN positive, whereas the remaining 24 cases (59%) were ALK GCN negative. No ALK translocations were detected. Overall response rate was 19/41 (46%). We observed a partial response in 3/17 patients with ALK GCN positive versus 16/24 patients with ALK GCN negative (18% versus 67%, respectively; P⫽0.0036). Kaplan-meier curves for comparison of median progression-free and overall survival, as well as correlation with ALK expression by immunohistochemistry, will be presented at the Meeting exploring the whole National Cancer Institute data-set. Conclusions: In this study population with KRAS/NRAS/BRAF/PI3KCA wild-type tumors, the response rate greater than 40% is in line with literature data. ALK GCN may be a biomarker for clinical outcome prediction in advanced chemorefractory CRC patients treated with cetuximab or panitumumab.

Background: Patients with stage IV colorectal cancer and peritoneal carcinomatosis are increasingly treated with curative intent and perioperative systemic chemotherapy combined with targeted therapy.The aim of the study was to analyze the potential impact of bevacizumab on early morbidity and survival after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal carcinomatosis of colorectal origin. Methods: From 2004 to 2010, in three referral centers, 182 patients with colorectal carcinomatosis were treated with complete cytoreduction followed by HIPEC after either preoperative systemic chemotherapy alone or in combination with bevacizumab. Because there was no control on treatment allocation, propensity score methods were used to control this bias. Results: The median time from discontinuation of bevacizumab to HIPEC was 7 weeks (range, 6-10). Major morbidity was greater in the Beva group (34 vs. 19%, p⫽0.020). Nine patients died postoperatively: 5 (6.2%) in the Beva group (n⫽80) and 4 (3.9%) in the group treated with chemotherapy alone (n⫽102) (p⫽NS). The rate of digestive fistulas was greater in the Beva group, although not significant (18 vs. 10%, p⫽NS). After matching, the effect of Bevacizumab on major morbidity (including death) was found to be significant (OR ⫽ 2.28, 95% CI; 1.05 - 4.95) (p⫽0.04). No difference in median of overall and disease free survival was found between the two groups (12 and 36 month in Beva group vs. 14.3 and 49 month in the control group, p⫽NS). Conclusions: Administration of bevacizumab before surgery with complete cytoreduction followed by HIPEC for colorectal carcinomatosis is associated with 2-fold increased morbidity. The oncologic benefit of bevacizumab before HIPEC remains to be evaluated with prospective randomized study.

3643

3644


Maintenance with the TLR-9 agonist MGN1703 versus placebo in patients with advanced colorectal carcincoma (mCRC): A randomized phase II trial (IMPACT). Presenting Author: Jorge Riera-Knorrenschild, Universitätsklinikum Giessen und Marburg, Marburg, Germany Background: Standard induction chemotherapy for mCRC is often discontinued in patients responding to the treatment. MGN1703, a synthetic DNA-based immunomodulator, acts as TLR-9 agonist. This trial has been conducted to assess clinical efficacy, safety, and immunogenicity of MGN1703 as maintenance therapy vs placebo. Methods: The IMPACT trial is an international, multicenter, randomized (2:1) double-blind placebocontrolled phase 2 trial in mCRC patients with disease control (CR, PR, SD) after 4.5 to 6 months of 1st-line induction chemotherapy with FOLFOX/ XELOX or FOLFIRI ⫹/- bevacizumab. Results: 59 patients have been randomized (43 MGN1703, 16 placebo). Median PFS from start of maintenance was not different with 2.8 vs 2.7 months, however the HR was 0.56 (CI 95%: 0.29-1.08; p⫽0.069) in favor of MGN1703, due to a small favorable subgroup with long-term PFS (20% vs 0% at 9 months; p⫽0.006). Total PFS from beginning of induction chemotherapy including maintenance was significantly improved: HR 0.49 (CI 95%: 0.25-0.94), p⫽0.029. After a median follow-up of 13 months 66% of patients are still alive (67% vs 62%), therefore survival data are still preliminary (HR 0.79; CI 95%: 0.3-2.1) and will be mature at the meeting. Activation of cellular immune function as indicated by significant increase of CD14⫹CD169⫹monocytes was observed in all but one of the MGN1703 treated patients, while absent in all placebo patients. Treatment was well tolerated: 46.5% vs 31.3% of patients (MGN1703 vs placebo) had any drug-related adverse events (AE) and 20.9% vs 18.8% had AE with grade 3 or 4 (including hypertension, ileus, sepsis, sensory polyneuropathy, nausea/ vomiting for MGN1703 and pain, popular exanthema for placebo). Conclusions: MGN1703 maintenance seems to prolong PFS in a subgroup of patients with disease control after induction chemotherapy vs placebo, and is associated with relative mild toxicity. This in an early signal in a selected and very limited patient population which supports further investigation. Predictive biomarkers are under evaluation to identify a potential subgroup which might have benefit from this TLR-9 MGN1703 maintenance. Clinical trial information: NCT01208194.


Association of aspirin use with improved 5-year survival in colorectal cancer patients with PIK3CA mutation. Presenting Author: Nishi Kothari, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL Background: Recent work has shown an association between longer survival and aspirin use in colorectal cancer (CRC) patients with mutated PIK3CA. It has been hypothesized that this survival advantage could occur via blocking the PI3K pathway and allowing apoptosis of mutated cancer cells. The goal of this work is examine the use of aspirin and outcome in CRC patients with PI3KCA mutation. Methods: PIK3CA mutation status was assessed in paraffin-embedded tumor samples from 471 CRC patients between 1998-2010. PIK3CA mutation was assessed by exome sequencing using an Illumina Next Generation (NGS) platform with 50-100X coverage on all patients. The BWA/GATK pipeline was used to identify variants and indels. Because matched normal samples were not available for comparison to identify somatic mutations, filtering of normal variants was performed using 1000 Genomes. The usage of aspirin was collected retrospectively with electronic chart review. Results: Out of 471 patients, 73 were found to have unique PIK3CA mutations by NGS (15.4%). The most common mutations were found at codon 9 (38%) and codon 20 (21%). Patients had a median follow up of 47 months. Initial stage at diagnosis for PIK3CA mutants were as follows: 11 pts were stage I, 31 pts were stage II, 24 pts were stage III and 16 patients were stage IV. Of patients who died, those taking ASA had a 5% cancer related mortality compared to 23% cancer related mortality in non-ASA users. In contrast, the non-cancer related mortality was 25% in ASA users and only 8% in non-ASA users. Cancer specific rates for five year survival were 90% in the ASA group and 57% in the non-ASA group for all stages. In stage IV patients, there was 80% five year survival in the ASA users and 32% in the non-ASA group. Conclusions: There was a trend toward improvement in five year survival for colorectal cancer patients with PIK3CA mutations who used ASA. This trend persisted even in stage IV patients. Notably, non-cancer related deaths were higher in the ASA users, most likely secondary to medical comorbidities that necessitated ASA use. As follow up continues and this data set matures, future work will focus on validating these preliminary results and relating specific PIK3CA mutations to ASA response.


Gastrointestinal (Colorectal) Cancer TPS3645


FOCUS4: A prospective molecularly stratified, adaptive multicenter program of randomized controlled trials for patients with colorectal cancer (CRC). Presenting Author: Kai-Keen Shiu, Medical Research Council Clinical Trials Unit, London, United Kingdom Background: Targeted therapies based on somatic gene mutations or activated pathways have inhibited progression of some cancers. However, although various targets are identifiable in CRC, KRAS mutation is currently the only validated predictive biomarker for selection of a targeted therapy. FOCUS4 is a rolling phase II-III trial for testing in a staged way both the utility of molecular stratification and the efficacy of novel agents in subpopulations of mCRC patients. It is also a trial of a new strategy for testing stratified approaches to therapy in any biologically complex tumour type using a Multi-Arm, Multi-Stage design. Methods: The study population consists of subjects with newly diagnosed inoperable mCRC. Subjects receive first-line chemotherapy for 16 weeks. During this time the tumour is tested for BRAF/PIK3CA/KRAS/NRAS mutations and PTEN loss. Subjects with responding or stable disease on CT, who would normally be candidates for a treatment break, are then randomised to four coherent biomarkerbased subgroups: FOCUS4-A: BRAF mutant, FOCUS4-B: PIK3CA mutant or complete loss of PTEN on IHC, FOCUS4-C: KRAS or NRAS mutant, FOCUS4-D: All wild type (no mutations of BRAF, PIK3CA, KRAS or NRAS). For each subgroup, a relevant novel agent or combination is to be tested in an adaptive double-blind placebo controlled randomised trial design with multiple interim analyses for early termination if there is no strong evidence of worthwhile activity. There will also be a 5thsubgroup FOCUS4-N testing maintenance capecitabine for unclassifiable tumours or for patients whose marker defined cohort is temporarily suspended. The primary endpoint is progression free survival. Promising results in any biomarker defined cohort will then be tested for response in cohorts without the biomarker. Within the overall trial, biomarker developments can be accommodated with changes in the distribution of the cohorts or testing of new targeted agents. Enrolment will commence in May 2013. Upto 3400 patients will be registered over a 4-5 year period depending on which cohorts pass their staged interim analyses and proceed to later stages, including an overall survival endpoint. Clinical trial information: 2012-005111-12.

TPS3647


TPS3646

241s


MLN0264, an investigational, first-in-class antibody-drug conjugate (ADC) targeting guanylyl cyclase C (GCC): Phase I, first-in-human study in patients (pts) with advanced gastrointestinal (GI) malignancies expressing GCC. Presenting Author: Khaldoun Almhanna, Moffitt Cancer Center, Tampa, FL Background: MLN0264, an investigational ADC that targets GCC, consists of a fully human monoclonal antibody conjugated to the cytotoxic microtubule disrupting agent monomethyl auristatin E (MMAE) via a proteasecleavable linker. MMAE and the linker technology are licensed from Seattle Genetics. GCC is a cell surface protein expressed by normal intestinal epithelial cells, ~95% of metastatic colorectal cancer (mCRC), and subsets of gastric and pancreatic cancers. In normal tissue, GCC is expressed on the apical side of epithelial cell tight junctions; therefore, systemically delivered GCC-targeting agents are expected to be preferentially delivered to tumor tissue in which cell polarity is disrupted. MLN0264 has demonstrated antitumor activity in mouse xenograft models of GCC-expressing tumors (Veiby et al. EORTC-NCI-AACR, 2012), supporting the scientific rationale for this first-in-human study. Methods: This study (NCT01577758) was designed to evaluate MLN0264 in ~60 adult pts with GI malignancies expressing GCC (ⱖ1⫹), measurable disease by RECIST, and ECOG PS 0/1. This study is being conducted at 4 centers in the US and EU and is estimated to last ~36 – 42 months. Pts receive IV MLN0264 on day 1 of 21-day cycles for up to 17 cycles or until disease progression/unacceptable MLN0264-related toxicity. Dose escalation is proceeding via an adaptive Bayesian continual reassessment model approach based on dose-limiting toxicities in cycle 1. Following determination of the maximum tolerated dose (MTD), up to 14 pts each will be enrolled to mCRC and gastric carcinoma expansion groups to further characterize the safety, tolerability, and pharmacokinetics (PK) of MLN0264 and evaluate its clinical activity. The primary objectives are to evaluate the safety and tolerability, determine the MTD, and describe the PK of IV MLN0264. Secondary objectives are to evaluate the antitumor activity and immunogenicity of MLN0264. An exploratory objective is to examine the relationship between levels of GCC protein expression in tumor tissue and clinical response. Enrollment as of Jan 2013 was 12 pts. Clinical trial information: NCT01577758.

TPS3648


A phase III study of the impact of a physical activity program on disease-free survival in patients with high-risk stage II or stage III colon cancer: A randomized controlled trial (NCIC CTG CO.21). Presenting Author: Christopher M. Booth, Queen’s University Cancer Research Institute, Kingston, ON, Canada

Dual anti-HER2 treatment of patients with HER2-positive metastatic colorectal cancer: The HERACLES trial (HER2 Amplification for ColorectaL Cancer Enhanced Stratification). Presenting Author: Silvia Marsoni, Clinical Trial Coordination Unit - IRCC Istitute for Cancer Research and Treatment at Candiolo, Candiolo, Italy

Background: Observational data indicate that physical activity (PA) is strongly associated with colon-cancer specific survival. NCIC CTG CO.21 (CHALLENGE) is designed to determine the effects of a structured PA intervention on disease-control outcomes for survivors of high-risk stage II or III colon cancer who have completed adjuvant chemotherapy within the previous 2-6 months. Methods: Phase III randomized controlled trial. Target sample size of 962 patients is powered to detect a Hazard Ratio of 0.75 for disease-free survival (DFS). Trial participants will be stratified by centre, disease stage, body mass index, and performance status, and will be randomly assigned to a structured, individualized PA intervention or to general health education materials. The PA intervention will consist of a behavioural support program and supervised PA sessions delivered over a 3-year period, beginning with regular face-to-face sessions and tapering to less frequent face-to-face or telephone sessions. The goal of the PA program is to increase weekly PA by 10 MET hours/week. The PA program is delivered by physical activity consultants trained in exercise physiology and behavior change. Outcomes: The primary endpoint is DFS. Important secondary endpoints include multiple patient-reported outcomes (including those that address fatigue), objective physical functioning, biologic correlative markers (including assessment of the insulin pathway), and an economic analysis. Current Enrollment: The study is open at 19 centers in Canada and 20 centers in Australia. Accrual as of February 4, 2013 includes 212 registered and 184 randomized patients. Summary: Cancer survivors and cancer care professionals are interested in the potential role of PA to improve multiple disease-related outcomes, but a randomized controlled trial is needed to provide compelling evidence to justify changes in health care policies and practice. Clinical trial information: NCT00819208.

Background: We identified HER2 amplification as a potential onco-driver and marker of de novo resistance to anti-EGFR therapy in mCRC PTS for which other known genetic alterations conferring resistance to anti EGFR antibodies were excluded. Exploiting direct transfer xenografts of mCRC surgical samples in mice (xenoPTS), we conducted a multi-arm study in HER2-amplified xenoPTS showing that combinations of lapatinib (L) and trastuzumab (T), or L and pertuzumab (P) induced long-lasting tumor regressions while monotherapy with L led to stabilization and either monotherapy with T or P were ineffective (Bertotti et al. Cancer Discov 2011). The combination of P⫹T has a strong rationale for treatment of HER2-amplified mCRC, since combining the two agents is synergic in HER2⫹ breast cancers failing T (Baselga et al. JCO 2010), suggesting a cooperative mechanism of inhibition. On these findings we designed the HERACLES trial. Methods: HERACLES is an independent Phase II, 2-sequential cohort trial, assessing the response rate (RR) of T combined with either L (Cohort A) or P (Cohort B), in m CRC PTS harbouring an amplified HER2 tumor (SISH). Endpoints are RR and PFS. For each cohort sample size was calculated according to the Fleming & Hern 1- stage design under identical assumptions: H0 ⫽ RR 10%, H1⫽ RR 30%. With a ⫽0.05, power⫽0.85, 27 patient are required in each cohort (54 patients overall). A or B will be considered positive if ⱖ 6 responses/27 PTS are observed. Detection and quantitation of genetic alterations in circulating tumor DNA (liquid biopsy) and Her2 ECD in plasma as potential markers of secondary resistance will be done q14 days until relapse. Eligibility: CRC histology with KRAS WT, HER2 IHC 3⫹ ⱖ50% cells, prior treatment with fluoropirimidines, oxaliplatin, irinotecan, anti EGFR moABs based regimens ⫾ Bevacizumab; measurable disease (RECIST v1.0), ECOG PS ⱕ1, adequate organ function. Response is assessed q8w. Treatment: L 1000 mg daily po ⫹ T 4 mg/kg iv load, then 2 mg/kg iv weekly. Enrollment: since trial start (8/12/12) 198 PTS have been HER2 screened, 10 found positive and 7 are in treatment. EudraCT number : 2012-002128-33. Clinical trial information: 2012-002128-33.


242s TPS3649


ICE CREAM: Irinotecan cetuximab evaluation and the cetuximab response evaluation among patients with G13D mutation. Presenting Author: Eva Segelov, St Vincent’s Hospital, Sydney, Australia Background: Patients with metastatic colorectal cancer (mCRC) whose disease has progressed despite oxaliplatin and irinotecan containing regimens may benefit from the use of EGFR-inhibiting monoclonal antibodies if the tumor contains no mutations in the KRASgene (i.e. WT). However, it is unknown whether antibodies used in this setting, such as cetuximab, are more efficacious alone or in combination with irinotecan, as suggested by the BOND study which did not select for KRASstatus. This international trial will also evaluate prospectively the activity of cetuximab in the subgroup of patients with mCRC with a specific KRASmutation in codon G13D. In selected retrospective analyses, tumors bearing this mutation appear to derive similar response from cetuximab as WT. Trials involving small molecular subsets (in this case approx. 5% of patients with mCRC, or 18% of patients with KRAS mutations) will provide framework for future collaborations. Methods: This randomised phase II study of cetuximab ⫹/irinotecan will recruit patients with metastatic colorectal cancer (mCRC) with either KRAS WT (n⫽50) or G13D mutation (n⫽50) over 2 years from sites in Australia (12), and three international sites (G13D mutations only): Spain (1), England (1), and Italy (1). The trial will prospectively select the KRAS WT arm for the “quadruple WT⬙ genotype (no mutations also in BRAF, NRAS, PIK3CA exon20). Primary objective is 6 month progression free survival. Secondary objectives are response rate, overall survival, quality of life, and translational research including markers that may predict response such as amphiregulin and epiregulin determined by immunohistochemistry. Eligibility: Patients with histologically confirmed CRC with either “quadruple WT⬙ genotype or KRAS G13D mutation; unresectable metastatic disease; measurable or evaluable disease; ECOG 0-2; life expectancy at least 12 weeks, and disease progression, or intolerance of thymidylate synthase inhibitor and irinotecan and oxaliplatin containing regimens. Status: Opened to accrual November 2012, at 31 Jan 2013 3/100 patients have been enrolled, all with G13D mutations. Clinical trial information: ACTRN12612000901808.


Gastrointestinal (Noncolorectal) Cancer LBA4001


LBA4002

243s Oral Abstract Session, Mon, 9:45 AM-12:45 PM

Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2 positive advanced or metastatic gastric (A/MGC), esophageal (EAC), or gastroesophageal (GEJ) adenocarcinoma: The LOGiC trial. Presenting Author: J. Randolph Hecht, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA

SAMIT: A phase III randomized clinical trial of adjuvant paclitaxel followed by oral fluorinated pyrimidines for locally advanced gastric cancer. Presenting Author: Kazuhiro Yoshida, Department of Surgical Oncology, Gifu University School of Medicine, Gifu, Japan



LBA4003

LBA4004



Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study. Presenting Author: Pascal Hammel, Hôpital Beaujon, Clichy, France

A phase III randomized trial of chemoimmunotherapy comprising gemcitabine and capecitabine with or without telomerase vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer. Presenting Author: Gary William Middleton, University of Birmingham, Birmingham, United Kingdom




244s 4005^

Gastrointestinal (Noncolorectal) Cancer Oral Abstract Session, Mon, 9:45 AM-12:45 PM

Results of a randomized phase III trial (MPACT) of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone for patients with metastatic adenocarcinoma of the pancreas with PET and CA19-9 correlates. Presenting Author: Daniel D. Von Hoff, Virginia G. Piper Cancer Center Clinical Trials at Scottsdale Healthcare/TGen, Scottsdale, AZ Background: nab-paclitaxel (nab-P; 130 nm albumin-bound paclitaxel) has demonstrated both single-agent activity and synergy with gemcitabine (G) in preclinical models of pancreatic cancer (PC). nab-P ⫹ G also demonstrated promising efficacy in a phase I/II study in metastatic PC (J Clin Oncol. 2011:4548-4554), warranting a phase III study of nab-P ⫹ G vs G for metastatic PC. Methods: 861 patients (pts) with metastatic PC and a Karnofsky performance status (KPS) ⱖ 70 were randomized at 151 community and academic centers 1:1 to receive nab-P 125 mg/m2 ⫹ G 1000 mg/m2 days 1, 8, and 15 every 4 weeks or G alone 1000 mg/m2weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 every 4 weeks (cycle ⱖ 2). The primary endpoint was OS; secondary endpoints were PFS and ORR by independent review. Results: The median age was 63 years (range 27 - 88). KPS was 100 (16%), 90 (44%), 80 (32%), and 70 (7%). Pts had advanced disease with liver metastases (84%), ⱖ 3 metastatic sites (46%), and CA19-9 ⱖ 59 ⫻ ULN (46%). nab-P ⫹ G was superior to G for all efficacy endpoints: median OS was 8.5 vs. 6.7 mo (HR 0.72; 95% CI, 0.617 - 0.835; P ⫽ 0.000015); median PFS was 5.5 vs. 3.7 mo (HR 0.69; 95% CI, 0.581 - 0.821; P ⫽ 0.000024), and ORR was 23% vs. 7% (P ⫽ 1.1 ⫻ 10⫺10) by RECIST v1.0. Metabolic response by PET in 257 patients was 63% for nab-P ⫹ G vs 38% for G (P ⫽ 0.000051). CA19-9 response (ⱖ 90% decrease) was 31% for nab-P ⫹ G vs. 14% for G (P ⬍ 0.0001). Grade ⱖ 3 AEs with nab-P ⫹ G vs. G included neutropenia (38% vs. 27%), fatigue (17 % vs. 7%), diarrhea (6% vs 1%), and febrile neutropenia (3% vs. 1%). Grade ⱖ 3 peripheral neuropathy (PN) occurred in 17% vs. 1% of pts who received nab-P ⫹ G vs. G, respectively; for nab-P ⫹ G, PN improved to grade ⱕ 1 in a median 29 days, and 44% of patients resumed nab-P treatment. The median duration of treatment was 3.9 mo for nab-P ⫹ G and 2.8 mo for G. Conclusions: MPACT was a large, international study performed at community and academic centers. nab-P ⫹ G was superior to G across all efficacy endpoints, had an acceptable toxicity profile, and is a new standard for the treatment of metastatic PC that could become the backbone for new regimens. Clinical trial information: NCT00844649.

4007


Randomized multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and a prospective evaluation of the of the association between tumor hENT1 expression and clinical outcome with gemcitabine treatment. Presenting Author: Elizabeth Poplin, The Cancer Institute of New Jersey, UMDNJRobert Wood Johnson Medical School, New Brunswick, NJ Background: Gemcitabine requires membrane transporter proteins to cross the cell membrane. Low expression of the human equilibrative nucleoside transporter-1 (hENT1) may play a role in gemcitabine resistance in PDAC. CO-101 (also known as CP-4126), a lipid-drug conjugate of gemcitabine, was rationally designed to enter cells independently of hENT1 and to circumvent transporter-mediated resistance. We conducted a randomized, controlled trial (LEAP) in patients with mPDAC to determine whether CO-101 improved survival vs gemcitabine in patients with low hENT1 tumors. The study also prospectively tested the hypothesis that gemcitabine is more active in patients with hENT1 high than hENT1 low tumors in metastatic disease. Methods: Patients were randomized to CO-101 or gemcitabine. An immunohistochemistry test measuring tumor hENT1 expression was developed in parallel with the recruitment phase of LEAP. To dichotomize the population, a hENT1 cut-off was defined using primary PDAC tumor samples from an adjuvant trial. LEAP participants provided a metastasis sample during screening for blinded hENT1 assessment, and the cut-off was applied to these samples. The primary endpoint of the study was overall survival in the low hENT1 subgroup. Results: 367 patients were enrolled, with metastasis hENT1 status available for 358/367 (97.5%). 232/357 (65%) were hENT1 low. There was no difference in overall survival between CO-101 and gemcitabine in the hENT1 low subgroup, or overall, with hazard ratios of 0.994 [95% CI 0.746, 1.326] and 1.072 [95% CI 0.856, 1.344] respectively. Within the gemcitabine arm, there was no difference in survival between the hENT1 high and low subgroups (HR 1.147 95% CI 0.809, 1.626). The observed side effect profile was typical of gemcitabine and was similar in both treatment arms, in the hENT1 low subgroups and overall. Conclusions: CO-101 is not superior to gemcitabine in patients with mPDAC and low tumor hENT1 expression. Metastasis hENT1 expression did not predict gemcitabine treatment outcome in patients with mPDAC. Clinical trial information: NCT01124786.

4006


HENT1 tumor levels to predict survival of pancreatic ductal adenocarcinoma patients who received adjuvant gemcitabine and adjuvant 5FU on the ESPAC trials. Presenting Author: John P. Neoptolemos, University of Liverpool, Liverpool, United Kingdom Background: Some studies in patients with resected pancreatic cancer have suggested that expression of the human equilibrative nucleoside transporter (hENT1) may be predictive of improved survival from gemcitabine but these have either been based on retrospective non-randomized studies or in one study the principal treatment was chemoradiation. The samples collected from the adjuvant ESPAC1/3 randomized trials have provided a unique opportunity to assess to REMARK standards the therapeutic predictability of hENT1 in patients undergoing resection for pancreatic cancer. Methods: Tissue Microarrays (TMAs) were prepared using paraffin embedded tumor specimens from patients randomized to gemcitabine or 5FU/Folinic acid in the ESPAC-1 and -3 trials. Cores were given an H-Score depending on the level of staining with the 10D7G2 anti-hENT1 antibody. Groups were compared using Kaplan-Meier and Cox proportional hazards. Results: Scores were obtained for 176 gemcitabine treated and 176 5FU treated patients. The overall median H-Score was 48 and patients were classified as having high hENT1 if the mean score for their cores was above this. Median overall survival for gemcitabine treated patients was 23.4 (95% CI: 18.3, 26.0) months versus 23.5 (95% CI: 19.8, 27.3) months for 5FU treated patients (␹21 ⫽ 0.24, P ⫽ 0.623). In the gemcitabine group A significantly lower survival (␹21 ⫽ 9.87, P ⫽ 0.002) was noted with low hENT1 (median survival 17.1 (95% CI: 14.3, 23.8) versus 26.2 (95% CI: 21.2, 31.4) months). Median survival was 25.6 (95% CI: 20.1, 27.9) and 21.9 (95% CI: 16.0, 28.3) months respectively for high and low hENT1 in the 5FU group, a non-significant difference (␹21 ⫽ 0.83, P ⫽ 0.362). Multivariate analysis confirmed hENT1 expression as a predictive marker in gemcitabine (Wald ␹2 ⫽ 7.10, P ⫽ 0.008) but not 5-fluorouracil (Wald ␹2 ⫽0.34, P ⫽ 0.560) groups. Conclusions: The study supports use of gemcitabine in patients with high tumor hENT1 expression and 5-fluorouracil in patients with low hENT1.

4008


JASPAC 01: Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 for patients with resected pancreatic cancer. Presenting Author: Akira Fukutomi, Shizuoka Cancer Center, Shizuoka, Japan Background: Adjuvant chemotherapy with gemcitabine (G) has been standard treatment for resected pancreatic cancer (PC). In the GEST study, S-1 (S) had shown non-inferiority to G in overall survival (OS) for unresectable PC. The aim of this phase III study is to investigate non-inferiority of S to G on OS as adjuvant chemotherapy for resected PC. Methods: Patients (pts) after macroscopically curative resection of PC with an ECOG PS of 0-1 and adequate organ functions were randomly assigned to G (1000 mg/m2, iv, d1, 8 and 15, q4w, for 6 courses) or S (80/100/120 mg/day based on BSA, po, d1-28, q6w, for 4 courses) with balancing by surgical margins (R), nodal status (N) and institution. Primary endpoint was OS. With 180 pts per arm, the study had 80% power to prove non-inferiority with a margin of hazard ratio (HR) 1.25 on the basis of expected HR 0.87, with 0.05 two-sided alpha. Secondary endpoints were relapse-free survival (RFS), safety, and quality of life (EQ-5D). One interim analysis was planned after 180 deaths. Results: From 4/2007 to 6/2010, 385 pts were enrolled from 33 hospitals in Japan. 378 pts (G/S: 191/187) were included in the full analysis set. Pts characteristics (G/S) were well balanced (PS0: 67%/70%, R0: 86%/88%, N0: 38%/36%). Based on the interim analysis with 205 OS events, IDMC recommended to publish the results. OS at 2-years were 53% for G and 70% for S. HR for S to G was 0.56 (95% CI, 0.42-0.74, p⬍0.0001 for non-inferiority, p⬍0.0001 for superiority). On subgroup analysis, HRs for R0/R1, N0/N1 pts were 0.57 (95% CI, 0.42-0.78)/0.53 (0.27-1.05), 0.48 (0.28-0.83)/0.58 (0.41-0.80), respectively. RFS at 2-years were 29% for G and 49% for S. HR of relapse for S to G was 0.56 (95% CI, 0.43-0.71, log-rank p⬍0.0001). Incidences of grade 3/4 toxicities in G/S were leukopenia 39%/9%, hemoglobin decrease 17%/ 13%, thrombocytopenia 9%/4%, elevated AST 5%/1%, fatigue 5%/5%, and anorexia 6%/8%. Relative dose intensity of G/S was 84%/97%. EQ-5D QOL score in S was significantly better than that in G (p⬍0.0001). Conclusions: S-1 adjuvant chemotherapy is shown non-inferior, and furthermore, even superior to GEM. S-1 is considered as the new standard treatment for resected PC pts. Clinical trial information: UMIN000000655.


Gastrointestinal (Noncolorectal) Cancer 4009

Poster Discussion Session (Board #1), Mon, 1:15 PM-5:15 PM and 4:45 PM-5:45 PM

4010

245s


Phase II, randomized, double-blind placebo-controlled trial of nimotuzumab plus gemcitabine compared with gemcitabine alone in patients (pts) with advanced pancreatic cancer (PC). Presenting Author: Dirk Strumberg, Marienhospital Herne, Herne, Germany

A phase Ib study of gemcitabine plus PEGPH20 (pegylated recombinant human hyaluronidase) in patients with stage IV previously untreated pancreatic cancer. Presenting Author: Sunil R. Hingorani, Fred Hutchinson Cancer Research Center, Seattle, WA

Background: FOLFIRINOX significantly increases survival in metastatic PC compared to gemcitabine, but its use is limited to selected pts, due its high toxicity. In the majority of cases, gemcitabine (gem) remains the mainstay of palliative treatment, although its modest impact on survival and disease progression. The addition of the EGFR tyrosine kinase inhibitor erlotinib prolonged median survival for only 2 weeks.This study was aimed to investigate the effect of adding Nimotuzumab (nimo), an anti-EGFR monoclonal antibody, to first-line gemcitabine, in PC. Methods: Pts with previously untreated, unresectable, locally-advanced or metastatic PC were randomly assigned to receive gem: 1000 mg/m2/ 30-min iv once weekly (d1, 8, 15; q28) and nimo: fixed dose of 400 mg once weekly as a 30-min infusion, or placebo, until progression or unacceptable toxicity. Primary endpoint was overall survival (OS) in the intention-to-treat (ITT) population. Secondary endpoints included PFS, safety, objective response rate (ORR), QoL. Results: Between 9/2007- 10/2011 a total of 192 pts were randomized (average age 63.6 ⫾10 years; 60% male; 69% ECOG PS 0), and 186 were evaluable at the ITT analysis. One-year OS was 19.5 % with gem⫹placebo and 34.4% with gem⫹nimo (HR⫽0.69; p⫽0.034). Median OS and PFS were 6.0 mo in the gem⫹placebo group, vs. 8.7 mo in gem⫹nimo (HR⫽0.83; p⫽0.21), and 3.7 vs. 5.4 mo, respectively (HR⫽0.73; p⫽0.06). One-year PFS was 9.5 % for gem⫹placebo, compared with 21.5% for gem⫹nimo (HR⫽0.71; p⫽0.05). Significantly, in pts ⱖ 62 years (60% of the population), median OS and PFS were 5.2 mo in the gem⫹placebo group vs. 8.8 mo in gem⫹nimo (HR⫽0.66; p⫽0.034), and 3.2 in gem⫹placebo vs. 5.5 mo in gem⫹nimo group, respectively (HR⫽0.55; p⫽0.0096). Nimo was safe and well tolerated, and no grade 3/4 toxicities were observed. Thirteen % of pts experienced grade 1/2 skin toxicity. Conclusions: This randomized study clearly showed that nimo in combination with gem is safe and well tolerated. The 1-year survival rate is significantly improved. Especially pts ⱖ 62 years seem to benefit, possibly due to a more aggressive biology in younger pts. Clinical trial information: NCT00561990.

Background: PEGPH20 is a PEGylated version of human recombinant hyaluronidase. In preclinical studies, PEGPH20 depleted pancreatic cancers of their high hyaluronan (HA) content. In a genetically-engineered murine model of PDA, PEGPH20 ⫹ gemcitabine (Gem) significantly prolonged survival compared to Gem alone. In Ph1 PEGPH20 monotherapy studies, the MTD was 3.0 ␮g/kg. The most common AEs were musculoskeletal events (MSEs). Methods: This was a dose-escalation study to find the recommended Phase 2 dose (RP2D) of PEGPH20 in combination with Gem in patients (pts) with Stage IV previously untreated pancreatic cancer. Pts received PEGPH20 at 1, 1.6, or 3 ␮g/kg IV twice a week for Wks 1-4, weekly for Wks 5-7, then 1 wk rest. Dose escalation was based on safety. Gem was given at 1000 mg/m2 IV once a week for Wks 1-7, then 1 wk rest. Thereafter, PEGPH20 ⫹ Gem were given once a week for 3 wks in 4-wk cycles. Dexamethasone was given pre and post PEGPH20 doses. Results: Of the 28 pts enrolled, the majority had a Karnofsky performance status of 80%, and 85%/19%/26% of pts had liver/lung/visceral metastases. The median age was 58 yrs. Four pts received PEGPH20 at 1 ␮g/kg, 4 at 1.6 ␮g/kg, and 20 at 3 ␮g/kg. The RP2D was 3 ␮g/kg. Treatment duration ranged from 1-274 days; 5 pts remain on study. Treatment was generally well tolerated. Ten pts had 1 Gem dose reduction, 2 pts had 1 PEGPH20 dose reduction (3 to 1.6 ␮g/kg), but no pt had a DLT. The most common PEGPH20-related AEs were MSEs (25% Gr1; 18% Gr2) and fatigue (21% Gr1; 11% Gr2). Objective response was assessed by an independent central radiologist using RECIST 1.1. Of the 21 pts evaluable for efficacy, 7 had partial response (PR) for an overall response rate (ORR) of 33%, and 9 had stable disease for ⱖ 2 mo. Tumor biopsies from 12 pts were evaluable for HA staining. HA was high in 9 and low in 3. Of the 9 with high HA staining, 5 had PR (56% ORR); HA data were not available for the other 2 PR pts. PK results show dose-dependent exposure consistent with data from PEGPH20 monotherapy studies. Conclusions: PEGPH20 in combination with Gem is generally well tolerated in advanced pancreatic cancer and shows promising efficacy, especially in pts with high intratumoral HA content. Clinical trial information: NCT01453153.

4011

4012



Vismodegib (V), a hedgehog (HH) pathway inhibitor, combined with FOLFOX for first-line therapy of patients (pts) with advanced gastric and gastroesophageal junction (GEJ) carcinoma: A New York Cancer Consortium led phase II randomized study. Presenting Author: Deirdre Jill Cohen, New York University Cancer Institute, New York, NY

Final analysis of a phase IB/randomized phase II study of gemcitabine (G) plus placebo (P) or vismodegib (V), a hedgehog (Hh) pathway inhibitor, in patients (pts) with metastatic pancreatic cancer (PC): A University of Chicago phase II consortium study. Presenting Author: Daniel Virgil Thomas Catenacci, University of Chicago, Chicago, IL

Background: The HH pathway is overexpressed in gastroesophageal (GE) tumors. Pre-clinically, HH inhibitors have demonstrated a reduction in GE tumor growth, cell motility and invasiveness. V, an oral small-molecule antagonist of the Hh pathway, has previously been safely combined with FOLFOX chemotherapy. Methods: Pts with untreated metastatic or locally advanced gastric or GEJ adenocarcinoma were randomized 1:1, stratified by institution and disease status (with or w/o distant mets) to FOLFOX (ox 85 mg/m2, LV 200 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2400 mg/ m2 over 48 hrs) q14d plus V or placebo (P) (150mg PO daily). Cycle defined as 2 weeks and no crossover allowed at progression. FFPET and blood were collected for biomarker analyses. Response assessed every 8 weeks (RECIST 1.1). Primary endpoint was progression-free survival (PFS), secondary objectives were overall survival (OS), response rate (RR), and toxicity. Results: 124 pts enrolled at 20 sites between 10/09-2/12. 123 pts eligible for analysis (V/P 60/63). Pt characteristics (V/P): median age 58/62; ECOG PS 0: 24 (40%) / 30 (48%); male 39 (65%) / 52 (83%); GEJ 37 (62%) / 39 (61%); diffuse or mixed histology 19 (32%) / 10 (16%), recurrent disease 10(17%) / 16 (25%). Median number of FOLFOX cycles 10/11. Most common Grade ⱖ3 toxicities: (% pts V/P) neutropenia 50/32 (p⫽0.07), neuropathy 19/13 (p⫽0.49), fatigue 15/10 (p⫽0.50), thrombosis 14/11 (p⫽0.92), anemia 10/10 (p⫽0.99), hemorrhage-GI 8/11 (p⫽0.77), hypokalemia 10/5 (p⫽0.76), nausea 8/8 (p⫽0.99). Death on or within 30 days of treatment 6.7%/15.6% (p⫽0.20). Median PFS in intent to treat population 7.3/8.0 mo (95% CI 4.6-10.1/5.1-11.0; p⫽0.64) and median OS 11.5/14.9 mo (95% CI 9.6-13.4/11.3-18.4; p⫽0.23). Overall RR (%) 35/35 (p⫽0.99). Conclusions: Addition of V to FOLFOX did not improve PFS in an unselected advanced GE carcinoma population. Blood and tissue biomarker analyses are ongoing to determine if there is a subset of patients who may derive benefit from V. Supported by: N01-CM-62204, -62201, -62207, -62206, -62209, -62208 and 2UL1 TR000457-06. Clinical trial information: NCT00982592.

Background: Sonic Hh (SHh), the ligand for the Hh pathway, is overexpressed in ⬎80% of PC. V had activity in preclinical murine PC models leading to increased tumor perfusion, enhanced tumor delivery of G, and an improvement in survival. Methods: We conducted a placebo-controlled, phase IB/randomized phase II trial of GV or GP. Eligible pts, KPS 80-100, had untreated metastatic PC, or had completed adjuvant therapy ⬎ 6 months (mo) prior. Primary endpoint: progression-free survival (PFS). Correlatives: serial SHh serum levels; serial perfusion CT imaging. All pts received G 1000mg/m2over 30 minutes, days (D) 1, 8, 15, Q28D. A lead-in phase IB was performed. Pts, stratified by KPS (80 v 90/100), and disease status (newly diagnosed/recurrent), were randomized to V (150 mg PO daily) or P. For pts on P, cross-over was allowed at progression. Assuming a mPFS of 3.5 months for GP and 5.7 months for GV (HR⫽0.61), a sample size of 106 subjects (53 per group) provided 85% power to detect this difference, using a one-sided test at the 0.10 significance level. Results: No safety issues were identified in 7 pts enrolled in the phase IB study. The phase II study enrolled 106 evaluable pts (V/P 53/53) at 13 sites 2/10-6/12. Pt characteristics: median age 65/64 (range 52-82/39-83); KPS (% pts) 80: 38/30; 90: 26/38; 100: 36/32; newly diagnosed 91%/91%; recurrent: 9%/9%. Grade 3/4 toxicity (V/P, % pts, ⬎5% in either arm): neutropenia 32/28; lymphopenia 4/15; thrombocytopenia 9/11; anemia 9/23; hyponatremia 4/15; fatigue 13/8; hyperglycemia 23/19; elevated ALT 13/9; hyperbilirubinemia 11/6; nausea 11/11. Response (%): CR 0/2, PR 8/11, SD 51/38. mPFS: 4.0/2.5 mo (95% CI: 2.5-5.3/1.9-3.8; HR 0.81 [0.54-1.21], p⫽0.30). 22 pts (42%) on GP crossed over to GV at progression. mOS: 6.9/6.1 mo (95% CI:5.8-8.0/5.08.0, HR 1.04, [0.69-1.58], p⫽0.84). Updated laboratory/radiological correlatives will be presented. Conclusions: Toxicity between the groups was similar. The addition of V to G in an unselected cohort does not improve response, PFS, or OS in pts with metastatic PC. Funding NCI N01-CM62201. Clinical trial information: NCT01064622.


246s 4013

Gastrointestinal (Noncolorectal) Cancer Poster Discussion Session (Board #5), Mon, 1:15 PM-5:15 PM and 4:45 PM-5:45 PM

Olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer: A randomized, double-blind phase II study. Presenting Author: Yung-Jue Bang, Seoul National University Hospital, Seoul, South Korea Background: Our multicenter study compared the efficacy of the oral PARP inhibitor olaparib plus paclitaxel (O/P) vs paclitaxel alone (P) as second-line therapy in pts with recurrent/metastatic gastric cancer (GC) (NCT01063517). As initial preclinical data suggested that responsiveness of GC cell lines to olaparib was associated with low ATM protein levels, our study was enriched for pts with low ATM tumors (ATM–) by IHC (50% randomized vs 14% screening prevalence). Methods: Eligible pts were randomized 1:1 (stratified by ATM status) to receiveolaparib 100 mg bid (tablet form) plus paclitaxel (80 mg/m2 iv on days 1, 8, 15 per 28-day cycle) or placebo plus paclitaxel until progression or investigator decision. After combination therapy, pts could take olaparib 200 mg bid monotherapy or placebo until progression. Co-primary endpoints: progressionfree survival (PFS; RECIST v1.1) in all pts and ATM– pts. Secondary endpoints: overall survival (OS), objective response rate (ORR), safety. Results: 123/124 randomized pts were treated (O/P⫽61; P⫽62). Baseline characteristics were generally well balanced. Use of post-progression therapy was similar in both arms (O/P⫽48.4%; P⫽43.5%) as was median paclitaxel duration (O/P⫽17 wks; P⫽16 wks); 18 pts received monotherapy (O/P⫽11; P⫽7). More pts in the O/P than P arm had delays (79 vs 63%) and reductions (41 vs 27%) in paclitaxel dosing. The most common grade ⱖ3 AEs in the O/P and P arms were neutropenia (56 vs 39%) and anemia (11 vs 11%). Conclusions: Olaparib plus paclitaxel was well tolerated and led to a statistically significant improvement in OS, but not PFS, vs paclitaxel alone in both all pts and ATM– pts, with a larger benefit in ATM– pts. Clinical trial information: NCT01063517. O/P

P

All pts PFS, m

n⫽62 3.9

n⫽62 3.6

OS, m

13.1

8.3

EFR ORR %

n⫽53 26.4

n⫽47 19.1

PD % ATM– pts PFS, m

26.4 n⫽31 5.3

44.7 n⫽32 3.7

OS, m

NC

8.2

EFR ORR %

n⫽26 34.6

n⫽23 26.1

PD %

15.4

34.8

HR⫽0.80; 95% CI 0.54, 1.18 P⫽0.261 HR⫽0.56; 95% CI 0.35, 0.87 P⫽0.010 OR⫽1.65; 95% CI 0.61, 4.68 P⫽0.323 HR⫽0.74; 95% CI 0.42, 1.32 P⫽0.315 HR⫽0.35; 95% CI 0.17, 0.71 P⫽0.003 OR⫽1.76; 95% CI 0.49, 6.89 P⫽0.390

4014


Dual MEK/EGFR inhibition for advanced, chemotherapy-refractory pancreatic cancer: A multicenter phase II trial of selumetinib (AZD6244; ARRY-142886) plus erlotinib. Presenting Author: Andrew H. Ko, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA Background: Pharmacologic inhibition of MEK leads to enhanced signaling through EGFR with hyperactivation of a parallel oncogenic pathway (PI3K) independent of mutant KRAS, supporting a therapeutic strategy of combined target inhibition in PDAC to overcome this negative feedback loop. Based on preclinical evidence of synergistic activity between EGFR and MEK inhibitors, we conducted a non-randomized phase II trial of erlotinib plus selumetinib, a selective, allosteric inhibitor of MEK1/2, in patients with PDAC who had received one prior line of chemotherapy. Methods: A Simon 2-stage design was used, with planned n ⫽ 46. Study treatment consisted of erlotinib 100 mg ⫹ selumetinib 100 mg daily in 3-week cycles, with CT evaluation every 2 cycles. 1o objective was overall survival (OS). Correlative studies include detection of circulating tumor cells using a novel nonenrichment high definition immunofluorescence assay, and tissue- and serum proteomic-based predictive biomarkers. Results: 46 patients enrolled at 2 sites between 1/2011 and 1/2013 (median age 67 y.o. [range 40-84]; ECOG PS (0/1): 31/15; prior gemcitabine-based vs. FOLFIRINOX vs. other 1st-line chemo: 34/10/2). Patients received a median of 2 cycles (range, 1-7). Of 41 evaluable patients to date, disease control rate is 51% (0 PR; 21 with stable disease (SD) ⬎ 6 weeks, 10 with SD ⬎ 12 weeks; 11 minor responses). 9/31 patients (29%) had CA19-9 decline ⬎ 50%. Estimated median PFS and OS by Kaplan-Meier are 2.6 and 7.5 months, respectively, with 21 patients still alive. Grade 3/4 AEs likely attributable to study treatment include rash (10 patients), hypertension (6), anemia (5), diarrhea (4), and nausea/vomiting (4); no studyrelated deaths have occurred. 38% of patients have required dose reduction of one/both agents. Conclusions: Dual targeting of MEK/EGFR signaling shows antitumor activity in PDAC in a subset of patients and warrants further exploration, possibly in combination with, or comparison to, cytotoxic therapy. Companion efforts are ongoing to assess candidate predictive markers of benefit to this combination. Supported by CTEP and NIH R21 CA149939. Clinical trial information: NCT01222689.

EFR, evaluable for response; m, median (months); NC, not calculable; PD, best response of progressive disease. HR⬍1, OR⬎1 favor O/P. P values: 2-sided.

4015


A Bayesian network meta-analysis of systemic regimens for advanced pancreatic cancer. Presenting Author: Kelvin Chan, Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada Background: For advanced pancreatic cancer, many regimens have been compared with gemcitabine (G) in randomized control trials (RCTs). Few have been compared with each other directly in RCTs and the relative efficacy and safety among them are unclear. Methods: A systematic review was performed through MEDLINE, EMBASE, Cochrane Central Register of Contorlled Trials and ASCO meeting abstracts up to Jan 2013 to identify RCTs that included metastatic pancreatic cancer comparing the following regimens: G, G⫹5-flourouracil (GF), G⫹capecitabine (GCap), G⫹S1 (GS), G⫹cisplatin (GCis), G⫹oxaliplatin (GOx), G⫹erlotinib (GE), G⫹Abraxane (GA) and FOLFIRINOX. Studies were reviewed by two authors and discrepancies were resolved by consensus or by a third author. Data including overall survival (OS), progression-free survival (PFS), response rate (RR), and side-effects were extracted. A Bayesian network meta-analysis with random effects was performed using WinBUGS to compare all regimens simultaneously. Results: Twenty-two studies involving 6,252 patients were identified, with 21 RCTs involving G, 4 with GF, 3 with GCap, 2 with GS, 6 with GCis, 3 with GOx, 1 with GE, 1 with GA and 1 with FOLFIRINOX. Median OS, PFS and RR for G arms from all trials were similar, suggesting the absence of significant clinical heterogeneity among RCTs. For OS, the results of the Bayesian network meta-analysis found that the probability that FOLFIRINOX was the best regimen was 71%, while it was 19% for GS, 7% for GA and 2% for GE respectively. The OS hazard ratio (HR) for FOLFIRINOX vs. GS was 0.82 (95% credible region (CR): 0.53-1.35), the OS HR for FOLFIRINOX vs. GA was 0.77 (95% CR: 0.51-1.23), and the OS HR for FOLFIRINOX vs. GE was 0.67 (95% CR: 0.45-1.08). Similar ranking and probabilities were observed for the best regimen for PFS. Conclusions: FOLFIRINOX appeared to be the best regimen for advanced pancreatic cancer probabilistically, with a trend towards improvement in OS and PFS when compared with GS, GA, or GE by indirect comparisons. In the absence of direct pairwise comparisons of these regimens from RCTs, network meta-analysis helps synthesize evidence and inform decision making.

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SPARC in pancreatic cancer: Results from the CONKO-001 study. Presenting Author: Marianne Sinn, Medical Oncology Charité - Universitätsmedizin Berlin, Berlin, Germany Background: Previous investigations in pancreatic cancer suggested an important prognostic role for SPARC (secreted protein acidic and rich in cysteine) expression in the peritumoral stroma but not for cancer-cell cytoplasmic SPARC expression. So far no data from prospective studies in patients after curatively intended surgery are available. Methods: CONKO001, a prospective randomized phase III study, investigated the role of adjuvant gemcitabine as compared to observation. Tissue samples of 160 patients were collected and analysed by immunohistochemistry for the expression of SPARC in the peritumoral stroma (strong versus not strong [⫽moderate to negative]) and in the tumor cell cytoplasm (immunoreactive score IRS 0-12, 0-2 ⫽ negative, 3-12 ⫽ positive) by a pathologist blinded to clinical outcome. Kaplan-Meier analyses for disease-free survival (DFS) and overall survival (OS) were performed in dependence of SPARC expression. Results: Strong stromal SPARC expression was associated with worse DFS and OS in the overall study population (strong vs not-strong DFS 9.0 vs 12.6 months, p⫽0.005; OS 19.8 vs 26.6 months (p⫽0.033). It was highly prognostic in the subgroup treated with gemcitabine (strong vs not-strong DFS 12.1 vs. 18.4 months; p⫽0.007, OS 17.9 vs 30.2 months, p⫽0.006), but not in the observation group (strong vs not strong DFS 6.6 vs 7.3 months p⫽0.767; OS 21.5 vs 18.2 months, p⫽0.765). Cytoplasmic SPARC expression in the adenocarcinoma cells was also associated with worse patient outcome (positive vs negative DFS 7.4 vs 12.1 months, p⫽0.041; OS 14.1 vs 25.6 months, p⫽0.011), again the effect was restricted to patients treated with gemcitabine (positive vs negative DFS 8.3 vs 15.3 months, p⫽0.002; OS 11.0 vs 28.8 months, p⫽ 0.003; control group DFS 5.8 vs 7.6 months, p⫽0.844; OS 14.9 vs 20.8 months, p⫽0.519). Conclusions: Our data confirm the prognostic significance of SPARC expression and demonstrate a significant prognostic factor of SPARC in patients with pancreatic cancer after curatively intended resection. The prognostic impact was restricted to patients who received adjuvant treatment with gemcitabine. In difference to former published data this was found for peritumoral SPARC as well as for SPARC expression in tumor cells.




Use of pharmacogenomic modeling in pancreatic cancer for prediction of chemotherapy response and resistance. Presenting Author: Kenneth H. Yu, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Pancreatic adenocarcinoma (PDAC) is uniformly lethal and is the 4th leading cause of cancer mortality. Despite this, modern cytotoxics (C) can induce tumor responses and extend life. Xenograft models have shown that pharmacogenomic (PGx) modeling of C can predict efficacy. Chemo-sensitivity and gene expression profiling of circulating tumor and invasive cells (CTICs) isolated from peripheral blood may predict tumor response, progression and resistance. Methods: A prospective MSKCC study has completed planned accrual of 50 patients. 10 mL of peripheral blood is collected from patients with unresectable PDAC prior to C and at disease progression. Clinical data is prospectively collected. CTICs are isolated (Vita-Cap, Vitatex Inc.), total RNA is extracted and gene-expression analysis is performed. PGx models for twelve chemotherapy drug combinations used in PDAC were created from the GI50 data obtained from the NCI-60 cell lines (CellPath Therapeutics, Inc., Baltimore, MD). Expression data were normalized through GCRMA then probed to identify expression differences between patients with short v long TTP and within patients at baseline v at time of progression. The analysis was performed at the pathway and individual gene level. Results: CTICs were isolated, and gene expression and chemo-sensitivity patterns were obtained in all 50 patients prior to initiating C and in 20 patients at 1st line disease progression. Preliminary analysis demonstrates clinical benefit for patients treated with C predicted to be effective versus ineffective (TTP 7.3 mo v 3.7 mo, p⫽0.017, HR 0.30). Changes in chemo-sensitivity patterns were evident at disease progression, reflecting treatment resistance. Pathway analysis revealed that E2F1 and NF␬B pathways are associated with prognosis, PLC and RB1 pathways become disrupted with disease progression. Conclusions: Isolation and gene expression profiling of CTICs can be performed reliably in unresectable PDAC. Preliminary analysis suggests that C profiling can predict response. Repeat PGx profiling identifies key pathways associated with treatment resistance. Clinical trial information: NCT01474564.

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Association of gene expressions of TOP2A, GGH, and PECAM1 with hematogenous, lymph-node, and peritoneal recurrence in patients with stage II/III gastric cancer enrolled in the ACTS-GC study. Presenting Author: Masanori Terashima, Shizuoka Cancer Center, Nagaizumi, Japan Background: Exploratory biomarker analysis was conducted to identify factors related to relapse sites in the ACTS-GC study, a randomized controlled trial comparing postoperative adjuvant S-1 therapy with surgery alone in 1,059 patients (pts) with stage II/III gastric cancer. Methods: Formalin-fixed, paraffin-embedded surgical specimens were retrospectively examined in 829 pts (78.3%), and 63 genes involved in pyrimidine metabolic pathway, growth factor signaling pathway, apoptosis, DNA repair, etc., were analyzed by quantitative RT-PCR after TaqMan assaybased pre-amplification. Gene expression levels were normalized to the geometric mean expressions of GAPDH, ACTB, and RPLP0, used as reference genes. The expression of each gene was categorized as lower or higher than the median value. The impact of gene expression on relapse site was analyzed using the 5-year relapse-free survival (RFS) data of the ACTS-GC. Results: Among the 829 pts, hematogenous, lymph-node, and peritoneal recurrence developed in 72, 105, and 138 pts, respectively. The hazard ratios (HR) (S-1 vs. surgery alone) were 0.79 (95%CI, 0.54-1.16) for hematogenous, 0.51 (95%CI, 0.31-0.82) for lymph-node, and 0.60 (95%CI, 0.42-0.84) for peritoneal recurrence. Among 63 screened genes, topoisomerase II alpha (TOP2A), gamma-glutamyl hydrolase (GGH), and platelet/endothelial cell adhesion molecule 1 (PECAM1) most strongly correlated with hematogenous, lymph-node, and peritoneal recurrence, respectively. Hematogenous RFS was significantly worse in TOP2A high pts than in low pts (HR, 2.35; 95% CI, 1.55-3.57). Lymph-node RFS was significantly worse in GGH high pts than in low pts (HR, 1.87; 95% CI, 1.13-3.08). Likewise, peritoneal RFS was significantly worse in PECAM1high pts than in low pts (HR, 2.37: 95% CI, 1.65-3.41). These factors were independent and stronger risk factors than tumor histological type on multivariate analysis. Conclusions: Expression levels of the TOP2A, GGH, and PECAM1 genes in primary tumors are respectively linked to high risks of hematogenous, lymph-node, and peritoneal recurrence in pts with stage II/III gastric cancer.

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KRAS mutation status-stratified randomized phase II trial of GEMOX with and without cetuximab in advanced biliary tract cancer (ABTC): The TCOG T1210 trial. Presenting Author: Li-Tzong Chen, Kaohsiung Medical Univesity Hospital, Kaohsiung Medical Univesity, Kaohsiung, Taiwan Background: Gemcitabine/platinum combination is considered as globally acceptable standard care in patients with ABTC. Two recently published randomized trials showed adding EGFR antagonist, either erlotinib or cetuximab, does not further improve the clinical outcomes of gemcitabine/ oxaliplatin (GEMOX)-treated ABTC patients. However, the impact of KRAS mutation status on the results of both studies was not properly addressed. Methods: A prospective, multicenter randomized, phase II trial to evaluate the therapeutic efficacies of adding cetuximab to GEMOX in patients with ABTC, in which eligible patients were stratified by status of KRAS mutation and ECOG PS, and tumor location then randomized to receive either GEMOX (gemcitabine 800 mg/m2, fixed-rate infusion and oxaliplatin 85 mg/m2, i.v., Q 2 weeks) or GEMOX plus cetuximab (500 mg/m2, i.v., Q 2 weeks, C-GEMOX). The primary endpoint was overall response rate (ORR). As an exploratory trial, 120 (60 per arm) patients was estimated to detect a two-tailed 10% difference in ORR (20% in GEMOX and 30% in C-GEMOX) with a significant level of a⫽0.2 and b⫽0.5. Results: Between Nov 2010 and May 2012, a total of 122 patients were accrued. The demography was male: 47.5%, median age: 60 y/o, ECOG PS 0/1: 28.7%/71.3%, IHCC/ EHCC/GBC: 71.3%/16.4%/12.3%, KRAS mutation: 36.1%, with locally advanced/metastatic diseases: 32.0%/68.0%, and prior surgical resection: 41.8%. On intent-to-treat analysis, the ORR and DCR in the C-GEMOX (N⫽62) and GEMOX (N-60) arms was 27.3% vs 15.0% (p⫽0.1223) and 82.2% vs 60.0% (p⫽0.0090), respectively (Fisher’s exact test); while the median PFS was 7.1 vs 4.0 months (p⫽ 0.0069) and median OS was 10.3 vs 8.8 months (p⫽0.4057), respectively (log-rank test). Planned subgroup analysis showed the 43 patients with KRAS mutated tumors benefited more from cetuximab therapy, with a DCR of 78.3% vs 38.1% (p⫽0.0132), median PFS of 7.0 vs 1.9 months (p⫽0.0351) and median OS of 10.3 vs 6.6 months (p⫽0.6924). Conclusions: Adding cetuximab significant improves the DCR and PFS of GEMOX in ABTC patients, notably in subpopulation with KRAS mutated tumors. Larger-scale phase III trial is warranted. Clinical trial information: NCT01267344.

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MAGIC trial gene expression profiling study. Presenting Author: Elizabeth C. Smyth, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom Background: The MRC MAGIC trial established perioperative epirubicin, cisplatin and 5FU (ECF) chemotherapy as a standard of care for patients (pts) with operable oesophagogastric (OG) cancer (Cunningham NEJM 2006). We performed transcriptomic profiling of archival MAGIC tissue to evaluate an existing intrinsic gastric cancer (GC) gene signature, to describe expression patterns of biologically informative genes and to identify prognostic or predictive markers. Methods: RNA was extracted from formalin fixed paraffin embedded (FFPE) resections and analysed with the NanoString nCounter system. Our panel comprised 151 genes including intrinsic GC (G-INT and G-DIFF) signature genes (Tan Gastroenterology 2011), and genes amplified/deleted in GC including the therapeutic targets FGFR2, EGFR, ERBB2 and c-MET (Deng Gut 2012). Data was preprocessed using nsolver analysis software with 2-step normalisation and log2 transformed. G-INT and G-DIFF subtype classification used the nearest template prediction algorithm; these were then correlated with pt characteristics and survival. The overexpression threshold was defined as deviation above the normal quantile-quantile plot. Results: Sufficient RNA for analysis was available for 209 resected pts. A pilot study (n⫽23) confirmed RNA quality and correlation between NanoString and Affymetrix results. RNA was more often available for pts with GC (p⬍0.001) and pts in the surgery alone arm (p⫽0.049). 70% of pts were classified into G-INT or G-DIFF intrinsic signature subtype (false discovery rate (FDR) ⬍0.05); 61 (30%) were ambiguous. Predominantly mutually exclusive overexpression of receptor tyrosine kinase (RTK) targets EGFR, ERBB2, FGFR, and c-MET was seen in 5%, 12%, 9% and 6% of pts respectively. Conclusions: Although bias may exist in tissue availability for chemosensitive pts, transcriptomic profiling of archival FFPE from this mature phase 3 study provides powerful insight into the molecular heterogeneity of OG cancer. 70% of evaluable MAGIC pts were classified unambiguously into intrinsic GC subtypes. Mutually exclusive overexpression of targetable RTKs supports a personalized approach in OG cancer evaluating targeted drugs in relevant biological subgroups. Survival analyses are ongoing.


248s 4021


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Clinical outcome according to tumor HER2 status and EGFR expression in advanced gastric cancer patients from the EXPAND study. Presenting Author: Florian Lordick, University Cancer Center Leipzig, Leipzig, Germany

25-hydroxyvitamin D levels and survival in patients with advanced pancreatic cancer (APC): Findings from CALGB 80303. Presenting Author: Katherine Van Loon, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA

Background: In the EXPAND study adding cetuximab to first-line capecitabine and cisplatin chemotherapy (CT) failed to improve clinical outcome in patients (pts) with advanced gastric or gastroesophageal junction cancer. This analysis assessed treatment outcome according to tumor HER2 status (a pre-defined subgroup) and EGFR expression in EXPAND study pts. Methods: Tumor HER2 status was determined primarily by immunohistochemistry (IHC), HER2 ⫹ve tumors were IHC 3⫹ or IHC 2⫹ and fluorescence in situ hybridization (FISH) ⫹ve. EGFR expression was assessed by IHC. A continuous scoring system (scale of 0 –300) was used to determine the level of EGFR expression. Biomarker status was correlated with clinical outcome. Results: In both treatment arms, pts with HER2 ⫹ve tumors (n⫽144) vs HER2 -ve tumors (n⫽535) had a longer median overall survival (OS): 13.3 (95% CI 10.9 –15.5) vs 9.2 (95% CI 8.1–10.5) months in the CT ⫹ cetuximab arm and 14.0 (95% CI 11.3–17.1) vs 9.7 (95% CI 8.6 –11.0) months in the CT arm, and a better overall response rate, 51.4 (95% CI 39.3– 63.3) vs 27.0 (95% CI 21.9 –32.6) % and 37.5 (95% CI 26.4 – 49.7) vs 26.4 (95% CI 21.1–32.3) % respectively. In stepwise multivariable models, pts with HER2 -ve vs HER2 ⫹ve tumors showed an increased risk of death (adjusted hazards ratio 1.552, 95% CI 1.244 – 1.936) and reduced odds of response (adjusted odds ratio 0.477, 95% CI 0.316 – 0.720). EGFR tumor expression was evaluable in 774 pts from the intent to treat population (n⫽904). The EGFR IHC score was low (median 0, range 0 –300). No discriminating threshold for the IHC score was identified. However in pt subgroups defined by a series of cut-off points from an IHC score of 10 upwards (rising incrementally by 10), there was a tendency for improved OS, progression-free survival, and tumor response when adding cetuximab to CT in pts with high tumor EGFR IHC scores. Conclusions: In this analysis of EXPAND study pts, those with HER2 ⫹ve tumors were associated with better outcome irrespective of the treatment arm compared with pts with HER2 -ve tumors. Tumor EGFR expression was generally low. Adding cetuximab to CT failed to improve outcome overall, but may benefit a small proportion of pts with high EGFR tumor expression. Clinical trial information: 2007-004219-75.

Background: Data from animal and cell line models suggest that vitamin D metabolism is important in pancreatic tumor maintenance and may contribute to this tumor’s chemoresistance. While vitamin D has been implicated in a variety of cancers, the prevalence of vitamin D deficiency among patients with advanced pancreatic cancer (APC) and the effect of baseline vitamin D levels on survival outcomes are unknown. Methods: CALGB 80303 was a randomized controlled trial of patients with APC which demonstrated no difference in OS among patients treated with gemcitabine (GEM) vs. GEM ⫹ bevacizumab. We retrospectively measured baseline serum 25(OH)D levels and examined associations between baseline 25(OH)D levels and selected patient characteristics. Using the Cox rank score test, we examined the association between 25(OH)D level and PFS and OS. The differences in the levels among racial populations were tested using the Kruskal-Wallis test. Results: Of 256 patients with available serum, the median 25(OH)D level was 21.7 (range 4 –77). 44.5% of patients were vitamin D deficient (25(OH)D ⬍20), 32.4% were insufficient (25(OH)D ⱖ20 and ⬍30), and 23% were sufficient (25(OH)Dⱖ30). Serum 25(OH)D levels were lower in patients self-reported as black compared to white patients and patients of other/undisclosed race (median 10.7 [4.0 –36.3] vs. 22.4 [4.0 –77.0] vs. 20.9 [12.6 – 31.8], respectively; p⬍0.00001). Adjusting for race, baseline 25(OH)D levels were not associated with PFS (HR 1.00, 95% CI 0.98 –1.01) or OS (HR 1.00, 95% CI 0.99-1.01). Conclusions: Vitamin D deficiency was highly prevalent among patients with a new diagnosis of APC. Black patients had significantly lower 25(OH)D levels than white patients. In this cohort of patients with APC receiving GEM-based chemotherapy, baseline 25(OH)D levels were not associated with PFS or OS.

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Cougar-02: A randomized phase III study of docetaxel versus active symptom control in patients with relapsed esophago-gastric adenocarcinoma. Presenting Author: Natalie Cook, Cambridge University Hospitals NHS Founsation Trust, Cambridge, United Kingdom Background: Survival in patients who relapse after first-line chemotherapy (CT) for advanced esophago-gastric adenocarcinoma (EGC) is poor though recently randomised trials (RCT) have suggested a small benefit for second line chemotherapy with taxanes or irinotecan. There is very little data on health related quality of life (HRQL) or overall survival (OS), particularly in patients who progress shortly after first-line therapy. Methods: COUGAR-02 was a multicentre open-label, phase III RCT for patients with locally advanced or metastatic EGC of performance status (PS) 0-2 who had progressed within 6 months of previous platinum/fluoropyrimidine CT. Patients were randomised (1:1) to receive either docetaxel 75mg/m2every 3 weeks for up to 6 cycles or active symptom control (ASC). The primary endpoint was OS. The secondary endpoint of HRQL, assessed using EORTC QLQ-C30 and QLQ-ST022, was analysed using standardised area under a curve and compared using Wilcoxon rank sum test. Sensitivity analysis adjusting for dropouts due to death were performed using quality adjusted survival. Results: 168 patients (84 patients in each arm) were recruited between April 2008 and April 2012. Median age was 65 years (range 28-84); 81% were males. PS at randomisation was 0 for 27%, 1 for 57% and 2 for 15%. 86% had metastatic disease. 43% progressed during previous CT, 28% progressed within 3 months of end of previous CT and 29% progressed between 3 and 6 months. Median number of cycles of docetaxel was 3. 23% completed 6 cycles. Docetaxel was well tolerated and resulted in a significantly improved OS over ASC alone (HR⫽0.67 (95% CI 0.49-0.92); p⫽0.01). Objective response rate was 7%. For QLQ-C30, patients on docetaxel arm reported significantly less pain (p⫽0.0008) and trend for less nausea and vomiting (p⫽0.02) and constipation (p⫽0.02) than those on ASC arm. Similar global HRQL seen (p⫽0.53).For QLQ-ST022, trend seen for less dysphagia (p⫽0.02) and pain symptoms (p⫽0.01) for patients on docetaxel arm than ASC Conclusions: Docetaxel provided a significant OS benefit over ASC with improvements in symptom scores and no loss in overall HRQL. Docetaxel can be considered a standard of care in this setting. Clinical trial information: NCT00978549.


Phase III trial of a 3-weekly versus 5-weekly schedule of S-1 plus cisplatin (SP) combination chemotherapy for first-line treatment of advanced gastric cancer (AGC): SOS study. Presenting Author: Min-Hee Ryu, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea





A phase III study of S-1 plus cisplatin versus fluorouracil plus cisplatin in patients with advanced gastric or gastroesophageal junction adenocarcinoma. Presenting Author: Rui-hua Xu, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China Background: A combination of S-1 and cisplatin (DDP) has been shown to be effective and safe for the first-line treatment of advanced gastric cancer in Japan. This is the first randomized phase III trial to compare S-1 plus DDP with 5-fluorouracil (5-Fu) plus DDP in Asia. Methods: This is an open-label, multicenter, phase 3, randomized controlled study. Patients with gastric or gastro-oesophageal junction adenocarcinoma were eligible for inclusion. Patients were randomly assigned in a 1:1 ratio to receive S-1 plus DDP (experiment group) or 5-Fu plus DDP (control group) for 6 cycles. In the experiment group, the dose of S-1 was 80 mg/m2/day, po, twice daily on day 1-21 and DDP was 20mg/m2 iv on day 1-4, repeat every 5 weeks. In the control group, 5-Fu was given as 0.8g/m2/d CI 120h ,and the dose of DDP was the same with the experiment group, while repeat every 4 weeks. Allocation was by block randomization stratified by Eastern Cooperative Oncology Group performance status, sites of metastasis and prior gastrectomy. The primary endpoint was time to progression (TTP). Secondary end points included time to failure (TTF), overall survival (OS), and quality of life. Results: Totally 255 patients were enrolled into the study, of whom 236 were included in the analysis (n⫽120; n⫽116). Median TTP was 5.51 months (95% CI 4.59-6.26) in those assigned to experiment group compared with 4.62 months (95% CI 4.00-6.33) in the control group (hazard ratio [HR] 1.03; 95%CI 0.76-1.39, p⫽0.86). In the experiment and control groups, response rates were 22.5% vs 21.5%; P⫽0.86. Median OS was 10.00 months (95% CI 8.59-14.52) in the experiment group compared with 10.46 months (8.92-13.84) in the control group (HR 1.05; 95%CI 0.71-1.54, p⫽0.82). The most common adverse events in both groups were anemia (S-1 plus cisplatin, 80.17% vs 5-Fu plus cisplatin, 71.19%), leukopenia (71.90% vs 62.71%), neutropenia (68.60% vs 55.93%), nausea (50.41% vs 60.17%), thrombocytopenia (44.63% vs 26.27%), vomiting (42.98% vs 42.37%) and anorexia (38.02% vs 41.53%). Conclusions: S-1 plus DDP is an effective and tolerable option for patients with advanced gastric or gastro-oesophageal junction adenocarcinoma. Clinical trial information: NCT01198392.

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Effectiveness of D2 gastrectomy for lymph node positive and advanced gastric cancer: Survival results of the Italian Gastric Cancer Study Group (IGCSG) randomized surgical trial on D1 versus D2 dissection for gastric carcinoma. Presenting Author: Maurizio Degiuli, Department of Surgery, Division of Surgical Oncology, Ospedale S G Battista, University of Turin, Italy, Pino Torinese, Italy Background: It is still unclear whether D2 lymphadenectomy can significantly improve survival of gastric cancer and therefore should be applied routinely or performed in selected cases. We conducted a multicenter randomized trial to compare the efficacy of D2 and D1 lymphadenectomy for gastric cancer. Primary outcome was overall survival; secondary endpoints were disease specific survival, morbidity and in-hospital mortality. Methods: Between June 1998 and December 2006 patients with gastric adenocarcinoma were randomly assigned to either D1 or D2 lymphadenectomy. Intraoperative randomization was implemented centrally by telephone. Results: A total of 267 eligible patients were allocated to either D1 (133) or D2 group (134). Morbidity (12·0% vs 17·9%, p⫽0·18) and mortality (3·0% vs 2·3%; p⫽0·72) were similar. There was no difference in the overall 5-year survival (66·5% vs 64·2%, p ⫽ 0.70). Subgroups analyses showed a 5-years disease specific survival benefit for pT1 cases treated with D1 dissection (98.0% vs 82.9%, p ⫽ 0.01) and of pT⬎1 LN⫹ patients treated with D2 resection (38·4% vs 59·5%, p ⫽ 0.05 at five years). Conclusions: In intention to treat analysis we observed no overall 5-year survival benefit from D2 resection. The trial showed a survival benefit of D1 procedure in early stages. On the opposite, despite evidence of contamination in the D1 arm, a survival advantage was documented in patients with advanced disease and lymph node metastases submitted to D2 procedure. Clinical trial information: ISRCTN11154654. Survival results. Survival (%) Survival

Disease-specific survival

All D1 D2 D1 T1 D2 T1 D1 T2⫹ D2 T2⫹ D1 LN⫹ D2 LN⫹ D1 T2⫹ LN⫹ D2 T2⫹ LN⫹ All D1 D2 D1 T1 D2 T1 D1 T2⫹ D2 T2⫹ D1 LN⫹ D2 LN⫹ D1 T2⫹ LN⫹ D2 T2⫹ LN⫹

65.4 (59.8-71.4) 66,5 64,2 91,7 80,7 51,2 58,5 42,5 54,3 35,0 51,0 71.8 (66.3-77.7) 71,0 72,6 98,0 82,9 54,5 68,7 46,0 61,1 38,4 59,5

Follow-up At 5 years Diff. I.C. 95%

P value*

Complete P value *

-2,3

-14,0

9,3

0,69

0,36

-11

-26,1

4

0,12

0,17

7,3

-7,8

22,3

0,35

0,59

11,8

-5

28,4

0,20

0,33

16

-2

34

0,09

0,19

1,6

-9,8

12,9

0,88

0,92

-15,1

-28,2

-2

0,014

0,019

14,2

-0,9

29,3

0,10

0,14

15,1

-2,0

32,1

0,15

0,19

21,1

2,5

39,6

0,05

0,08

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Randomized phase II trial of extended versus standard neoadjuvant therapy for esophageal cancer, NCCTG (Alliance) trial N0849. Presenting Author: Steven R. Alberts, Mayo Clinic, Rochester, MN Background: Patients (pts) with locally advanced esophageal or gastroesophageal junction (GEJ) adenocarcinoma commonly receive neoadjuvant chemoradiotherapy (chemo-RT). Despite this approach the rate of recurrence remains high. Given the difficulties of postoperative therapy, the efficacy of extended neoadjuvant therapy was assessed. Methods: Eligibility criteria included T3-4,N0 – Tany,N(⫹) disease amenable to radiation and surgery. Pts were randomized to either arm A (docetaxel 60 mg/m2 day 1 , oxaliplatin [Oxal] 85 mg/m2 day 1, and capecitabine 1250 mg/m2/day days 1-14 x 2 cycles [DOC] followed by 5-FU 180 mg/m2/day continuous IV through radiation ⫹ Oxal 85 mg/m2 days 1,15,29 ⫹ 50.4 Gy radiation (chemo-RT)) or arm B (chemo-RT alone). Randomization was stratified by ECOG PS (0/1 vs 2) and stage (II vs III/IVA). Primary endpoint was pathologic complete response (PCR) rate, defined as no gross or microscopic tumor identified in the surgical specimen. Interim analysis assessed efficacy and futility of the experimental intervention. Wilcoxon rank sum and Fisher’s exact tests were used to compare clinical/pathologic factors between arms. Results: Baseline and stratification factors were well balanced between arms. Of 42 pts included in the interim analysis (86% male; age [median 63, range 38-88], 100% PS 0/1; 71% stage III; 55% esophagus, 40% GEJ; 36% measurable disease), 4 and 1 pts in arms A and B, respectively, did not have surgery due to death (A, 2), progressive disease (A, 1), alternative treatment (A, 1) or adverse event (B, 1). Among 21 arm A pts, 21, 20, and 19 pts started 1st cycle of DOC, 2nd cycle of DOC and chemo-RT, respectively. All arm B pts received chemo-RT. 33% (7/21) of arm A and 48% (10/21) of arm B pts achieved PCR (p⫽0.53). Among pts undergoing surgery, 94% (16/17) and 100% (20/20) of arm A and B pts had complete resection (p⫽0.46). 38% and 24% of arm A and B pts experienced at least one grade 4⫹ adverse event at least possibly related to treatment (p⫽0.51). Conclusions: Extended neoadjuvant therapy in pts with locally advanced esophageal or GEJ adenocarcinoma failed to improve the PCR rate. Follow-up in regard to survival and rate of recurrence is ongoing. Clinical trial information: NCT00938470.

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Sorafenib (S) alone versus S combined with gemcitabine and oxaliplatin (GEMOX) in first-line treatment of advanced hepatocellular carcinoma (HCC): Final analysis of the randomized phase II GONEXT trial (UNICANCER/FFCD PRODIGE 10 trial). Presenting Author: Eric Assenat, Centre Hospitalier Régional Universitaire Montpellier, Montpellier, France Background: HCC is a vascular tumor with poor prognosis. Although S has been shown to improve survival, its ability to induce tumor shrinkage is very low. Given the activity of Gemcitabine and Oxaliplatin (GEMOX) in HCC, a phase II trial combining S with GEMOX was undertaken to define efficacy and safety profile. Methods: Patients with inoperable advanced and/or metastatic HCC (BCLCC B or C), with or without prior palliative chemoembolization, Child pugh score A, WHO performance status (PS) 0-1, were eligible for this two-stage, randomized phase II trial. Patients received S (400 mg BID) alone (arm A) or in combination with GEMOX every 2 weeks (gem. 1000 mg/m² [10 mg/m²/min] on D1; oxaliplatin, 100 mg/m² on D2) (arm B). Randomization was stratified according to CLIP score (0-1 vs. 2-3) and center. Primary endpoint was crude 4-mo Progression-Free Survival (PFS) rate (H0, ⬍ 50%; H1, ⱖ 70%; ␣ ⫽ 10%; 1- ␤⫽ 90%). Results: From Dec 2008 to Oct. 2011, 94 pts were enrolled: median age, 64 yrs; male, 88%; PS 0 (69%) 1(31%), CLIP 0-1 (48%) 2-3 (52%), cirrhosis (63%), portal vein thrombosis (29%), extra liver metastasis (69%). These characteristics were well balanced in both arms. Median duration and dose intensity of S were 4 mo (1-27) and 81% in both arms, respectively. Median number of GEMOX cycles was 7 (1-12) in arm B. Main severe (grade 3-4) toxicity (arm A/B) consisted of neutropenia (grade 3-4: 0%/7%), fatigue (18%/24%), thrombocytopenia (0%/9%), diarrhea (grade 2-4: 10%/21%), peripheral neuropathy (grade 2-3: 0%/10%), and hand foot syndrome (grade 2-3: 13%/7%). For evaluable pts (n ⫽ 83), ORR was 9% / 16% and DCR was 70%/77% in arms A/B, respectively. For all pts (median follow-up, 17.6 mo), 4-mo PFS rate was 54%/61%, median PFS was 4.6 (3.9-6.2)/6.2 (3.8-6.8) mo, and median OS was 13.0 (10.4-22.2) /13.5 (7.5-19.1) mo in arms A/B, respectively. Conclusions: S plus GEMOX was feasible in HCC. This trial met its primary endpoint (4-mo PFS ⱖ 50%) and ORR, median PFS and OS were encouraging data. Exploratory analyses are underway to identify subgroups of patients likely to derive most benefit from this combination. Clinical trial information: NCT00941967.

* Log-rank test.


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The impact of diabetes on HCC. Presenting Author: Suzanne Graef, The University of Birmingham, School of Cancer Sciences, Birmingham, United Kingdom Background: The incidence of hepatocellular carcinoma (HCC) in the UK has increased by 40% over the last 20 years, with a corresponding increase in mortality rate. The rising incidence of obesity and type II diabetes are believed to be contributing factors due to the association with nonalcoholic fatty liver and steatohepatitis. We aimed to examine if diabetes was as an independent risk factor for the development of HCC and to assess the impact of diabetes on overall survival (OS). Methods: Data from 724 patients with HCC and a control group comprising 340 patients with chronic liver disease were collected prospectively between 2007 and 2012. The odds ratio (OR) for HCC in diabetic versus non-diabetic patients was calculated. Univariate and multivariate analysis was performed using logistic regression. Cox proportional hazards analysis was used to estimate hazard ratio (HR) for death for HCC patients, with and without diabetes and for the impact of variation in diabetic treatments. Results: The prevalence of diabetes was 39% within the HCC population and 10.3% within the chronic liver disease group. Univariate analysis demonstrated increased risk of HCC associated with age, sex, diabetes, haemochromatosis, cirrhosis, alcohol abuse and Child’s score. In patients with diabetes OR for HCC was 5.74 (CI 3.9-8.3; p⬍0.001). Age, sex, cirrhosis, Child’s score, diabetes and diabetes treatment with insulin, retained significance as independent risk factors in multivariate analysis. There was no survival difference for HCC patients with and without diabetes. In diabetic patients with HCC, treatment of diabetes with metformin, compared against other diabetic treatment options, was associated with a significantly longer OS (31 versus 24 months, p ⫽ 0.016; HR 0.74, p ⫽ 0.027). Conclusions: This study has demonstrated that diabetes is an independent risk factor for the development of HCC in a high risk population and that treatment with insulin appears to confer further independent risk. Diabetes has no effect on survival following the development of HCC but treatment of diabetes with metformin is associated with prolonged survival. In considering the optimal treatment for diabetes in chronic liver disease the beneficial effects of metformin on OS, if HCC develops, should be taken into account.

4031


A multicenter, randomized, blinded, phase III study of pasireotide LAR versus octreotide LAR in patients with metastatic neuroendocrine tumors (NET) with disease-related symptoms inadequately controlled by somatostatin analogs. Presenting Author: Edward M. Wolin, Cedars-Sinai Medical Center, Los Angeles, CA Background: The novel somatostatin analog (SSA) pasireotide has a broader binding profile than currently available SSA (octreotide and lanreotide). Results from a phase III study (NCT00690430) of pasireotide LAR (P) vs octreotide LAR (O) in patients (pts) with NET and disease-related symptoms uncontrolled by the maximum approved dose of available SSA are shown. Methods: Pts (N⫽110) were randomized and stratified by predominant symptom at baseline (diarrhea [D], flushing [F], or D⫹F) 1:1 to P (60 mg IM) or O (40 mg IM) q28d. Primary objective was symptom response at month (M) 6. Secondary objectives included tumor response and safety. Progression-free survival (PFS) was an exploratory analysis. Results: 53 and 57 pts were enrolled in the P and O arms when the study was halted due to an interim analysis suggesting futility for symptom response. Baseline characteristics were similar between arms. Majority of primary tumor locations were small intestine (72% and 81% in the P and O arms). Symptom response at M6 was 9/43 (21%) and 12/45 (27%) in the P and O arms, odds ratio 0.73 (95% CI, 0.27-1.97; p⫽0.53). Median numbers of D/day and F/2 weeks and change in symptom from baseline to M6 are in Table. Hyperglycemia (11% vs 0%), diarrhea (9% vs 7%), and abdominal pain (2% vs 9%) were the most common grade 3/4 AEs in the P vs O arms in the core phase, and 7 (13%) and 4 (7%) pts discontinued due to AEs. Median investigator-assessed PFS was 11.8 months and 6.8 months in the P and O arms (HR⫽0.46; p⫽0.045). Conclusions: P and O showed a similar safety profile except for the higher frequency of hyperglycemia in P. Pts on P had PFS 5 months longer than pts on O (investigator assessment), despite no differences in symptom response rates. These results warrant a large phase III trial to clarify the role of P as a therapy for NET. Clinical trial information: NCT00690430. Pasireotide LAR Nⴝ53

n Baseline meanⴞSD M6 mean change, %ⴞSD

Octreotide LAR Nⴝ56*

D

F

D

F

26 4.9⫾1.4

28 74.0⫾50.3

32 6.7⫾3.3

29 76.6⫾64.5

-25.1⫾24.0

-42.1⫾38.8

-36.5⫾29.1

-49.4⫾36.7

Between treatment Least-squares mean (95% CI) D

F

6.9 (-8.0, 21.9)

4.5 (-15.9, 24.8)

4030


Placebo controlled, double blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors (PROMID): Results on long-term survival. Presenting Author: Rudolf Arnold, Philipps University Marburg, Department of Internal Medicine, Division of Gastroenterology and Endocrinology, Marburg, Germany Background: Octreotide LAR (O) compared to placebo (P) lengthens significantly time to tumor progression (TTP) in patients with metastatic midgut neuroendocrine tumors (Rinke et al. 2009). The antiproliferative response was more pronounced in patients with low (ⱕ 10%) hepatic tumor load (HL). To investigate whether this beneficial effect also affects overall survival (OS), patients included in the PROMID trial were followed until January 2013 at least once a year. Methods: Between July 2001 and January 2008, 42 and 43 patients were randomly assigned to receive O or P. Post study treatment was at the discretion of the local investigator. Data on cause of death and on post study treatment were documented. OS was analyzed using the Kaplan-Meier method. Treatment groups (O vs. P; HL at study entry ⱕ 10% vs. ⬎10%) were compared using the log rank test and hazard ratios were estimated with the use of the Cox proportional hazards model. Results: 41 of 85 patients died until January 2013. 19 in the octreotide and 22 in the placebo arm. Median OS for all 85 patients was 85 months, “not reached” in the O arm and 84 months in the P arm (p⫽0.59, HR⫽0.85 [CI 0.46; 1.56]). Cause of death was unrelated to the tumor disease in 8 patients. 26 of 64 patients (10 in the O vs. 16 in the P arm) died in the HL ⱕ 10% subgroup and 15 of 21 patients (9 in the O vs. 6 in the P arm) in the HL ⬎ 10 % (p⫽0.002, HR⫽2.7). Median OS in the HL ⱕ 10% subgroup was “not reached” (octreotide) vs 80.5 months (placebo) (p⫽0.14, HR⫽0.56 [CI 0.25; 1.23]). In the HL ⬎ 10% subgroup the respective numbers were 35 vs. 84 months (p⫽0.14, HR⫽2.18 [CI 0.75; 6.33]). Post study treatment in the O and P groups included octreotide LAR (29 vs. 38 patients), hepatic CHE (5 vs. 12 patients), PRRT (13 vs. 13 patients) and CHT (4 vs. 5 patients). Conclusions: Octreotide LAR not only prolongs TTP but also extends OS in the subgroup of patients with metastatic midgut NETs and a low HL (ⱕ 10% at study entry) but not in the high (HL ⬎ 10%) subgroup. Almost all patients who were randomized at study entry in the P group received octreotide LAR after disease progression, but these experienced a less favourable OS in the low HL subgroup. Clinical trial information: NCT00171873. 4032


Multicenter phase II trial of temsirolimus (TEM) and bevacizumab (BEV) in pancreatic neuroendocrine tumor (PNET). Presenting Author: Timothy J. Hobday, Mayo Clinic, Rochester, MN Background: PNET has long had few effective therapies other than chemotherapy. Placebo-controlled phase III trials of the mTOR inhibitor everolimus and the VEGF/PDGF receptor inhibitor sunitinib noted improved progression-free survival (PFS). However, objective response rates (RR) with these agents are still ⬍10%. Preclinical studies suggest enhanced anti-tumor effects with combined mTOR and VEGF targeted therapy. Methods: We conducted a phase II trial of the mTOR inhibitor TEM (25 mg IV q week) and the VEGF-A monoclonal antibody BEV (10 mg/kg IV q 2 weeks) in patients (pts) with well or moderately differentiated PNET and progressive disease by RECIST within 7 months of study entry. Co primary endpoints were RR and 6-month PFS. Planned enrollment was 50 patients, with interim analysis for futility after the first 25 evaluable pts. Pts had no prior mTOR or VEGF targeted agents, ECOG PS 0-1, and adequate hematologic and organ function. Continued octreotide was allowed, but not required. Prior interferon, embolization, and ⱕ 2 chemotherapy regimens were allowed. Results: 55 pts were eligible for response assessment. Confirmed PR was documented in 20 of 55 patients (37%). 44 of 55 (80%) patients were progression-free at 6 months. Of 49 pts evaluable for this endpoint, 12 month PFS is 49%. 15 patients remain on therapy. For evaluable patients, the most common grade 3-4 adverse events attributed to therapy were hypertension (18%), hyperglycemia (13%), fatigue (11%). leukopenia (9%), headache (9%), proteinuria (7%), and hypokalemia (7%). Conclusions: The combination of TEM/BEV has substantial activity in a multi-center phase II trial with RR of 37%, well in excess of single targeted agents in PNET. 6-month PFS was a notable 80% in a population of patients with RECIST criteria progression within 7 months of study entry. Phase III trials of combined VEGF/mTOR inhibition in PNET should be pursued. Clinical trial information: NCT01010126.

* One pt in the O arm had no baseline information.




Effectiveness of peptide receptor radionuclide therapy for neuroendocrine neoplasms: A multi-institutional registry study with prospective follow-up. Presenting Author: Dieter Hörsch, Zentralklinik Bad Berka, Bad Berka, Germany Background: Peptide receptor radionuclide therapy targets somatostatin receptors expressed on well differentiated neuroendocrine neoplasms. Retrospective monocentric studies indicate that peptide receptor radionuclide therapy is an effective treatment for patients with neuroendocrine neoplasms. Methods: We initiated a multi-institutional, prospective and board reviewed registry study for patients treated with peptide receptor radionuclide therapy. 450 patients were included and followed for a mean of 24.4 months. Patients were treated with Lutetium-177 (54%), Yttrium-90 (17%) or both radionuclides (29%). Primary neuroendocrine neoplasms were derived of pancreas (38%), small bowel 30%), unknown primary (19%), lung (4%) and colorectum (3,5%). Most neuroendocrine neoplasms were well differentiated with a proliferation rate below 20% in 54% and were pretreated by 1 or more therapies in 73%. Results: Overall survival of all patients from the beginning of therapy was 59 months in median. Median survival depended on radionuclides used (Yttrium-90: 38 months; Lutetium-177: not reached; both: 58 months), proliferation rate (G1: median not reached; G2: 58 months; G3: 33 months; unknown: 55 months) and origin of primary tumors (pancreas: 53 months; small bowel: not reached; unknown primary: 47 months; lung: 38 months) but not upon number of previous therapies. Median progression-free survival measured from last cycle of therapy accounted to 41 months for all patients. Progression-free survival of pancreatic neuroendocrine neoplasms was 39 months in median. Similar results were obtained for neuroendocrine neoplasms of unknown primary with a median of 38 months whereas neuroendocrine neoplasm of small bowel were progression-free for a median of 51 months. Side effects like G3-G4 nephrotoxicity or hematological function were observed in 0.2% and 2% of patients. Conclusions: Peptide receptor radionuclide therapy is effective for patients with G1-G2 neuroendocrine tumors irrespective of previous therapies with a survival advantage of several years compared to other therapies and only minor side effects.

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Prospective randomized phase II trial with gemcitabine versus gemcitabine plus sunitinib in advanced pancreatic cancer: A study of the CESAR Central European Society for Anticancer Drug Research-EWIV. Presenting Author: Heike Richly, West German Cancer Center, University Duisburg-Essen, Essen, Germany Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most common malignant tumours, but PDAC is still associated with a poor prognosis in advanced disease with an overall 5-year survival of only about 15%. Therefore there is a need for new treatment strategies. To improve the standard therapy with gemcitabine we initiated a prospective randomized phase-II trial with gemcitabine (GEM) vs. gemcitabine plus sunitinib (SUNGEM) based on data of in vitro trials and phase-I data for the combination treatment. Methods: Patients (N⫽113) with locally advanced or metastatic PDAC were prospectively randomized to receive gemcitabine alone (GEM) at a dosage of 1000 mg/m² day 1, 8, 15 q28 or to a combination of gemcitabine and sunitinib (SUNGEM) at a dosage of GEM 1000 mg/m² d1⫹8 and sunitinib 50mg p.o. d1-14, qd21 (based on a phase-I trial). The primary endpoint was progression-free survival (PFS), secondary endpoints were overall survival (OS), time to progression (TTP), overall response rate (ORR) and toxicity. Results: The confirmatory analysis of PFS was based on the ITT population (N⫽106). The median PFS was 13.3 weeks (95 %-Cl: 10.4-18.1 weeks) in the GEM group and 11.6 weeks in the SUNGEM arm (95 %-Cl: 7.0-18.0 weeks) (one-sided logrank: p⫽0.74). The 6-month PFS rate was 26.8 % (95 %-Cl: 15.4-39.5 %) in GEM arm and 25.0 % in SUNGEM arm (95 %-Cl: 14.0-37.8 %). The overall response rate was 6.1 % (95 %-Cl: 0.7-20.2 %) in the GEM arm and was a slightly but not significantly higher for the SUNGEM arm with 7.1% (95%-Cl: 0.9 – 23.5%).The median time to progression (TTP) was 14.0 weeks (95 %-Cl: 12.4-22.3 weeks) for the GEM arm and 18.0 weeks (95 %-Cl: 11.3-19.3 weeks) for the SUNGEM arm (two-sided logrank: p⫽0.60). The median OS was 30.4 weeks (95 %-Cl: 18.1-37.6 weeks) for the SUNGEM and 36.7 weeks (95 %-Cl: 20.6-49.0 weeks) for the GEM arm (two-sided logrank: p⫽0.44). With regard to toxicities, at least one AE of grade 3 or 4 was reported in 78.8% in the SUNGEM arm and 72.2% in the GEM arm. Conclusions: The combination of gemcitabine plus sunitinib (SUNGEM) did not improve the PFS in locally advanced or metastatic PDAC compared to gemcitabine alone. Clinical trial information: NCT00673504.

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DOCOX: A phase II trial with docetaxel and oxaliplatin as a second-line systemic therapy for patients with advanced and/or metastatic adenocarcinoma of the pancreas. Presenting Author: Thomas Jens Ettrich, Department of Internal Medicine I, University of Ulm, Ulm, Germany Background: In Europe and the USA, pancreatic ductal adenocarcinoma (PDAC) is the fifth most common cause of cancer-related death. For patients with metastatic disease, palliative cytostatic systemic treatment is the only option. There is no established standard for 2nd-line treatment. Fluoropyrimidines either alone or in combination with Oxaliplatin or other chemotherapeutic agents are increasingly used. There are interesting data regarding the combination of Gemcitabine with Oxaliplatin or Docetaxel with respect to progression free survival (PFS) and tumor response in 1st-line. For the first time, the DocOx-trial investigates the combination of Oxaliplatin with Docetaxel as 2nd-line treatment after progression under palliative first-line systemic treatment with Gemcitabine. Methods: Prospective, single arm, non-randomized, multicenter, Simon´s two stage phase II trial using Docetaxel (75 mg/m2, 60 min, d 1) plus Oxaliplatin (80 mg/m2, 120 min, d 2, qd 22). Duration of the trial is scheduled up to 8 cycles. Primary endpoint: tumor response (RR) according to RECIST 1.0. Secondary endpoints: PFS, OS, safety/toxicity, QoL/clinical benefit. Results: Here we present the data on response rate (RR), median progression free survival (mPFS) and median overall survival (mOS) as of February 4th, 2013. Data represents the Intention to treat-analysis of the 44 patients included between 2009 and 2012. 5 patients did not obtain any treatment. RR was 16% (7 partial remissions, no complete remission) with a disease control rate (DCR) of 48% after the first two treatment cycles. Median PFS was 7 weeks ( 95%-CI: 6-16 w.) and median OS after start of 2nd-line therapy was 36 weeks ( 95%-CI: 19-55 w.). Conclusions: In this single-arm 2nd-line trial for the treatment of PDAC, the combination of Doxcetaxel and Oxaliplatin shows very promising results compared to other 2nd-line-protocols such as OFF. Some patients seem to benefit particularly as indicated by long periods of treatment in this setting. Even after 8 cycles of treatment with DocOx, partial response was observed in 2 patients and stable disease in another 6 patients corresponding a disease control rate of 18%. Clinical trial information: NCT00690300.

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Predictive value of phase II clinical trials in pancreatic cancer: Rethinking the road to progress. Presenting Author: Daniel M. Halperin, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Few new therapies for pancreatic adenocarcinoma (PC) have been approved by the Food and Drug Administration (FDA) or recommended by the National Comprehensive Cancer Network (NCCN), reflecting frequent failures in phase III trials. We hypothesize that the high failure rate in large trials is due to a low predictive value for “positive” phase II studies. Methods: Given a median time from initiation of clinical trials to FDA approval of 6.3 years, we conducted a systematic search of the clinicaltrials.gov database for phase II interventional trials of antineoplastic therapy in PC initiated from 1999-2004. We reviewed drug labels and NCCN guidelines for FDA approval and guideline recommendations. Results: We identified 70 phase II trials that met our inclusion criteria. Forty-five evaluated compounds without preexisting FDA approval, 23 evaluated drugs approved in other diseases, and 2 evaluated cellular therapies. With a median follow-up of 12.5 years, none of these drugs gained FDA approval in PC. Four trials, all combining chemotherapy with radiation, eventually resulted in NCCN recommendations. Forty-two of the trials have been published. Of 16 studies providing pre-specified type I error rates, these rates were ⱖ0.1 in 8 studies, 0.05 in 6 studies and ⬍0.025 in 2 studies. Of 21 studies specifying type II error rates, 7 used ⬎0.1, 10 used 0.1, and 4 used ⬍0.1. Published studies reported a median enrollment of 47 subjects. Fourteen trials reported utilizing a randomized design. Conclusions: The low rate of phase II trials resulting in eventual regulatory approval of therapies for PC reflects the challenge of conquering a tough disease as well as deficiencies in the statistical designs. New strategies are necessary to quantify and improve odds of success in drug development. Statistical parameters of individual or coupled phase II trials should be tailored to achieve the desired predictive value prior to initiating pivotal phase III studies. Positive predictive value of a phase II study assuming a 1%, 2%, or 5% prior probability of success and 10% type II error rate. Type I error 0.1 0.05 0.01 0.0025

1% Prior

2% Prior

5% Prior

0.08 0.15 0.48 0.78

0.16 0.27 0.65 0.88

0.32 0.49 0.83 0.95


252s 4037

Gastrointestinal (Noncolorectal) Cancer General Poster Session (Board #15G), Sun, 8:00 AM-11:45 AM

A phase I trial of a local delivery of siRNA against k-ras in combination with chemotherapy for locally advanced pancreatic adenocarcinoma. Presenting Author: Talia Golan, Sheba Medical Center, Tel HaShomer, Israel Background:K-Ras mutation G12D is most prevalent in pancreatic adenocarcinoma (PDAC). siRNA against the K-RasG12D(siG12D) mutant had showed significant preclinical anti-tumor effects. siG12D LODER - miniature biodegradable polymeric matrix that encompasses anti-K-RasG12D siRNA drug, is placed with Endoscopic US biopsy and designed to continuously release the drug regionally over a period of 4 months. Methods: Open label phase I study of patients with locally advanced non-operable PDAC in the first-line setting. Patients were assigned to receive siG12D LODERs in dose escalation cohorts: 0.025mg, 0.75mg and 3.0mg. Gemcitabine 1000 mg/m2IV was given weekly, following siG12D LODER insertion. The RP2D (recommended phase II dose) was further examined in 3.0 mg dose cohort in combination with modified Folfirinox (Oxaliplatin 85mg/m2, Irinotecan 150mg/m2, Fluorouracil infusion 2,400mg/m2 46 hours, every 2 weeks). Follow up period was 8 weeks and survival follow up until death. Primary study objectives were to determine the dose-limiting toxicities (DLT) and maximum tolerated doses (MTD). Results:15 patients have been enrolled. 2 patients were omitted from study due to metastatic disease detected on day 1 post siG12D LODER implant imaging . Median age ⫽ 70 (range 52-85); male:female 8:7. Among 13 treated patients, the most frequent adverse events observed in the study were typically grade 1- 2 in severity; 4 patients experienced serious adverse events (SAE), one procedure related. No DLTs were observed. MTD was not reached. CT performed 8-10 weeks following the procedure showed stable disease in all patients. Reduction in tumor marker CA 19-9 was observed in 64% (7/11) of patients. The median survival of 13 patients was 16 months ( 8/13 patients still alive at analysis). Conclusions: The combination of siG12D LODER and chemotherapy is well tolerated. The combination has demonstrated promising efficacy in locally advanced PDAC with durable responses. Phamocodynamic endpoints are currently being examined in an expansion cohort in operable patients. A phase II randomized trial is planned in order to investigate efficacy of siG12D LODER in locally advanced non-operable PDAC. Clinical trial information: NCT01188785.

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Hemoglobin-A1c level to predict for clinical outcomes in patients with pancreatic cancer. Presenting Author: Katherine Y. Fan, Johns Hopkins University School of Medicine, Baltimore, MD Background: An association between diabetes mellitus (DM) and pancreatic ductal adenocarcinoma (PDA) has long been recognized. While longstanding DM may be a risk factor for developing PDA, new-onset DM may be a manifestation of the cancer. Here we assess the role of an objective and quantifiable measure of glucose intolerance, hemoglobin-A1c (HbA1c), in predicting clinical outcomes in PDA. Methods: HbA1c values were prospectively collected on 656 consecutive patients presenting to the Johns Hopkins Pancreas Multidisciplinary Cancer Clinic from 2009-2012. Patients were diagnosed with benign pancreatic disease (BPD) or biopsyconfirmed resectable (R), borderline/locally advanced (BL), or metastatic (M) PDA. Patients with prior treatment for PDA or a history of DM greater than a 1-year were excluded. Univariate Cox regression analyses and multivariable proportional hazards models were used to identify poor prognostic factors for overall survival. Results: Of 284 patients included, 44 had benign disease, 62 R-PDA, 115 BL-PDA, and 63 M-PDA. Patients with malignant disease (R-, BL-, and M-PDA) collectively had higher HbA1c values on average at presentation than patients with BPD (6.1% vs. 5.6%, p⬍0.001). There was a trend towards higher HbA1c at presentation in patients with advanced PDA (BL and M) compared to patients with R-PDA (6.2% vs. 5.9%, p⫽0.100); moreover, the proportion of patients with HbA1c levels in the diabetic range (⬎6.4%) increased with more advanced stage of disease. Among patients with PDA (n⫽240), univariate analyses showed HbA1cⱖ6.5, ageⱖ65, ECOGⱖ1, CA19-9⬎90, tumor size ⬎3cm, and advanced stage to be significantly associated with inferior survival (all HR⬎1, p⬍0.05). After multivariate analysis with backward elimination, all of the above factors except for tumor size ⬎3cm remained in the model for inferior survival. Conclusions: HbA1c level at presentation appears to correlate with disease stage and, moreover, to predict for survival among all stages of PDA. Patients with PDA have significantly higher HbA1c levels at presentation than patients with BPD. This study highlights the potential utility of HbA1c as a screening tool and prognostic factor.

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A pilot phase II multicenter study of nab-paclitaxel (Nab-P) and gemcitabine (G) as preoperative therapy for potentially resectable pancreatic cancer (PC). Presenting Author: Shawn MacKenzie, Virginia G. Piper Cancer Center at Scottsdale Healthcare/TGen, Minneapolis, MN Background: Nab-P plus G is a new option for advanced PC. This combination was evaluated as a preoperative regimen for potentially resectable PC. Methods: Patients (pts, n⫽25) with resectable PC (NCCN criteria) were treated with 3 cycles of Nab-P (125mg/m2) & G (1000mg/ m2) on day 1, 8, and 15, followed by surgical resection. The chosen endpoint was Grade III/IV histological changes (Arch Surg.127:1335-39: 1992) in ⬎ 30% of resected tumor specimens. Results: Accrual is complete with 25 pts (median age 65, 10 F:15 M), 14/25 completed 3 cycles of treatment. Early drug discontinuation or drug interruption prior to the completion of 3 cycles occurred in 11 pts due to azotemia, cholangitis, pneumonia, catheter infection and pt decision. One pt had a fatal (grade 5) non-neutropenic aspergillus pneumonia. There was one episode of neutropenic fever (4%), and 3 episodes of cholangitis (12%) due to biliary stent malfunction. Other adverse events (grade 3/4) include neutropenia 64%, anemia 20%, dehydration 12%, nausea 12% and thrombocytopenia 12%. Dose reductions due to AEs were required in 5 pts, (3-neutropenia, 2-rash). Surgical resection was successful in 20/25 pts: 12- Pancreaticoduodenectomy, 8- Distal Pancreatectomy, 19/20 pts underwent an R0 resection. Surgical resection was not done in 5/25 pts due to: pre-operatively identified metastatic disease (2), blood vessel involvement at surgery (1), pt declined (1) and a pre-operative death (1).Post-operative tumor staging identified a complete response (n⫽1); stage IA (n⫽1); stage IIA (n⫽6); and stage IIB (n⫽12). Radiological partial response (PR) was documented in 4 pts prior to surgery. CA19-9 levels decreased from baseline by ⬎ 50% in 60% (n⫽15) of pts and by ⬎ 90% in 16% (n⫽4). Post-operative ⬎ 90% histological tumor response (Grade 3/4) was seen in 6 of 20 (30%) resected specimens. Conclusions: Preoperative therapy with Nab-P plus G is feasible with evidence of activity by radiological (PR in 16%), CA19-9 (decrease ⬎ 50% in 60% of pts) and pathological down staging (Grade 3/4 in 30% in resected tumor specimens). A larger study is warranted. Supported by Abraxis/Celgene Pharmaceuticals and the TGen foundation. Clinical trial information: NCT01298011.

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Interim safety and efficacy analysis of a phase II, randomized study of GVAX pancreas and CRS-207 immunotherapy in patients with metastatic pancreatic cancer. Presenting Author: Dung T. Le, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD Background: GVAX is composed of GM-CSF-secreting allogeneic pancreas cancer cell lines and administered with low-dose cyclophosphamide (CY) to inhibit regulatory T cells. In prior studies, GVAX induced mesothelinspecific T cell responses that correlated with survival. CRS-207 is a live-attenuated Listeria monocytogenes engineered to express human mesothelin. CRS-207 stimulates potent innate and adaptive immunity and has shown synergy with GVAX in mouse tumor models. Anecdotal survival benefit was observed in the CRS-207 phase I study in patients who received prior GVAX. Methods: Patients were enrolled with metastatic pancreatic ductal adenocarcinoma (PDA) who received or refused ⱖ 1 prior chemotherapy, had ECOG ⱕ 1 and adequate organ function. Patients were randomized 2:1 to receive 2 doses of CY/GVAX followed by 4 doses of CRS-207 (Arm A) or 6 doses of CY/GVAX (Arm B) every 3 weeks. Clinically stable patients were offered additional 20-week courses. The primary endpoint was comparison of OS between treatment arms. Secondary endpoints were to evaluate safety, clinical and immune responses. Results: 90 patients were treated (Arm A: 61, Arm B: 29). As of Jan 2013, 27 patients completed 1 course (A: 24, B: 3) and 17 patients (A: 15, B: 2) initiated a 2nd course. Median age was 63. Median number of prior regimens was 3. No treatment-related serious adverse events (SAEs) or unexpected toxicities were observed. The most frequent Grade (G) 3/4 related toxicities were fever, lymphopenia, hypophosphatemia, elevated liver enzymes, and fatigue following CRS-207 in ⬍5% of subjects. Of 51 patients evaluated post-treatment, 34% had stable disease in Arm A vs. 19% in Arm B. OS for all patients treated was 6 months in Arm A vs. 3.4 months in Arm B (two-sided, p⫽0.0114). Conclusions: Combined CY/GVAX pancreas and CRS-207 was generally well-tolerated with no treatmentrelated SAEs or unexpected G3/4 toxicities. The significant difference in OS between treatment arms met the criteria for early stopping. This indicates that the combination immunotherapy may extend OS for metastatic PDA patients with minimal toxicity and should continue to be developed as an effective therapy. Clinical trial information: NCT01417000.




Pimasertib plus gemcitabine in metastatic pancreatic adenocarcinoma: Results of a safety run-in part of a phase II trial. Presenting Author: Chris Verslype, UZ Leuven, Gasthuisberg Campus, Leuven, Belgium Background: Activating MAPK pathway mutations (predominantly RAS) occur with a high incidence in metastatic pancreatic adenocarcinoma (mPaCa). Pimasertib is a MEK1/2 inhibitor with potent activity in cell lines and xenografts with an activated MAPK pathway. This two-part trial in patients (pts) with mPaCa comprises a dose-escalation safety run-in and a randomized phase II part (EudraCT 2009-011992-61). We defined the maximum tolerated dose (MTD), safety, pharmacokinetics (PK) and antitumor activity of two pimasertib dosing schedules (S), and the recommended phase II dose (RP2D). Methods: Dose-escalation (3⫹3 design) in two dosing S of oral pimasertib: once-daily (qd) - 5 days on, 2 days off (S1); and twice-daily (bid) - continuous (S2) combined with the standard dose of gemcitabine (gem). Results: 53 pts (median age 61 years and ECOG performance status 0-1) have been treated at six dose levels in S1 (15 to 120 mg qd) and at 60 and 75 mg bid in S2. MTDs were defined as 120 mg qd and 75 mg bid. Two pts had a dose-limiting toxicity (DLT) in the DLT observation period: a grade (G) 3 confusion with ataxia and disorientation at 60 mg bid and a G4 suicidal ideation at 75 mg bid. G3-4 adverse events (AEs) in ⬎5% of pts were: neutropenia (32%), thrombocytopenia (25%), asthenia (19%), dyspnea (9%), transaminitis (9%), anemia (8%), and diarrhea, pulmonary embolism, pulmonary sepsis (6% each). Most common AEs were asthenia (70%), ocular AEs (68%), skin rash (62%), nausea (58%), diarrhea (58%), peripheral edema (51%), thrombocytopenia (49%), vomiting (45%), mucositis (43%), neutropenia (38%), decreased appetite (36%) and anemia (34%). The main ocular AE was serous retinal detachment (58%); manageable retinal vein occlusion occurred in five pts. PK data were comparable to pimasertib monotherapy and published gem data. Partial responses were noted in 10 pts and stabilisation ⱖ3 months in 13 pts. Hot spot mutations in genes activating the MAPK and PI3K/AKT pathway and correlation with clinical outcome are being investigated. Conclusions: Pimasertib MTDs were reached. The RP2D was defined as 60 mg bid. PK was dose proportional and associated with target inhibition. Sustained responses were seen in both dosing schedules. Clinical trial information: 2009-011992-61.

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Extended neoadjuvant chemotherapy (CT) in borderline resectable pancreas cancer (BRPC). Presenting Author: J Bart Rose, Virginia Mason Medical Center, Seattle, WA Background: The optimal surgical (S) approach to BRPC is unknown. We evaluated an approach to BPRC using extended course chemotherapy (CT) without routine neoadjuvant chemoradiation (CRT). Clinical outcomes were evaluated on an ⬙intent to treat⬙ basis. Methods: Patients (pts) were identified from a prospectively-maintained database started in 2008. Pts required 1) Dx BRPC with non-tail primary per radiographic staging using AHPBA/NCCN guidelines 2) No prior therapy (Rx) 3) Negative staging/ exploratory laparoscopy prior to S 4) All cancer Rx at VMMC prior to S. Pts received gemcitabine/docetaxel (G/D) as initial CT. Pts with systemic progression/comorbid complication prior to 24 wks were not offered local Rx; pts with localized cancer at 24 wks judged likely to achieve R0 resection were offered S; all other pts were offered fluoropyrimidine-based CRT. Results: Of 76 identified pts (median age 66), 12 (16%) are on initial CT and not fully evaluable. G/D as sole CT achieved 24 wk disease control in 46/64 (72%) pts and ⬎50% decline in baseline CA 19.9 in 39/55 pts (71%). 53/64 fully evaluable pts (83%) completed 24 wks CT, 11/64 pts (17%) did not (4 systemic progression, 3 Rx- related, 4 intercurrent illness). 50/53 pts attempted local Rx (40 S, 10 CRT, 2 unfit, 1 refused). 30/40 pts (75%) had successful S (all R0), 10/40 pts (25%) had inoperable disease (4 local-subsequently received CRT, 6 systemic). 23/30 pts (77%) have received some form Rx post R0 resection. With median f/o of 20 mo, 23/44 (52%), 17/30 (57%), and 6/14 (43%) receiving any local Rx, S, and CRT-only remain progression free. 13/30 S pts recurred, 3 local (10%) and 10 systemic (33%). 1-yr, 2-yr, 3-yr, and median overall survivals (OS) for fully evaluable pts respectively are 82%, 50%, 36%, and 27 mo. Median OS for pts receiving CT-only (20 pts), CT⫹CRT (14 pts), and R0 pts are 12 mo, 17 mo, and ⬎20 mo, respectively. 25/30 R0 pts remain alive (range 6-54 mo). Conclusions: 1) Extended neoadjuvant CT without routine neoadjuvant CRT is a feasible approach to BRPC. 2) G/D has significant activity in BRPC. 3) Pretreatment surgical staging combined with the above Rx yields a high probability of R0 resection. 4) OS for both resected and non-resected pt was superior to usual literature comparators.

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Circulating cytokines and angiogenic factors (CAF) as markers of clinical response in the study of trametinib (T) plus gemcitabine (G) versus placebo (P) plus gemcitabine for patients (pts) with untreated metastatic adenocarcinoma of the pancreas (MEK113487). Presenting Author: John Heymach, The University of Texas MD Anderson Cancer Center, Houston, TX Background: T is a reversible and highly selective allosteric inhibitor of MEK1/MEK2. The addition of T to G did not improve overall survival (OS) as first-line treatment for pts with metastatic adenocarcinoma of the pancreas (ASCO GI 2013 #291). CAF profiles have shown potential for identification of prognostic and predictive markers in cancer pts (Tran, Lancet, 2012). Methods: Plasma samples (n ⫽ 144 baseline [BL]; n ⫽ 112 day 15) from pts who consented to participate in MEK113487 study were analyzed for 30 CAFs (ANG2, IGFBP3, IL2R, IP10, MMP2, MMP9, OPN, PDGFBB, SCF, TIMP1, IL6, MIP1B, SDF1, TRAIL, VEGF, MIP3A, MCP2, FGFB, IL8, VEGFR1, IL10, IL1A, IL12P40, PIGF, EGF, IL1B, TNFA, IL4, MIP1A, MCP3) using SearchLight multiplex assays in a CLIA-certified laboratory. Change from BL was assessed using either paired t tests or Wilcoxon tests. BL and change from BL CAF levels were tested for association with clinical outcome using proportional hazards regression within arm (P ⬍ .01 for significance) and between arms (treatment arm by CAF level interaction, P ⬍ .05 for significance). Results: Lower levels (⬍ median) of BL ANG2, IL6, TIMP1, and IL8 were associated with an average of 5 mo longer OS in both the T⫹G and G arms. Lower BL levels (less than first quartile) of IGFBP3 and PDGFBB were associated with 6 mo longer OS in the T⫹G arm, while higher levels (greater than third quartile) of IGFBP3 and PDGFBB were associated with 4.8 mo longer OS in the G arm. A combined model of low IGFBP3 and/or PDGFBB showed improved survival for T⫹G vs G (median OS, 10.3 vs 5.6 mo). Decreases of ANG2 and IL2R levels at day 15 from BL were observed in the T⫹G arm only; additional results will be presented. Conclusions: This study suggests that plasma CAF profiling may aid in the prognostic evaluation of pts, assessing therapeutic response, and identifying pathways modulated by treatment in pancreatic cancer pts. Low IGFBP3 and PDGFBB may identify patients who receive greater benefit from T⫹G compared with G in this population and merit further investigation as predictive markers. Clinical trial information: NCT01231581.

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The impact of diabetes mellitus and metformin on survival of patients with advanced pancreatic cancer receiving chemotherapy. Presenting Author: Do-Youn Oh, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea Background: A causal relationship between diabetes mellitus (DM) and pancreatic cancer (PC) is well established. However, in patients with advanced PC (APC) who receive palliative chemotherapy, the impact of DM on prognosis is unclear. Methods: Between 2003 and 2010, we enrolled consecutive patients with APC, all recipients of palliative chemotherapy, with the provision that DM disease status could be properly defined. Enrollees were stratified by diagnosis, in accordance with 2010 DM criteria (AHA/ADA). DM at least 2 years’ duration prior to diagnosis of APC qualified as remote-onset DM (vs recent-onset). Clinical characteristics and outcomes were then analyzed. Results: Of the 349 enrollees with APC, 183 (52.4%) had DM. In patients with DM, 160 had DM at the time APC was diagnosed (remote onset, 87; recent onset, 73); and the remaining 23 developed DM during the course of APC treatment. Ultimately, 73.2% (134/183) of DM patients received antidiabetic medication (metformin (56), sulfonylurea (62), insulin (43)). By multivariate analysis, cancer extent (HR, 1.792; p ⬍ 0.001) and weight loss during chemotherapy (HR, 1.270; p ⫽ 0.08) were associated with diminished overall survival (OS), whereas a diagnosis of DM (HR, 0.788; p ⫽ 0.05) conferred a positive effect on OS ( OS 8.4 months in DM patients vs 7.5 months in non-DM patients, p ⫽ 0.04). Among DM patients, recent-onset DM trended toward prolonged OS, compared with remote-onset/subsequent DM (9.8 months vs. 7.9 months, respectively; HR, 0.789; p ⫽ 0.142). Neither antidiabetic medication in general nor sulfonylurea or insulin specifically affected OS. However, recipients of metformin survived longer than non-recipients (HR, 0.693; 95% CI, 0.492-0.977; p ⫽ 0.036). Relative to the APC cohort overall including non-DM patients, metformin conferred better survival as well (11.0 months vs. 7.8 months, HR 0.712, p ⫽ 0.067), given similar baseline clinical characteristics. Conclusions: In patients with APC receiving palliative chemotherapy, recent-onset DM (within 2 years of APC diagnosis) and metformin treatment are positive prognosticators, associated with prolonged OS.


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Development and validation of a predictive model to assess an individual’s risk of pancreatic cancer. Presenting Author: Byung-Ho Nam, National Cancer Center, Goyang, South Korea

Circulating tumor cells in locally advanced pancreatic adenocarcinoma: The ancillary study Circe 07 of the LAP 07 trial. Presenting Author: Florence Huguet, Hopital Tenon, Paris, France

Background: Due to the very low survival of pancreatic cancer (PC), early detection is a critical strategy to improve the outcome of PC.Screening individuals with genetic syndromes associated with a high incidence of PC or families predisposed to PC is increasing. However, those populations account for only 10% of all PC cases. A different approach for developing an effective surveillance tool is needed to identify high-risk individuals without hereditary risks. The goal of this study was to develop and validate risk prediction models for filtering purposes as part of the sporadic PC surveillance activities. Methods: Based on an eight-year follow-up of a cohort study involving 1,289,933 men and 557,701 women in Korea who had biennial examinations in 1996-1997, gender-specific risk prediction models were developed using the Cox proportional hazards model. The models were validated using independent data of 500,046 men and 627,629 women who had biennial examinations in 1998-1999. The models’ performance was evaluated with respect to their discrimination and calibration abilities based on the C-statistic and the HosmerLemeshow (H-L) type ␹2-statistic. Results: Age, height, BMI, fasting glucose, urine glucose, smoking, and age at smoking initiation were included in the model for men. In the model for women, height, BMI, fasting glucose, urine glucose, smoking, and drinking habits were included. Smoking was the most significant risk factor for developing pancreatic cancer in both men and women. Model validation showed excellent model performance with C-statistics (95% confidence interval) of 0.813 (0.800⫺0.826) and 0.804 (0.788⫺0.820) for men and women, respectively. The H-L type ␹2-statistics (P-values) were 7.478 (0.587) and 10.297 (0.327) for men and women, respectively. Five different risk groups could be identified with hazard ratios (HR) greater than 20 in the highest risk group compared to the lowest risk group in both the men and women. Conclusions: Gender-specific individualized risk prediction models for PC were developed and validated with a high level of performance. These models can be used to identify high-risk individuals who may benefit from increased surveillance of PC.

Background: Pancreatic carcinoma is one of the leading causes of cancerrelated mortality. At time of diagnosis, 30% of patients present with a locally advanced unresectable but non metastatic carcinoma (LAPC). Theoretically, patients with micrometastatic dissemination at diagnosis should benefit from systemic treatments, whereas radiation therapy should be favored in the others. Based on the hypothesis that circulating tumor cells (CTC) count is a surrogate of the cancer metastatic abilities, CTC detection rates and prognostic value were studied in a prospective cohort of LAPC patients. Methods: LAP07 international multicenter randomized study assesses in patients whose LAPC is controlled after 4 months of gemcitabine-based chemotherapy whether to administrate a chemoradiotherapy could increase overall survival versus continuation of chemotherapy alone. A subgroup of patients included in LAP 07 trial were prospectively screened for CTC before the start of the chemotherapy and after two months of treatment, using the CellSearch technique. Clinicopathological characteristics and survival of patients were obtained prospectively and were correlated with CTC detection. Results: Seventy-nine patients were included in this ancillary study. One or more CTC/7.5ml were detected in 5% of patients before treatment and in 9% of patients after two months of chemotherapy (overall detection rate: 11% of patients). CTC positivity was associated with poor tumor differentiation (p⫽0.04), and with shorter overall survival in multivariable analysis (RR⫽2.5, p⫽0.01), together with anemia (p⫽0.005). Conclusions: The evaluation of micrometastatic disease using CTC detection appears as a promising tool which could help to personalize treatment modalities in LAPC patients. Clinical trial information: NCT00634725.

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Genetic, tissue, and plasma biomarkers of outcomes from a prospective study of neoadjuvant short course proton-based chemoradiation for resectable pancreatic ductal adenocarcinoma (PDAC). Presenting Author: Theodore S. Hong, Massachusetts General Hospital, Boston, MA Background: The prognosis of resectable PDAC reflects a complex interaction between genotype, growth factor levels, and tumor microenvironment. We performed genetic, plasma, and tissue-based biomarker analysis for a phase I/II study of neoadjuvant short course proton-based chemoradiation. Methods: Patients with radiographically resectable PDAC were treated on an IRB approved, phase I/II trial of neoadjuvant short course-proton-based chemoradiation. Genotyping included KRAS, BRAF, NRAS, TP53, and PIK3CA. Tissue-based IHC on resection specimens included DPC4, CXCR4, CXCR7, and SDF1a in the central and peripheral regions of PDAC. The trial was amended to evaluate plasma biomarkers, drawn before and after chemoradiation, including HGF, VEGF, sVEGFR2, SDF1␣, bFGF, PlGF, TNF-␣, CAIX, sFLT1, IL-6, IL-8, and IL-1␤. Correlation with OS was evaluated by the Wald test in a univariable Cox regression using logtransformed covariates. Results: Surgical specimens from all 38 patients who underwent resection and serial plasma samples from the last 12 patients enrolled were analyzed. Disease-specific results were previously reported (ASCO 2012, abs 4021). DPC4 intact (37% of evaluated patients) was associated with oligometastatic disease (p⬍0.05) but not OS. KRAS mutation 31/38 patients (82%), did not affect OS (HR⫽1.57, p⫽0.88) , but the specific KRAS G12D mutation (14/38, 37%) had a worse OS (HR⫽2.44, p⬍0.05). SDF1␣ and CXCR7 expression was higher and CXCR4 expression was lower in the tumor center versus periphery. Higher CXCR7 expression in the periphery was associated with poor OS (HR⫽2.29, p⬍0.05). High baseline plasma HGF was associated with a worse OS (HR⫽6.60, p⬍0.05), with a trend for association between high post-treatment plasma HGF and poor OS (HR⫽9.28, p⫽0.08). No other biomarker evaluated was significantly associated with OS. Conclusions: In this exploratory analysis, KRAS G12D status, CXCR7 expression, and plasma HGF level were associated with worse OS. DPC4 status correlated with oligometastatic disease. Additional IHC evaluations, including c-MET expression, are ongoing and will be reported. Clinical trial information: NCT00438256.


Whole-transcriptome paired-end sequencing and the pancreatic cancer genetic landscape. Presenting Author: Marina Macchini, Oncology Department, S.Orsola-Malpighi Hospital, Bologna, Italy Background: A deeper knowledge of the pancreatic cancer (PDAC) biology is needed to improve the prognosis of the disease. Methods: 17 PDAC samples were collected by ultrasound-guided biopsy used for DNA and RNA extraction. 14 samples were analyzed by high resolution copy number analysis (CNA) on Affymetrix SNP array 6.0 and with segmentation algorithm against a reference of 270 Ceu HapMap individuals (Partek Genomic Suite). 17 samples were analyzed by whole transcriptome massively parallel sequencing, performed at 75x2 bp on a HiScanSQ Illumina platform. An average of 7, 3x107 reads per sample were generated, with a mean read depth of 50X. Single nucleotide variants (SNVs) were detected with SNVMix2 and compared with genetic variation databases (dbSNP, 1000genomes, Cosmic). Non-synonimous SNVs were analyzed with the predictors SNPs and GO and PROVEAN. Results: CNA results in 9/14 samples exhibited both macroscopic and cryptic cytogenetic alterations, with a mean of 10 CNA per patient. Most frequent gains were observed in 18q11.2 involving GATA6 (3/14) and 19q13 targeting AKT2 (3/14) while hotspot deletions were found on 18q21 (7/14), 17p13 (6/14), 9p21.3 (6/14), 15q (5/14) and 1q35 (4/14). RNAseq showed that samples exhibited a mean of 145 (range: 61-240) non-synonimous SNVs, of which 16 on average are potentially disease-related. Merging copy number and RNAseq data we highlighted the major oncogenic hits of PDAC, confirming the prevalence (14/17) of KRAS mutations, in one case also NRAS (G13D), and the three oncosuppressor CDKN2A (mutated in 3 cases and deleted in 6 cases, in hetero- or homozygosity), SMAD4 (altered by point mutation or gene deletion in 7/14), and TP53 (lost in 6/14 and mutated in 5/17). The signaling pathways affected were: KRAS/MAPK, TGFbeta and integrin signaling, proliferation and apoptosis, DNA damage response, and epithelial to mesenchymal transition. Moreover we found new oncogenic alterations, such as HMGCR, that displayed mutations in 17% of the analyzed patients (3/17). Conclusions: NGS combined with high resolution cytogenetic analysis can improve the understanding of pancreatic carcinogenesis.




Clinical characterization of hypoxia in pancreatic ductal adenocarcinoma (PDAC) by 18F-FAZA PET and pimonidazole. Presenting Author: Cristiane Metran Nascente, Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada Background: We previously demonstrated correlation between hypoxia and aggressive tumor biology in orthotopic, patient-derived pancreatic xenografts (Chang et al. Cancer Res 2011). With the development of hypoxiadirected therapies, there is a need to understand the range and relevance of hypoxia in PDAC patients. We therefore launched two complementary clinical trials using 2-nitroimidazole-based hypoxia probes. Methods: PIMOPANC involves pre-operative administration of pimonidazole to patients (pts) undergoing PDAC resection. Hypoxic percent (HP) of tumors is determined by semi-automated image analysis (on Aperio’s Genie) of multiple histological sections stained for pimonidazole by immunohistochemistry (IHC). FAZA-PANC uses the positron emission tomography (PET) tracer fluoroazomycin arabinoside (18F-FAZA) to evaluate hypoxia by functional imaging. 2 hours post-injection of (5.2 MBq/kg) 18F-FAZA, static scans are acquired followed by computed tomography for anatomic registration. Skeletal muscle is a non-hypoxic reference tissue to define standardized uptake values (SUV), tumor to muscle uptake ratios (T/M’s) and a threshold for hypoxia. Results: PIMO-PANC has enrolled 29 pts and FAZA-PANC 16. IHC analysis of the first 10 pt tumors demonstrates considerable intra- and inter-tumoral heterogeneity of hypoxia (HP: 1 to 26% across pt tumors); minimal hypoxia (⬍ 5%) was observed in 3 pts. 18 F-FAZA-PET in the first 11 pts demonstrates SUVmax from 1.02 to 1.83, median T/M’s from 0.84 to 1.31. A threshold of 1.27 SUVmax defines HP of 0 to 60% with minimal hypoxia (⬍10%) in 5 pts. Conclusions: There is significant heterogeneity of hypoxia across the spectrum of clinical PDAC (local to metastatic disease) using the 2-nitroimidazole hypoxia probes pimonidazole and 18F-FAZA. Given the intra-tumoral heterogeneity of hypoxia by histopathology, functional imaging is the preferred method to assess hypoxia in PDAC patients. Importantly, both methods identified a group of PDAC tumors with low levels of hypoxia. This is relevant to the on-going development of hypoxia-targeting strategies. Accrual to PIMOPANC is on-going and will address the prognostic relevance of hypoxia in PDAC. Clinical trial information: NCT01542177 and NCT01248637.

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A network meta-analysis (NMA) of randomized controlled trials (RCT) of chemotherapy regimens for metastatic pancreatic cancer (mPC). Presenting Author: Gillian Gresham, University of Ottawa, Ottawa, ON, Canada Background: Recent RCTs suggest a survival benefit for combination therapy in mPC compared to gemcitabine alone. Such combinations include FOLFIRINOX and gemcitabine plus nab-paclitaxel (G⫹nab-P). Survival and safety outcomes of these regimens were analyzed using gemcitabine as the reference comparator. Methods: Systematic review and NMA included data from reported phase III RCTs meeting quality standards and compared chemotherapy treatment to gemcitabine for mPC between 2000 and 2013. Excluded were trials assessing locally advanced pancreatic cancer. Following inter-trial heterogeneity assessment (patient characteristics, trial methodologies, treatment protocols), Bayesian NMAs were conducted for primary (overall survival [OS]) and secondary (progression free survival [PFS]) outcomes, overall response rate [ORR], and safety. Results: 27 studies were included involving 10 429 patients and 18 different treatments. No significant heterogeneity was observed between trials. When indirectly compared, FOLFIRINOX, PEFG and G⫹nab-P were top ranked for OS, PFS and ORR (Table). Comparing FOLFIRINOX and G ⫹nab-P, there was no significant difference in odds ratios (OR) for febrile neutropenia, diarrhea or sensory neuropathy. FOLFIRINOX caused more gr3-4 neutropenia (OR 1.85 (95%Cl 1.1-3.4),p⬍0.05), and G⫹nab-P trended more gr3-4 fatigue (OR 2.03 95% Cl 0.95-3.8). Conclusions: Survival and safety outcomes were comparable amongst the three regimens identified from this network meta-analysis for mPC. FOLFIRINOX tended towards a greater survival benefit over G⫹nab-P and PEFG although comparisons did not reach statistical significance.Head-to-head trials between FOLFIRINOX, G⫹nab-P and PEFG are needed to further compare the survival benefits and safety profiles of these treatments. Direct comparison FOLFIRINOX vs. Gem Gⴙnab-P vs. Gem PEFG* vs. Gem Indirect comparison FOLFIRINOX vs. GⴙnabP FOLFIRINOX vs. PEFG*

OS

PFS

0.57 (0.45-0.73) 0.72 (0.62-0.835) 0.65 (0.43-0.99)

0.47 (0.37-0.59) 0.69 (0.581-0.821) 0.51 (0.42-0.96)

0.81 (0.55-1.14) 0.90 (0.55-1.47)

0.70 (0.44-1.04) 0.95 (0.52-1.62)

* PEFG – cisplatin, epirubicin, 5FU, gemcitabine.

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Identifying targetable pathways in pancreatic cancer from endoscopic ultrasound-guided fine-needle aspirates (EUS/FNA): Providing a personalized approach to targeted therapy. Presenting Author: Andrea WangGillam, Washington University School of Medicine in St. Louis, St. Louis, MO Background: Targeted therapy trials in pancreatic cancer patients have either failed or, at most, provided only marginal benefit. Identification of activated key signaling pathways would allow the optimal selection of patients for kinase inhibitor trials. Hence, we launched a study to profile targetable pathways from EUS/FNA samples using an ultrasensitive multiplexed protein microarray platform (CEER, Prometheus). Methods: Patients who underwent routine diagnostic FNA for a suspicious lesion in the pancreas underwent two dedicated passes for CEER profiling of the following phosphorylated (activated) key molecules: HER1, HER2, HER3, c-met, IGF-IR, PI3K, AKT, MEK, ERK, and other signaling proteins. Results: Of 100 participants, final cytology results were: 73 carcinomas, 8 indeterminate, 13 negative, and 5 neuroendocrine. Pathway activation was heterogeneous in patients with carcinoma. Among 61 pancreatic cancer patients with adequate HER evaluation, a high prevalence of HER3 activation (62%) was observed, and concomitant activation of two or more HER pathways was seen in 52% of patients. In particular, activation of HER2 and HER3 was noted in 23% of carcinoma patients. High concordance of HER, PI3K and AKT activation was seen. Conclusions: Our study confirmed the feasibility of profiling targetable pathways from FNA samples. Furthermore, it illustrates highly variable and concomitant pathway activation among pancreatic cancer patients, suggesting the feasibility of a personalized approach to targeted therapy. Future trials will need to be designed to explore the clinical benefit of combinations of HER-targeted agents in defined subsets of pancreatic cancer patients, and further evaluation of the HER3 pathway is especially warranted. An analysis of pathway interactions and prognostic effects is in progress. Activated HER pathways. p-HER1 p-HER2 p-HER3 p-HER1/2 p-HER1/3 p-HER2/3 p-HER1/2/3 p-HER neg

p-HER (nⴝ61)

p-PI3K

p-AKT

1 3 6 1 1 14 (23%) 16 (26%) 19 (31%)

1 1 2 1 1 14 15 5

0 3 3 1 1 13 10 6

4052


MicroRNA biomarkers in whole blood for detection of pancreatic cancer. Presenting Author: Nicolai Aagaard Schultz, Department of Surgical Gastroenterology and Transplantation, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark Background: There is a great need for biomarkers for early diagnosis of patients with pancreatic cancer (PC) to improve their poor prognosis. The aims were (1) to describe differences in miRNA expression in whole blood between patients with PC, healthy subjects (HS) and patients with chronic pancreatitis (CP); and (2) to identify panels of miRNAs for early diagnosis of PC. Methods: Case-control study. 409 patients with PC, 33 patients with other periampullary cancers (PAC) and 25 patients with CP were included prospectively in the Danish BIOPAC biomarker study. 312 blood donors were included as HS. MiRNA expressions in pretreatment 2.5 ml whole blood samples collected in PAXgene RNA tubes were investigated in three independent cohorts: “Discovery Study” (PC n⫽143, CP n⫽18, HS n⫽69); “Training Study” (PC n⫽180, HS n⫽199); and “Validation Study” (PC n⫽86, PAC n⫽33, CP n⫽7, HS n⫽44). TaqMan Human MicroRNA assay was used to screen 754 miRNAs in the “Discovery Study”. Fluidigm BioMark PCR System was used in the “Training Study” (38 miRNAs) and “Validation Study” (13 miRNAs). Results: The “Discovery Study” demonstrated that 38 miRNAs (out of a total of 754 miRNAs) in whole blood were significantly deregulated between patients with PC and controls. These miRNAs were tested in the “Training Study” and two diagnostic indexes were constructed including 4 miRNAs in bPANmiRC index I (⫽ miR-150 ⫹ miR-636 – miR-145 – miR-223) or 10 miRNAs in bPANmiRC index II (⫽ 6.9275 – 0.2134xmiR-122 – 0.3560xmiR-34a – 0.8577xmiR-145 ⫹ 1.0043xmiR-636 – 0.6725xmiR-223 ⫹ 0.7018xmiR-26b – 0.3233xmiR885.5p ⫹ 1.1304xmiR-150 – 0.2204xmiR-126* - 0.1730xmiR-505) (AUC 0.86/0.93, sensitivity 85%/85% and specificity 64%/85%). Conclusions: We identified two diagnostic indexes, using 4 or 10 miRNAs in peripheral whole blood, with a potential clinical value in the evaluation of patients with uncharacteristic symptoms to identify PC at an early stage.


256s 4053


4054


Significance of baseline quality of life scores in predicting clinical outcomes in an international phase III trial of advanced pancreatic cancer: NCIC CTG PA.3. Presenting Author: Michael M. Vickers, Tom Baker Cancer Centre, Calgary, AB, Canada

Randomized, open-label, phase II trial of gemcitabine with or without bavituximab in patients with nonresectable stage IV pancreatic adenocarcinoma. Presenting Author: Shuchi Sumant Pandya, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA

Background: There is insufficient information regarding the prognostic significance of baseline Quality of life (QoL) scores on overall survival (OS) and adverse events (AEs) in advanced pancreatic cancer. Methods: QoL was assessed prospectively using the EORTC QLQ-C30 and AEs were graded using the NCI Common Toxicity Criteria version 2.0 as part of the PA.3 trial of gemcitabine ⫹ erlotinib (G⫹E) vs. gemcitabine ⫹ placebo (G⫹P). Relevant clinical variables, ECOG performance status (PS), and QoL scores at baseline were analyzed by Cox stepwise regression to determine predictors of OS and AEs. QoL scores were transformed by square root. Results: 222 of 285 patients (pts) (78%) treated with G⫹E and 220 of 284 pts (77%) treated with G⫹P completed baseline QoL assessments. In a multivariate Cox analysis (MVA) combining all pts, better QoL physical function (PF) score independently and incrementally predicted longer OS (HR 0.91; CI: 0.83-1.00), as did non-white race (HR 0.62; CI: 0.42-0.91), PS 0-1 (vs. PS 2 - HR 0.64; CI: 0.49-0.84), locally advanced pancreatic cancer (LAPC) (vs. metastatic - HR 0.54; CI: 0.42-0.69) and G⫹E (vs. G⫹P - HR 0.79; CI: 0.64-0.98). More financial difficulty (HR 0.92; CI: 0.87-0.98) and PS 0-1 (HR: 0.36; CI: 0.17-0.77) predicted a lower risk of grade 3 or higher AEs. In a MVA of pts treated with G⫹E, pain intensity ⬍20 (vs. ⱖ 20 - HR 0.68; CI:0.52-0.88) and LAPC (HR 0.67; CI: 0.48-0.91) were associated with longer OS, while better QoL cognitive (HR 0.71; CI: 0.50-1.00), worse constipation (HR 0.89; CI: 0.81-0.98) and worse financial scores (HR 0.86; CI: 0.78-0.94), better dyspnea score (HR 0.82; CI: 0.71-0.93) and PS 0-1 (HR 0.21; CI: 0.05-0.78) predicted for lower risk of AEs. In a MVA of pts treated with G⫹P, better global QoL score (HR 0.91; CI:0.85-0.98) and LAPC (HR 0.57; CI: 0.40-0.82) were predictors of longer OS while no variables predicted grade 3 or higher AEs. Conclusions: In addition to clinical variables (including physician assessed PS), patient reported QoL scores added incremental predictive information regarding survival and adverse events for advanced pancreatic cancer patients treated with systemic chemotherapy.

Background: Despite advances in the treatment of metastatic pancreatic cancer (PC), there is critical need to develop novel therapies.Median survival with combination chemotherapy is limited to less than one year and only the optimally conditioned patients can tolerate these therapies. Bavituximab (B) is a monoclonal antibody (mAB) directed againstphosphatidylserine (PS) that causes vascular shutdown and reactivation of the innate and adaptive immunity in animal models. Preclinical data in mouse PC models indicate that gemcitabine (G) increases PS exposure and the addition of a mAb targeting PS reduces tumor burden, visible liver metastases, microvessel density, and increases tumor macrophage infiltration compared to G alone (Beck et al. 2006). The purpose of this trial is to evaluate and compare the efficacy and safety of the combination of G⫹B vs. G alone as first line therapy in pts. with nonresectable Stage IV PC. Methods: Seventy patients were randomized (1:1) to receive G 1000 mg/m2 on days 1, 8, and 15 every 28Edays with or without weekly B 3mg/kg IV until disease progression or unacceptable toxicities. Key eligibility criteria were Stage IV PC, ECOG ⱕ2, measurable disease, ageⱖ18 years, total bilirubin ⱕ1.5xULN, and adequate renal, hematologic, and hepatic function. The primary efficacy endpoint was overall survival (OS) and secondary endpoints included overall response rate (ORR) and progression free survival (PFS). Results: Of the 70 (G/G⫹B 34/36) patients randomized, 67 (G/G⫹B 33/34) received study treatment and 63 (G/G⫹B 31/32) were evaluable. No significant difference was seen in age, gender, race or ECOG. At analysis 87% deaths had been reported in G and 72% in G⫹B group. Median OS estimate is 5.2 months for G and 5.6 months for G⫹B. No difference between groups was observed in PFS (median 3.9 months for G and 3.7 months for G⫹B). ORR was 13% for G and 28% for G⫹B. Most AEs were grade 1-2 and typical of exposure to G. Conclusions: In this patient population with extensive disease burdens and limited treatment options, G⫹B was well tolerated and demonstrated moderate activity in tumor response and survival. Clinical trial information: NCT01272791.

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Willingness of patients with pancreatic cancer to participate in clinical trials. Presenting Author: Pelin Cinar, University of California, San Francisco, San Francisco, CA Background: Recruitment of oncology patients into clinical trials continues to be a challenge as ⬍5% of patients are accrued. Low accrual rates may be due to reduced awareness of trial availability and eligibility by physicians/patients. Our objective was to study the attitudes of patients with pancreatic cancer (PC) regarding clinical trial participation and to identify possible barriers to recruitment. Methods: In this cross-sectional study, we collaborated with Pancreatic Cancer Action Network (PanCAN) and invited patients with PC or their caregivers to complete a survey. The survey that was developed consisted of 22 questions and inquired about patients’ previous clinical trial enrollment experiences and their views on participation. The surveys were collected over a 6-month period via the PanCAN website and regional meetings. Comparison analyses between groups were done by Chi-square and Fisher’s test using STATA software. Results: Of the390 surveys received, 149 were included in the final analyses. 30% of the patients were offered to participate in a trial by their physicians. When asked to participate, 62% of the patients agreed. Of the patients who were not enrolled in a clinical trial, 61% were offered to participate in a trial but did not agree. This suggests that these patients were eligible to participate but declined. Conclusions: Majority of the patients with pancreatic cancer were not offered to participate in clinical trials by their physicians but would have agreed if asked. While low clinical trial recruitment rates for PC may be multifactorial, further research may focus on the important role of physicians in clinical trial recruitment efforts.

Gender Male Female Race White Hispanic African-American/Black Asian/Pacific Islander Native American/Alaska Native Other Histology Pancreatic adenocarcinoma PNET Unknown IPMN Stage Localized Locally advanced Metastatic ECOG performance status 0 1 2 3 4

Patient nⴝ70 n(%)

Caregiver nⴝ79 n(%)

28(40) 42(60)

8(10) 71(90)

63(90) 2(3) 4(6) 0 1(1) 0

64(81) 3(4) 3(4) 5(6) 1(1) 3(4)

48(69) 12(17) 9(13) 1(1)

62(79) 6(8) 10(13) 1(1)

27(39) 11(16) 32(46)

16(20) 12(15) 51(65)

23(33) 33(47) 10(14) 3(4) 1(1)

10(13) 22(28) 15(19) 29(37) 3(4)


A randomized phase II trial of adjuvant chemotherapy with S-1 versus S-1 and gemcitabine (GS) versus gemcitabine alone (GEM) in patients with resected pancreatic cancer (CAP-002 study). Presenting Author: Hideyuki Yoshitomi, Department of General Surgery, Chiba University Graduate School of Medicine, Chiba, Japan Background: Although the adjuvant therapy using GEM is now the standard therapy for patients with resected pancreatic cancer (PC), the prognosis still remains poor. Resent study demonstrated the non-inferiority of S-1 and superiority of GS to GEM with respect to progression free survival in patients with unresectable pancreatic cancer. Methods: Patients with invasive ductal PC who underwent radical surgery were enrolled. After stratification for R0/1, stage and institution, patients were randomized to receive GEM (GEM 1g/ m2, iv, d1, 8, and 15, q4w X12), S-1 (80/100/ 120mg/day based on BSA, po, d1-14, q3w X 16) or GS (S-1 60/80/100mg/ day based on BSA po, d1-14 plus GEM 1g/ m2, iv, d8, 15, q3w X 16) within 8weeks after operation. Eligibility included histological residual tumor (R) 0 or 1, and no previous chemo- or/and radiation therapy. Primary endpoint was 2y disease free survival (DFS) rate and secondary endpoints included overall survival (OS), and safety. Results: Between January 2007 and October 2010, 96 patients were randomized into the three arms of the trial (32 pts to each group). Patients’ characteristics were well balanced (GEM/S-1/GS) with regard to age (66/67/66y), tumor location (head 66/69/75%), tumor status (T3⫹4 88/78/91%), and nodal status (positive 75/69/75%). Until November 2012, 74 events (77%) have occurred for DFS. Two year DFS rate was 24.2%, 28.1% and 34.4% in GEM, S-1 and GS, respectively and there was no significant difference between groups. The median OS was 21m in GEM, 26m in S-1 and 27.9m in GS (Log rank test: N.S.). Grade 3/4 toxicities in GEM/S-1/GS were hematological 63/10/74% and non-hematological 17/10/23%, respectively. No treatment related death was observed during the study. Conclusions: S-1 and GS provided similar efficacy to GEM as the adjuvant chemotherapy for resected PC. According to the results, S-1 and GS is the adequate combination for phase III trial to examine the efficacy of adjuvant chemotherapy for PC. Clinical trial information: UMIN000002000.




Is successful resection following neoadjuvant radiation therapy for borderline resectable pancreatic cancer dependent on improved tumor-vessel relationships? Presenting Author: Avani Satish Dholakia, Johns Hopkins University School of Medicine, Baltimore, MD Background: Margin-negative (R0) surgical resection is the only potentially curative therapy for pancreatic cancer. For patients deemed borderline resectable (BL), neoadjuvant chemoradiotherapy (NRT) increases the likelihood of subsequent R0 resection and improves overall survival. Prognostic factors for achieving resection following NRT have yet to be clearly identified. Methods: Fifty consecutive patients with BL-PDAC evaluated by a multidisciplinary tumor board who received NRT from 2007-2012 were retrospectively identified. Computed tomography (CT) scans pre- and post-radiation and surgical specimens were centrally reviewed. Results: 29 patients underwent resection following NCRT, while 21 remained unresectable. Between the two groups, age, gender, mean RT dose, and proportion of pancreatic head tumors were not significantly different. Smaller tumor volume and lack of the following factors was associated with selection for resection: superior mesenteric/portal vein encasement (p⫽0.01), superior mesenteric artery involvement (p⫽0.02), ascites (p⫽0.01), and questionable/overt metastases (p⫽0.01). Notably, celiac artery involvement/encasement, common hepatic artery encasement, and percentage change in tumor volume were not significant predictors of resection (all p⬎⬎0.05). Interestingly, tumor volume and degree of individual vessel involvement did not significantly change from scans before and after NCRT (all p⬎⬎0.05). Median OS was 22.9 vs.13.0 months in resected and unresected patients, respectively (p⬍0.001). Of resected patients, 93% had negative margins, 28% had positive nodes, 27% demonstrated ⬍10% viable tumor, and 12% had pathologic complete response at surgery. Dpc4 expression was retained in 68% of specimens with viable tumor. Conclusions: Although the apparent radiographic extent of vascular involvement does not change significantly after NRT, subsequent R0 resection rates are high, nodal involvement is low, and outcomes are similar to resected patients who receive adjuvant therapy. Resection attempts should not be deferred solely based on lack of improvement in tumor-vessel interactions.

4059^


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257s


CA19-9 decrease at 8 weeks as a predictor of overall survival (OS) in a randomized phase III trial (MPACT) of weekly nab-paclitaxel (nab-P) plus gemcitabine (G) versus G alone in patients with metastatic pancreatic cancer (MPC). Presenting Author: E. Gabriela Chiorean, University of Washington, Seattle, WA Background: nab-P ⫹ G showed promising efficacy in a phase I/II study in MPC, and decreases in CA19-9 correlated with OS. In MPACT, patients (pts) who received nab-P ⫹ G vs G had improved median OS (8.5 vs 6.7 mo; HR 0.72; p ⫽ 0.000015), PFS (5.5 vs 3.7 mo; HR 0.69; p ⫽ 0.000024) and ORR (23% vs 7%; p ⫽ 1.1 ⫻ 10⫺10). Here we present a prespecified exploratory analysis of CA19-9 from the MPACT trial. Methods: 861 previously untreated pts with MPC were randomized 1:1 to receive nab-P 125 mg/m2 ⫹ G 1000 mg/m2 days 1, 8, and 15 every 4 weeks or G alone 1000 mg/m2 weekly for 7 weeks followed by a week of rest (cycle 1) and then days 1, 8, and 15 every 4 weeks (cycle ⱖ 2). CA19-9 was evaluated at baseline and then every 8 weeks. OS comparisons at different CA19-9 criteria were performed by stratified Cox proportional hazards model (P by stratified log-rank test using randomization criteria). Results: 750 pts had an evaluable CA19-9 at baseline. More pts in the nab-P ⫹ G arm vs the G arm demonstrated a best CA19-9 decrease from baseline of ⱖ 20% and ⱖ 90% (61% vs 44% and 31% vs 14%, respectively; Table). At the first postbaseline assessment (week 8), greater proportions of pts in the nab-P ⫹ G arm vs the G arm had CA19-9 decreases of ⱖ 20% and ⱖ 90% (Table). At that time point, for pts with a decrease of ⱖ 20% in CA19-9, nab-P ⫹ G demonstrated a significantly longer OS vs G. The risk reduction for pts with a ⱖ 90% decrease was greater than in pts with a ⱖ 20% decrease. In pts with an 8-week CA19-9 decrease ⬍ 20%, median OS for nab-P ⫹ G vs G was 8.3 vs 8.0 mo (HR 0.92; p ⫽ 0.705). The relationship of CA19-9 kinetics with OS will also be examined. Conclusions: Higher proportions of pts in the nab-P ⫹ G arm had CA 19-9 responses of ⱖ 20% and ⱖ 90% vs the G arm. Pts who achieved a CA19-9 decrease at 8 weeks of ⱖ 20% or ⱖ 90% had significantly longer OS with nab-P ⫹ G than with G. Clinical trial information: NCT00844649.

Best CA19-9 decrease > 20%, n (%) 8-week CA19-9 decrease > 20%, n (%) Median OS, mo 1-year OS, % HR p Best CA19-9 decrease > 90%, n (%) 8-week CA19-9 decrease > 90%, n (%) Median OS, mo 1-year OS, % HR p

4060

nab-P ⴙ G n ⴝ 379

G n ⴝ 371

230 (61) 196 (52) 13.2 53

162 (44) 140 (38) 9.4 34 0.59 ⬍ 0.001

117 (31) 59 (16) 13.4 57

51 (14) 33 (9) 9.4 20 0.44 0.0022


Prognostic factors (PFs) of survival in a randomized phase III trial (MPACT) of weekly nab-paclitaxel (nab-P) plus gemcitabine (G) versus G alone in patients (pts) with metastatic pancreatic cancer (MPC). Presenting Author: Malcolm J. Moore, Princess Margaret Hospital, Toronto, ON, Canada

Prognostic value of an immune score combining intra- and peritumoral T-cell subset density in patients with pancreatic adenocarcinoma. Presenting Author: Simon Turcotte, Research Center of the Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada

Background: In MPACT, pts who received nab-P ⫹ G vs G had improved overall survival (OS; median 8.5 vs 6.7 mo; HR 0.72; p⫽ 0.000015). Here we assessed potential PFs of OS. Methods: 861 pts with MPC were randomized 1:1, stratified by region, presence of liver metastases, and Karnofsky performance status (KPS), to nab-P ⫹ G or G. OS was described in subgroups. A step-wise multivariate analysis (with significance level for entry of 0.20 and for stay of 0.10) was performed to evaluate the treatment effect and identify possible predictors of OS. Results: Pts with poorer PFs had a shorter median OS, consistent with the literature, and OS consistently favored nab-P ⫹ G in pts with these PFs (Table). Region of Eastern Europe, age ⱖ 65 years, poorer KPS, presence of liver metastases, and number of metastatic sites all predicted OS (increased risk of death). The treatment effect remained significant (HR 0.72; 95% CI, 0.605 - 0.849; p ⬍ 0.0001, Cox proportional hazards [CPH] model). In another multivariate analysis in which baseline CA19-9 was added to the final model described above, the treatment effect HR was 0.67 (95% CI, 0.573 0.794; p ⬍ 0.0001, CPH model). Baseline CA19-9, a predictor of OS by univariate analysis, was not predictive after correction for the above factors. Conclusions: In MPACT, the most important predictors of OS were KPS, age, presence of liver metastases, number of metastatic sites, and region. After correcting for these factors, assignment to nab-P ⫹ G was an independent significant predictor of improved survival. Clinical trial information: NCT00844649.

Background: Immune scoring based on T-cell subsets and density can add prognostic value to conventional TNM staging for patients with solid tumors, but limited data are available for pancreatic adenocarcinoma. Methods: Using tissue microarrays, CD3, CD4, CD8, CD45RO, and FOXP3 T-cells were quantified by immunohistochemistry in the intratumoral (IT) compartment and peritumoral (PT) parenchyma of 111 consecutively resected specimens. T-cell counts were correlated with patient overall survival, disease-free survival, and time to recurrence (OS, DFS, TTR) by Cox regression, controlling for clinicopathological factors. An immune score (IS) based on IT CD4 T-cell count ⬎ median, PT CD8 T-cell count ⱕ median, and IT/PT CD3 T-cell ratio ⬎1, grouped patients into high, intermediate, or low categories if all 3, 1 to 2, or none of these immune features were present, respectively. Results: Median follow-up time was 20 months, and 85% of patients either died or recurred during the study period. By univariate analysis, PT CD8 T-cell count was associated with shorter OS (p⫽0.02), whereas both IT CD4 T-cell count and IT/PT CD3 T-cell ratio were associated with longer OS (p⫽0.01 and p⫽0.05, respectively). Alone, none of these immune features predicted TTR. Combined into an IS, patients in the high (n⫽23), intermediate (n⫽60), or low (n⫽23) categories had significantly different OS (respective medians 30, 17, and 13 months, log-rank p⫽0.01), DFS (28, 16, and 12 months, p⫽0.01), and TTR (21, 14, and 10 months, p⫽0.02). By multivariate analysis, the association between IS and clinical outcomes was independent of tumor size, extra-pancreatic invasion, and nodal metastases (TNM staging). The IS discriminated outcomes among patients with nodal metastases (n⫽80), such that node-positive patients with a high IS had a median survival similar to node-negative patients (30 and 33 months, p⫽0.7). FOXP3 and CD45RO T-cell counts did not appear to add prognostic value to the IS. Conclusions: An immune score that combines specific T-cell location and density may have prognostic value in patients with resected pancreatic adenocarcinoma, independently from pathologic features currently used for staging.

Factors predictive of OS Treatment (nab-P ⴙ G vs G) Region (E Europe vs N America) Age (< 65 vs > 65 years) KPS (70 - 80 vs 90 - 100) Liver metastases (yes vs no) No. of metastatic sites (1, 2, 3, > 3) Pt subgroups Region N America E Europe Age < 65 > 65 years KPS 70 80 90 100 Liver metastases Yes No No. of metastatic sites 1 2 3 >3

nab-P ⫹ G

n

HR

P value

0.72 1.22 0.81 1.60 1.81 1.08

0.0001 0.0765 0.0190 ⬍ 0.0001 ⬍ 0.0001 0.0864 G

Median OS, mo

n

268 64

8.7 7.7

271 62

Median OS, mo

254 177

9.2 7.8

242 188

6.8 6.6

30 149 179 69

3.9 8.1 8.9 12.6

33 128 199 69

2.8 5.6 7.1 10.9

365 66

8.3 11.0

360 70

5.9 10.7

33 202 136 60

13.5 8.3 8.0 8.6

21 206 140 63

9.0 7.1 5.9 5.0

6.8 5.9


258s 4061


Assessment of the association of the VeriStrat test with outcomes in patients (pts) with advanced pancreatic cancer (PC) treated with gemcitabine (G) with or without erlotinib (E) in the NCIC CTG PA.3 phase III trial. Presenting Author: Daniel John Renouf, British Columbia Cancer Agency, Vancouver, BC, Canada Background: VeriStrat is a mass spectrometry based assay performed on serum or plasma that has been shown to be prognostic in several tumor types, and may predict differential drug benefit in several settings. We investigated the association of VeriStrat with outcomes in the NCIC CTG PA.3 randomized phase III trial of G and E vs. G and placebo (P) in pts with advanced PC. Methods: Pre-treatment plasma samples were available for 499/569 (87.7%) enrolled pts. VeriStrat testing was performed in a CLIA-certified laboratory; pts were classified as either Good, Poor, or indeterminate. The relationship between VeriStrat results and overall survival (OS) and progression free survival (PFS) was assessed by KaplanMeier curves and log-rank test in univariate analysis and Cox model adjusting for gender, age [⬎60 vs. ⱕ60], race [Caucasian vs. other], ECOG [0-1 vs. 2], and pain intensity at baseline [ⱕ20 vs. ⬎20] in multivariate analysis. The predictive effect was assessed by interaction test. All statistical analyses were performed by the NCIC CTG. Results: Of the 499 samples, 11 were hemolyzed and 4 had acquisition failures. VeriStrat was performed on 484 samples, 9 failed quality control, 22 had indeterminate results. Of the remaining 452, 353 (78%) were classified as Good and 99 (22%) as Poor. In the G and P arm, median OS was 7.16 months (ms) for VeriStrat Good vs. 3.78ms for VeriStrat Poor (p⬍0.0001); Adjusted Hazard Ratio (AHR) 0.59 (0.43-0.82), p⫽0.002. In the G and E arm, median OS was 7.33ms for VeriStrat Good vs. 4.50ms for VeriStrat Poor p⬍0.0001; AHR 0.47 (0.32-0.70), p⫽0.001. A similar relationship was seen for PFS (G and P arm: median PFS 3.91 vs. 2.07ms (p⫽0.001); AHR 0.67 [0.49-0.92], p⫽0.01); G and E arm: median PFS 4.24 vs. 2.86ms (p⫽0.0004); AHR 0.54 [0.37-0.80], p⫽0.002). Tests of interaction of VeriStrat status and treatment for OS and PFS were not significant: AHR 0.78 (0.48-1.25), p⫽0.30 and AHR 0.80 (0.50-1.30), p⫽0.37 respectively. Conclusions: VeriStrat results were significantly associated with OS and PFS for both regimens in this study. VeriStrat was not predictive of benefit from the addition of E to G.

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The effect of anti-IGF1 therapy on muscle mass in metastatic pancreatic cancer. Presenting Author: David R. Fogelman, The University of Texas MD Anderson Cancer Center, Houston, TX Background: IGF-1 plays a role in the growth of multiple tumor types, including pancreatic cancer. IGF-1 also serves as a growth factor for muscle. The impact of therapeutic targeting of IGF-1 on muscle mass is unknown. Methods: We evaluated muscle mass at L3 in patients enrolled in a randomized phase II study of MK-0646 (M), a monoclonal antibody directed against the IGF-1 protein, in patients with metastatic pancreatic cancer (MPC). We used the Slice-o-matic (ver 4.3) software to segregate CT images into muscle and fat components and measured muscle area (cm2) at baseline and after 2 and 4 months of treatment. Patients received either gemcitabine with erlotinib (G⫹E), G⫹E⫹M, or G⫹M. Differences between the groups were compared using t-tests. Results: 58 patients had both baseline and 2 month imaging available for analysis. Of these, 44 received M and 14 had G⫹E only. Baseline muscle mass between the two groups was similar: 146 cm2 and 142 cm2, respectively (P⫽0.47). After two months of treatment, both groups demonstrated decrease in muscle mass: 134 cm2 (8% loss) vs. 130 cm2 (6% loss) (P⫽ 0.19). Of the 37 patients who had either PR or SD at 2 months, there was a non-significant increase in muscle mass loss among the patients receiving M (7.8% vs. 4.5%, p⫽.31). At 4 months, those remaining patients in the M group lost 6% (n⫽14) of muscle mass compared to 3% in the non-M group (n⫽5) (P⫽0.54). Each 1% loss of muscle mass increased the odds of dropout by 13% (p⫽.03, CI 1.0-27%) and predicted for poor survival (p⫽HR 1.08, p⫽.02). Conclusions: MPC patients can be expected to lose muscle mass even while having clinical benefit (PR or SD) from chemotherapy. Muscle loss correlated with a risk of study drop-out and death. There was a non-significant trend towards greater muscle mass loss in patients on anti-IGF-1R therapy. However, it is unclear if this loss translates into functional differences between patients. Clinical trial information: NCT00769483.

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Phase II study of neoadjuvant chemotherapy with modified FOLFOXIRI in borderline resectable or unresectable stage III pancreatic cancer. Presenting Author: Enrico Vasile, U.O. Oncologia Medica 2, Azienda OspedalieroUniversitaria Pisana, Istituto Toscano Tumori, Pisa, Italy Background: FOLFIRINOX has shown high activity in metastatic pancreatic cancer (PC) patients and could be an interesting regimen also for patients with inoperable locally advanced disease. Our group had developed a similar schedule in metastatic colorectal cancer named FOLFOXIRI with good tolerance and activity. Therefore, we have decided to perform a phase II trial to prospectively evaluate the activity of modified FOLFOXIRI in borderline resectable or unresectable PC. Methods: Modified FOLFOXIRI consisted of a lower dose of irinotecan (150 mg/sqm) and of infusional 5-fluorouracil (2800 mg/sqm as a 48-hour continuous infusion on days 1 to 3) with no bolus 5-fluorouracil. Folinic acid and oxaliplatin (85 mg/sqm) remained unchanged. The study enrolled patients with diagnosis of pancreatic adenocarcinoma, stage III borderline resectable or unresectable disease (cT4,cN0-1,cM0), ECOG PS 0-1, age 18-75. The primary endpoint of the study was the percent of patients who undergo radical surgical resection after chemotherapy. Results: Thirty-two patients have been enrolled; M/F⫽12/20; PS 0/1⫽16/16. Median age was 60 years (range 44-75). Median number of FOLFOXIRI cycles was 6 (range 2-14). Grade 3-4 toxicities was experienced by 20 patients during chemotherapy. Twelve partial responses (37%) and 14 stable diseases (45%) have been observed; 2 patients had progressive diseases (6%). The remaining 4 patients (12%) have not been yet evaluated because are still in the first months of treatment. A local treatment was received after chemotherapy by 18 patients until now: 13 (41%) received radical surgical resection and 5 received concomitant chemo-radiotherapy. Three explorative laparotomy showed occult metastases. In other 7 cases surgery is planned while 2 patients refused surgery. Median progression-free survival is 14.0 months and median overall survival is 24.2 months with a two-year survival rate of 54%. Conclusions: Chemotherapy with FOLFOXIRI seems active in locally advanced PC and may allow to obtain a downstaging of disease leading to achieve a curative surgical resection in some cases. Longer follow up is needed to better evaluate long-term outcome of this strategy.

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HPV status to predict outcome for anal cancer treated with radiochemotherapy. Presenting Author: Sabine Kathrin Mai, Department of Radiation Oncology, Mannheim Medical Center, University of Heidelberg, Mannheim, Germany Background: Evaluation of the HPV infection- and transformation-status as a predictor of the response to definitive radio-chemotherapy for anal cancer. Methods: 80 patients (54 fm, 26 m) with histologically confirmed anal cancer and known HPV-Infection- (determined by PCR) and p16expression-status (determined by immunohistochemistry) were analyzed. All pts. were treated with definitive radio-chemotherapy (RCT) with 5-FU/ MMC, median age 60ys (35– 86), median follow up 54mo (4 –180). 41 pts. were HPV⫹ and p16⫹ (group 1), 10 pts. were HPV-/p16⫹ (group 2), 9 pts. were HPV⫹/p16- (group 3) and 17 pts. were HPV⫹/p16- (group 4). Endpoints were local control (LC) at 5ys and overall survival (OS) at 5ys. In addition to HPV/p16 status, the influence of T-stage and tumor localization (canal vs. margin) was analyzed. Results: More women than men were HPV⫹ (fm 77% vs. m 33%) while gender was evenly distributed among HPV-pts. (fm 48% vs. m 53%). Upon univariate analysis, gender, HPV⫹ and p16⫹ were significant predictors of both LC and OS (p⬍0.05) while T-Stage was predictive for LC (p⬍0.05). Upon multivariate analysis, gender and T-Stage significantly influenced LC (w85.2% vs. m54.9%, p⫽0.028; ⬍T3 84.2% vs ⱖ T3 48,1%, p⫽0,019). OS was significantly influenced by gender (w95% vs. m59.2%, p⫽0.005), while the influence of HPV/p16-status did not reach significance when all four groups were analyzed simultaneously in this moderately sized cohort. Upon direct univariate comparison of HPV⫹/p16⫹ und HPV-/p16-pts, both gender and combined HPV/p16-positivity had a significant influence on LC and OS. Upon multivariate analysis, combined HPV/p16-positivity resulted in better LC (HPV⫹/p16⫹: 85% vs. HPV-/p16-: 38.7%, p⫽0.003), while, as a consequence of moderate patient numbers, only gender significantly predicted OS (fm93.7% vs. m62.6%, p⫽0.015). Viral status, however, showed a trend for significance. Conclusions: The data from one of the largest monocentric series treated with a uniform treatment regimen suggest that HPV-status predicts response to RCT in pts. with anal cancer. Patients with tumors not associated with HPV whatsoever (HPV-/P16-) have both inferior LC and a clear trend for inferior OS and might require an intensified treatment regimen.




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Adjuvant chemoradiotherapy versus chemotherapy for resectable gastric cancer: A systematic review and meta-analysis. Presenting Author: Yu Yang Soon, National University Cancer Institute, Singapore, Singapore

Prognostic implications of signet ring cell histology in esophageal adenocarcinoma: A SEER database analysis Presenting Author: Saikrishna S. Yendamuri, Roswell Park Cancer Institute, Buffalo, NY

Background: The benefits of adjuvant chemo-radiotherapy (ChRT) over chemotherapy (Ch) for resectable gastric cancer are currently unclear. We performed a systematic review and meta-analysis (direct and indirect) of published randomized controlled trials (RCT) to compare the effects of adjuvant chemo-radiotherapy with chemotherapy on overall and diseasefree survival for patients with resectable gastric cancer. Methods: We searched MEDLINE and CENTRAL from the date of inception and annual meeting proceedings of ASCO and ASTRO from 1999 to November 2012 for RCTs comparing adjuvant ChRT with Ch, adjuvant ChRT with surgery alone and adjuvant Ch with surgery alone. The primary outcome was overall survival (OS); secondary outcomes included disease-free survival (DFS) and toxicity. Hazard ratios (HR), confidence intervals (CI) and p values (p) were estimated with fixed effects models using Revman 5.1. Results: We found five trials comparing adjuvant ChRT with Ch (n ⫽ 1110), three trials comparing adjuvant ChRT with surgery alone (n ⫽ 651) and 31 trials comparing adjuvant Ch with surgery alone (n ⫽ 8273). Meta-analysis of direct comparison trials showed that adjuvant ChRT significantly improved both OS (HR 0.79, 95% CI 0.64-0.98, p ⫽ 0.03) and DFS (HR 0.76, 95% CI 0.64-0.92, p ⫽ 0.004) when compared with Ch. Subgroup analyses showed that the effects on OS and DFS were similar regardless of use of D2 nodal dissection, intensity modulated radiotherapy techniques, fluorouracil or platinum-based chemotherapy. There were no significant differences in toxicity between the two groups. The results for the direct and indirect comparisons were statistically consistent. Conclusions: There was a significant survival benefit of adjuvant chemo-radiotherapy over chemotherapy, with no increase in toxicity for patients with resected gastric cancer. Future efforts should also focus on predictive markers, and toxicity or quality-oflife assessments, to individualize adjuvant therapy and optimize the therapeutic ratio.

Background: Signet ring cell esophageal adenocarcinoma histology has been difficult to study in a single institution series because of its relative rarity, yet has an anecdotal reputation for poor prognosis. We examined the Surveillance Epidemiology and End Results (SEER) database to assess the prognostic implications of this esophageal adenocarcinoma subtype. Methods: All patients with esophageal adenocarcinoma in the SEER database from 2004 – 2009 were included. Characteristics of patients with signet ring cell histology were compared to those without it. Univariate and multivariate analyses examining the relationship of signet ring cell histology with overall survival (censored at 72 months) were performed in all patients, as well as those undergoing surgical resection. Results: 597 of 11,838 (5%) study patients had signet ring cell histology. Patients with signet ring cell histology were similar in age, race, and gender distribution, but had a higher grade (p⬍0.001) and higher stage (p⬍0.001) at diagnosis. In both all-comers as well as those undergoing surgical resection, univariate analyses showed a worse survival in patients with signet ring cell esophageal cancer (HR ⫽ 1.24; 95% CI 1.13-1.37 and HR ⫽ 1.57; 95% CI 1.29-1.92 respectively). In multivariate analyses adjusting for age, gender, grade, stage, and race, patients with signet ring cell cancer had a worse prognosis than those with non-signet ring cell adenocarcinoma (HR ⫽ 1.20; 95% CI 1.09 -1.33). In surgically resected patients, this remained a trend, but did not reach statistical significance (HR ⫽ 1.16; 95% CI 0.94-1.42). Conclusions: This large study of esophageal adenocarcinoma confirms the clinical impression that signet ring cell variant of adenocarcinoma is associated with an advanced stage at presentation and a worse prognosis independent of stage of presentation.

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Search for biomarkers of stage II/III gastric cancer and development of individualized therapy. Presenting Author: Takashi Oshima, Gastroenterological Center, Yokohama City University, Yokohama, Japan Background: Standard therapy for stage II/III gastric cancer is curative resection followed by adjuvant chemotherapy. Treatment outcomes are expected to be further improved by the development of individualized therapy based on new biomarkers. We have extracted mRNA from frozen specimens of gastric cancer to construct a cDNA bank and searched for new biomarkers of stage II/III gastric cancer. We report currently available results. Methods: The study group comprised 256 patients with stage II/III gastric cancer in whom at least 5 years had passed since surgery (among whom 149 received S-1 as adjuvant chemotherapy). A total of 130 genes were selected on the basis of the results of comprehensive DNA microarray analyses and extraction from serial analysis of gene expression (SAGE) libraries, and other studies. Relative expression levels of each gene in gastric cancer tissue and adjacent normal mucosa were measured by quantitative PCR, and the relations between clinicopathological factors and treatment outcomes were studied. In addition, using 9 types of gastric cancer cell lines, we knocked down the new cancer biomarkers obtained in this study with small interfering RNA (siRNA) and performed functional analysis. Results: In patients with resected stage II/III gastric cancer, INHBA, IGF-1R, CLDN7, and DPD genes were independent prognostic factors. In the subgroup of patients who received S-1-based adjuvant chemotherapy, IGF-1R, INHBA, SULF1, REG4, MMP11, and KIAA1199 genes were independent prognostic factors. Knockdown of the KIAA1199 gene with siRNA markedly inhibited the proliferative and invasive activities of the gastric cancer cell lines and lowered resistance to 5-fluorouracil. Conclusions: Investigatory studies of new biomarkers of gastric cancer identified prognostic factors for patients with resected stage II/III gastric cancer and those who received adjuvant chemotherapy with S-1. At present, the development of small molecule drugs that target KIAA1199 and the joint development of risk stratification tools with the goal of individualized therapy for stage II/III gastric cancer are ongoing.


Comparison of HER2 expression in paired biopsies and surgical specimen of gastric and esophageal adenocarcinoma: Impact of neoadjuvant chemotherapy. Presenting Author: Sarah Watson, Department of Oncology, Institut Mutualiste Montsouris, Paris, France Background: HER2 is overexpressed in 10 to 20% of gastro-esophageal adenocarcinoma (GE-ADK), and is a target for trastuzumab in metastatic patients. We conducted a study to compare HER2 expression between diagnostic biopsies (DB) and surgical specimens (SS) of GE-ADK, and to determine the influence of non-trastuzumab containing neoadjuvant chemotherapy (NAC) on this expression. Methods: Pathological specimens from biopsies of 228 patients operated on with a curative aim in two French hospitals between 2004 and 2011 were collected. Two cohorts treated (n⫽141) or not (n⫽87) with a NAC were constituted. Two blind independent pathological HER2 analyses on DB and on SS were performed using IHC and CISH. HER-2 overexpression (HER2 ⫹) was defined by a score 3⫹ in IHC, or 2⫹ with a positive CISH test, and according to the specific HER2 scoring guidelines for GE-ADK. Results: Paired HER2 status could be determined for 218 out of the 228 patients (95.6%). HER2 ⫹ rates were 13.3% on DB (29/218) and 14.7% on SS (32/218). HER2 ⫹ tumors were mainly cardial or esophageal adenocarcinomas, with a well-differentiated, intestinal histological type. HER2 status differed between DB and SS in 13 patients (6%). When DB analyses were added to SS analyses, 5 additional patients were HER2 ⫹, the relative increase in HER2 ⫹ cases being 13.5% (17.1% for patients with NAC versus 7.1% for patients without NAC, p⫽0.4, NS). Differences between DB and SS HER2 expression could be explained by the intratumoral heterogeneity and also by a possible HER2 expression decrease in SS after NAC. Conclusions: The determination of HER2 status on DB provides results that complete those obtained with SS. Combining the analysis of DB and of SS enables to optimize the selection of trastuzumab-eligible patients in case of metastatic relapse, especially in patients previously treated with NAC. Diagnostic Biopsy Surgical Specimen

No NAC (N ⴝ 83)

NAC (N ⴝ 135)

Total

HER2 ⴙ HER2 HER2 ⫹ HER2No NAC HER2 ⫹ 9 4 13 (15.7%) (N ⴝ 83) HER2 1 69 70 NAC HER2 ⫹ 15 4 19 (14.1%) (N ⴝ 135) HER2 4 112 116 Total 10 (12.0%) 73 19 (14.1%) 116 218


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Gastrointestinal (Noncolorectal) Cancer General Poster Session (Board #19H), Sun, 8:00 AM-11:45 AM

A phase II trial of definitive chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) in advanced esophageal cancer (KDOG 0501P2). Presenting Author: Katsuhiko Higuchi, Department of Gastroenterology, Kitasato University East Hospital, Sagamihara, Japan Background: Our previous phase I study (Radiother Oncol 2008,87:398) provided evidence that definitive chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) was tolerable and active in patients with advanced esophageal cancer (AEC). This phase II study was conducted to confirm the efficacy and toxicity of DCF-R in AEC. Methods: Patients with previously untreated carcinoma of the thoracic esophagus who had T4 tumors, M1 lymph-node metastasis, or both received an infusion of docetaxel (35 mg/m2) and an infusion of cisplatin (40 mg/m2) on day 1 and a continuous infusion of 5-fluorouracil (400mg/m2/day) on days 1-5, every 2 weeks, plus concurrent radiation (RT). The total RT dose was initially 61.2, but was lowered to multiple-field irradiation with 50.4 Gy to decrease esophagitis and late toxicity. Consequently, the number of cycles of DCF administered during RT was modified from 4 to 3. After DCF-R, patients received at least 2 cycles of DCF (docetaxel 40 mg/m2 on day 1, cisplatin 60 mg/m2 on day 1, and 5-fluorouracil 600 mg/m2on days 1-5, every 4 weeks). The primary endpoint was the clinical complete response rate (cCRR). Secondary endpoints were response rate (RR), progression free survival (PFS), overall survival, and safety. Results: 42 patients (36 men, 6 women) were enrolled. The median age was 62 years (range: 46-75). PS 0/1/2 was 14/25/3. TNM classification T4M0/non-T4M1LYM/T4M1LYM was 20/12/10. The total scheduled dose of RT 61.2Gy /50.4Gy was 12/30 patients. The RR was 90.5% and the cCRR was 52.4% (95% CI:37.367.5%). As of January 2013, the median PFS was 11.1 months and the median survival time was 23.1 months. Grade 3 or higher major toxicities comprised leukopenia (71.4%), neutropenia (57.2%), anemia (16.7%), febrile neutropenia (38.1%), anorexia (31.0%), and esophagitis (28.6%). There was one treatment-related death caused by aspiration pneumonia. Grade 3 or higher late toxicities comprised one pericardial effusion (Grade 4), one case of esophagitis (Grade 3), and one case of thoracic aortic aneurysm (Grade 3). Conclusions: DCF-R frequently caused myelosuppression, but was highly active and suggested be a promising regimen in AEC. Clinical trial information: 000002029.

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Background: Selection of patients for HER2-targeted therapy is based on HER2 analysis in primary EACs. Since EACs metastasize via regional lymph nodes, concordance of HER2 gene amplification results between primary tumors and their metastatic lymph nodes (MLN) is a clinically important issue. Methods: Resected EACs (N ⫽ 103) having at least three distinct regional MLNs (total 508 MLNs; median 4 [range 3-11]) were sectioned using routine procedures and tested for HER2 amplification by fluorescence in situ hybridization (FISH). Primary tumors were also evaluated for HER2 protein expression by immunohistochemistry (IHC) and by FISH. Amplification was defined as HER2/CEP17 ⱖ 2. IHC was scored as 0, 1⫹, 2⫹, or 3⫹. Primaries whose HER2 status was positive by both FISH and IHC (ie, amplified and IHC3⫹), or negative by both (ie, nonamplified and IHC0-1⫹), were selected. HER2 status was compared between primaries and their MLNs (kappa). Results: Concordant HER2 results between primaries and their MLNs were found in 92% (95/103) of EACs (Table; ␬ ⫽ .76 [95% CI .60 - .92]). However, among patients with HER2-positive primaries, 19% (4/21) had HER2-nonamplified MLNs; among these cases, either all MLNs were HER2-nonamplified (n ⫽ 2), or both HER2nonamplified and –amplified MLNs were present (n ⫽ 2). Among HER2negative primary EACs, 5% (4/82) of cases had MLNs that were all HER2-amplified (n ⫽ 3) or both HER2-nonamplified and -amplified (n ⫽ 1). Conclusions: A patient subset whose primary EACs were HER2-positive (by both FISH and IHC) were unexpectedly found to lack HER2 amplification in corresponding MLNs. Conversely, a subgroup with HER2-negative primaries had HER2-amplified MLNs, and would have been deemed ineligible for HER2-targeted therapy. These preliminary data suggest that evaluating MLNs in resected EACs has the potential to better identify patients who benefit from HER2-targeted therapy. HER2 status in primary tumor (103 patients) All MLNs amplified nⴝ21 Positive, nⴝ21 Negative, nⴝ82 a

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HER2 status in primary tumors and metastatic regional lymph nodes in patients with esophageal adenocarcinoma (EAC). Presenting Author: Harry H. Yoon, Mayo Clinic, Rochester, MN

HER2 status in MLNs (>3 MLNs tested per patient) No. patients (%) All MLNs nonamplified nⴝ82 17 (81) 4 (5)a

4 (19)a 78 (95)

Includes patients with HER2-positive and -negative MLNs.

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A phase ll study of new combination regimen with trastuzumab, S-1, and CDDP in HER2-positive advanced gastric cancer (HERBIS-1). Presenting Author: Keisuke Koeda, Department of Surgery, Iwate Medical University School of Medicine, Morioka, Japan

Nomogram for predicting the benefit of neoadjuvant chemoradiotherapy for esophageal cancer: A SEER-Medicare analysis. Presenting Author: Robert Eil, Oregon Health & Science University, Department of Surgery, Portland, OR

Background: S-1, a novel oral fluoropyrimidine, plus cisplatin (SP) regimen is one of the standard chemotherapy as first-line for advanced gastric cancer. ToGA study demonstrated that trastuzumab (T-mab) combination regimen improved the overall survival of patients with HER2-positive advanced gastric cancer. However, there was no study evaluating the efficacy and the safety of T-mab in combination with S-1 plus cisplatin (SP) regimen. Therefore, we planned this study to examine the efficacy and the safety of the SP plus T-mab. Methods: Patients confirmed to be HER2positive by IHC and/or FISH (IHC 3⫹ or IHC 2⫹ and FISH positive) received S-1 at 80 mg/m2 po, day 1-14, and cisplatin 60 mg/m2 iv, day 1 plus trastuzumab 8 mg/kg iv, day 1 (6 mg/kg iv, d1 from 2nd course), repeated every 3 weeks until disease progression. Primary endpoint was response rate (RR). Secondary endpoints were progression-free survival, overall survival and safety. The threshold response rate was defined as 35%, and the expected rate was set at 50% with a 80% power and a 1-sided alpha value of 0.1 and the calculated sample size was 50 patients. Results: A total of 56 patients (median age 66) were enrolled in this study. The efficacy and the safety analyses were conducted in the full analysis set of 53 patients. (Two patients were excluded for ineligibility and one was for no treatment). The confirmed RR assessed by the independent review committee was 67.9% (95% CI: 53.7 – 80.1), and the disease control rate was 94.3%. The median PFS was 7.1 months (95% CI: 6.0 – 10.1). The median OS was not reached. (The median follow-up time: 9.2 months) The main grade 3/4 adverse events were as follows: neutropenia 34%, leucopenia 8%, anorexia 23%, diarrhea 8%, hypoalbuminemia 4%, vomiting 6%, and increased creatinine 6%. Conclusions: This tri-week regimen with SP plus T-mab showed promising results in patients with HER2-positive advanced gastric cancer. Clinical trial information: UMIN000005739.

Background: The impact of neoadjuvant chemoradiotherapy for esophageal cancer remains difficult to establish for specific patient (pt) populations. The primary aim of this study was to create a web-based prediction tool that provides individualized survival projections based on clinically relevant tumor and treatment data. Methods: Pts diagnosed with esophageal cancer between 1997 and 2005 were selected from the Surveillance, Epidemiology, and End Results (SEER) Medicare database. The covariates chosen for retrospective analysis were: sex, T and N stage, histology, total lymph nodes examined, and receipt of neoadjuvant chemotherapy (CT), radiotherapy (RT), or chemoradiotherapy (CRT). After weighting correction by treatment groups, a log logistic regression model for overall survival (OS) was selected based on goodness of fit analysis. Based on bootstrap resampling with 100 repetitions the Concordance Index (CI) was 0.703. Results: 1,128 resected esophageal pts that either did or did not receive neoadjuvant treatment were appropriate for analysis. On log logistic multivariate analysis: age, sex, T stage, N stage, number of lymph nodes harvested, receipt of neoadjuvant CRT, and receipt of chemotherapy were significantly associated with OS. All T stages greater than 1 benefitted from neoadjuvant CRT (p⫽⬍0.001). No T stage benefitted from isolated neoadjuvant CT or RT. Patients with nodal metastases benefitted from neoadjuvant CRT (p⫽⬍0.001) and CT (p⫽0.002). Conclusions: SEER-Medicare pts with resected esophageal cancer can be used to produce a survival prediction tool that can: 1) serve as a counseling and decision aid to pts and caregivers regarding their postoperative prognosis and 2) assist in research protocol design. Patients T2 or greater or with lymph node metastases benefitted from neoadjuvant CRT based on our data. This nomogram may underestimate the benefit of neoadjuvant CRT due to its variable downstaging effect on final pathologic stage. This web based tool is available for use at http://skynet.ohsu.edu/nomograms.




Phase I/II trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil (DCF) followed by concurrent chemoradiotherapy in locally advanced esophageal squamous cell carcinoma. Presenting Author: Hironaga Satake, National Cancer Center Hospital East, Kashiwa, Japan Background: Standard of care for unresectable locally advanced esophageal squamous cell carcinoma (ESCC) is concurrent chemoradiotherapy (CRT). However, its survival remains limited. Neoadjuvant chemotherapy with docetaxel, cisplatin and 5-FU (DCF) demonstrated promising activity with pathological complete response (CR) of 22% for resectable stage II/III ESCC (Hara H et.al, ASCO 2012). This study was performed to assess the efficacy and safety of induction chemotherapy with DCF followed by CRT in patients with unresectable locally advanced ESCC. Methods: Eligibility criteria included clinically T4 and/or M1 lymph node (LYM) ESCC, PS 0-1, and 20-70 years old. Treatment consisted of docetaxel 70 mg/m2, cisplatin 70 mg/m2 on day 1 and fluorouracil 750 mg/m2 on days 1 to 5, repeated every 3 weeks for three cycles, followed by cisplatin 70 mg/m2 on days 64 and 92, and fluorouracil 700 mg/m2on days 64 to 67 and 92 to 95 concurrently with radiotherapy (60Gy in 30 fractions, 5 days/week). Results: From August 2009 to November 2011, 33 patients were enrolled.There were 16 pts with T4M0 disease, 13 with nonT4M1 LYM, and 4 with T4M1 LYM.Most grade 3 or 4 toxicities were neutropenia (66%), leukopenia (39%), anorexia (18%), dysphasia (12%), nausea (9%), febrile neutropenia (6%), and hyponatremia (6%) during induction chemotherapy. Most grade 3 or 4 toxicities were leukopenia (27%), neutropenia (20%), dysphasia (17%), anorexia (13%), esophagitis (13%), nausea (10%), and febrile neutropenia (3%) during CRT. No treatment related death was observed. The completion rate of protocol treatment was 88% (29/33). The overall response rate after completion of induction chemotherapy was 61%. Eleven pts (38%) achieved CR after completion of protocol treatment. With a median follow-up period of 14 months, 1y-PFS and 1y-OS are 38.5 and 78.6 %, respectively. Of a total of 33 patients, eighteen patients (55%) received secondary treatment. Conclusions: Induction chemotherapy with DCF followed by CRT in unresectable locally advanced ESCC was well tolerated. Although these data are preliminay, this approach warrants further evaluation. Clinical trial information: UMIN000003370.

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Prognostic impact of human epidermal growth factor-2 (HER2) status on overall survival (OS) of advanced gastric cancer (AGC) patients (pts) treated with standard chemotherapy without trastuzumab as a first-line treatment: A Japanese multicenter collaborative retrospective study. Presenting Author: Tomohiro Nishina, National Hospital Organization, Shikoku Cancer Center, Matsuyama, Japan Background: The prognostic impact of HER2 status on OS of AGC pts treated with standard chemotherapy without trastuzumab for first-line treatment remains controversial. This study investigated whether HER2 status is an independent prognostic factor for AGC pts. Methods: Formalinfixed paraffin-embedded tumor samples from 293 eligible pts were examined for HER2 by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). Eligible criteria included: 1) histologically confirmed gastric or gastroesophageal junction adenocarcinoma, 2) unresectable or recurrent cancer, 3) treated with S-1 plus cisplatin as first-line chemotherapy, 4) age: ⱖ20, 5) ECOG performance status score: 0-2 and 6) with archived tumor sample. HER2⫹ was defined as IHC 3⫹ or IHC 2⫹/FISH⫹. Results: Of 293 pts, 43 (15%) were HER2⫹. Baseline pt characteristics between HER2⫹ and HER2- pts were significantly different by histology (intestinal/diffuse, 65%/35% vs. 39%/61%; p⫽0.001), measurable disease by RECIST v1.0 (91% vs. 69%; p⫽0.003), No. of metastatic sites (ⱖ2, 72% vs. 46%; p⫽0.003) and presence of liver metastasis (56% vs. 31%; p⫽0.003). After median follow-up time of 48.9 months with 270 (92%) death events, there was no significant difference in OS between HER2⫹ and HER2- pts (median, 11.7 vs. 13.7 months; hazard ratio [HR] 1.11, 95% CI 0.79 –1.55; log rank p⫽0.550). After adjusting other prognostic factors with Cox hazard model, HER2⫹ was still not prognostic for OS (HR 0.890, 95% CI 0.627–1.262, p⫽0.513). Conclusions: HER2 status has no significant prognostic impact on OS of AGC pts treated with S-1 plus cisplatin without trastuzumab as a first-line treatment.

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Randomized phase II study comparing dose-escalated weekly paclitaxel versus standard dose weekly paclitaxel for patients with previously treated advanced gastric cancer. Presenting Author: Kohei Shitara, National Cancer Center Hospital East, Kashiwa, Japan

Promoter polymorphisms of the SWI/SNF chromatin remodeling complex molecule, BRM, and esophageal adenocarcinoma outcome. Presenting Author: Grzegorz Korpanty, Princess Margaret Hospital, Ontario Cancer Institute, Toronto, ON, Canada

Background: Retrospective analyses of neutropenia during chemotherapy of weekly paclitaxel (wPTX) suggested better overall survival (OS) among patients with neutropenia. We conducted a randomized phase II trial comparing dose-escalated wPTX with dose adjustments determined by degree of neutropenia versus standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC). Methods: Ninety-patients with AGC that progressed during one or more previous chemotherapy regimens were randomized to a standard dose of wPTX (80 mg/m2, standard dose arm) or an escalated dose of wPTX (80 mg/m2 on day 1, 100 mg/m2 on day 8, and 120 mg/m2 on day 15 unless severe toxicity nor neutropenia⬍1.5 x 109/L is observed, escalated dose arm) to assess superiority with a one-sided alpha of 0.3 and a power of 0.8. Results: The primary endpoint of median OS showed a trend towards longer survival in the dose-escalated arm (11.8 vs. 9.6 months; hazard ratio [HR], 0.75; 95% CI, 0.45-1.22; one-sided P⫽0.12). Median progression-free survival (PFS) was significantly longer in the dose-escalated arm (4.3 vs. 2.5 months, HR, 0.55; 95% CI, 0.34-0.90; P⫽0.017). Objective response rate was 30.3% with dose-escalation and 17.1% with standard dose (P⫽0.2). The disease control rate (DCR) was significantly higher with dose-escalation (78.8% vs. 48.6%, P⫽0.009). Subset-analysis according to stratification factors including ECOG PS, presence of measurable lesions and lines of previous chemotherapy indicated that OS benefit of the dose escalation is more prominent in PS 0-1 patients (N⫽81, median 13.6 vs. 9.8 months, HR 0.68, 95% CI 0.41-1.11) than PS2 patients with significant interaction (p⫽0.01) Conclusions: Dose escalated wPTX was associated with sufficiently longer OS in patients with pretreated AGC. In addition, significant longer PFS and higher DCR associated with dose-escalation and subset analysis according PS warrant further investigations in phase III trials, especially in patients with favorable PS patients. Clinical trial information: UMIN000004055.

Background: Better understanding of the biology of esophageal cancer may help improve its treatment. The SWI/SNF chromatin remodeling complex is an important regulator of gene expression that has been linked to cancer development and outcome. Expression of Brahma (BRM), a critical catalytic subunit of SWI/SNF, is lost in a variety of solid tumors. Two novel BRM promoter polymorphisms (BRM -741 and BRM -1321) have been correlated with BRM loss and elevated cancer risk in upper aerodigestive cancers (Wang et al, Carcinogenesis, 2012) and more recently in lung cancer outcome (Cuffe et al, ESMO, 2012) by our research teams. Objectives: We evaluated BRM polymorphisms and their role in the survival of esophageal cancer patients. Methods: 223 histologically-confirmed esophageal adenocarcinoma patients of all stages were evaluated. The two BRM polymorphisms utilized Taqman genotyping. Cox proportional hazards models adjusted for clinical prognostic variables and determined the association of polymorphisms with overall survival (OS) and progression free survival (PFS). Adjusted hazard ratio (aHR) and 95% confidence intervals (CI) were calculated. Results: Among our patients, 85% were male; the mean age was 63 years. 37% had stage IV advanced tumors. The median PFS was 1.03 years, while median OS was 1.82 years. After adjustment for known prognostic clinical variables, carrying homozygous variants of both BRM polymorphisms (double homozygotes) was associated with a worse outcome: aHR 1.84 (1.06-2.34, p⫽0.03) for OS and aHR 1.93 (1.10-2.48, p⫽0.02) for PFS. The direction and magnitude of associations were similar in subsets of patients by age, gender, smoking status, use of platinum agents, and disease stage. Non-significant trends in the same direction but of aHR magnitudes 1.34-1.54 were seen in the patients who carried one homozygous variant or who were double heterozygotes. Conclusions: We report the initial association of BRM polymorphisms with survival in esophageal cancer. We plan to explore additional relationships and validate these findings in other datasets.


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A validated miRNA expression profile for response to neoadjuvant therapy in esophageal cancer. Presenting Author: Heath D. Skinner, The University of Texas MD Anderson Cancer Center, Houston, TX Background: For patients with esophageal adenocarcinoma (EAC) preoperative chemoradiation (trimodality therapy) is the preferred approach. We examined several patient cohorts to create and validate a miRNA signature predictive for response to this therapy in esophageal carcinoma. Methods: Pre-treatment tumor specimens from 10 patients with EAC treated with trimodality therapy were examined using a TaqMan Human MicroRNA Card Set (v3.0) for expression of 754 miRNAs, of which 306 were overexpressed. miRNA expression between patients with a pathologic complete response (pCR) and those with a non-pCR was then analyzed. 44 miRNAs differentially expressed between pCR and non-pCR patients were then examined in an additional 42 EAC patientsÕ tumors (model set) using the Fluodigm 48.48 Dynamic Array and were used to generate a miRNA expression profile (MEP) predicting for response in three groups: low, intermediate and high-risk. The MEP was then validated in an additional 72 EAC patients using the Illumina miRNA Expression Array. ROC curves were generated for clinical stage, MEP and a combination of both. Results: For the model set, pCR rates in low risk patients based on the MEP were 75%, 42.9% in intermediate risk and 12.5% in high-risk patients (ptrend⫽0.008). In the validation set the pCR rates were 66.7%, 36.5% and 15.7% for low, intermediate and high-risk patients respectively (ptrend⫽0.025). The AUC for the ROC using the MEP was 0.72 (p⫽7.8x10-12) in the model set, 0.69 (p⫽1x10-4) in the validation set and 0.7 for the two cohorts combined (p⫽1.4x10-18). When clinical stage was added to the predictive model, the ROC for each group was 0.79 (p⫽2.6x10-19), 0.75 (p⫽8.7x1027) and 0.77 (p⫽2x10-41) respectively. Conclusions: The MEP represents the first validated miRNA signature for therapeutic response in esophageal carcinoma and improves significantly on clinical staging. Its use could select patients at high-risk for therapeutic resistance for trial-based therapy, as well as low-risk patients for whom resection may possibly be safely omitted.

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Safety, tolerability, and efficacy of the first-in-class antibody IMAB362 targeting claudin 18.2 in patients with metastatic gastroesophageal adenocarcinomas. Presenting Author: Martin H. Schuler, West German Cancer Center, University Hospital Essen, Essen, Germany Background: IMAB362 is a monoclonal antibody targeting isoform 2 of the tight junction component claudin 18 (CLDN18.2), a tumor-selective antigen frequently expressed in several types of epithelial adenocarcinomas. Preclinically, IMAB362 exerts its antitumor activity by ADCC, CDC, induction of apoptosis and inhibition of cell proliferation. Methods: Patients with treatment-refractory, metastatic gastroesophageal adenocarcinomas with CLDN18.2-positive tumors as determined by immunohistochemistry were enrolled in two clinical trials of IMAB362 monotherapy. A phase I inter-patient single dose escalation study (n⫽15, 5 dose groups from 33 mg/m² to 1000 mg/m² with 3 patients each, follow-up 4 weeks) was conducted followed by a phase II study (n⫽34, 300 mg/m2 [n⫽4] and 600 mg/m2[n⫽30]) administered every two weeks for 5 courses, imaging in week 11. Patients with disease control allowed to continue IMAB362 therapy until progression. Analysis of the phase II trial is ongoing. Results: In the phase I trial, all dose levels of IMAB362 were generally well tolerated. Nausea and vomiting were the most common adverse events (AEs). No dose limiting toxicity was observed at single doses up to 1,000 mg/m². Based on pharmacokinetic considerations and preclinical dose/ response data, the recommended doses for the phase II multidose trial was 600 mg/m². In the phase II study, 34 patients were evaluable for safety. No grade 4 AEs occurred, grade 3 AEs were vomiting (n⫽8, 24%), nausea (n⫽4, 12%) and hypersensitivity (n⫽1, 3%). As of January 2013, 31 patients were evaluable for efficacy analysis. Four patients had achieved a confirmed partial response, and eight patients had disease stabilization (ORR⫽13%, DCR⫽39%). The longest observed response duration thus far was 40 weeks. Conclusions: IMAB362 antibody therapy of patients with advanced CLDN18.2-positive gastroesophageal adenocarcinomas is safe and well tolerated. Early evidence for antitumoral activity was observed in the phase II trial. Further clinical evaluation of IMAB362 in patients with CLDN18.2 tumors is warranted. Clinical trial information: NCT01197885.

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Interim safety analysis of a phase III trial with 5-FU, oxaliplatin, and docetaxel (FLOT) versus epirubicin, cisplatin, and 5-FU (ECF) in patients with locally advanced, resectable gastric/oesophagogastric junction (OGJ) cancer: The AIO-sto-0210 FLOT4 study. Presenting Author: Claudia Pauligk, Krankenhaus Nordwest, UCT University Cancer Center, Frankfurt, Germany Background: Perioperative ECF is a standard treatment for localized gastric/OGJ adenocarcinoma. However, 5-year survival rate remains below 40%. The FLOT regimen is an effective combination with pathologic response rates in the 15% range. This phase III study compares both regimens in resectable stages. Methods: Pts are stratified by different baseline criteria and randomized to either 3 ⫹ 3 perioperative cycles of ECF (epirubicin 50 mg/m2, d1; cisplatin 60 mg/m², d1; 5-FU 200 mg/m², d1-d21, qd21) or 4 ⫹ 4 cycles of perioperative FLOT (docetaxel 50mg/m2, d1; 5-FU 2600 mg/m², d1; leucovorin 200 mg/m², d1; oxaliplatin 85 mg/m², d1, qd14). 5-FU can be replaced by capecitabine in the ECF-arm (ECX). Central pathology is performed. This is a preplanned safety analysis after 300 patients. Results: The ongoing studyhas enrolled 380 of planned 590 pts, so far. 305 pts were included in this analysis. Median age is 62 yrs; 78% of pts are male. The primaries were gastric in 44.9%, OGJ in 50.4% and not evaluable/documented in 4.7% of pts. 281 pts were eligible for safety analyses. Median no. of preoperative cycles was 3 and 4 with ECF/ECX and FLOT, respectively, 35.9% vs. 44.6% of pts (ECF/ECX vs. FLOT) started postoperative chemotherapy (ct) and 22.5% vs 33.1% received all planned cycles. Grade 3/4 neutropenia was observed in 28.0% of ECF/ECX and 45.3% of FLOT pts (p⫽.0026). Thromboembolic events occurred in 14.1% vs. 5.8% in pts with ECF/ECX vs. FLOT (p⫽.027). Serious adverse events occurred in 52.1% vs. 47.5% of pts with ECF/ECX vs. FLOT (p⫽.48). Preoperative delay/interruptions of ct were observed in 71.1% vs. 56.8% of pts with ECF/ECX vs. FLOT (p⫽.013). Dose modifications of preoperative ct were performed in 27.5% vs. 20.1% of treatment cycles with ECF/ECX vs. FLOT, respectively. 197 pts have undergone surgery so far. Severe surgical morbidity was similar in both arms (ECF/ECX, 19.8%; FLOT, 16.8%). Surgical mortality was observed in 4 and 2 pts with ECF/ECX and FLOT. Toxic deaths were observed in 1 pt each. Conclusions: Perioperative FLOT is feasible and safe. Clinical trial information: NCT01216644.

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Final results of AGITG ATTAX3 study: Randomized phase II study of weekly docetaxel (T), cisplatin, and fluoropyrimidine (F) with or without panitumumab (P) in advanced esophagogastric (OG) cancer. Presenting Author: Niall C. Tebbutt, Austin Health and University of Melbourne, Heidelberg, Australia Background: This randomized phase II study evaluated the efficacy and safety of P, a fully human mAb against the epidermal growth factor receptor combined with T-based chemotherapy in advanced OG cancer. Methods: Eligible pts had histologically confirmed metastatic OG cancer (adenocarcinoma and squamous cell carcinoma) were ⱖ18 years of age, PS 0-2, with adequate renal, haematologic and liver function with measurable disease. All pts provided informed consent. Selection was not based on kras determination. Pts received T 30mg/m2 d1,8, C 60mg/m2 d1 and F; investigator choice of 5FU infusion 160mg/m2/d or capecitabine 500mg/ m2bd continuous ⫾P 9 mg/kg d1 q3w. Treatment was administered for 8 cycles or until PD. The primary endpoint was response rate according to RECIST (1.1) assessed q6w. Planned enrolment target was 100 pts. Stratification variables included histology, PS and choice of F. Results: From April 2010 to November 2011, 77 pts were enrolled from 15 institutions. A safety alert from the REAL3 study (also involving P in OG cancer) prompted an unplanned review of data from ATTAX3 by the IDMC. The IDMC found no evidence of adverse outcomes associated with P, but as it did not appear that P would significantly improve efficacy, they recommended cessation of the study to new enrolment. Previously enrolled pts were treated and followed according to protocol. Median follow up is 24m. Treatment arms were well balanced; median age 59, 64y, male 77%, 87%, PS0-1 95%,90%, adenocarcinoma 90%,90%, capecitabine 67%, 66% for TCF/TCF-P, respectively. Common grade 3/4 toxicities include infection 18%,24%, febrile neutropenia 10%, 5%, anorexia 10%, 24%, nausea 18%,30%, stomatitis 3%,5%, diarrhoea 15%,24% , acneiform rash 0%, 8%, fatigue 18%, 30%, hypomagnesemia 10%, 16% for TCF/TCF-P. Efficacy outcomes are summarized in Table. Conclusions: The addition of P to T-based chemotherapy in advanced OG cancer did not improve efficacy and was associated with an increase in some toxicities. Clinical trial information: ACTRN12609000109202. Response rate % (95% CI) Median PFS (m) (95% CI) Median OS (m) (95% CI)

TCF (nⴝ39)

TCF ⴙP (nⴝ38)

49 (34-64) 6.9 (5.7-8.5) 11.7 (7.8-15.9)

58 (42-72) 6.0 (4.4-7.3) 10.0 (8.3-12.0)




Variable penetrance of CDH1 mutation diffuse gastric cancer: A genomic analysis. Presenting Author: David Paul Kelsen, Memorial Sloan-Kettering Cancer Center, New York, NY Background: CDH1 encodes E-cadherin; mutations (CDH1mut) increase the risk of diffuse gastric (DGC) and lobular breast cancers. Life-time risk of DGC is estimated at 80%. Current recommendations are prophylactic gastrectomy (PG) in CDH1mut carriers after age 20. Foci of DGC are found in some PG; others have none at PG, and some CDH1mut without PG never develop cancer. Identifying risk modifying alleles or other genomic events which increase the risk of DGC may improve understanding of DGC and may provide a biomarker for when to perform PG. Methods: For a Gastric Cancer Registry, we collected family pedigrees, germline DNA and FFPE tumor from CDH1mut DGC patients (pts) and their families. From 24 families, with 52 CDH1mut individuals, we identified 4 families in which a young CDH1mut pt developed advanced DGC while their CDH1mut parent and siblings had no clinical evidence of DGC. Several relatives had undergone PG with no DGC found. We hypothesize that there are risk modifying alleles and/or a “second hit” that causes variable penetrance and early onset of DGC in the young CDH1mut pts. Whole genome sequencing was performed on germ line DNA (Complete Genomics, Inc. Mountain View, CA); and whole exome sequencing on tumor specimens (MSKCC). Results: To date, 4 DGC pts and 8 relatives from 4 families have been studied. All 4 affected pts were women (ages 17, 25, 27, 42); their unaffected CDH1mut parents were 41, 51, 54, and 70 years old. The families are of Kenyan, Scandinavian, Italian, Eastern European, and Scottish origin. CDH1 mutations for the pts and their families were confirmed on WGS, and were as follows: 1451C⬎A(pro484his);c. 1792C⬎T (arg598ter);c. 1893dupA in exon 12;c. 1565⫹1G⬎A (IVS10⫹1G⬎A). Analysis of germline DNA for modifying alleles is being performed (Ingenuity Systems, Redwood, Ca.); whole exome sequencing of tumor to identify a possible ⬙second hit⬙ is underway. These data will be presented. Conclusions: Since at least some older pts with proven CDH-1mut do not develop DGC while their children do, CGH-1mut alone may not be sufficient to cause early onset DGC. We hope to identify the additional genomic events associated with early onset advanced DGC. Supported in part by grants from the Gerstner and DeGregorio Foundations.

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Pattern of local-regional relapse and survival after bimodality therapy for esophageal cancer: Implications for the surveillance strategy. Presenting Author: Kazuki Sudo, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Evidence for definitive chemoradiotherapy (bimodality therapy [BMT]) has been established for patients with esophageal and gastroesophageal junction cancer (EGEJC) who do not qualify for surgery. Surveillance for these patients is often recommended but the literature lacks guidance for an evidence-based surveillance strategy after BMT. Methods: We analyzed 276 patients with EGEJC who underwent BMT and had pre- and postchemoradiation endoscopic biopsies and imaging studies available for review. Patients who underwent planned surgery or salvage surgery (SS) within 6 months from BMT were excluded. We reviewed the pattern of relapse over time. Local-regional disease (LRD) after BMT was classified as regional disease (RD) or luminal-only disease (LD). Overall survival (OS) probabilities were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: For 276 patients, the median follow-up time was 53.0 months (95% confidence interval [CI], 47.3-58.7). A total of 184 (66.7%) patients had a persistent disease or relapse after BMT: 120 distant metastases (43.5% of 276) and 64 LRD (23.2% of 276). Of 64 LRD, 58 (91%) were diagnosed within 2 years of BMT and 63 (98%) were diagnosed within 3 years (see Table). Twenty-three of 64 LRD patients underwent SS. For patients with SS, the median OS time from diagnosis of LRD was 58.0 months (95% CI, not reached), and that for patients without SS was 9.0 months (95% CI, 7.3-10.7); this difference was highly significant (p ⬍ 0.001). Conclusions: Our data suggest that 91% of LRD occurred within 2 years after BMT and the OS with SS for LRD was better than that without SS. These data can contribute to the development of an evidence-based surveillance strategy. Duration-specific rate of relapse from BMT or persistent disease (months). Persistent disease at 1st surveillance after BMT -12M*** 13-24M 25-36M 37-48M 49MLuminal-only * ** Regional * **

15 5.4% 23.4% 5 1.8% 7.8%

25 12 4 9.1% 4.3% 1.4% 39.1% 18.8% 6.3% 1 0 1 0.4% 0.0% 0.4% 1.6% 0.0% 1.6%

0 0.0% 0.0% 0 0.0% 0.0%

1 0.4% 1.6% 0 0.0% 0.0%

* Total denominator: 276. ** Total local-regional disease after BMT: 64. *** Not including persistent disease at the 1st surveillance.

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Phase II study of mFOLFOX with bevacizumab (Bev) in metastatic gastroesophageal and gastric (GE) adenocarcinoma (AC). Presenting Author: Jia Li, VA Connecticut Healthcare System, Yale Cancer Center, West Haven, CT Background: The median survival for patients (pts) with metastatic GE AC in phase III studies is ⬍12 mos. Bev has demonstrated promising activity in metastatic GE AC when used in combination with cisplatin-based regimens in studies with patients from the Americas. We conducted a prospective phase II trial to investigate the efficacy of Bev in combination with mFOLFOX6 in pts with metastatic GE AC. Methods: Pts with previously untreated metastatic GE AC (gastric, GE junction, distal esophagus) received mFOLFOX6 (LV 400 mg/m2, 5-FU 400 mg/m2 bolus and 2400 mg/m2 over 46 hr continuous infusion, Ox 85 mg/m2) and Bev 10 mg/kg q 2 wks. Response by RECIST was evaluated by CT q 8 wks. Primary objective was time to progression (TTP); secondary objectives were safety, response rate (RR), and overall survival (OS). Results: 39 pts were enrolled between 09/08 and 06/12. Pt characteristics are as follows: median age, 59 yo (range 27-79); M/F, 31/8; ECOG PS 0/1, 11/28; gastric/distal E and GEJ, 13/26; metastatic sites: lymph nodes 23, liver 19, lung 9, peritoneum 9; ⬎2 metastatic sites, 20; prior gastrectomy or esophagectomy, 7. Nine pts remain on study, and 15 pts are alive. Median # of cycles administered is 11 (range 4 - ⬎31). RR is 56.4% (4 CR, 18 PR). Median TTP is 8.2 mos. Median OS is 15.2 mos. Three pts survived ⬎24 mos. Grade 3/4 toxicities include neutropenia (13, 33.3%), neuropathy (8, 20.5%), DVT/PE (5, 12.8%), thrombocytopenia (3, 7.7%), anemia (1, 2.6%), hypertension (1, 2.6%), and proteinuria (1, 2.6%). We observed no GI perforations or grade 3/4 GI hemorrhagic events. Conclusions: FOLFOX6/Bev is well tolerated and associated with increased TTP and OS in pts with metastatic GE AC compared to historical data from similar populations treated without Bev. Our findings validate previous studies with Bev in combination with cisplatin-based regimens in pts from the Americas with metastatic GE AC. This study is supported by Genentech. Clinical trial information: NCT00673673.

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Customizing surveillance of patients with esophageal or esophagogastric junction adenocarcinoma (E-EGA) after trimodality therapy (TMT). Presenting Author: Takashi Taketa, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Follow-up strategy for E-EGA patients after TMT has varied and is debated often due to the lack of evidence. It is an expensive endeavor and the literature provides little guidance. Methods: Between 2000 and 2010, we identified 518 E-EGA patients who had TMT. We reviewed the timing/pattern of recurrence after TMT and grouped them as local-regional (LR) or metastatic (M). Results: The median follow-up time from date of surgery was 29.3 months (range, 0.8 to 149.2 months). 215 (41.5%) had a relapse (M⫽188 [87.5%] and LR⫽27 [12.5%]). Among LRs, regional node only in 16 (7.4%) and intra-luminal only occurred in 11 (5.1%). The frequency of relapses was highly associated with the surgical stage (p⬍0.001). ⬎90% of all relapses occurred within 29.2 months of surgery. In addition, almost all intra-luminal only relapses occurred within 24 months (see Table). Conclusions: Our data suggest that it may be possible to customize surveillance of patients after TMT based on the surgical stage. Additionally, intra-luminal only relapse are rare and are unlikely after 24 months. Our data can contribute to the development of an evidence-based surveillance strategy. Surgical stage No. of recurrence/patient 0/I II / III

0-12M 2 / 191 1.0% 9 / 327 2.8%

Time to luminal only recurrence from surgery 13-24M 25-36M 37-48M 49-60M 61M0 1 0 0 0 1 1

7

1

0

0

0


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FOLFIRI plus sunitinib versus FOLFIRI alone in advanced chemorefractory esophagogastric cancer patients: A randomized placebo-controlled multicentric AIO phase II trial. Presenting Author: Markus Hermann Moehler, Arbeitsgemeinschaft Internistische Onkologie - University of Mainz, Mainz, Germany Background: Sunitinib is an receptor tyrosine kinase (RTK) inhibitor of VEGFR1-3, PDGFR-␣-␤, and other RTK. After we established Sunitinib (Sun) alone associated with limited response rate (RR) and good tolerability in refractory advanced esophagogastric cancer patients (Moehler et al. EUR J Cancer. 2011, 47: 1511), this double-blinded placebo-controlled phase II evaluated safety and efficacy of SUN as add-on in second-line or third-line FOLFIRI (ClinicalTrials.gov NCT01020630). Methods: Patients with failure of any prior docetaxel and/or platinum-based chemotherapy were randomized to receive 6-week cycles including FOLFIRI two weekly and SUN (25 mg) versus (vs) placebo (PLA) daily for 4 consecutive weeks followed by a 2-week rest. Primary endpoint was progression-free survival (PFS). Results: 91 randomized patients (ITT) had similar characteristics in both groups (SUN/PLA 45/46). Both groups had 2.7 treatment cycles. Objective RR was 20/29%, and tumor control rate was 58/56 % for SUN/PLA, respectively. Median PFS was similar for SUN vs. PLA with 3.6 vs. 3.3 months, respectively (HR 1.11; 95%CI 0.70-1.74, P ⫽ 0.66). Median overall survival (OS) was longer for SUN vs. PLA with 10.5 vs. 9.0 months, in ITT (HR 0.816; 95%CI 0.50 - 1.34, P ⫽ 0.42, one-sided 0.21) and in the per protocol population (HR 0.71; 95%CI 0.41 - 1.24, P ⫽ 0.23) respectively. No unexpected higher toxicities, SAE or SUSAR occurred with SUN. For SUN/PLA, all grade AEs (%) possibly related to study drug were nausea 49/47%, fatigue 36/29%, vomiting 27/29%, diarrhoea 36/38%, neutropenia 62/22%, stomatitis 27/20%, and palmarplantar erythrodysaesthesia 13/3%, and Grade 3⫹ AEs (%) were neutropenia 56/20%, diarrhoea 2/13%, nausea 7/7%, fatigue 0/9% and pain 0/9%, respectively. Performed quality of life outcomes were mostly in favor of Sunitinib. Conclusions: In our phase II trial, Sunitinib added to FOLFIRI increased hematotoxicity and did not improve response rates or PFS in chemotherapy-resistant GC patients. Since the regimen was safe and patients had a trend to better OS, biomarker analyses will be performed to identify subgroups that benefit from add-on Sunitinib. Clinical trial information: NCT01020630.

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A phase II trial of induction epirubicin, oxaliplatin, and flourouracil, surgery and post-operative concurrent cisplatin and fluorouracil chemoradiotherapy (CRT) in patients (pts) with loco-regionally advanced (LRA) adenocarcinoma (ACA) of the esophagus (E) and gastroesophageal junction (GEJ). Presenting Author: Michael J. McNamara, Cleveland Clinic Foundation, Cleveland, OH Background: In pts with LRA ACA of the E/GEJ, CRT and surgery results in excellent locoregional control. Distant failure remains common, however, suggesting potential benefit from additional chemotherapy. This single arm phase II study investigated the addition of induction chemotherapy to surgery and post-operative CRT. Methods: Pts with an ultrasound-based clinical stage of T3, N1 or M1a (AJCC 6th) ACA of the E/GEJ were eligible. Induction chemotherapy with epirubicin 50mg/m2 d1, oxaliplatin 130mg/m2 d1, and flourouracil 200mg/m2/day continuous infusion for 3 weeks, was given every 21 days for 3 courses and was followed by surgical resection. Adjuvant CRT consisted of 50-55Gy at 1.8-2.0 Gy/d and 2 courses of cisplatin (20mg/m2/d) and flourouracil (1000mg/m2/d) given as 96 hour infusions during weeks 1 and 4 of radiotherapy. Results: Between 2/08 and 1/12, 60 evaluable pts enrolled; 95% male, 97% white and 78% with GEJ tumors. Resection was accomplished in 54 pts (90%) and adjuvant CRT in 48 (80%). Toxicity included 1 death during induction (2%), and 2 post-operative deaths (4%). Unplanned hospitalization was required in 18% of pts during induction and 19% during adjuvant CRT. Induction chemotherapy produced a symptomatic response in 79% of pts, a clinical (ultrasound) response in 48% and a pathologic response in 41% (5% complete). With a median follow-up of 31 months, the Kaplan-Meier 3-year projected locoregional control (LRC) is 84%, distant metastatic control (DMC) 44%, relapse-free survival (RFS) 39%, and overall survival (OS) 42%. Symptomatic response to induction and the percentage of remaining viable tumor at surgery proved the strongest predictors of DMC, RFS, and OS. Conclusions: Induction chemotherapy, surgery and adjuvant CRT is feasible and produces outcomes similar to other multimodality treatment schedules in LRA E/GEJ ACA. Despite excellent LRC, projected DMC and OS remain poor. A symptomatic response to induction and less residual viable tumor at surgery are associated with improved outcomes. Clinical trial information: NCT00601705.

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A comparison of postoperative quality of life after open and laparoscopic gastrectomy for early gastric cancer: A multicenter, nonrandomized, controlled study (CCOG 0802). Presenting Author: Chie Tanaka, Gastroenterological Surgery, Nagoya Graduate School of Medicine, Nagoya, Japan

PI3K pathway as a major determinant of resistance to HER2-targeted therapy in advanced gastric cancer. Presenting Author: Hyo Song Kim, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea

Background: The aim of this study was to compare the postoperative health-related quality of life (HRQoL) between open and laparoscopic distal gastrectomy. Methods: A multi-institutional non-randomized study was conducted, and early gastric cancer patients were prospectively enrolled and underwent distal gastrectomy either by the open or laparoscopic approach. HRQoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life QuestionnaireCancer (QLQ-C30) and the site-specific module for gastric cancer (QLQSTO22). Questionnaires were completed at baseline and at 1, 3, 6 and 12 months postoperatively. Clinicopathological characteristics and short term outcome including postoperative morbidity and HRQoL were compared between the approaches. Results: A total of 159 patients with clinical T1 tumors were enrolled between September 2008 and January 2011. Those who were found upon pathologic examination to have ⱖaStage II disease (n⫽14) were excluded, and the remaining 145 patients (open: n⫽72, laparoscopic: n⫽73) were analyzed. There were no significant differences between the two groups regarding age, gender, macroscopic type, depth of invasion, lymph node metastasis, and pathologic type. Laparoscopic approach was associated with longer operating time, smaller blood loss, and similar incidence of postoperative complications. At each time point, the questionnaires were sent to the data center from ⬎90% of the patients. The worst scores for most of the items were observed at 1 month postoperatively and improved thereafter. The role, emotional, cognitive, and social functioning scores were superior in the laparoscopic group at 6 and 12 months postoperatively. Symptom scales including fatigue, pain, anxiety, eating restriction, and taste problem were better in the laparoscopic group before 6 months but not at 12 months. Conclusions: Patients treated by the laparoscopic approach benefitted from better HRQoL in terms of symptoms scores during the first 6 months, while the superiority in several functioning scores lasted for 12 months.

Background: Despite the improvement of survival with trastuzumab treatment, it is still unclear why majority of patients are initially nonresponsive or eventually become resistant to HER2-based therapy. To evaluate resistant mechanism and stimulate the development of rational drug, we investigated the role of phosphoinisitide 3-kinase (PI3K) pathway activation. Methods: With tumor tissues from HER2-overexpressing advanced gastric cancer, PIK3CA mutation status (by pyrosequencing of exon 9 and 20) and phosphatase and tensin homolog (PTEN) expression levels (using immunohistochemical analysis) were evaluated for the therapeutic response to HER2-based therapy. Results: Forty nine patients received trastuzuamb (n⫽39) or lapatinib (n⫽10) in combination with chemotherapy regimen. The age at diagnosis was 61 years and all the cases were HER2 positive and/or amplified. PTEN-loss was found in 67% (n⫽33) and all the patients showed PIK3CA wild-type tumors. Twenty nine patients (59%) responded to HER2-based therapy (complete and partial response), without significant difference between PTEN-loss and normal tumors (61% vs 62%). Among the patients with responsive disease, time to best response was not different but duration of response was shorter for the PTEN deficient patients (155 vs 244 days, P⫽0.016). In addition, PTEN-deficient patients have significantly shorter progression-free survival (median 160 vs 286 days, P⫽0.018), which implying the functional role of PTEN for the acquired resistance to HER2-based therapy. Conclusions: This data suggests PTEN as an important predictor for the early progression and acquired resistance to HER2-based therapy. Activated PI3K pathway may provide a biomarker to identify patients who may need additional or alternative therapies.




A phase II clinical trial of ganetespib (STA-9090) in previously treated patients with advanced esophagogastric cancers. Presenting Author: Eunice Lee Kwak, Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA Background: Subsets of esophagogastric (EG) cancers harbor genetic abnormalities, including amplification of HER2 or MET, or mutations in PIK3CA, EGFR, or BRAF. These genes encode clients of the molecular chaperone heat-shock protein 90 (HSP90), and inhibition of HSP90 may promote the degradation of these oncogenic signaling proteins. Ganetespib is a novel triazolone heterocyclic inhibitor of HSP90 that is a biologically rational treatment strategy for advanced EG cancers. Methods: This was a multicenter, single-arm Phase 2 trial. Eligibility: Histologically confirmed advanced EG cancer; progression on ⱕ 2 lines of systemic therapy; ECOG PS 0-1. Treatment: Ganetespib 200mg/m2IV on Days 1, 8, and 15 of a 28-day cycle. Primary endpoint: overall response rate (ORR). Results: 26/28 patients enrolled received ⱖ 1 dose of drug. The characteristics of the 26 patients were: male 77%, median age 64 years old; ECOG PS 0/1 42/58%; median number of prior therapies 2; esophageal/GEJ/gastric 27/42/31%; prior platinum 92%, prior fluoropyrimidine 88%, prior taxane 38%, prior trastuzumab 15%. Median follow-up was 83 days. The most common drug-related adverse events were: diarrhea (77%), fatigue (65%), elevated ALKP (42%), and elevated AST (38%). The most common Grade 3/4 AEs included: leucopenia (12%), fatigue (12%), diarrhea (8%), and elevated ALKP (8%). 14/26 required ⱖ 1 dose modification. 22/26 patients completed at least 2 cycles of ganetespib and were evaluable for response. One complete response was seen, and this patient continues on treatment as of cycle 31 (27.5 mos). Molecular characterization of this patient’s tumor revealed a KRAS mutation in codon 12. The ORR was 1/26 (4%). Two of six patients with HER2-positive disease achieved 12% and 19% tumor reduction from baseline, respectively. TTP was 48 days (1.6 mos) and OS was 83 days (2.8 mos). Conclusions: Ganetespib showed manageable toxicity. While the study was terminated early due to insufficient evidence of single agent activity, the durable CR and 2 minor responses suggest that there may be a subset of EG patients who could benefit from this drug. The molecular determinants of response, however, have yet to be fully characterized. Clinical trial information: CT01167114.

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Natural history of malignant bone disease in gastric cancer: Final results of a multicenter bone metastasis survey. Presenting Author: Nicola Silvestris, Medical Oncology Unit - National Cancer Institute , Bari, Italy Background: Bone metastasis represents an increasing clinical problem in advanced gastric cancer (GC) as disease-related survival improves. In literature few data on the natural history of bone disease in this malignancy are available. Methods: A retrospective, observational multicenter study aimed to define the natural history of GC patients with bone metastasis was conducted in 22 Italian hospital centres in which these patients received diagnosis and treatment of disease from 1998 to 2011. Data on clinicopathology, skeletal outcomes, skeletal-related events (SREs), and bonedirected therapies for 208 deceased GC patients with evidence of bone metastasis were statistically analyzed. Results: Median time to bone metastasis was 8 months (CI 95%, 6.125–9.875 months) considering all included patients. Median number of SREs/patient was one; less than half of the patients (31%) experienced at least one event and only 4 and 2% experienced at least two and three events, respectively. Median times to first and second SRE were 2 and 4 months, respectively. Median survival was 6 months after bone metastasis diagnosis and 3 months after first SRE. Median survival in patients who did not experience SREs was 5 months. Among patients who received zoledronic acid (ZOL) before the first SRE, median time to its appearance was significantly prolonged compared to control (7 months vs 4 months for control; P:0.0005). Conclusions: To our knowledge, this retrospective analysis is the largest multicenter study to demonstrate that bone metastases from GC are not so rare, are commonly aggressive and result in relatively early onset of SREs in the majority of patients. Furthermore, our large study, which included 90 patients treated with ZOL, showed, for the first time in literature, a significant extension of time to first SRE and increase in the median survival time after diagnosis of bone metastasis.

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Surgery-induced peritoneal metastasis and its intraoperative treatment. Presenting Author: Satoshi Murata, Department of Surgery, Shiga University of Medical Science, Otsu, Japan

Who benefits from radiotherapy for gastric cancer? A meta-analysis. Presenting Author: Nitin Ohri, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY

Background: A large number of advanced gastric cancer patients undergoing curative gastrectomy with D2 lymph node dissection (D2 gastrectomy) show peritoneal metastasis. The source of these metastatic cells and their treatment remain unclear. We examined the mechanism of surgeryinduced peritoneal metastasis and determined the appropriate intraoperative treatment. Methods: (1) Curative gastrectomy was performed for 102 gastric cancer patients. Peritoneal lavage fluid was collected before and after gastrectomy. Cytology, RT-PCR, and cell culture were used to determine the presence of cancer cells. Proliferative potential of tumor cells was evaluated using Ki-67 staining. Tumorigenic capacity was assessed by cell injection into the peritoneal cavity of NOD/ShiJic-scid mice. (2) Fifty clinical T3(SE) or T4(SI) advanced gastric cancer patients undergoing curative D2 gastrectomy prospectively received intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) in a phase II trial. HIPEC comprised 50 mg CDDP, 10 mg MMC, and 1000 mg 5-FU in 5 L saline maintained at 42– 43C° for 30 min. Results: (1) Of 102 peritoneal lavage fluid samples obtained before gastrectomy, 57 from both early and advanced cancer patients did not contain CEA or CK20 mRNA amplification products or cancer cells. Of these 57 samples, CEA or CK20 mRNA was detected in 35 and viable cancer cells were identified in 24 after gastrectomy. Viable cancer cells in all 24 cases showed Ki-67 positivity, indicating proliferative activity. Cultured viable cancer cells developed into peritoneal tumor nodules after spill over into the peritoneal cavity in NOD/ShiJic-scid mice. (2) Fifty patients were eligible for the phase II clinical trial. The overall 5-year survival rate for all patients was 92.4%. This rate in patients with pT2(ss) (n ⫽ 12), pT3(se) (n ⫽ 35), and pT4(si) (n ⫽ 3) disease was 90.0%, 92.3%, and 100%, respectively. Only 2 patients (4%) showed peritoneal relapse. Conclusions: Viable tumorigenic cancer cells spilled over the peritoneal cavity during curative gastrectomy. Intraoperative HIPEC following curative D2 gastrectomy effectively prevented peritoneal metastasis, thereby potentially improving the prognosis of patients with advanced gastric cancer.

Background: Randomized trials have demonstrated significant survival benefits with the use of adjuvant (including neoadjuvant) chemotherapy or chemoradiotherapy for gastric cancer. The importance of adjuvant radiotherapy (RT) remains unclear. Here we perform an up-to-date meta-analysis of randomized trials testing the use of radiotherapy for resectable gastric cancer. Methods: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized trials testing adjuvant RT for resectable gastric cancer. Hazard ratios describing the impact of adjuvant RT on overall survival (OS) and disease-free survival (DFS) were extracted directly from the original studies or calculated from survival curves. Pooled estimates were obtained using the inverse variance method. Subgroup analyses were performed to determine if the efficacy of RT varies with chemotherapy use, RT timing, geographic region, type of nodal dissection performed, and lymph node status. Results: Thirteen studies met all inclusion criteria and were used for this analysis. Adjuvant RT was associated with a significant improvement in both OS (HR⫽0.78, 95% CI: 0.70 to 0.86, p⬍0.001) and DFS (HR⫽0.71, 95% CI: 0.63 to 0.80, p⬍0.001). In the five studies that tested adjuvant chemoradiotherapy against adjuvant chemotherapy, similar effects were seen for OS (HR⫽0.83, 95% CI: 0.67 to 1.03, p⫽0.087) and DFS (HR⫽0.77, 95% CI: 0.91 to 0.65, p⫽0.002). Available data did not reveal any subgroup of patients that does not benefit from adjuvant RT. Conclusions: In randomized trials for resectable gastric cancer, adjuvant RT provides an approximately 20% improvement in both DFS and OS. Available data do not reveal a subgroup of patients that does not benefit from adjuvant RT. Further study is required to optimize the implementation of adjuvant RT for gastric cancer with regards to patient selection and integration with systemic therapy.


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Nomogram predicting long-term survival probability of thoracic esophageal squamous cell carcinoma after radical esophagectomy. Presenting Author: Weimin Mao, Key Laboratory Diagnosis and Treatment Technology on Thoracic Oncology & Cancer Research Institute, Zhejiang Cancer Hospital, Hangzhou, China

The association of objective response and overall survival in patients with inoperable or metastatic gastric and esophagogastric junction (EGJ) cancer: A pooled analysis of individual patient data from first-line clinical trials. Presenting Author: Toki Anna Bolt, Krankenhaus Nordwest, UCT University Cancer Center, Frankfurt, Germany

Background: Nomograms have been widely and successfully used for numerous cancers to obtain reliable prognostic information for each individual patient.To date, however, no studies have conducted survival estimates using nomograms for esophageal squamous-cell carcinoma (ESCC) in Chinese population.The purpose of this study is to develop a nomogram to predict the long-term survival probabilities in patients diagnosed with ESCC after radical esophagectomy. Methods: This study involves a dataset containing 1923 patients who underwent radical esophagectomy for ESCC at Zhejiang Cancer Hospital in Hangzhou, China. Among them, 1,578 patients with no missing data were used to build a prognostic nomogram based on Cox proportional hazard regression model. A multivariate survival analysis using Cox regression model was applied to identify significant variables with P-values ⬍0.05. On the basis of the predictive model with the identified variables, a nomogram was constructed for predicting five-year and ten-year overall survival probabilities. The prediction model was internally validated using bootstrap resampling, assessing its optimism-corrected discrimination and calibration. Results: The median of overall survival times of 1578 ESCC patients was 35.6 months, and the 5-year and 10-year survival rate was 32% and 20%, respectively. The multivariate Cox model identified alcohol, tumor length, surgical approach, number of surgical removed lymph node, ratio of metastatic lymph nodes, region of lymph nodes dissection, depth of invasion, differentiation of tumor, postoperative complications as covariates significantly associated with survival. Across the 100 bootstrap replicates, the median optimism-corrected summary C-index for predicting survival was 0.713 (SE⫽0.011). Conclusions: A nomogram predicting 5and 10-year overall survival after radical esophagectomy for ESCC in Chinese population was constructed and validated based on nine significant variables. The nomogram can be applied in daily clinical practice for individualized survival prediction of ESCC patients after potentially curative esophagectomy.

Background: The aim of the study is to determine whether the achievement of an objective response to first-line chemotherapy is prognostic of patient’s outcome in gastric/EGJ adenocarcinoma. Methods: Individual patient (pts) data from prospective first-line trials conducted by a single study group were used. Patients received platin/5-FU based chemotherapy with or without docetaxel. Responses were evaluated according to WHO criteria in all trials. Response data, patients’ characteristics (age, sex, entity, histological type, primary location, ECOG PS, and type and number of metastatic sites), type of chemotherapy, and overall survival data were analyzed. Results: 612 pts were included. Median age was 66 yrs; 31.5% had ECOG status 0, 58.3% ECOG 1, and 9.8% ECOG 2 & 3. Gastric primaries were found in 44.4% and EGJ in 35.8% of pts (19.7% were overlapping/not evaluable). According to Lauren classification, 36.8% had intestinal, 32.4% diffuse, and 8.5% mixed types (22.4% were not classifiable). 64.5% had positive non-regional lymph nodes (LN) involvement, 14.1% LN involvement without other metastases, 33.3% had peritoneal carcinomatosis, 44.0% liver and 16.7% lung metastases. Response rates were complete (CR) in 3.1%, partial (PR) in 36.4%, stable disease (SD) in 34.5%, and progressive disease (PD) in 15.0% pts (10.9% were not evaluable). Overall response rate (OR; CR ⫹ PR) was 39.5%. Median overall survival times in pts with CR vs PR vs SD vs PD were 37.9 vs 14.7 vs 10.9 vs 5.2 months, respectively; p⫽1.26 x 10-33). OR (CR or PR) also strongly predicted OS (16.7 vs 8.1 months in pts with vs no OR, p⫽1.08 x 10-17). OR remained the strongest predictor of OS in the multivariate analysis (p⫽6.55 x 10-7) including all baseline criteria mentioned above followed by ECOG PS (p⫽0.048) and the presence of non-regional LN as the only site of metastasis (p⫽0.034). Conclusions: The achievement of an objective response is the strongest predictor of survival in pts with gastric and EGJ cancer and could serve as a surrogate marker if validated.

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Multicenter, phase II study of trastuzumab and paclitaxel to treat HER2positive, metastatic gastric cancer patients naive to trastuzumab (JFMC451102). Presenting Author: Satoru Iwasa, Gastrointestinal Oncology Division, National Cancer Center Hospital, Tokyo, Japan Background: The ToGA study indicated that first-line treatment using trastuzumab (T-mab) combined with capecitabine and cisplatin conferred a survival (OS) benefit to patients with HER2-positive metastatic gastric cancer (mGC). However, no reports have described the efficacy and safety of second-line treatment of HER2-positive mGC patients with T-mab who were naïve to the drug. Methods: JFMC45-1102 was a multicenter, Phase II study. Patients positive for HER2 (IHC3⫹ or IHC2⫹/FISH⫹) with gastric adenocarcinoma confirmed histologically; older than ⱖ 20 y; who received one or more prior chemotherapies but no prior therapy with T-mab; and normal left ventricular ejection fraction (LVEF ⱖ 50%) were eligible. Patients received paclitaxel (80 mg/m2on days 1, 8, and, 15 q4w) plus T-mab (8 mg/kg initial dose, followed by 6 mg/kg q3w). Treatment continued until their disease progressed; there was unacceptable toxicity or patient’s refused further treatment. The primary endpoint was overall response rate (ORR) evaluated according to RECIST ver. 1.0. Threshold and expected ORR were estimated at 15% and 30%, and secondary endpoints included progression free survival (PFS), time to treatment failure (TTF), overall survival (OS) and safety. Results: Fourty-six patients were enrolled between September 2011 and March 2012. Patients characteristics were: gender (M/F) 37/9; median age 69; ECOG PS0/1/2, 35/10/1; unresectable/recurrence 25/21; number of prior treatments (1/2), 41/5. The ORR was 37.2% (95% CI: 23.0-53.3%). The median PFS and TTF were 5.2 months (95% CI 3.9-6.6) and 5.2 months (95% CI 3.9-6.6), respectively. The protocol was discontinued for 27 patients (87.1%) for disease progression, and one patient each (3.2%) for severe adverse events, physician’s recommendation, patient refusal, and treatment related death. Conclusions: Combination chemotherapy of paclitaxel plus T-mab showed promising activity and was tolerated well by patients naïve to T-mab who were positive for HER2 and treated previously for mGC. Clinical trial information: UMIN000006223.


Nimotuzumab plus paclitaxel and cisplatin as first-line treatment for esophageal squamous cell cancer: A single center prospective clinical trial. Presenting Author: Xiaodong Zhang, Department of Gastrointestinal Oncology, Peking University School of Oncology, Beijing Cancer Hospital and Institute, Beijing, China Background: The aim of this present phase II study is to explore the safety and efficacy of paclitaxel (T), cisplatin (C), and nimotuzumab (N), a humanized anti-EGFR monoclonal antibody combination (TCN) as first-line treatment in advanced esophageal squamous cell cancer (ESCC). Methods: Patients with histologically confirmed advanced ESCC, measureable tumor, and no prior chemotherapy and radiotherapy except adjuvant treatment were enrolled. Patients were given cisplatin 60mg/m2, paclitaxel 175mg/m2per 21 days for at least 2 cycles. The nimotuzumab was given 200mg weekly. Radiotherapy was admitted for patients with unresectable local advanced disease after 4 cycle of TCN treatment. The primary endpoints were safety and objective response rate (ORR). The secondary endpoints were progression-free survival (PFS) and over-all survival (OS). The expression of EGFR and ERCC1 were also analyzed by histoimmunochemical staining. Results: Between Mar. 2011 and Dec. 2012, 55 patients with advanced ESCC were enrolled and 53 (96.4%) were eligible for evaluation. The ORR was 54.7% (29/53) and the DCR was 94.3% (50/53). The expression of EGFR and ERCC1 were detected in 46 and 31 patients respectively. The ORR had no relation to both the expression of EGFR (55.3% vs 62.5%, p⫽0.71) and ERCC1 (41.7% vs 58.3%, p⫽0.47). As a median follow-up of 15months, the median PFS was 10.5 months (95% CI 8.7 to 12.3 months).The TCN combination treatment was well tolerated and the most common adverse events were alopecia (86.8%), leukopenia (84.9%), anorexia (84.9%), vomiting (73.6%), fatigue (73.6%), pain (66.0%), and anaemia (39.6%). And 18 (34%) patients had Grade 3 to 4 leukopenia. The median OS have not yet been reached. Conclusions: In this study, the ORR, DCR and PFS are superior to previous published studies. The addition of anti-EGFR treatment of nimotuzumab to standard chemotherapy was well tolerated with no serious AEs. But the expression of EGFR by IHC could not predict the outcome of nimotuzumab treatment. A phase III study of TCN followed by radiotherapy in unresectable local advanced ESCC had been designed to explore the survival benefits. Clinical trial information: NCT01336049.




NeoHx study: Perioperative treatment with trastuzumab in combination with capecitabine and oxaliplatin (XELOX-T) in patients with HER2 resectable stomach or esophagogastric junction (EGJ) adenocarcinoma—R0 resection, pCR, and toxicity analysis. Presenting Author: Fernando Rivera, Hospital Universitario Marqués de Valdecilla, Santander, Spain Background: Perioperative chemotherapy has demonstrated better OS and DFS than surgery alone in resectable stomach or EGJ adenocarcinoma. Trastuzumab has improved OS when added to chemotherapy in pts with HER-2 ⫹ metastatic gastric cancer and is interesting to explore its role in the perioperative setting. Methods: A Spanish, multicenter, open-label phase II study evaluated the efficacy and toxicity profile of perioperative XELOX-T (capecitabine 1000 mg/m2/12h po days 1-14, oxaliplatin 130 mg/m2 day 1, trastuzumab 8 mg/kg¡ mg/kg day 1, q3w ; 3 preoperative cycles and 3 postsurgery cycles followed by 12 cycles of trastuzumab monotherapy) in patients with T1-2N⫹M0 or T3-4NxM0 resectable stomach or EGJ adenocarcinoma, HER-2⫹ ( IHQ3⫹ or IHQ2⫹/FISH⫹). The primary endpoint was 18 months DFS, secondary endpoint included pCR, R0 resection rate, ORR and toxicity of preoperative treatment (NCI CTC v3.0 criteria). Results: From June 2010 to March 2012, 36 pts were included: median age 65 (39-85); ECOG 0/1/2: 16/19/1 pts; localization: stomach 21 pts, EGJ 15 pts; histologic type: intestinal: 23 pts, diffuse: 4 pts, mixed: 1pt, not specified 8 pts; TNM: T 4: 7 pts; N⫹: 31 pts. Preoperative XELOX-T: Response: PR: 14 pts (39%), SD: 18 pts, PD: 0 pts, NE: 4 pts. G-3-4 toxicity (ⱖ 5% of pts): diarrhea 22% and asthenia 5%. Surgery was performed in 31 pts: R0: 28 pts (78%, 95% CI: 61-90%), R1: 1 pt, R2: 2 pts (1 had peritoneal carcinomatosis); pCR was observed in 7 pts (19 %; 95% CI: 8-36%) and 22 pts (61%) were pN0. Two pts died due to surgical complications,. We do not have mature data about postoperative XELOX-T yet. Follow-up is still too short for DFS and OS. Conclusions: This preliminary analysis suggests that perioperative XELOX⫹T in HER-2 positive resectable stomach or esophagogastric junction adenocarcinoma is feasible and has interesting activity. Clinical trial information: NCT01130337.

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A comparison of immunohistochemistry (IHC) and dual-color silver in situ hybridization (SISH) with a novel method combining both gene and protein platforms on a unique slide for testing the HER2 in gastric carcinoma. Presenting Author: Dominique Werner, Krankenhaus Nordwest, UCT University Cancer Center, Frankfurt, Germany Background: Amplification and/or protein overexpression of HER2 in gastric cancer is a prerequisite to establish an adequate treatment strategy. The European standard defined HER2 positivity by IHC as first evaluation assay followed by ISH in 2⫹ cases. Gastric tumors are heterogeneous and separate evaluations lead to uncertainties and in localizing distinct clones and are time consuming. The aim of this study was to evaluate the feasibility of gene-protein platform in comparison to single staining methods. Methods: IHC plus SISH and gene-protein platform (IHC/SISH, protein/gene) method for HER2 were performed in randomly collected 100 cases of gastric carcinoma. Results of IHC and SISH were compared with IHC/SISH staining. Rüschoff criteria were applied. Tumors were HER2 positive when expression 3⫹ or 2⫹ plus gene amplification (EU-Norm) was found. In Second definition (US-Norm), tumors showing HER2 expression 3⫹ or amplification were considered HER2 positive. Results: 96 of 100 samples were eligible. Amplification was observed in 14.6% and 15.6% by SISH and IHC/SISH. 71.9% by IHC vs. 75.0% by IHC/SISH had no expression (0) and 10.4% (IHC vs. IHC/SISH) had weak (1⫹) HER2 expression. Moderate expression (2⫹) and overexpression (3⫹) were observed in IHC 6.3%/11.5% and IHC/SISH 6.3%/8.3%, respectively. There were high concordances in IHC assessment of cases with score 0 (94.8%; ␬⫽0.87) and 3⫹ (96.9%; ␬⫽0.83) and moderate concordances in 1⫹/2⫹ cases (89.6%; ␬⫽ 0.44 vs. 93.8%; ␬⫽0.47). Rate of HER2 positivity was similar in standard or novel method. In EU Definition 14.6% vs. 10.4% (p⫽0.52) were positive, respectively, with very good concordance (95.8%; ␬⫽0.81).Concordance between HER2 positivity in standard or novel method was very good (99.0%; ␬⫽0.96) in US definition with no significant differences (17.7% vs. 16.7%; p⫽1). Conclusions: Geneprotein platform has been tested for first time in gastric carcinoma. Results showed that this novel platform can be a feasible alternative to single methods. Discrepancies in cases with weak or moderate HER2 expression can be a result of observer variability.

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Concurrent chemoradiotherapy with cetuximab plus twice-weekly paclitaxel and cisplatin followed by esophagectomy for locally advanced esophageal squamous cell carcinoma. Presenting Author: Chia-Chi J. Lin, National Taiwan University Hospital, Taipei, Taiwan Background: We investigated the efficacy and safety of adding cetuximab to twice-weekly paclitaxel/cisplatin-based concurrent chemoradiotherapy (CCRT), followed by surgery, for patients with locally advanced esophageal squamous cell carcinoma (ESCC). Methods: Patients with locally advanced ESCC (T3N0-1M0 or T1-3N1M0 or M1a by AJCC 2002) were treated with paclitaxel (35 mg/m2 1 h D1, 4/wk), cisplatin (15 mg/m2 1 h D2, 5/wk), cetuximab (400 mg/m2 2 h D-5, then 250 mg/m21 h D3/wk) and radiotherapy (2 Gy D1-5/wk). The feasibility of esophagectomy was evaluated for all patients at the accumulated radiation dose of 40 Gy. If esophagectomy was not feasible, CCRT was continued to a radiation dose of 60-66 Gy. Results: 66 patients were enrolled between Oct 2008 and Jun 2010, and 61 (94%) of them had T3N1M0 or M1a tumors by endoscopic ultrasonographic staging. All patients received CCRT to 40 Gy. Forty-three patients underwent surgery, and 17 patients continued definitive CCRT to 60-66 Gy. Of the scheduled doses of paclitaxel, cisplatin, and cetuximab, 80%, 79%, and 99% were given, respectively. The most common grade 3/4 toxic effects were leukopenia (51%), neutropenia (15%), esophagitis (19%), and infection (12%). The pathological complete response rate was 24% (intent-to-treat, 16/66) (95% confidence interval: 13-35%) and 37% (who underwent resection, 16/43). At the median follow-up of 34.6 months, the median progression-free (PFS) and overall survivals were 21.6 and 33.9 months, respectively. No KRAS codon 12/13 mutations were identified in 47 tumor samples. The median PFS for patients with two, one, and no adverse tumor biomarkers (Tau⫹, ERCC1⫹, pEGFR-) (n ⫽ 40) was 12.3 months, 27.6 months, and greater than 33.6 months, respectively (p ⫽ .087). Conclusions: Adding cetuximab to twice-weekly paclitaxel/cisplatinbased CCRT prior to esophagectomy is an active and tolerable treatment for locally advanced ESCC. Clinical trial information: NCT01034189. Thrombocytopenia Neutropenia Infection Stomatitis Esophagitis Skin rash Hypomagnesemia

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Grade 3

Grade 4

10 (17%) 33 (56%) 8 (14%) 33 (56%) 43 (73%) 57 (97%) 14 (24%)

2 (3%) 8 (14%) 7 (12%) 1 (2%) 11 (19%) 1 (2%) 0

1 (2%) 1 (2%) 0 0 0 0 3 (5%)


Preoperative chemotherapy plus bevacizumab with early salvage therapy based on FDG-PET response in locally advanced gastroesophageal junction and gastric adenocarcinoma. Presenting Author: Geoffrey Yuyat Ku, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Response on FDG-PET scan during preoperative chemotherapy has prognostic significance. We performed a phase II trial to examine the effectiveness of FDG-PET directed early switching to salvage chemotherapy measured by 2-year disease free survival (DFS). Methods: Pts with PET avid, endoscopic ultrasound and laparoscopically staged T3 or N⫹ resectable gastric or GEJ adenocarcinoma received induction epirubicin 50mg/m2, cisplatin 60mg/m2 Day 1, capecitabine 625mg/m2 BID Days 1-21 (ECX) and bevacizumab 15mg/kg Day 1. PET scan was repeated at Week 3. PET responders (ⱖ35% decline in SUV) continued with ECX for 2 more cycles. PET non-responders were switched to 2 cycles of salvage therapy: docetaxel 30mg/m2 and irinotecan 50mg/m2Days 1 and 8 q21 days and bevacizumab 15mg/kg Day 1. All pts went to surgery 4 weeks after Cycle 3. Results: Twenty of planned 60 pts were enrolled before the study closed for poor accrual. Eleven (55%) had a PET response after induction. Ten of 11 underwent R0 resection: 1/10 path complete response, 3/10 path partial response. Nine PET non-responders were switched to the salvage regimen. Seven of 9 non-responders had R0 resection, none achieved a pathological response. The median DFS for PET responders was 27.8 mos (95% CI 10.3-27.8) and DFS in salvage group has not been reached. There was no significant difference in DFS between the two groups (p⫽ 0.4). Follow up for overall survival is ongoing. Conclusions: Response on PET scan during induction chemotherapy can identify early treatment failures. The results for therapy cross-over indicate a potentially improved DFS with salvage chemotherapy. Results from this trial are hypothesis generating and merit evaluation in a larger clinical trial. Updated survival data will be presented. Clinical trial information: NCT00737438.


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Early results of a randomized phase II, compass trial to compare regimen and duration of neoadjuvant chemotherapy for gastric cancer. Presenting Author: Takaki Yoshikawa, Kanagawa Cancer Center, Yokohama, Japan

Effect of the revised AJCC staging (7th edition) on prognostic stratification in patients with surgically resected esophageal squamous cell carcinoma. Presenting Author: Gloria Terase Minella, UPMC Shadyside, Pittsburgh, PA

Background: Prognosis for stage III gastric cancer was not satisfactory even by D2 gastrectomy and adjuvant chemotherapy. Neoadjuvant chemotherapy is another promising approach. This study investigated the outcomes of two and four courses of neoadjuvant S-1/cisplatin (SC) and paclitaxel/cisplatin (PC) using a two-by-two factorial design for locally advanced gastric cancer. Methods: Patients with stage II schirrhous/ junctional tumors, stage III, or resectable stage IV, received S-1 (80 mg/m2 for 21 days with 1 week rest)/cisplatin (60 mg/m2 at day 8) or paclitaxel/ cisplatin (80 mg/m2 and 25 mg/m2, respectively, on days 1, 8, and 15 with 1 week rest). The primary endpoint was 3-year OS. Key secondary endpoints included pathological/clinical response, R0 resection, and adverse events. Sample size was set at 60 to 80 to achieve 10% improvement of 3-year OS by four courses or by PC with approximately 80% probability of the correct selection. Results: Between Oct 2009 and July 2011, 83 patients were assigned to arm A (2 courses of SC, n⫽21), arm B (4 courses of SC, n⫽20), arm C (2 courses of PC, n⫽21), and arm D (4 courses of PC, n⫽21). Clinical response (arm A/B/C/D) was 29%/40%/33%/ 24%. R0 resection (arm A/B/C/D) was 76%/75%/57%/76%. Pathological response (arm A/B/C/D), defined as tumor regression more than two third in the primary tumor, was 43%/40%/29%/38%. Pathological complete response (arm A/B/C/D) was 0%/10%/0%/10%. Major grade 3/4 toxicities (arm A/B/C/D) were anemia (14%/15%/0%/28.6%), neutropenia (10%/ 15%/14%/33%), nausea (0%/10%/5%/5%), and appetite loss (5%/10%/ 0%/5%). Pathological complete response by per-protocol analysis (arm B/D) was 17% and 12%. Treatment discontinuation (number of patients, arm A/B/C/D) was disease progression (1/3/0/1), toxicities (1/4/0/3), and others (0/1/0/0). No surgical mortality was observed. Grade 3 morbidity classified by Clavien-Dindo was leakage in 5% (arm A), pancreatic fistula in 5% (arm C), and postoperative hemorrhage in 5% (arm B). Conclusions: Pathological complete response could be induced by four courses of neoadjuvant chemotherapy without a marked increase of toxicities, regardless of a SC or PC regimen. Clinical trial information: UMIN000002595.

Background: Historically, the AJCC esophageal staging system separated patients into prognostic groups based on tumor, node, and metastasis (TNM) classifications. In 2010, the 7th edition (AJCC 7) significantly modified esophageal squamous cell cancer (ESCC) staging by separating ESCC from adenocarcinoma, incorporating tumor grade and location for node negative cancers, and stratifying by the number of involved regional nodes for node positive cancers. Our study aim was to determine whether AJCC 7 stage groupings provide improved survival prognostication compared to 6th edition (AJCC 6). Methods: We abstracted pathology and survival for 150 consecutive ESCC patients who underwent esophagectomy (1994-2012); 44 patients received induction therapy. AJCC 6 and AJCC 7 stages were assigned and overall survival analyzed from esophagectomy to death or most recent alive contact and censored at 60 months. Discriminatory ability and homogeneity within subgroups was assessed with KaplanMeier curves and monotonicity comparisons were evaluated with linear trend chi-squared tests. Overall survival was compared using Cox regression and Akaike Information Criterion (AIC) used to assess model fit. Results: Compared to AJCC 6, AJCC 7 upstaged 32 patients from IIa to IIb and 1 patient from IIb to IIIa and downstaged 3 patients from stage IIa to Ib. AJCC 7 subclassified 42 AJCC 6 stage III patients (17 IIIa, 10 IIIb and 15 IIIC). Median overall survival was 19 months. Kaplan-Meier log-rank statistic indicated stronger differentiation in AJCC 7 (19.8 vs 29.7). Cox regression likelihood (19.5 vs 26.1), AIC (618.1 vs 611.6), and linear trend chi-squared at 24- (17.5 vs 24.3) and 60-months (13.3 vs 17.3), were all superior for AJCC 7 stage groupings (AJCC 6 vs AJCC 7, respectively). Conclusions: AJCC 7 stage groupings demonstrate superior homogeneity, discriminatory ability and monotonicity compared to AJCC 6. Incorporating the extent of nodal disease, tumor location and tumor grade into the revised AJCC 7 stage classification improves prognostic stratification of surgically resected ESCC patients, including patients who received induction therapy.

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Determination of the optimal cutoff percentage of residual tumors to define the pathologic response rate (pathRR) of gastric cancer (GC) treated with preoperative therapy (JCOG1004-A). Presenting Author: Kenichi Nakamura, JCOG Operations Office, National Cancer Center, Tokyo, Japan

Result of clinical study on feasibility of laparoscopy-assisted D2 distal gastrectomy to treat advanced gastric cancer (COACT_1001). Presenting Author: Young Woo Kim, Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, South Korea

Background: PathRR is a common endpoint used to assess the efficacy of preoperative therapy for GC. PathRR is estimated based on the percentage of the residual tumor area in the preexisting tumor bed. Various cut-off definitions that have used for past studies (e.g. 10%, 33%, 40%, 50%, 67%) often impair the comparability of pathRRs between studies. Methods: Individual patient data from four JCOG trials evaluating preoperative chemotherapy were used (JCOG0001, irinotecan⫹cisplatin, n⫽55; JCOG0002, S-1, n⫽55; JCOG0210, S-1⫹cisplatin, n⫽50; JCOG0405, S-1⫹cisplatin, n⫽53). Pathological specimens were evaluated from 173 out of 188 patients (92%) who underwent surgery. Residual and preexisting tumor areas were traced on a virtual microscopic slide by one pathologist and another confirmed these areas. The hazard ratio (HR) in overall survival was calculated for each cut-off percentage by stratified Cox regression analysis including the study as a stratification factor, and concordance probability estimates (CPE) were also calculated. Results: The numbers of patients with 0-10%/11-33%/34-50%/51-66%/67-100% residual tumors were 43/33/27/23/47, respectively. Overall, HR was the largest in the 10% cut-off and CPE was the largest in 33%. When patients with R1/R2 resections were excluded, both HR and CPE were the largest in the 10% cut-off. In subgroup analyses, almost all cut-offs predicted survival well regardless of the histologic type (intestinal/diffuse), and no cut-off predicted survival for type 4 (linitis plastica type) tumors. Conclusions: PathRR is not recommended for clinical trials including type 4 tumors. The 10% cut-off is recommended for non-type 4 tumors, though 33% is also applicable.

Background: Benefit of quality of life made laparoscopic gastric cancer surgery attractive, but there are still concerns about laparoscopic lymph node dissection. The aim of this study was to evaluate a feasibility of laparoscopy-assisted distal gastrectomy (LADG) with D2 lymph node dissection compared with open distal gastrectomy (ODG) for advanced gastric cancer (AGC). Methods: Patients with cT2-T4a and cN0-2 (AJCC 7th staging system) distal gastric cancer were randomly assigned to LADG or ODG. The primary endpoint was the non-compliance rate of the lymph node dissection defined as rate of cases where there was more than one missing lymph node station according to the guidelines of the Japanese Research Society for Gastric Cancer lymph node grouping. Secondary endpoints were perioperative complications, changes of inflammatory and immunological parameters, postoperative hospital stay, and 3 year disease free survival. This trial was registered at ClinicalTrials.gov as NCT01088204. Results: Between Jun 2010 and Oct 2011,204 patients were randomly allocated and underwent either LADG (n⫽105) or ODG (n⫽99). 8 patients were excluded in the intention to treatment analysis because of protocol violation and patient’s withdrawal of permission, and finally 100 patients in LADG and 95 patients in ODG were analyzed. There were no significant differences of overall non-compliance rate of lymph node dissection between LADG and ODG groups; they were respectively 47.0% and 43.2%. (p⫽0.648). In the subgroup analysis according to the stratified risk groups, non-compliance rate in LADG was significantly higher than ODG (52.0% vs. 25.0%, p⫽0.043) for clinical stage III but it was not significantly different for stage II (46.2% vs. 48.9%, p⫽0.788). Intraoperative event rate was not significantly different between groups (LADG;6.0% and ODG;4.2%, p ⫽0.748). Complications rate in early postoperative period up to 1 month was also not different between groups (LADG;17.0 %, ODG;18.8%, p⫽0.749). Conclusions: LADG was feasible in AGC compared with ODG, especially in clinical stage II in terms of non-compliance rate of D2 lymph node dissection and perioperative complications. Clinical trial information: NCT01088204.

Cut-off percentage Overall (nⴝ173) Only R0 resection (nⴝ134) Non-Type 4 (nⴝ105) Type 4 (nⴝ68)

10% 33% 50% 67% 10% 33% 50% 67% 10% 33% 50% 67% 10% 33% 50% 67%

HR

P value

CPE

1.91 1.700.010 0.0090.559 0.565 1.55 0.027 0.552 1.71 0.011 0.552 1.87 1.540.036 0.0790.561 0.553 1.24 0.397 0.524 1.38 0.233 0.528 2.59 2.400.004 0.0030.591 0.602 1.91 0.012 0.576 2.16 0.004 0.592 1.25 1.100.579 0.7620.518 0.512 1.08 0.799 0.510 1.62 0.165 0.550




Comprehensive genetic mutation analysis of human gastric adenocarcinomas. Presenting Author: Jinfei Chen, Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China Background: Gastric cancer is the one of the major cause of cancer-related death, especially in Asia. Gastric adenocarcinoma, the most common type of gastric cancer, is heterogeneous and its incidence and cause varies widely with geographical regions, gender, ethnicity, and diet. Since unique mutations have been observed in individual human cancer sample, identification and characterization of the molecular alterations underlying individual gastric adenocarcinoma is a critical step for developing more effective, personalized therapies. Until recently, identifying genetic mutations in an individual basis by DNA sequencing remains a daunting task. The recent advance of new next-generation DNA sequencing technologies, such as the semiconductor-based Ion Torrent sequencing platform, makes DNA sequencing cheaper, faster and more reliable. Methods: In this study, we aim to identify genetic mutations in the genes, which are targeted by drugs in the clinical use or under development, in individual human adenocarcinoma sample by using Ion Torrent sequencing. We sequenced 739 loci from 46 cancer-related genes in 242 human gastric adenocarcinoma samples using the Ion Torrent Ampliseq Cancer Panel. Results: The sequencing analysis revealed frequent mutations in MLH1 (8.3%), MET (11.2%), KIT (21.5%), and PIK3CA (40.5%) genes in the human gastric adenocarcinomic samples. Many mutations that are not previously reported in gastric adenocarcinomas were also identified. Moreover, distinctive patterns and the combination of mutations in various sets of genes, including HER2, EGFR, MET, FGFR, PI3K/MTOR, MLH1, MET, KIT, PIK3CA, and P53, were also identified in these gastric adenocarcinoma samples. Conclusions: Thus, this study indicates the necessity of sequencing individual human adenocarcinoma in order to match the use of personalized single targeted drugs or two or more targeted drugs in combination against individual adenocarcinoma-specific mutations.

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Concordance of HER2 and its related molecules between primary and paired liver metastatic sites in gastric cancer. Presenting Author: Eiji Shinozaki, Department of Gastroenterology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan Background: Trastuzumab is the 1st molecular targeting drug in HER2positive advanced gastric cancer that has been shown to confer overall survival benefit adding to chemotherapy. In breast cancer it has been already used long time, it is known that there are the discordance of its target; HER2 between primary and metastatic site. Although molecular targeting drugs as Trastuzumab are expected to control the metastatic disease, molecular status is usually evaluated in the primary site because metastatic sites are difficult to biopsy. In this study we attempted to compare HER2 and its related molecular status, which have interaction each together, between primary and paired liver metastatic sites in gastric cancer. Methods: Total 58 consecutive cases with gastric cancer who underwent surgical resection of primary site and synchronous or metachronous liver metastasis were examined. HER2, EGFR, c-MET and IGF-1R status were evaluated by immunohistochemistry(IHC) in primary and paired liver metastasis. HER2 expression by IHC using HercepTest (DAKO) were assessed according to Gastric Cancer Scoring System. On the other molecular expression by IHC, positive expression was defined as 25% or more staining with intensity 2 or 3⫹. We analyzed the concordance of their expression in both sites. Results: The patient cohort consists predominantly of male (78%), with Lauren’s diffuse (37%) and intestinal tumors (62%). Fifty three percent of cases were synchronous liver metastasis. The positive rate of primary and paired liver metastatic sites were 10.3%, 8.6% in HER2, 1.7%, 5.1% in EGFR, 44.8%, 31.0% in c-MET and 31.0%, 29.3% in IGF-1R. The concordance between primary and paired liver metastatic sites were 91.3%, 93.1%, 75.8%, and 70.6%, respectively. Conclusions: Our data suggested that in HER2 and EGFR the concordance between primary and metastatic site were high, other hands the concordance of c-MET and IGF-1R were relatively low. It might be necessary to rebiopsy to estimate the expression of c-MET and IGF-1R in gastric cancer.

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Evaluation of serum HER2 extracellular domain in in metastatic gastric or gastroesophageal junction cancer: Correlation with HER2 status by immunohistochemistry and fluorescence in situ hybridization and clinicopathologic parameters. Presenting Author: Xin An, Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China Background: To explore the association between serum human epidermal growth factor receptor-2 (HER2) extracellular domain (ECD) and tissue HER2 status, their relationship with clinicopathological parameters and impact on overall survival (OS) in metastatic gastric or gastro-oesophageal junction (GEJ) adenocarcinoma. Methods: A total of 219 histologically confirmed inoperable locally advanced, recurrent, or metastatic gastric or GEJ adenocarcinoma were included. Serum HER2 ECD was measured by chemiluminescent assay. Tissue HER2 status was accessed by fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) assay. Results: The median serum ECD level was 9.3 ng/ml (range 3.0 to ⬎350). Tissue HER2 status was positive (IHC3⫹ or 2⫹ with FISH amplification) in 37 patients (16.9%) and negative in 182 patients (83.1%). Statistically significant associations were found between serum HER2 ECD level and HER2 status assessed by IHC and FISH. The ROC-analysis suggested the cutoff of 16.35 ng/ml (24 of 219 patients had HER2 ECD ⬎16.35 ng/ml ) could produce a sensitivity of 51.4% and a specificity of 97.3% to predict tissue HER2 status. If the cutoff value was increaseed to 22 ng/ml, then all 12 patients with serum HER2 ECD ⬎22 ng/ml were HER 2 positive in primary tumor, corresponding to a specificity of 100% and a sensitivity of 32.4%. High serum HER2 ECD levels were strongly associated with liver metastasis (P ⬍ 0.001), the intestinal histologic type (Lauren’s classification) (P ⫽0.003), large number of metastais (⬎2) (P⫽0.012) and increased LDH level (P ⬍ 0.001) . High serum HER2 ECD levels were more common in GEJ adenocarcinoma although the difference had no stastical significance. HER2 ECD levels did not show a significant impact on OS. Conclusions: A significant association was observed between serum HER2 ECD levels and tissue HER2 status in metastasis gastric or GEJ adenocarcinoma. The high specificity of serum HER2 ECD assay to predict tissue HER2 status suggests its potential use as a surrogate marker of the HER2 status in gastric cancer.

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The Chinese subgroup from a randomized phase III study of lapatinib in combination with weekly paclitaxel versus weekly paclitaxel alone as second-line treatment of HER2-amplified advanced gastric cancer (AGC) in Asian countries. Presenting Author: Guo-ping Sun, Department of Oncology, The First Affiliated Hospital of An Hui Medical University, Hefei, China Background: TyTAN is a randomized phase III study to evaluate lapatinib (L) plus paclitaxel (P) in pretreated HER2 amplified (HER2⫹) advanced gastric cancer (AGC). The disease characteristics and GC treatment pattern differed in Japan and in China, so a subgroup analysis was done for subjects recruited in mainland China. Methods: AGC subjects with prior 5-FU and/or cisplatin and HER2 amplification by fluorescence in situ hybridization (FISH) in tumor tissue were randomized 1:1 to L (1500mg QD) and P (80mg/m2, Day 1, 8, 15 q4w) or P alone (80mg/m2, Day 1, 8, 15 q4w). 1st endpoint was overall survival (OS). 2nd endpoints included progression free survival (PFS), overall response rate (ORR) and safety. A total of 95 subjects recruited from mainland China. Results: TyTAN was not significant in OS (HR0.84), but 2 months OS improvement was observed in L⫹P arm. The results from Chinese subgroup are shown in the Table. The most common adverse events in Chinese subjects were similar as in whole population (neutropenia, diarrhea, rash, leukopenia, anemia, fatigue). Compare to the overall results, less Chinese subjects reported nausea and vomiting. Conclusions: This analysis showed that there were clear regional differences as observed between subjects in China and Japan. The addition of L to P was associated with a clinically meaningful benefit in subjects recruited from mainland China. These data warrants further prospective evaluations on the impact of regional differences in the outcome of HER⫹ GC in East Asian patients. Clinical trial information: NCT00486954. Overall (nⴝ261) Mainland Chinese (nⴝ95) Disease Type of gastric cancer 34/43/23 Diffuse/intestinal/mixed (%) PS 0/1 (%) 41/59 Gastrectomy pylorus removed (%) 49 HER2 FISHⴙ and IHC ⴙⴙⴙ (%) 53 Treatment Median treatment duration (weeks) 16.6 Post-study chemotherapy (treatment 58 vs 64 vs control arm; %) Efficacy OS (HR; 95%CI); median 0.84 (0.64-1.11) 11.0 vs 8.9 months PFS (HR; 95%CI); median 0.85(0.63-1.13) 5.4 vs 4.4 months ORR (treatment vs control) 27% vs 9%

51/13/37 21/79 37 65 18 42 vs 42 0.62 (0.39-0.98) 9.7 vs 7.6 months 0.52(0.32-0.86) 7.2 vs 4.7 months 42% vs 8%


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Prognostic outcome of gastric cancer patients with cancer stem cell SNPs in Asian versus western countries. Presenting Author: Melissa Janae Labonte, Azusa Pacific University, Azusa, CA Background: The clinical significance of cancer stem cells (CSC) has been well established; however, its prognostic role remains controversial. CD44 is recognized as a CSC marker in gastric cancer (GC) and, recently, the clinical impact of CD166 in GC was reported. Our group previously reported SNPs of CD44 and CD166 are associated with outcome in US patients (pts) with adjuvant GC and colorectal cancer, respectively. Since GC has regional differences in epidemiology and clinicopathology, we hypothesized that ethnicity and regional differences in GC could influence the prognostic role of CD44 and CD166. Methods: A total of 369 pts with histopathologicallyconfirmed localized (stage Ib to IV; AJCC-6th) GC were enrolled from Japan (n⫽169), the US (n⫽137), and Austria (n⫽63) between 2002 and 2010. CD44 rs187116 G⬎A and CD166 rs1157 G⬎A were analyzed. Genomic DNA was extracted from blood or tissue, and all samples were analyzed by PCR-based direct DNA-sequencing. Results: Pts homozygous for A/A CD44rs187116 (n⫽20) showed a median OS of 2.0 yrs vs not reached for patients harboring at least one-G allele (n⫽144) (HR: 2.87 [95%CI: 1.61-5.13], p⬍0.001) in Japanese cohort, while pts homozygous A/A (n⫽30) showed a median OS of 7.3 yrs vs 4.1 yrs for pts harboring at least one-G allele (n⫽94) (HR: 2.0 [95%CI: 0.90-4.55], p⫽0.079) in the US cohort. There were no significant differences in Austrian cohort alone or in combination with US cohort. In CD166 rs1157, pts harboring at least one-A allele (n⫽27) showed a median OS of 3.9 yrs vs not reached for pts homozygous G/G (n⫽142) (HR: 1.81 [95%CI: 1.05-3.12], p⫽0.033) in Japanese cohort., Although there were no significant differences in the US or Austrian cohort when analyzed separately, combining cohorts demonstrated that pts homozygous A/A (n⫽12) showed a median OS of not reached yrs vs 4.7 yrs for pts harboring at least one-G allele (n⫽179) (HR: 5.00 [95%CI: 0.70-35.95], p⫽0.073). Conclusions: SNP profiles in CSC markers predicted opposite prognostic outcomes in patients with GC among Asian and Western countries. This is the first report suggesting that the prognostic role of CSC markers in GC may differ based on ethnic groups or etiology differences.

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Efficacy and safety of dose-dense modified TCF regimen (TCF-dd) in metastatic or locally advanced gastroesophageal cancer (GEC). Presenting Author: Laura Toppo, Istituti Ospitalieri di Cremona, Cremona, Italy Background: TCF is a standard first line option for GEC. The Norton-Simon hypothesis suggests that chemotherapy efficacy can be enhanced by decreasing intervals between cycles. We previously reported on the high activity of TCF-dd in GEC (Tomasello 2010). The aim of this study is to investigate the efficacy and safety of this intensified dose-dense regimen in a single-center large cohort of patients (pts). Methods: 150 pts with measurable or evaluable GEC, PS 0-2, with adequate organ function, treated in our center from 2004 to 2012 received TCF-dd: Docetaxel (60-85 mg/m2 d 1), Cisplatin (50-75 mg/m2 d 1), l-Folinic Acid (100 mg/m2 d 1-2), 5-FU (400 mg/m2 bolus d 1-2, and 600 mg/m2 as a 22 h continuous infusion d 1-2), plus Pegfilgrastim 6 mg d 3, every 14 days. Pts aged ⱖ 65 years received the same schedule with a dose reduction by 30%. Analysis was based on the intention to treat population. Results: At a median follow-up of 44 months, 128 pts were evaluable for response, all for survival. Median age 65 (range 31-81), M:F 112:38. 17 pts (11%) with locally advanced inoperable GEC, 133 pts (89%) with metastatic GEC. Metastatic sites: liver 40%, peritoneum 31%, bone 14%, lung 12%. A median of 4 cycles (range 1-7) per patient was administered. 33% required a dose reduction. 33% were treated without any delay. 10 CR, 74 PR, 24 SD and 20 PD were observed, for an ORR of 66% (95% CI 57-74). Median OS was 13 months (95% CI 9.7-14.2). Most frequent grade 3/4 toxicities: neutropenia (34%), asthenia (28%), thrombocytopenia (17%), hypokalemia (16%), diarrhea (11%), febrile neutropenia (10%), anemia (9%), and stomatitis (4%). 11 pts (7%) [7 metastatic, 4 locally advanced] became operable after TCF-dd and underwent surgery. We identified 12 metastatic pts (8%) with overall survival ⬎ 3 years and 7 (5%) still maintaining a long lasting CR at the time of the current analysis. Conclusions: TCF-dd in GEC is very active and may be an option for conversion therapy. Toxicity can be relevant and requires a careful monitoring.

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Association of transcription factor 7-like 2 (TCF7L2) polymorphisms with worse survival in three independent cohorts from the United States, Austria, and Japan in patients with gastric cancer. Presenting Author: Rita Elie El-Khoueiry, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA Background: The Wnt/␤-catenin signaling pathwaycontrols cell proliferation and differentiation. Disruption of this pathway has been shown in the majority of colorectal (CRC) and gastric cancer (GC). The TCF7L2 complex plays a critical role in this pathway. Interaction of TCF7L2 and ␤-catenin results in translocation to the nucleus and leads to up-regulation of target genes, including c-myc and cyclin D1. Previous reports have shown that TCF7L2 polymorphism rs7903146 C/T is associated with CRC risk and outcome; however, the prognostic role of this polymorphism in GC is unknown. Therefore, we tested the hypothesis of whether this polymorphism could predict outcome in GC in three independent cohorts. Methods: A total of 369 patients (pts) with histopathologically-confirmed localized GC were enrolled from Japan (n⫽169), the US (n⫽137), and Austria (n⫽63) between 2002 and 2010. Results: In the US cohort, pts with at least one-T allele ((T/T or C/T; n⫽46) showed a median TTR of 1.7 yrs vs. 4.4 yrs compared to pts homozygous C/C (n⫽76) (HR: 2.09 95%CI: 1.213.59, p⫽0.0053). A similar trend was shown in the Austrian cohort, where pts harboring at least one-T allele (n⫽25) showed a median DFS of 2.08 yrs vs. 5.42 yrs for pts homozygous C/C (n⫽38) (HR: 1.79 [95%CI: 0.903.55], p⫽0.092). Moreover, in the Japanese cohort, pts homozygous for T/T demonstrated (n⫽2) a median DFS of 0.15 yrs vs. 4.82 yrs for pts harboring at least one-C allele (n⫽165) (HR: 10.5 [95%CI: 2.46-45.5], p⫽0.001). These results were confirmed in the OS in the US and Japanese cohorts. Pts at least one-T allele (n⫽46) showed a median OS of 3.3 yrs vs. 5.5 yrs for pts homozygous C/C (n⫽76) (HR: 2.41 95%CI: 1.28-4.53, p⫽0.0043) in the US cohort, while pts homozygous T/T showed (n⫽2) a median OS of 0.22 yrs vs 5.76 yrs for pts harboring at least one-C allele (n⫽165) (HR: 15.2 [95%CI: 3.50-66.7], p⬍0.001). Conclusions: TCF7L2 polymorphism was associated with worse prognosis in recurrence in pts with GC in three independently global cohorts. This polymorphism may be negative prognostic factor in GC regardless of ethnicity and etiology, suggesting the importance role of Wnt/␤-Catenin signaling in GC.

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Association of YAP1 activation with poor patient prognosis and effect on chemoresistance in gastric cancer. Presenting Author: Sung Sook Lee, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea Background: Clinical heterogeneity in gastric cancer is likely due to biological differences among patients. Molecular subtypes and their associated biomarkers need to be established to improve treatment of this disease. We aimed to uncover subgroups of gastric cancer that have distinct biological characteristics associated with clinical outcome and to identify potential best treatments or therapeutic targets for each subgroup. Methods: We analyzed gene expression profiling data from gastric cancer cell lines and 267 patients with gastric cancer to uncover tumor subtypes and identify a gene expression signature associated with prognosis and response to adjuvant chemotherapy. The association of the signature with prognosis was validated in an independent cohort of 200 patients, and its association with response to adjuvant therapy was validated by cell culture experiments. Results: We identified an expression signature of 88 genes that specifically reflected activation of the oncogene YAP1. Compared with patients without this signature, patients with the YAP1 signature had significantly poorer prognosis. In multivariate analysis, the signature was the strongest indicator of overall survival among all demographic and clinical variables examined together (hazard ratio, 2.1; 95% confidence interval, 1.3-3.3;P ⫽ .002). Activation of YAP1 was significantly associated with resistance to adjuvant chemotherapy. We also demonstrated that the Notch pathway is a potential therapeutic target for overcoming chemoresistance mediated by YAP1. Conclusions: Activation of the oncogene YAP1 is significantly associated with poorer survival of patients with gastric cancer and induces chemoresistance to this disease. Therefore, YAP1 may be highly attractive therapeutic target for patients with gastric cancer resistant to standard chemotherapy.




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A phase II study of perioperative S-1 combined with weekly docetaxel in patients with locally advanced gastric cancer: Clinical and pharmacogenetic results. Presenting Author: Sook Ryun Park, Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, South Korea

Vascular endothelial growth factor expression in hepatitis C virus (HCV)related advanced hepatocellular carcinoma (HCC) compared with hepatitis B virus (HBV)-related advanced HCC. Presenting Author: Yu Yun Shao, Graduate Institute of Oncology, National Taiwan University, Taipei City, Taiwan

Background: We conducted a phase II study to evaluate the efficacy and safety of perioperative S-1 ⫹ docetaxel (DS) in locally advanced gastric cancer (LAGC), and to investigate the association between CYP2A6 genotypes and treatment outcomes. Methods: Eligibility criteria included 18-70 yrs, PS 0-1, measurable lesion(s), and LAGC (clinical stage III-IV (M0) by Japanese staging system). Pts were given each 3 cycles of pre- and post-operative chemotherapy (S-1 40 mg/m2 bid on D1-14, docetaxel 35 mg/m2iv on D1, 8 q 3 wks), and underwent surgery (ⱖD2). Results: From Oct 2006 to June 2008, 44 pts entered into the study, and 43 pts were eligible. Median age⫽53 yrs (range, 33-69); PS 0/1⫽2/41; M/F⫽29/14; and stage IIIA/IIIB/IV (M0)⫽20/18/5. All 43 eligible pts completed preoperative DS and 40 pts (93%) completed postoperative DS. The most common G3/4 toxicities during pre- and post-operative DS were neutropenia (28% vs. 65%), stomatitis (19% vs. 5%), and abdominal pain (5% vs. 18%). The clinical response rate was 74.4% (95% CI, 61.4-87.4%) with 1 CR (2.3%) and 31 (72.1%) PRs. R0 resection rate was 97.7%, major pathologic response rate was 48.8% with 1 CR, and pathologic stage was 0/1/2/3/4 (%) ⫽ 2.3/44.2/20.9/20.9/11.6. With a median follow-up of 66.6 months, 3-yr PFS and 5-yr OS was 62.8% and 69.6%, respectively. Survival differed according to clinical response, clinical downstaging, and CYP2A6 genotypes (Table). Pts with two CYP2A6 variant alleles (V/V) had higher Cmax (27.7⫾4.6 vs. 20.3⫾1.2; p⫽0.045) and AUCinf (220.4⫾43.1 vs. 172.5⫾12.5; p⫽0.187) of tegafur, and lower Cmax (1.4⫾0.2 vs. 1.8⫾0.1; p⫽0.178) and AUCinf (8.4⫾1.2 vs. 9.7⫾0.5; p⫽0.308) of 5-FU than those with no or one variant allele (W/W or W/V). Conclusions: DS is active with a manageable toxicity profile in the perioperative setting in pts with LAGC. CYP2A6 genotype may be predictive of efficacy (S-1 and docetaxel was provided by JEIL Pharm. Co., Ltd. and sanofi-aventis Korea Co., Ltd., respectively). Clinical trial information: NCT00587145. 3-yr PFS (%) P 5-yr OS (%) P

Background: HCC with different etiologic factors may result in activation of different signaling pathways. This study aimed to clarify if HBV-related HCC (HBV-HCC) and HCV-related HCC (HCV-HCC) may have difference in the expression of key molecules that are relevant to contemporary molecular targeted therapy. Methods: We enrolled patients diagnosed with advanced HCC from 2001 to 2011 who had tumor tissues obtained upon the diagnosis of advanced HCC at our center. Tumor slides were immunohistochemically stained for phosphorylated extracellular signal-regulated kinases (p-ERK), Raf kinase inhibitory protein (RKIP), and vascular endothelial growth factor (VEGF). The expressions of p-ERK and RKIP were evaluated according to percentages of positive-staining cells and graded as: 0: 0; 1⫹: 1-10%; 2⫹: 11-50%; 3⫹: ⬎ 50%. Grades 0 and 1 were considered negative, and grades 2 and 3 positive. VEGF staining was evaluated as strong or weak according to staining intensity. The staining results of VEGF were further recorded as H scores, defined as intensity (0, 1, 2, or 3) ⫻ percentages of positive staining. Results: In total, 131 patients were enrolled in this study; 94 (72%) patients had HBV-HCC, and 37 (28%) patients had HCV-HCC. HBV-HCC and HCV-HCC had similar expression of p-ERK (positive: 45% vs. 51%, p ⫽ 0.491) and RKIP (positive: 83% vs. 84%, p ⫽ 0.912). HCV-HCC was more likely to have strong VEGF staining than HBV-HCC (95% vs. 72%, p ⫽ 0.005) and higher H scores for VEGF staining (289.5 vs. 248.8, p⬍ 0.001). In multivariate analysis adjusting for age, sex, macrovascular invasion, extrahepatic metastasis, and ␣-fetoprotein level, HCV-HCC remained an independent factor associated with strong VEGF staining. VEGF staining intensity was not associated with age, sex, macrovascular invasion, extrahepatic metastasis, and ␣-fetoprotein level. Conclusions: HCV-HCC has stronger VEGF expression than HBV-HCC. (This study was supported by the grant of NSC101-2314-B-002-141, 100CAP1020-2, and NTUH.101-N1965.)

Clinical response CR/PR SD PD Clinical downstaging Yes No CYP2A6 genotypes W/W or W/V V/V

4116

78.1 22.2 0

⬍0.0001

81.1 44.4 0

0.01 87.5 48.1

⬍0.0001

0.055 83.0 60.0

0.102 67.6 33.3

0.032 75.6 33.3


Hepatic arterial infusion for unresectable intrahepatic cholangiocarcinoma: An update on survival from two prospective clinical trials. Presenting Author: Ioannis Konstantinidis, Department of Surgery, Memorial SloanKettering Cancer Center, New York, NY Background: Patients with unresectable intrahepatic cholangiocarcinoma (IHC) experience poor survival. This study summarizes the long-term outcome of two previously reported clinical trials using hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone (Dex) (with or without bevacizumab (Bev)) in advanced IHC. Methods: Prospectively collected clinicopathologic and survival data were retrospectively reviewed. Disease response was based on RECIST. All patients underwent pretreatment dynamic contrast enhanced MRI (DCE-MRI), and tumor perfusion data were correlated with outcome. Results: Forty-four patients were analyzed (FUDR⫽26, FUDR/Bev⫽18). At a median follow-up of 30 months, 41 patients had died of disease and 3 were alive. Partial response was observed in 48% of patients, and another 50% had stable disease. Three patients underwent resection after HAI and 84% received additional HAI after removal from the study. Median survival was similar in both trials (FUDR⫽29 months vs. FUDR/Bev⫽28.5 months p⫽0.96). Ten patients (23%) survived ⱖ3 years including 5 (11%) ⱖ 5 years. Tumor perfusion, as measured on pre-treatment DCE-MRI (area under the gadolinium concentration curve (AUC180)), was significantly higher in ⱖ3-year survivors, and was the only factor that distinguished this group from ⬍3-year survivors (mean AUC180 48.9mM.s vs 32.3mM.s, respectively; p⫽0.003). Time to liver progression was longer in ⱖ3-year survivors (19.8 months vs 11.2 months, respectively; p⫽0.02). Conclusions: HAI chemotherapy can result in prolonged survival in unresectable IHC. Pre-treatment DCE-MRI may predict response and survival. Factors Mean age (yr) Male gender Mean tumor size (cm) Single tumor Previous chemotherapy Mean AUC180 (mM.s) Partial response (RECIST) Relative dose intensity (6mo) Grade 3/4 toxicity Stable liver disease (mo)

>3Y survivors (nⴝ10) 3000 Sor-treated patients (pts): Clinical findings in pts with liver dysfunction. Presenting Author: Jorge A. Marrero, The University of Texas Southwestern Medical Center, Dallas, TX

Gemcitabine and oxaliplatin (GEMOX) alone or with cetuximab in first-line treatment of advanced biliary cancers (ABC): Exploratory analyses according to tumor KRAS/BRAF mutations and EGFR expression in a randomized phase II trial (BINGO). Presenting Author: David Malka, Institut Gustave Roussy, Villejuif, France

Background: GIDEON is a prospective, non-interventional study. Completion of GIDEON creates a large, global database of ⬎3000 Sor-treated unresectable HCC (uHCC) pts, allowing for evaluation of a broad pt population, including Child-Pugh (CP) B pts with more advanced liver dysfunction. Methods: Baseline characteristics were collected in pts for whom a decision to treat with Sor had been made in clinical practice. Adverse events (AEs), dosing, and outcomes data were collected during follow-up. Results: 3,202 pts were evaluable for safety. Overall, the incidence of AEs and drug-related (DR) AEs was similar across CP subgroups, although serious AEs (SAEs) were more common in CP-B than CP-A pts. The rate of DR AEs (event per patient-year) was also comparable between CP-A and CP-B pts. The average daily Sor dose was slightly higher in CP-B than CP-A pts; duration of treatment was longer in CP-A (Table). In the intent-to-treat population (n⫽3,213), median overall survival (OS) (months [95% CI]) was longer in CP-A (13.6 [12.8-14.7]) than CP-B pts (5.2 [4.6-6.3]); time to progression was similar: CP-A (4.7 [4.3-5.2]); CP-B (4.4 [3.5-5.5]). Median OS was shorter in pts with a higher CP-B score: 7 (6.2 [4.9-8.7]); 8 (4.8 [4.1-6.9]); 9 (3.7 [3.0-5.1]). Conclusions: Sor safety and dosing during treatment are generally consistent across pts irrespective of liver function. As anticipated, CP status is a strong prognostic factor for OS in uHCC pts. Total CP-A CP-B Nⴝ3202a (100)nⴝ1968 (61.5)nⴝ666 (20.8) All DR All DR All DR

Background: Gemcitabine-platinum regimens are the standard of care for ABC. Whether GEMOX-cetuximab may be beneficial in ABC patients (pts) was tested in BINGO, an international, open-label, randomized phase II study (ASCO 2012). With a 4-month progression-free survival (PFS) rate of 63% [CI: 52-74], the primary endpoint was met (target, ⱖ60%; GEMOX, 54% [43-65]). However, median PFS (6.1 vs. 5.5 months) and overall survival (OS) (11.0 vs. 12.4 months) were similar in both arms. Available data on KRAS/BRAF mutation rates in ABC pts are sparse. Methods: Planned exploratory endpoints included tumor KRAS/BRAF mutational status (high-resolution melting and DNA sequencing) and EGFR expression score (immunohistochemistry [IHC]), and their impact on patient outcome according to treatment arm. Results: Tumor samples were collected for 91 (61%) consenting pts among the 150 randomized pts, and were suitable for DNA analysis and IHC in 75 (50%) and 77(51%) pts, respectively. Tumor KRAS and BRAF mutations (MT) were found in 14 (19%) and 4 (5%) pts, respectively. High EGFR score (ⱖ 200) was observed in 18 (23%) pts. 4-month PFS rates did not differ according to tumor KRAS MT (wild-type [WT] vs. MT: 62% vs. 57%, p⫽0.72), BRAF MT (61% vs. 75%, p⫽1.00) or EGFR score (ⱖ vs. ⬍200: 56% vs. 63%, p⫽0.42) overall, or according to treatment arm (table). PFS and OS (log rank test) also did not significantly differ according to these biomarkers, overall or between treatment arms. Conclusions: Tumor KRAS/BRAF mutations and EGFR overexpression were found in 24% and 23% of pts respectively. With the limit of statistical power in these exploratory analyses, they had no statistically significant prognostic or predictive impact. Clinical trial information: 2007-001200-20.

AEs, %b All grades Grade 3/4 SAEs AE rate (event per patient-year)b,c Any AE Diarrhea Hand-foot skin reaction Fatigue Discontinuation due to AEs, %b Daily dose, median, mgd Treatment duration, median, weeksd

85.3 31.7 43.3

66.0 23.5 9.3

1.61 1.24 0.58 0.51 0.51 0.50 0.45 0.29 31.4 688.0 15.0

84.0 32.4 36.0

68.5 88.6 64.4 25.6 31.5 21.9 8.8 60.4 14.1

1.44 1.17 0.54 0.48 0.55 0.54 0.38 0.27 28.9 677.0 17.6

2.14 1.55 0.71 0.62 0.42 0.41 0.62 0.34 40.1 741.5 9.9

a Includes CP-C, 74 pts; not evaluable, 493 pts; bTreatment-emergent; cCalculated based on 365.25 days per year; dPts with dosing data.

Odds ratio [95% confidence interval]

4-month PFS (%) GEMOX GEMOX ⫹ cetuximab KRAS WT (nⴝ61) 58 KRAS MT (nⴝ14) 50 KRAS/BRAF WT (nⴝ57) 59 KRAS or BRAF MT (nⴝ18) 50 EGFR score < 200 (nⴝ59) 64 EGFR score > 200 (nⴝ18) 50

65 63 63 70 68 58

1.32 [0.46-3.79]* 1.67 [0.20-14.27]* 1.17 [0.39-3.49]* 2.33 [0.34-16.18]* 1.19 [0.39-3.61]* 1.40 [0.20-10.03]*

* Interaction test, not significant.

4128


4129


Impact of gender on survival of patients (pts) with hepatocellular carcinoma (HCC): A SEER analysis. Presenting Author: Dongyun Yang, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA

Postoperative nomogram for predicting survival after resection for intrahepatic cholangiocarcinoma. Presenting Author: Dario Ribero, Ospedale Mauriziano, Torino, Italy

Background: The incidence of HCC is significantly higher in males (M) than females (F). Preclinical models suggest a role for estrogen in attenuating progression of HCC by various mechanisms such Il-6 suppression or estrogen receptor ␣-mediated inhibition of NF-␬B activity. We investigated the impact of age and gender on survival in patients with HCC using the SEER data. Methods: We identified all patients diagnosed with HCC (ICD-O-3 Site code C22.0 and Histology Code 8170-8175) from 1988 to 2009 from the SEER registry. Pts with information on gender, age, ethnic background, and staging were included in the analysis. Exclusion criteria included fibrolamellar histology, diagnosis at autopsy or by death certificate, and absence of survival data. Hazard ratios (HR) for survival were derived using Cox regression model adjusted for race, year of diagnosis, marital status, treatment, birthplace, differentiation and tumor size. Results: A total of 38,250 pts were identified; 76% males; 50% White, 12% African American, 21% Asian, 16% Hispanic, and 1% Native American. 45% had liver limited disease (44%M, 50%F), 37% had macrovascular invasion (37%M, 35%F), 18% had metastatic disease (19%M, 15%F). Treatment information was available for pts diagnosed after 1998 (n⫽32,938): 11% received liver directed therapy, 11% had surgical resection, and 7% underwent liver transplantation. Median age at diagnosis was 61 years for M versus 68 years for F. HR for OS of F versus M was 0.83 (95%CI:0.78-0.89) for pts ⬍ 55 years old. In contrast, the OS HR of F versus M was 0.95 (95%CI:0.92-0.98) for pts ⱖ 55 years old and 0.98 (95%CI: 0.94-1.01) for pts ⱖ 65 years old. The F vs. M (⬍55 yrs old) HR for OS by stage of disease was: liver limited disease: HR 0.90, CI: 0.81-1.01; macrovascular invasion: HR 0.81, CI: 0.73-0.89; metastatic disease, HR 0.80, CI: 0.70-0.92. Conclusions: Females under the age of 55 appear to have superior survival compared to males with HCC based on a SEER data analysis. This finding is in line with preclinical reports of estrogen attenuation of HCC development and progression.

Background: Conventional staging systems have limited value for survival estimation in individual patients because of the multiple predictors of outcome. Nomograms may overcome these limitations. Thus we developed and internally validated a postoperative nomogram to predict survival after resection of intrahepatic cholangiocarcinoma (IHC) and compared its predictions to those obtained using the 7th Ed. AJCC/UICC stage groupings. Methods: Prospective clinicopathologic data from 574 patients who underwent hepatic resection at 12 tertiary hepatobiliary centres (1995-2011) were used. After inputting missing values with regression imputation, the nomogram was developed from a Cox regression model with overall survival (OS) as the primary end-point. Calibration and internal validation were performed calculating the agreement between observed and predicted outcomes in terms of percentage of predicted errors (PE). Discrimination was quantified with the concordance index (CI). Both CI and PE were then corrected for over-optimism using bootstrapping with 100-fold crossvalidation sampling. Credibility intervals around 3- and 5-year predicted survival were estimated from an empirical Bayesian model. Results: At last follow-up (median duration 27.6 months) 243 patients had died. Three and five-years OS were 52% and 39%. The predictive accuracy of the nomogram (CI: 66.5), which includes 7 variables (tumour size and number, lymph-node metastases, vascular invasion, perineural invasion, CA19.9 level, and radicality of resection), was good and superior to that of the current AJCC/UICC staging system (CI: 58.4). Percentage of PE for the AJCC/UICC staging system were 24%, while the studied model offered a PE slightly under 20%. Heterogeneity was observed in the distribution of nomogram-predicted survival probabilities within stage groups. Conclusions: The nomogram developed in this study overcomes some of the prognostic limitations associated with simple models by including all prognostic variables excluded from the AJCC/UICC staging system and may serve as an instrument for future refinements in determining individual patient prognosis necessary for accurate patients stratification.




Neutrophil/lymphocyte ratio (NLR) as a prognostic factor in biliary tract cancer (BTC). Presenting Author: Mairead G. McNamara, Princess Margaret Hospital, Toronto, ON, Canada Background: BTCs include intrahepatic (IHC), hilar, distal bile duct (DBD), and gallbladder carcinoma (GBC). Risk factors include conditions associated with chronic inflammation. NLR, an inflammatory marker, is prognostic in several cancers but has not been reviewed in large BTC series, hilar or GBC. Methods: Baseline demographics and NLR at diagnosis were evaluated in 864 patients (pts) with BTC from 01/87 - 12/12 treated at Princess Margaret Cancer Center. Their prognostic significance for overall survival (OS) was determined using a Cox proportional hazards model. Results: High NLR ⱖ3.0 was associated with poor survival using univariable analysis as was stage/site of primary (P⬍0.05), age ⬎65yrs, lymphocytes ⱕ1.6 (P⬍0.01), neutrophils ⱖ5.0, platelets ⱖ280, hemoglobin (Hb) ⬍ 110 g/L (P⬍0.001). Median OS in pts with NLR⬍3.0 was 21.6 mo, 12.0 mo with NLR ⱖ3.0 (P⬍0.001). NLR retained its significance as a prognostic marker on multivariable analysis (Table), along with GBC (P⬍0.05), age⬎65yrs, DBD primary (P⬍0.01), stage and Hb ⬍110g/L (P⬍0.001). NLR was prognostic for OS on multivariable analysis for hilar: overall (Table) and advanced grp (n⫽102) (HR 1.68, 95%CI 1.07-2.64, P⬍0.05) and in advanced DBD (n⫽102) (HR 1.63, 95%CI 1.03-2.57,P⬍0.05). On subgrp analysis, NLR was prognostic for OS in advanced BTC (ABTC) (n⫽538) (P⬍0.01) but not in surgical grp. NLR did not predict RECIST response to first line palliative chemotherapy in ABTC. Conclusions: Baseline NLR is prognostic in BTC, specifically ABTC and hilar subgrp, suggesting the importance of systemic inflammation influencing outcome in pts with ABTC, thus providing a simple inexpensive prognostic biomarker while also possibly identifying pts that may benefit from antiinflammatory mediation. NLR was not predictive for response in BTC. OS univariable analysis HR (95% CI, p value)

OS multivariable analysis HR (95% CI, p value)

4131


Use of the mitotic kinase aurora-A activation to predict outcome for primary duodenal adenocarcinoma. Presenting Author: Jie Chen, Department of Medical Oncology, the Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China Background: We and others had proved that hypoxia-inducible factor-1␣ (HIF-1␣) and transcriptionally upregulated Aurora-A were required for disease progression in several tumors. Methods: We addressed the clinicopathologic value of HIF-1␣ and Aurora-a in primary duodenal adenocarcinoma (PDA). Aurora-a and HIF-1␣ expression were semi-quantitative evaluated by immunohistochemistry in 140 PDA. Among which, 76 patients from one institute acted as training set, and 64 cases from another two institutes were used as testing set to validate the prognostic effect of Aurora-a and HIF-1␣. Results: We found that Aurora-a was high or sufficient expressed in tumor zone, whereas low-expressed in the normal adjacent epithelia. Moreover, Aurora-a high expression, classified by training set ROC analysis-generated cutoff score, predicted an inferior overall survival both in testing set and training set. Multivariate Cox regression confirmed that Aurora-a was indeed an independent prognostic factor (Table). Contrary to previous studies, we did not detect any correlation between Aurora-a and HIF-1␣ in PDA. Additionally, survival analysis showed that HIF-1␣ level was not correlated with patient outcome (p ⫽ 0.466). Conclusions: Activation of Aurora-A, an independent negative prognostic biomarker, might be used to identify particular patients for more selective therapy. Variable

Testing set

Overall 864 NLRⱖ3.0 1.60 (1.37-1.87, ⬍0.001) 1.46 (1.25-1.72, ⬍0.001)

Tumor stage (T3ⴙT4 vs. T1ⴙT2) Node stage (N0ⴙN1 vs. N2ⴙN3) TNM stage (IIIⴙIV vs. IⴙII) CEA level (high vs. normal) Bilirubin level (normal vs. high) Tumor size (2.5cm) Differentiation (moderate ⴙhigh vs. poor) Aurora-A level (high vs. low) Hypoxia (vs. normoxia)

4132

4133

Location N

Variable

GBC

304 NLRⱖ3.0 1.80 (1.39-2.34, ⬍0.001) 0.87 (0.58-1.30, 0.21)

DBD

220 NLRⱖ3.0

Hilar

161 NLRⱖ3.0 1.53 (1.06-2.20, ⬍0.05) 1.64 (1.12-2.41, ⬍0.05)

IHC

179 NLRⱖ3.0 2.20 (1.49-3.26, ⬍0.001) 1.38 (0.91-2.08, 0.13)

1.21 (0.90-1.62, 0.21)

1.55 (1.12-2.13, 0.18)


275s

Training set

HR

95% CI

P value

HR

95% CI

P value

2.591

0.854-7.856

0.093

2.620

0.882-7.781

0.083

3.062

0.783-11.975

0.108

7.189

1.144-45.163

0.035

2.046

0.999-4.192

0.050

2.146

1.022-4.507

0.044

2.063 1.205

0.962-4.423 0.555-2.618

0.063 0.638

1.221 1.741

0.581-2.566 0.637-4.760

0.599 0.280

0.660

0.330-1.321

0.241

.861

0.449-1.653

0.654

0.426

0.199-0.911

0.028

.380

0.174-.830

0.015

2.111 1.003

1.041-4.281 0.510-1.974

0.038 0.992

2.861 1.325

1.326-6.172 0.701-2.503

0.007 0.387


Cost-effectiveness and optimal diagnostic sequence of CT, MRI, and PET-CT in the management of colorectal liver metastases. Presenting Author: Vincent S. Yip, University Hospital Aintree, Liverpool, United Kingdom

Diagnostic utility and prognostic performance of a 92-gene cancer classifier to molecularly profile periampullary adenocarcinomas (PAA). Presenting Author: Michael J. Overman, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: CT, PET-CT and MRI play a role in the decision making process in managing colorectal liver metastases (CRLM). This study aimed to determine the optimal sequence of these investigations in order to reduce the rate of futile laparotomy and improve cost effectiveness of treatment. Methods: All patients referred to our specialist multidisciplinary team (sMDT) with CRLM were reviewed to investigate specific reason(s) for not offering potentially curative surgery. Clinical parameters were recorded for analysis. Three hypothetical scenarios were derived for cost-effectiveness analyses: 1) “up-front” with all imaging prior to sMDT, 2) “sequential”, with individual imaging following each sMDT, and 3) “hybrid” with PET-CT and MRI after review of the initial CT scan. Results: 644 consecutive patients were reviewed. Following assessment of initial CT, 165 patients (26%) were referred for palliative chemotherapy. After further evaluation by PET ⫹/- MRI, 307 patients proceeded for potentially curative resection. Of those excluded from surgery, 48% were following PET-CT. Median overall survival (OS) for the resection and palliative groups were 46 and 14 months respectively (p⬍0.001). Futile laparotomy rate was 5.5%.The optimum strategy of lowest average time to decision, and lowest average cost is the hybrid model. Cost-utility analyses demonstrated a saving of approx. £319 (USD$ 515) per patient compared to the other 2 models. Conclusions: Decision making regarding further imaging after initial CT scan for CRLM should be performed at the sMDT to minimise delays and maximise efficiency of resources allocation. Triple assessment with CT, PET and MRI and sMDT decision process may reduce risk of futile laparotomy. A hybrid model using PET and MRI following a sMDT discussion of the initial CT provides the most cost effective algorithm for the management of CRLM.

Background: Due to the small anatomic size, multiplicity of epitheliums, and suboptimal diagnostics determining the site of origin of PAA is a challenge. We investigated the ability of a 92-gene RT-PCR assay (CancerTYPE ID) to categorize PAA and to prognostically stratify ampullary adenocarcinomas. Methods: 171 PAA patients who underwent pancreaticoduodenectomies were included; samples were histopathologically verified for tumor subtype determination: pancreatic (PAN), extrahepatic biliary (EB), ampullary (AMP), or duodenal (DOUD). Blinded FFPE tumor sections underwent molecular testing. Analytical sets were an initial 45 PAA set evaluating concordance to histopathological tumor types and prognostic performance, and a second set of 126 AMP and DOUD adenocarcinoma for validation of prognostic performance. Results: Of the initial 45 patient cohort, molecular classification of 43 (96%) evaluable samples (13 AMP, 10 PAN, 10 EB, 10 DOUD) showed 91% concordance: AMP [5 intestinal (int), 7 pancreaticobiliary (pb)], PAN [10 pb], DOUD [3 int, 7 gastroesophageal (ge)], EB [7 pb]. The 92-gene assay was prognostic with a median OS of 70 m for ge/int cases vs. 32 m for pb cases, P⫽0.05. Discordant classifications were ge for 1 AMP and 2 EB samples, and ovary for 1 EB case. Previous unsupervised RNA hierarchical clustering (Overman GI ASCO 2011 a161) of all 13 AMP cases had identified two prognostic groups (a good-prognosis int-like and a poor-prognosis pb-like), which were identical to the 92-gene classification for 12 of the 13 cases. Conclusions: In the initial cohort of 45 patients, the 92-gene assay demonstrated diagnostic utility for molecular site-of-origin classification of PAA; evaluation of the remaining 126 ampullary and duodenal cases will be presented. Results support exploration of this approach for the management of metastatic PAA (in which pathologic review of a primary resection specimen is not an option). Molecular classification of ampullary adenocarcinomas into intestinal and pancreaticobiliary subgroups is prognostically relevant; these and the gastric-like molecular profile of duodenal adenocarcinomas may have therapeutic implications.


276s 4134

Gastrointestinal (Noncolorectal) Cancer General Poster Session (Board #30D), Sun, 8:00 AM-11:45 AM

Impact of multidisciplinary therapy on high-grade appendiceal adenocarcinoma (AA). Presenting Author: Karen A. Beaty, The University of Texas MD Anderson Cancer Center, Houston, TX Background: AA is a rare malignancy ranging from well-differentiated to poorly differentiated carcinoma, including those with signet ring cells. Optimal therapy for low grade peritoneal disease is cytoreductive surgery (CRS) combined with heated intraperitoneal chemotherapy (HIPEC). However, some patients (pts) are suboptimal for CRS/HIPEC, and are considered for systemic chemotherapy (SC) alone, or SC ⫹ CRS. In light of our previously reported overall survival (OS) benefits for the role of SC in metastatic AA, here we explore the impact of surgical intervention on OS in these pts. Our aim was to clarify the OS benefit of multidisciplinary therapy (SC ⫹ CRS ⫹ HIPEC) in those pts with aggressive tumor biology. Methods: A retrospective chart review of AA pts registered in our tumor registry between Jan. 2005 to Dec. 2009 was undertaken to identify patients with AA who received SC. Electronic medical records (EMR) were reviewed for CRS, HIPEC, histology, SC, and OS. The K-M method and Log-Rank test were used for statistical analysis. Results: Of 143 AA pts, 52 (36%) pts were high grade with 33 (23%) having signet ring cells. After a median follow-up of 35M, high grade tumors were noted to have worse OS overall (24M vs 56M, p⬍.001). When comparing treatment received, and adjusting for tumor biology, those pts with high grade disease again fared worse, and experienced comparatively worse OS. However, those treated with SC ⫹ CRS ⫹ HIPEC experienced the longest median survival. Conclusions: Pts with peritoneal disease from high grade AA who completed SC with CRS ⫹ HIPEC experienced prolonged OS compared to those treated by SC ⫹/CRS. Our data suggest that SC ⫹ palliative CRS offers minimal benefit for high grade disease. Selection bias influences these results heavily; as those who do well proceed to complete all components of therapy. A treatment plan that includes SC ⫹ CRS ⫹ HIPEC can result in durable survival, and is a strategy that warrants further study emphasizing the importance of multidisciplinary management. Group

N

Therapy

Median OS (95% CI)

P value

High grade

52 91

21M (16.7 – 25.3) 29M (22.8 – 35.2) 46M (33.2 – 58.8) 39M (33.2 – 44.8) 56M (45.4 – 66.6) 83M (50.3 – 115.7)

0.025

Other

SC alone SC ⫹ CRS SC ⫹ CRS ⫹ HIPEC SC alone SC ⫹ CRS SC ⫹ CRS ⫹ HIPEC

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Everolimus in combination with octreotide LAR as the first-line treatment for advanced neuroendocrine tumors: A phase II trial of the I.T.M.O. (Italian Trials in Medical Oncology) group. Presenting Author: Emilio Bajetta, Istituto di Oncologia, Policlinico di Monza, Monza, Italy Background: Everolimus has shown antitumor activity in patients (pts) with advanced pancreatic neuroendocrine tumors (NETs). We aimed to assess efficacy and safety of everolimus in combination with octreotide longacting repeatable (LAR) in patients with well differentiated NETs of gastroenteropancreatic and of lung origin. Methods: We performed a phase II, multicenter trial using a Simon two-stage minmax design. Pts with advanced well differentiated, previously untreated NETs of the gastroenteropancreatic tract and of the lung received octreotide LAR 30 mg every 28 days in conjunction with everolimus 10 mg per day continuously. The primary endpoint was objective response rate (ORR). Results: A total of 50 pts (58% males) were enrolled. The median age was 60.5 years (range 25-76). Primary tumor site was pancreas in 14 (28%), unknown in 14 (28%), lung in 11 (22%), ileum in 9 (18%) and jejunum and duodenum in 2 (4%) of pts. 13 (26%) pts had carcinoid syndrome. The ORR, calculated on the ITT population, was 20.0% (95% CI 8.9-31.1): 2 patients (4%) had a complete response (CR), 8 (16%) a partial response (PR). Thirty-six patients (72%) achieved stable disease (SD). All CR and all PR as well as 91.7% of SD had a duration ⱖ 6 months. Clinical benefit (CR⫹PR⫹SD) was 92%. At a median follow-up of 277 days, the median time to progression (TTP) was 16.3 months (95% CI 10.7-20.1). Overall survival could not be assessed. Treatment-related adverse events (AEs) were mostly of grade 1 or 2; the only grade 4 AE was mucositis in 1 patient, while grade 3 AEs included skin rash in 1 case, stomatitis in 4 cases (8%) and diarrhea in 11 cases (22%). Conclusions: Everolimus in combination with octreotide LAR has shown to be active and well tolerated in advanced NETs and, in this study, not only in primary pancreatic tumors. Compared to other clinical trials with everolimus in NETs, the observed ORR in this study was higher. Aknowledgements: The Authors thank the Italian Trials in Medical Oncology (I.T.M.O.) group and Novartis Pharma for the support provided. Clinical trial information: 2008-007153-13.

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Molecular characterization of nonpancreatic neuroendocrine neoplasms (NENS): First description of mutations in the tumor suppressor gene (TSG) SMARCB1 in NENS of colorectal origin using next-generation sequencing (NGS). Presenting Author: Jaume Capdevila, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, Barcelona, Spain Background: The knowledge of molecular aberrations that characterize the different types of NENS is still limited. Recent exome sequencing data has allowed the definition of the genetic basis of pancreatic NENS. We aimed to define the tumor genomic profiling in non-pancreatic NENS using NGS. Methods: FFPE samples from NENS of different non-pancreatic origins were analyzed. A single pathologist evaluated them for tumor content (cutoff ⬎30% tumor cells) and lymphocyte infiltration. DNA was obtained and quality assessed by a qPCR-based method. We performed ampliconseq using 476 primer pairs targeting hotspot mutation loci in oncogenes as well as TSG. An initial amplification step was performed, amplicon sizes ranging 80-120 bp. After that, 100 ng of dsDNA were used for standard indexed TruSeq Genomic sample preparation. Samples were pooled in two groups and sequenced in a MiSeq instrument (Illumina) in a 2X100 run. Reads were aligned (BWA), variants called (GATK) and annotated. Final individual manual check of mutations was performed. NENS types were classified following the 2010 WHO classification. Results: We analyzed 38 NENS samples of different origins and grades: 7 G3 colon, 8 G1/2 colon, 8 G1/2 ileum, 8 G1/2 gastric, and 7 G1/2 lung. We identified 24 mutations in several genes and different distribution regarding tumor origin was observed. G3 colon NENS presented mutations in KRAS (43%), APC (28%), and VHL (14%). Ileum NENS showed mutations in TP53 (50%), VHL (37%), FGFR3 (12%) and APC (12%). In G1/2 NENS of colon origin, mutations in SMARCB1 (37%), KRAS (12%) and NF2 (12%) were identified. Less frequent mutations were present in gastric and lung samples (KRAS, TP53 and FGFR3 in 12% each). Conclusions: A tumor origin specific mutation pattern has been observed for NENS. To our knowledge this is the first time to describe mutations in SMARCB1 TSG in this setting. Further investigation is warranted to define the role of SMARCB1 in the pathogenesis of NENS.

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A multitranscript blood neuroendocrine tumor molecular signature to identify treatment efficacy and disease progress. Presenting Author: Irvin M. Modlin, Yale School of Medicine, New Haven, CT Background: Gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs) or NETs (also called “carcinoids”) are problematic since they present with advanced disease and have limited treatment options. Imaging has proved to be insensitive in identifying treatment effect. Similarly, the currently used biomarker, a neurosectory peptide, Chromogranin A (CgA) is of limited value as a predictor of treatment efficacy. We have developed a multi-transcript (n⫽51 genes) molecular signature for PCR-based blood analysis which exhibits a high sensitivity (85-98%), specificity (93-97%), positive predictive value (95-96%) and negative predictive value (87-98%) for the identification of GEP-NENs. This test significantly outperforms (p⬍0005) plasma CgA (measured by ELISA). Methods: The candidate gene signature was examined by a 2-step PCR method in a training set of 130 blood samples (GEP-NENs: n⫽63, treatment-naïve (n⫽28)) and validated in an independent set ([n⫽182, GEP-NENs: n⫽133, including complete remission (n⫽4), clinically stable disease (n⫽82) and non-responders/clinically progressive disease (n⫽47). Results: The PCR score was significantly elevated (p⬍0.0001) in the treatment-naïve group compared to treated GEP-NENs, while levels were significantly reduced (p⬍0.004) in 11 matched samples (pre- and posttreatment – surgical removal (n⫽10), RFA (n⫽1)). In the independent set, the scores for complete remission were not different to controls (0.5⫾0.25 vs. 0.4⫾0.16), while scores for stable disease (0.63⫾0.12) were significantly lower than for non-responders (5.85⫾0.34, p⬍0.002). Stable disease could be differentiated from clinically progressive disease since the latter exhibited a high score (85% vs. 10%, p⬍0.0001). The performance metrics for differentiation were: sensitivity (91%), specificity (91%), PPV (86%), NPV (95%). Conclusions: This study demonstrated that the multitranscript molecular signature is both sensitive and specific for the detection of neuroendocrine tumor disease and is capable of differentiating clinically stable from progressive disease. It therefore has potential utility as a measure for monitoring treatment efficacy for GEP-NENs.




Open-label, phase IIIb, multicenter, expanded access study of everolimus in patients with advanced neuroendocrine tumors (NET). Presenting Author: Oliver Edgar Bechter, Universitz Hospital Leuven, Leuven Cancer Institute, Leuven, Belgium Background: Everolimus (EVE) antitumor efficacy in patients (pts) with advanced NET was demonstrated in 2 double-blind, placebo (P)– controlled, phase III trials (RADIANT-2 and RADIANT-3). Median PFS in pancreatic (pNET) pts was 11.0 months (EVE) vs. 4.6 months (P) (HR 0.35, 95% CI 0.27-0.45, P ⬍0.001) in RADIANT-3. Median EVE exposure in RADIANT-3 was 38 wks. EVE was approved for advanced pNET in the US and Europe in 2011. An expanded access protocol was launched to gather additional safety data and provide access to EVE for pts with advanced NET while awaiting regulatory approval. Methods: Pts aged ⱖ18 years with biopsy-proven NET; WHO performance status 0-2; and adequate bone, hepatic, and renal function were enrolled. Main exclusion criteria were poorly differentiated NET and cytotoxic therapy within 4 wks of enrollment. EVE (10 mg/d) was administered until disease progression, unacceptable toxicity, discontinuation, death, commercial availability of EVE, or until May 30, 2012. Pts were enrolled from April 21, 2011 to April 20, 2012. Primary objective was grade 3/4 and serious adverse events (AEs). Secondary objectives included investigator-assessed best overall response rate and PFS. Results: The full analysis set included 246 pts (pNET, n⫽126; non-pNET, n⫽120); the safety set included 240 pts (pNET, n⫽123; non-pNET, n⫽117). Median age was 61 and 66 years; 54% and 49% were male. Main primary tumor sites in non-pNET pts included small intestine (40%) and lung (22%). Median duration of EVE exposure was 12.1 wks and 24 wks in pNET and non-pNET. At data cutoff, there were 21 and 32 PFS events; 105 and 88 pts were censored. Grade 3/4 AEs were reported in 42.3% and 69.2% of pNET and non-pNET; those reported in ⱖ10% of pts in pNET and non-pNET included hyperglycemia (12.2% and 5.1%), diarrhea (10.6% and 31.6%), stomatitis (9.8% and 11.1%), nausea (8.1% and 10.3%), and anemia (5.7% and 11.1%). Median investigator-assessed PFS was 7.6 (95% CI 5.52-7.62) months and 10.8 (8.77-Not Estimable) months in pNET and non-pNET. Conclusions: EVE was well tolerated in pts with advanced NET. AEs were similar to those previously reported. Protocol-specified early termination of pts limits the interpretation of PFS medians. Clinical trial information: EudraCT Number: 2010-023032-17.

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Study on activation of the IGF-1R mTOR pathway in neuroendocrine tumours (NETs). Presenting Author: Oriol Casanovas, IDIBELL, Institut Català d’Oncologia L’Hospitalet, Barcelona, Spain Background: NETs are a heterogeneous group of rare neoplasms. Preclinical studies have shown that IGFR overestimulation can lead to constitutional activation of mTOR pathway. The main objective of this study is to describe the activation status of IGF1R-mTOR pathway by immunohistochemistry in a series of NETs and to assess the association with IGF1R expression. Methods: We studied 69 paraffin tumour blocks: 28 pancreatic NETs (pNETs) (2 gastrinomas, 1 glucagonoma, 4 insulinomas and 21 nonfunctioning (nf) pNETs), 32 GI NETs (4 stomach, 8 colorectum, 18 ileum and 2 dudodenum) and 9 NETs from other origins (2 anterior mediastinum, 2 ovary, 3 bile duct and 2 kidney). The expression of IGF1R, phosphorylated (p) mTOR and (p)S6 has been determined by immunohistochemistry using anti-IGF1R␤ (sc-713), anti-Phospho-mTOR (S2448) (49F9, Cell Signaling) and anti-Phospho-S6 Ribosomal Protein (S235/336)(91B2, Cell Signaling). Results: Expression of IGF1R has been observed in 46 of 69 (66%) samples with the highest expression in 2/4 (50%) insulinomas, 5/21 nf pNETs (23%) and 3/18 ileum (17%). We have observed activation of the mTOR pathway by immunodetection of (p)mTOR in 14 of 69 samples (20%): 2/21 nf pNETs (9.5%), 1/8 colorectum (12.5%), 8/18 ileum (44%), 1/2 anterior mediastinum, 1/2 ovary, 1/3 biliar tract. We haven’t detected any (p)S6 activation in these samples. Consistent IGF1R-mTOR pathway activation was detected in 11/14 (78%) samples with mTOR positivity that also showed expression of IGF1R. The most relevant finding is that all of the 8 samples from ileum with activation of mTOR showed some degree of expression of IGF1R. Conclusions: 2/3 of NETs show varying levels of expression of IGF1R, but only 16% demonstrate activation of the IGF1R-mTOR pathway. While the positivity of (p)mTOR in pNETs is lower than expected, we have identified a subgroup of ileal NETs with consistent activation of both IGF1R and (p)mTOR which could help stratify patients in clinical trials involving modulation of this pathway. In contrast, none of the 69 samples studied was positive for (p)S6 which suggests this marker is not valid to be used in the clinic. Further validation studies are required to help clinical stratification for therapies against IGF1R mTOR pathways.

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sVEGFR2 and circulating tumor cells to predict for the efficacy of pazopanib in neuroendocrine tumors (NETs): PAZONET subgroup analysis. Presenting Author: Enrique Grande, Ramón y Cajal University Hospital, Madrid, Spain

Gene expression profiling (GEP) to predict the primary site of metastatic neuroendocrine tumors (NETs) presenting with an unknown primary. Presenting Author: Eugene Woltering, Louisiana State University Health Sciences Center, Kenner, LA

Background: The PAZONET trial (Grande et al, ESMO 2012) performed by the GETNE group analyzed the efficacy and safety of the use of pazopanib (800 mg/qd) in patients (pts) with progressive metastatic NETs that had been previously treated with other novel targeted agents. Here we report on the relationship between clinical outcome and circulating and tumorrelated biomarkers. Methods: Kaplan-Meier analysis was used to correlate progression-free survival (PFS) with: blood circulating markers at baseline and after 12 weeks of treatment (VEGF-A and sVEGFR2 circulating plasma, Circulating Tumor Cells (CTC) and Circulating Endothelial Cells (CEC)), tumor functional status, Ki67, concomitant somatostatin analogues (SSA), chromogranin A (CgA) and primary tumor location. Results: 44 pts were enrolled, 42 were evaluable for response. sVEGFR2 decreased after 12 weeks of treatment (median decrease 20%, p⬍0.0001) and the duration of treatment with pazopanib was associated with a decrease in sVEGFR2 (p⫽0.0046). Pts with a decrease in sVEGFR2 of ⬎20% and ⬍⫽20% had a median progression-free survival (mPFS) of 12.6 and 9.1 months (mo) respectively (p⫽0.067). Pts with and without CTC at baseline had a mPFS of 5.8 and 9.1 mo respectively (p⫽0.12). VEGFA and CEC were not found to predict PFS. mPFS in the intention to treat population was 10.0 mo (95% CI 4.3-15.6). Significant differences in mPFS were found in concomitant SSA treatment (11.9 mo [10.6-13.2]) vs. pazopanib alone (4.8 mo [3.0-6.6]) (p⫽0.007); decrease of CgA (3.4 mo [0.0-6.8]) vs no decrease (11.2 mo [8.4-14.1]) (p⫽0.024) and pancreatic (12.8 mo [11.0-14.6]) vs gastrointestinal (10.0 mo [4.9-15.1]) vs other primary tumors (3.4 mo [0.0-7.0]). No differences in mPFS were seen in functioning (10.0 mo) and non-functioning tumors (9.3 mo) and Ki67 status (⬍ 2% 10.0 mo, 3-10% 10.8 mo or ⬎10% 4.1 mo). Conclusions: sVEGFR2 and baseline CTC are promising predictive biomarkers for pazopanib in NETs. The updated results confirm the efficacy of pazopanib as a sequencing treatment of pts with progressive NETs, particularly in those with pancreatic primary tumors. The combination of pazopanib and SSA seems to be synergistic. Clinical trial information: NCT01280201.

Background: NETs often present as liver metastasis with an unknown primary. Accurate subtyping of NETs has important clinical implications for staging and site-specific targeted therapy. Traditionally, the work-up to identify a primary NET as being lung, pancreatic or gut-based can be challenging and time-consuming. Methods: GEP was performed on formalinfixed, paraffin-embedded tumor samples using a 92-gene RT-PCR assay (CancerTYPE ID, bioTheranostics Inc.) as part of the clinical work-up for patients diagnosed with NETs and unknown primaries. Results: Results were categorized by level of agreement (Table). Of the 39 patients tested with the assay, 82% presented with liver metastasis. Assay results from those patients with adequate work-up were concordant with clinical data in 77% (23/30) of cases. Surgery was performed in 12 of these cases and 100% accuracy of the molecular assay was confirmed, resulting in 75% of primary tumors being found in the gut and 25% in the pancreas or duodenum. Assay predictions were clinically plausible but inconsistent in 13% (4/30) of cases and were discordant with histology, IHC, imaging/ radiological findings, and clinical impression in 10% of the cases. Conclusions: The 92-gene assay accurately predicted tumor subtype in patients presenting with NETs and an unknown primary. These findings have clinical utility for appropriate treatment selection, particularly where targeted therapies are available (everolimus, sunitinib). We believe the 92-gene assay can be useful in clinical management, and that our approach will lead to effective diagnosis and treatment algorithms to streamline extensive pre-operative work-up. Level of agreement 1 1a 2 3

Criteria GEP result concordant with surgical results GEP result concordant with histology, IHC, imaging/radiological findings, and clinical impression GEP result provided additional information that was inconsistent with histology, IHC, imaging/radiological findings, and clinical impression GEP result discordant with histology, IHC, imaging/radiological findings, and clinical impression Insufficient information on additional work-up

92-gene assay results (Nⴝ39) 12 11 4 3 9


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Dosing patterns for octreotide LAR in neuroendocrine tumor (NET) patients: NCCN NET outcomes database. Presenting Author: Jonathan R. Strosberg, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL Background: Among patients (pts) with neuroendocrine histology, 10 mg – 30 mg of octreotide-LAR administered intramuscularly every 4 weeks is FDA-approved for the long term treatment of severe diarrhea and flushing episodes associated with metastatic carcinoid tumors and pancreatic VIPomas. In clinical practice, higher doses and/or more frequent administration is often prescribed for pts who experience refractory symptoms (e.g., flushing and/or diarrhea) on the maximal labeled dose. Methods: National Comprehensive Cancer Network (NCCN) created a comprehensive longitudinal database to characterize pts treated for NETs. This database was queried to identify pts presenting to 7 NCCN institutions, from 2004 to 2010, with a confirmed carcinoid or pancreatic NET (pNET) diagnosis who received octreotide LAR. The primary aim of this analysis was to describe octreotide LAR dosing patterns when beyond label recommendations, clinical characteristics, reasons for dose increase, and maximal dose. Results: Among 1,886 pts in the database, 271 carcinoid and pNET pts received octreotide LAR. 40% of carcinoid pts (n⫽82) and 23% of pNET pts (n⫽15) received octreotide LAR above-label dosing, defined by dose and/or frequency greater than 30 mg every 4 weeks. The primary tumor sites among carcinoid pts receiving above label dosing were small bowel (n⫽40), colorectal (n⫽4), and unknown (n⫽34). Reasons for above label dosing among carcinoid pts included uncontrolled symptoms (n⫽53, 65%), tumor progression (n⫽21, 25%), high urine 5-HIAA (n⫽1, 1%) and unknown (n⫽7, 9%). The most common dose/frequency combinations for carcinoid pts were 40 mg every 4 weeks (32 pts, 39%), 40 mg every 3 weeks (15 pts, 18%), and 30 mg every 2 weeks (14 pts 17%). Among pNET pts, reasons for change included uncontrolled symptoms (n⫽5, 33%), tumor progression (n⫽9, 60%), and unknown (n⫽1, 7%). The most common maximal dose/frequency combinations among pNET pts were 40mg every 4 weeks (n⫽5, 33%), 30mg every 2 weeks (n⫽4, 27%), and 60 mg every 4 weeks (n⫽4, 27). Conclusions: Above label dosing of octreotide LAR is common in NCCN institutions. The primary indication is refractory carcinoid syndrome. Prospective studies are planned to validate this strategy.

TPS4144


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Treatment of liver metastases in patients with neuroendocrine tumors: A National Comprehensive Cancer Network analysis. Presenting Author: Michael A. Choti, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD Background: The choice of therapy in patients with hepatic metastases from neuroendocrine tumors is controversial. The purpose of this study was to describe the utilization of liver resection and other locoregional therapies in the management of NET hepatic metastases in NCCN centers. Methods: The National Comprehensive Cancer Network (NCCN) Neuroendocrine Tumor Database tracks longitudinal care for patients treated at seven specialty cancer centers in the U.S. from 2004 to 2010. Patient and tumor characteristics, as well as the use of liver-directed therapy (LDT) in patients with neuroendocrine liver metastases (NELM) were evaluated. Results: Among 907 patients presenting with metastatic disease, 606 patients presenting with newly diagnosed disease or previously diagnosed disease with first distant recurrence of NELM were evaluated. LDT was used during some component of the patient care in only 43% of patients with NELM, the remainder received only systemic or no therapy. LDT varied by extent of disease (p⫽0.002) with a higher proportion of patients with liver-only disease receiving LDT (45%) compared to those with liver and extrahepatic disease (26%). There was a significant difference in LDT by functional tumor status (⌾2⫽6.84, p⫽0.03) and primary site of disease (⌾2⫽14.95, p⫽0.001) where a higher proportion of patients with hormonally functional tumors received LDT when compared to non-functional tumors (48% vs 42%) as well as those with primary small bowel carcinoid vs pancreatic NET (56% vs 39%). Among those treated with LDT, 39% underwent surgical resection, 57% intra-arterial therapy (IAT), and 4% ablation alone. Major hepatectomy was performed in 21%, multiple resections in 13%, and resection combined with ablation in 24% of patients receiving surgical therapy. Among the 147 patients treated with IAT, 52% received standard chemoembolization, 23% bland embolization, and 18% yttrium-90 therapy. Conclusions: Even at specialty centers less than half of patients received LDT, among which one-fifth had a hepatic resection. Future studies on this cohort will measure outcomes based on type of LDT.

TPS4145


Randomized phase II study of gemcitabine (G), cisplatin (C) with or without veliparib (V) (arms A, B) and a phase II single-arm study of single-agent veliparib (arm C) in patients with BRCA or PALB2-mutated pancreas adenocarcinoma (PC). Presenting Author: Eileen Mary O’Reilly, Memorial Sloan-Kettering Cancer Center, New York, NY

SWOG S1115: Randomized phase II clinical trial of selumetinib (AZD6244; ARRY 142886) hydrogen sulfate (NSC-748727) and MK-2206 (NSC749607) versus mFOLFOX in patients withmetastatic pancreatic cancer after prior chemotherapy. Presenting Author: Vincent M. Chung, City of Hope, Duarte, CA

Background: Germline mutations in BRCA1, 2 predispose to PC (Lal, G. Cancer Res, 2000). 5-8% PC have BRCA 1,2 mutations; higher in Ashkenazi Jewish (10-15%). Pre-clinical data demonstrates that platinums and poly-ADP ribose polymerase inhibitors (PARPi) have activity in BRCA-mutated PC models. Early clinical data supporting (Lowery, M. Oncol, 2011). We are evaluating the role of platinum agents and PARPi, veliparib (ABT-888), in BRCA or PALB2-mutated PC. Methods: Arm A, B: Includes non-randomized phase to optimize V dose combined with G, C (Arm A). Subsequently randomized phase II study will evaluate G, C ⫹/- V. Primary endpoint: RECIST 1.1 response rate (RR) G, C, V (Arm A) and G, C (Arm B). Secondary endpoints: Progression-free survival, safety, diseasecontrol rate, overall survival and correlatives involving pre, post biopsies to evaluate mechanisms of sensitivity, resistance to platinums, PARPi. Arm C: Evaluates single-agent V in previously-treated PC. Primary and secondary endpoints similar. Eligibility: BRCA, PALB2-mutated, measurable, stage III/IV PC; Untreated (Arm A, B), ⱕ 2 lines therapy (Arm C); ECOG 0-1 (Arm A, B), ECOG 0-2 (Arm C). Treatment Plan: Arm A, B: V PO BID d1-12 (Arm A), q 3 weeks, G 600mg/m2 IV, C 25mg/m2IV, both d3, 10, q 3 weeks (Arm A, B). Arm C: V 400mg PO BID d1-28 q 4 weeks. Biostatistics: Arms A, B: Simon’s 2-stage minimax design per arm. Unacceptable RR 10%, promising 30%, type I, II errors 10%. N⫽ 16 stage I, ⫹N⫽ 9 (stage II). If ⱖ 5/25, then promising. If both arms promising, option to add N⫽ 10, allows distinction between RR 20% and 40%, 83% power. Arm C: Simon’s 2-stage, single-arm, uninteresting RR 10%, promising if ⱖ 28%. N⫽ 15 stage I, ⫹N⫽ 18 (stage II). Promising RR ⱖ 6/33. Total N 47- 95. Contingency for slow accrual. Progress to Date: Accrual: Arm A (nonrandomized): 13 screened, N⫽ 5 enrolled. Arm C: 9 screened, N⫽ 4 enrolled. Israeli, Canadian, other U.S. sites opening 2013. Funding and acknowledgements: National Cancer Institute, Lustgarten Foundation. NCT01585805. Clinical trial information: NCT01585805.

Background: Pancreatic cancer remains a deadly disease and despite advances in chemotherapy treatment, survival for most patients is still less than one year. Over 80% of pancreatic cancers are KRAS mutant which activates the PI3K/AKT pathway and signals downstream to mTOR leading to cell growth, proliferation and survival. Recent data has shown that blocking both the PI3K/AKT and MEK pathways simultaneously is effective in KRASmutant tumors. Our trial is a novel, molecular targeted treatment approach for patients with metastatic pancreatic cancer that has the potential to establish a new treatment paradigm. Methods: S1115 was activated in SWOG in August 2012 and is currently IRB approved at 130 institutions within SWOG and the Clinical Trials Support Unit (CTSU). Patients (performance status 0 or 1) with metastatic pancreatic cancer failing standard gemcitabine chemotherapy are randomized to MK-2206 135 mg orally weekly plus selumetinib 100 mg orally daily or mFOLFOX IV every 2 weeks. Eligibility criteria allow metastatic patients who have progressed within 6 months of receiving adjuvant gemcitabine. Patients receiving prior 5-fluorouracil (excluding radiation-sensitizing doses), capecitabine, oxaliplatin, MEK or PI3K/AKT inhibitors are not eligible. Stratification factors include duration of prior systemic therapy and presence of liver metastases. The primary endpoint of this study is overall survival (OS) in patients treated with the combination of MK-2206 and selumetinib compared with those treated with mFOLFOX. Based on previous studies, median OS in the control group is approximately 6 months. Assuming a one-sided type 1 error of 10%, 80% power, approximately 2 years of accrual and 1.5 years of follow-up, 120 eligible patients will be accrued to detect an improvement in median survival from 6 to 9 months (corresponding to a 1.5 hazard ratio). Prospective tumoral tissue collection will be undertaken. ClinicalTrials.gov Identifier: NCT01658943. Support: NCI grants CA32102 & CA38926 Clinical trial information: NCT01658943.


Gastrointestinal (Noncolorectal) Cancer TPS4146


Pilot, proof-of-concept studies for determining the feasibility of the use of FLT-PET in patients with pancreatic adenocarcinoma. Presenting Author: Angela Lamarca, Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom Background: Pancreatic cancer (PC) has one of the lowest 5-year survival rates. Gemcitabine (G)-based chemotherapy is standard-of-care first-line systemic therapy. Fluorine-18 radiolabelled 3-deoxy-3-fluorothymidine (FLT), a thymidine analogue, is a substrate for thymidine kinase 1 (TK1), which is highly expressed in proliferating cells in late G1/S phase. FLT uptake (imaged and quantified by positron emission tomography (PET)) correlates with pathology-based proliferation markers and with decreases with therapy in a number of cancers. G, a nucleoside analogue, decreases proliferation by inhibiting DNA synthesis, primarily acting on S and G1/S phase thus decreasing tumour FLT uptake. Human equilibrative nucleoside transporter (hENT1) transports G and FLT into cells, making hENT1 activity a key determinant of both FLT uptake and G efficacy. Methods: Two parallel proof-of-concept studies are designed to explore the feasibility of assessing proliferation, nucleoside transport, magnitude of treatmentrelated FLT uptake changes and understanding the pathophysiological basis of FLT-PET imaging in patients (pts) with (1) localized or (2) advanced PC. Up to 24 PC pts with ECOG PS 0-2, able to undergo imaging and with at least one potentially evaluable lesion larger than 2cm on CT/MRI are eligible. Pts with localized disease (study 1) will have dynamic FLT-PET pre-operatively preceded by a radiolabelled H2O PET scan to assess tumour perfusion. These pts will also undergo 2-deoxy-2-fluoro-Dglucose (FDG)-PET and diffusion-weighted MR scans. For pts with metastatic disease (study 2), dynamic FLT-PET will be performed before and after G-based chemotherapy. FLT uptake expressed as a standardized uptake value (SUV), will be determined. Tumour pathological markers from the surgical samples and imaging parameters will be correlated; hENT1 status will be assessed (by immunohistochemistry) after surgery (study 1) and before treatment (study 2). Reproducibility FLT-PET studies will be performed in a cohort of subjects to assess the variability in uptake quantification.

TPS4148


TPS4147

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Phase II clinical trial of biomarker-directed therapy for localized pancreatic cancer. Presenting Author: Susan Tsai, Medical College of Wisconsin, Milwaukee, WI Background: Several candidate biomarkers exist for the common chemotherapeutic agents used to treat pancreatic cancer (PC) (Table). The predictive value of these markers in the treatment of PC has not been established. This is the first prospective clinical trial utilizing biomarker-directed therapy for localized pancreatic cancer. Methods: Patients with localized pancreatic cancer undergo endoscopic ultrasound-guided fine needle aspiration (FNA) for confirmation of diagnosis and immunohistochemical profiling . Six biomarkers (STREET profile) were selected based on their relevance to accepted pancreatic chemotherapy regimens (table). The treatment algorithm selected for each individual patient is based on the clinical stage of resectability (resectable/borderline resectable) and the STREET profile results. Neoadjuvant therapy is followed by restaging (CT and serum Ca19-9) and in the absence of disease progression, patients undergo surgery. Post-surgical (adjuvant) therapy is determined by the STREET profile of the resected specimen. The primary endpoint is an increase in the rate of surgical resection 20% compared with historical controls treated with best available neoadjuvant therapy which was not biomarker-directed. Secondary endpoints include assessment of overall and progression-free survival, comparative STREET profiling of pre- and post-treatment specimens, and changes in radiographic response. Eligbility Criteria: Patients with resectable or borderline resectable pancreatic cancer undergo endoscopic ultrasound-guided fine needle aspiration (FNA) for confirmation of diagnosis and immunohistochemical profiling. Enrollment: 26 of planned 100 patients have been enrolled. Clinical trial information: NCT01726582. STREET panel SPARC TOPO1 RRM1 ENT1 ERCC1 TYMS

TPS4149

Function Cellular matrix protein DNA relaxation Nucleotide synthesis Membrane transporter Nucleotide excision repair complex Nucleotide synthesis

Expression

Favored agent

High SPARC Nab-paclitaxel High TOPO Irinotecan Low RRM1 Gemcitabine High ENT1 Gemcitabine Low ERCC1 Platinum analog Low TYMS 5-FU


Efficacy and safety of gemcitabine in combination with TH-302 compared with gemcitabine in combination with placebo in previously untreated patients with metastatic or locally advanced unresectable pancreatic adenocarcinoma: The MAESTRO trial. Presenting Author: Eric Van Cutsem, University Hospitals Leuven, Leuven, Belgium

A phase II randomized, double-blinded, placebo-controlled study to evaluate the efficacy and safety of simtuzumab (GS-6624) combined with gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma. Presenting Author: Al Bowen Benson, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL

Background: Tumors often consist of highly hypoxic subregions that are resistant to chemotherapy and radiotherapy. The investigational hypoxiatargeted drug TH-302 is reduced at its nitroimidazole group, and under hypoxic conditions releases the DNA alkylator bromo-isophosphoramide mustard (Br-IPM). A randomized Phase IIb trial of TH-302 in pts with metastatic or locally advanced unresectable pancreatic adenocarcinoma (PDAC) confirmed a significant PFS improvement (p⫽0.008) in pts treated with TH-302 at 340 mg/m2⫹ gemcitabine compared with gemcitabine alone (Borad et al, ESMO 2012). Skin and mucosal toxicities, mainly Grade 1/2, and myelosuppression (thrombocytopenia, neutropenia and anemia) were the most common AEs related to TH-302 and did not lead to increases in treatment discontinuation. Grade 3/4 myelosuppression was more frequent in the TH-302 ⫹ gemcitabine arm. AEs leading to treatment discontinuation as well as non-hematological serious AEs were balanced across arms. Methods: This is a Phase III, randomized, double-blind, placebo-controlled trial (NCT01746979) of gemcitabine ⫹ TH-302 compared with gemcitabine ⫹ placebo in pts with locally advanced unresectable or metastatic PDAC. The study is designed to detect a 25% risk reduction of death with 90% power and two-sided alpha of 5%. A total of 660 pts are planned to be randomized 1:1. Key eligibility criteria include histologically or cytologically confirmed disease, no prior chemotherapy or systemic therapy (except as specified in the protocol), ECOG performance status 0 – 1, and bilirubin ⱕ 1.5x upper limit of normal. Randomized pts receive TH-302 ⫹ gemcitabine or gemcitabine ⫹ placebo in 4-week cycles until progressive disease, intolerable toxicity, or pt withdrawal. The primary objective is to evaluate OS. Secondary objectives include PFS, objective response, and disease control; safety and tolerability; pt-reported QoL and pain; CA 19-9 levels and PK of TH-302; exploratory pharmacogenomic markers and potential predictive biomarkers. Enrollment to the study is ongoing. Clinical trial information: NCT01746979.

Background: Lysyl oxidase-like molecule 2 (LOXL2) is an extracellular matrix enzyme that catalyzes the covalent cross-linking of collagen and is widely expressed across desmoplastic tumors. Simtuzumab (GS-6624) is a humanized antibody that specifically inhibits LOXL2 enzymatic activity. Inhibiting LOXL2 is expected to block formation of desmoplasia, which is thought to play an important role in tumor progression and metastasis. Methods: The primary objective and of the study is to compare the additive efficacy of simtuzumab vs. placebo in combination with gemcitabine as measured by improvement in progression free survival (PFS). The secondary objective is to compare the additive efficacy of simtuzumab vs. placebo as measured by overall survival (OS) and objective response rate. Study Design: The study is a randomized, double-blind, placebo controlled Phase 2 trial in subjects with metastatic pancreatic adenocarcinoma. A total of 234 subjects will be randomized to 200 mg simtuzumab, 700 mg simtuzumab, or placebo at a 1:1:1 ratio (78 subjects per treatment group) in combination with gemcitabine in cycles of 28 days. In each cycle, subjects will receive IV GS-6624 or placebo infused on Days 1 and 15, and IV gemcitabine (1000 mg/m2) on Days 1, 8, and 15. CT or MRI scans will be performed every 8 weeks to evaluate response to treatment. Subjects will continue courses of treatment every 28 days in the absence of disease progression or unacceptable toxicity. As of January 30, 2013, 162 subjects have been randomized. Clinical trial information: NCT01472198.


280s TPS4150


Pertuzumab (P) with trastuzumab (T) and chemotherapy (CTX) in patients (pts) with HER2-positive metastatic gastric or gastroesophageal junction (GEJ) cancer: An international phase III study (JACOB). Presenting Author: Josep Tabernero, Vall d’Hebron University Hospital, Barcelona, Spain Background: Human epidermal growth factor receptor 2 (HER2) is overexpressed in ~20% of gastric cancers. Specific targeting of HER2 by T in combination with CTX has demonstrated significantly improved overall survival (OS) vs CTX in pts with advanced gastric or GEJ cancer (Bang Lancet 2010). In HER2-positive 1L metastatic breast cancer the combination of T plus docetaxel with a second HER2-targeted antibody, P, demonstrated significant improvement of progression-free survival (PFS) and OS vs placebo⫹T⫹docetaxel (Baselga NEJM 2012; Swain SABCS 2012). Based on these positive findings with HER2-targeted therapies in gastric and breast cancer, JACOB, a double-blind, placebo-controlled, randomized Phase III study, is designed to evaluate efficacy and safety of P⫹T⫹CTX in pts with HER2-positive 1L metastatic gastric or GEJ cancer. Methods: Pts will be randomized 1:1 to receive P⫹T⫹cisplatin ⫹fluoropyrimidine or the same regimen replacing P with placebo, q3w (P: 840 mg; T: 8 mg/kg first dose, then 6 mg/kg; cisplatin: 80 mg/m2; 5-fluorouracil: 800 mg/m2/24 h given continuously for 120 h or capecitabine: 1000 mg/m2 bid for 14 days). P/placebo⫹T will be given until progressive disease (PD) or unacceptable toxicity. On or before Cycle 6, CTX should only be discontinued for PD or unacceptable toxicity. Continuation of CTX after Cycle 6 is at the discretion of pt and physician. Randomization will be stratified by region (Japan vs North America/Western Europe/Australia vs Asia [excluding Japan] vs South America/Eastern Europe), prior gastrectomy, and HER2-positivity (IHC 3⫹ vs IHC 2⫹ and ISH⫹). Primary endpoint: OS; secondary endpoints include PFS, objective response rate, duration of response, clinical benefit rate, safety, pharmacokinetics of P, and patient-reported outcomes. Tumor and blood samples for biomarker evaluation will be collected. The study is estimated to have 80% power to detect a significant improvement in OS at a two-sided ␣-level of 5% (HR⫽0.777), with ~502 deaths required for the primary analysis. Target enrollment is 780 pts from ~200 sites and 35 countries; FPI is planned for April 2013. NCT01774786 Clinical trial information: NCT01774786.

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TPS4151


Sequential ipilimumab (Ipi) versus best supportive care (BSC) following first-line chemotherapy (Ctx) in patients (pts) with unresectable locally advanced or metastatic gastric or gastro-esophageal junction (GEJ) cancer: A randomized, open-label, two-arm, phase II trial (CA184-162) of immunotherapy as a maintenance concept. Presenting Author: Markus Hermann Moehler, Department of Internal Medicine, Johannes Gutenberg Universität Mainz, Mainz, Germany Background: First-line systemic CTX is standard-of-care for advanced gastric cancer. However, most pts relapse or have severe adverse events (AEs), creating a need for new therapies with better benefit/risk and toxicity profiles. Endogenous immune activity against tumor cells has been demonstrated in the human gastric cancer tumor microenvironment, supporting a role for immunotherapy. As a new maintenance concept, sequential administration of immunotherapy may prolong clinical benefit of first-line CTX before disease progression (PD). Ipi, a fully human monoclonal antibody which binds CTLA-4, augments the antitumor immune response. Ipi improved overall survival (OS) in patients with advanced melanoma with AEs managed using product-specific treatment guidelines.This global (32 sites among 10 countries), multicenter, randomized, open-label, phase II trial (ClinicalTrials.gov identifier NCT01585987) will compare the efficacy of Ipi and BSC after first-line CTX. Methods: Pts with good performance status (0 or 1) and histologically confirmed, unresectable locally advanced or metastatic gastric or GEJ cancer without PD after first-line CTX with a fluoropyrimidine (F) and platinum (P) doublet will be eligible. Pts with radiological evidence of brain metastases, autoimmune/ immune-mediated disease, inadequate hematologic, renal, and hepatic function, or are HER2⫹ will be ineligible. Pts will be randomized to Ipi (4 doses [10 mg/kg, IV Q3W], followed by Q12W) until confirmed immunerelated PD or unacceptable toxicity, or to BSC (continuing F used in lead-in CTX or no active systemic therapy). The primary objective is to compare immune-related progression-free survival (PFS): immune-related response criteria were derived from World Health Organization (WHO) criteria to better capture Ipi response patterns. Secondary objectives are to compare PFS per mWHO criteria and OS, and estimate immune-related best overall response rate. The study is planned to randomize 114 pts. Clinical trial information: NCT01585987.

TPS4153


Next study (JCOG1109): A three-arm randomized phase III study comparing preoperative CDDPⴙ5-FU(CF) versus docetaxelⴙCF versus CFradiation followed by esophagectomy with D2-3 lymphadenectomy for locally advanced esophageal squamous cell cancer. Presenting Author: Ken Kato, Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan

RILOMET-1: An international phase III multicenter, randomized, doubleblind, placebo-controlled trial of rilotumumab plus epirubicin, cisplatin, and capecitabine (ECX) as first-line therapy in patients with advanced MET-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Presenting Author: David Cunningham, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom

Background: Based on the results of JCOG9907, preoperative cisplatin plus 5- fluorouracil (CF) followed by esophagectomy with D2-3 lymphadenectomy has become standard care for advanced esophageal cancer in Japan, while the standard therapy in Western countries is preoperative chemoradiotherapy. A new clinical question has thus arisen of whether CF plus docetaxel (DCF) or CF plus radiotherapy (CF-RT) shows a survival benefit over preoperative CF even with intensive surgery. Methods: Eligibility criteria include histologically proven thoracic esophageal squamous cell carcinoma with stage IB/II/III (excluding T4) based on the 7th UICC-TNM, age 20 to 75, and performance status 0 to 1. No prior chemotherapy, radiotherapy, or hormonal therapy is allowed. Adequate organ function and written informed consent are required. Patients are randomized into any of the following three arms by a minimization method balancing the arms in terms of institution and tumor depth (T1–2 versus T3). Patients in arm A (CF) receive two courses of cisplatin at 80 mg/m2 on day 1 and fluorouracil at 800 mg/m2 on days 1–5, repeated every three weeks. Patients in arm B (DCF) receive three courses of docetaxel at 70 mg/m2, cisplatin at 70 mg/m2 on day 1, and fluorouracil at 750 mg/m2 on days 1–5, repeated every three weeks. Patients in arm C (CF-RT) receive two courses of cisplatin at 75 mg/m2 on day 1 and fluorouracil at 1000 mg/m2 on days 1– 4, repeated every four weeks concurrently with radiotherapy at 41.4Gy/ 23fr. This trial is designed to demonstrate the superiority of preoperative DCF and/or CF-RT over CF in terms of overall survival. We assumed three-year survival with preoperative CF to be 63% and expected a 10% increase in three-year survival for DCF and CF-RT. The sample size was calculated as a total of 501 patients (167 patients per arm) with a study-wise one-sided alpha level of 5%, power of 70% for each pair comparison, an accrual period of 6.25 years, and a follow-up period of three years. This trial was registered as UMIN000009482 and started in December 2012. Clinical trial information: UMIN000009482.

Background: Rilotumumab is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor that inhibits signaling through the MET receptor. In a randomized phase II study in patients with advanced G/GEJ adenocarcinoma, addition of rilotumumab every 3 weeks (Q3W) to ECX showed trends toward improved overall survival (OS) and progression-free survival (PFS) compared with ECX alone. In patients with high tumor MET expression and high rilotumumab exposure, the treatment effect of rilotumumab combined with ECX was significantly enhanced. Methods: In this phase III study, patients (planned N⫽450) are randomized 1:1 to ECX (intravenous [IV] epirubicin 50 mg/m2 on day 1, IV cisplatin 60 mg/m2 on day 1, and oral capecitabine 625 mg/m2 twice daily on days 1⫺21) plus double-blind rilotumumab 15 mg/kg or placebo IV Q3W. Randomization is stratified by disease extent (locally advanced vs metastatic) and Eastern Cooperative Oncology Group (ECOG) score (0 vs 1). Key eligibility criteria include previously untreated, pathologically confirmed unresectable locally advanced or metastatic G/GEJ adenocarcinoma; ECOG score 0 or 1; ⱖ18 years old; MET-positive by centralized immunohistochemistry; HER2-negative; adequate organ function; and ⱖ6 months since neoadjuvant/adjuvant therapy. The primary endpoint is OS. Key secondary endpoints include PFS, 12-month survival rate, objective response, OS in MET expression tertiles, safety, and pharmacokinetics. An exploratory objective is to assess associations between outcomes and tumor and circulating biomarkers. Enrollment began in November 2012, and the trial continues to accrue. An independent data monitoring committee will conduct planned interim reviews for safety and efficacy. Status: recruiting participants. Sponsored by Amgen Inc. Clinical trial information: NCT01697072.




A UGT1A1 genotype-directed phase II toxicity and efficacy-finding study of irinotecan combined with S-1 as first-line treatment in advanced gastric cancer. Presenting Author: Xiaofeng He, The Department of Medical Oncology, Cancer Center, Chengdu, China Background: The best chemotherapy regimen for advanced gastric cancer (AGC) is uncertain, but promising findings have been reported with Irinotecan (IRI) plus S-1. However, IRI can induce severe neutropenia or diarrhea associated with homozygosity of the UGT1A1*28 or UGT1A1*6 alleles. This trial was designed to compare the toxicity and efficacy on different doses of IRI combined with S-1 according to UGT1A1 genotype as first-line chemotherapy in AGC in Chinese patients. Methods: Previously untreated patients with histologically proven gastric or gastroesophageal junction adenocarcinoma, aged between 18 and 75 years with ECOG performance status 0-2 were classified according to UGT1A1 genotype: wild-type (none of *28 or *6 allele); heterozygous (only one of *28 or *6 allele); or homozygous (*28/*28, *6/*6, or double heterozygous for *28 and *6). Patients were randomized (1:1) to receive either low or high dose of IRI given i.v. (90 min) on day 1 in each genotype group. The low and high dose of IRI were 80mg/m2 and 200 mg/m2 in the wild-type group, 80 mg/m2 and 150 mg/m2 in the heterozygous group, 40 mg/m2 and 80 mg/m2 in the homozygous group. S-1 was administered orally at a dose level set on the basis of the body surface area (BSA): 40 (BSA⬍1.25 m2), 50 (BSAⱖ1.25 to⬍1.5 m2 ) or 60 mg (BSAⱖ1.5 m2) twice a day on day1-7. Courses were repeated every 2 weeks, unless disease progression, unacceptable toxicity or patient refusal. The primary endpoint was to explore the safety and efficacy on different doses of IRI combined with S-1 according to UGT1A1 polymorphism. Based on the frequency of UGT1A1*28 and UGT1A1*6 gene polymorphism in Asian gastrointestinal cancer patients, the chi-square test and fisher exact test were used to evaluate the planned sample size which is 100 in total: 40 for the wild-type, 40 for the heterozygous and 20 for the homozygous group. Until now, 8 patients have been enrolled. Clinical trial information: ChiCTR-OCH12002472.

TPS4156


TPS4155

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MetGastric: A randomized phase III study of onartuzumab (MetMAb) in combination with mFOLFOX6 in patients with metastatic HER2-negative and MET-positive adenocarcinoma of the stomach or gastroesophageal junction. Presenting Author: David Cunningham, Royal Marsden NHS Foundation Trust, Surrey, United Kingdom Background: Dysregulation of the HGF/MET pathway in patients with gastroesophageal cancer (GEC) is associated with diminished survival and poor prognostic features, such as nodal and organ metastasis, disease stage and tumor invasiveness. Preclinical data suggest that inhibition of the HGF/MET axis may increase the anti-tumor properties of platinum agents by overcoming HGF-mediated resistance mechanisms. Overexpression and inappropriate activation of the MET pathway has been shown to promote peritoneal metastasis in murine models of GEC. Overexpression of HGF or MET has also been linked to metastatic spread to the liver and peritoneum in patients with GEC. Clinical studies suggest that antibody-based inhibitors of the HGF/MET pathway are active in GEC. Onartuzumab, a monovalent monoclonal antibody, specifically binds to the MET receptor preventing HGF binding thereby inhibiting signal transduction. The most commonly reported adverse events associated with onartuzumab are grade 1–3 peripheral edema, hypoalbuminemia and fatigue. Methods: MetGastric is a randomized placebo-controlled, international phase III study in patients with previously untreated metastatic GEC. Only patients with tumors classified as both HER2-negative and MET-positive (by IHC) are eligible. Patients will be randomized (1:1) to receive mFOLFOX6 plus onartuzumab or mFOLFOX6 plus placebo. A maximum of 12 cycles of mFOLFOX6 are permitted. Onartuzumab or placebo will be continued until disease progression. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, overall response rate, safety and correlative biomarker studies. Primary and secondary analyses will include all randomized patients, analyzed according to treatment arm assignment and MET IHC score. Safety will be assessed in all patients who receive at least one dose of study treatment. This study is open for accrual. Clinical trial information: NCT01662869.

TPS4157


ST03: A randomized trial of perioperative epirubicin, cisplatin plus capecitabine (ECX) with or without bevacizumab (B) in patients (pts) with operable gastric, esophagogastric junction (OGJ), or lower esophageal adenocarcinoma. Presenting Author: Elizabeth C. Smyth, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom

INTEGRATE: A randomized phase II double-blind placebo-controlled study of regorafenib in refractory advanced esophagogastric cancer (AOGC)—A study by the Australasian Gastrointestinal Trials Group (AGITG). Presenting Author: Nick Pavlakis, Royal North Shore Hospital, Sydney University, Sydney, Australia

Background: Perioperative ECX chemotherapy is a standard of care for localised operable gastric/OGJ/lower oesophageal adenocarcinoma (Cunningham, NEJM 2006). In combination with chemotherapy B, a monoclonal antibody targeting VEGF-A, results in improved response rates (RR) and progression free survival in advanced gastric cancer (Ohtsu, JCO 2011). ST03 aims to assess the safety and feasibility (stage I, 200 pts) and efficacy (stage II) of the addition of B to perioperative ECX chemotherapy. Methods: ST03 is a multicentre, open-label, phase II/III randomised trial open at 106 UK centres. Eligibility criteria are histologically proven, untreated, resectable, lower oesophageal, OGJ or gastric adenocarcinoma; age ⱖ18 years; WHO PS 0-1; and adequate cardiac ejection fraction (EF). Exclusion criteria are TIA/CVA or MI ⱕ1 year; uncontrolled hypertension; ⱖ Grade 2 NYHA heart failure; recent gastrointestinal inflammatory conditions or major surgery/trauma/open biopsy ⬍28d of study entry. Pts receive 3 pre- and 3 postoperative ECX (epirubicin 50 mg/m2 iv D1, cisplatin 60 mg/m2 iv D1 and capecitabine 1250mg/m2/D1-21) ⫹/- B 7.5mg/kg D1 q3wk during chemotherapy, then 6 B q3wk (investigational arm). Surgery is pre-specified and laparoscopic procedures allowed only after quality assurance review. All specimens undergo central pathology review; blood and tissue collection for translational studies is ongoing. Stage I Safety results including cardiac EF have been reported (Okines Ann Oncol 2012). The stage II primary outcome measure is overall survival. Secondary outcome measures are RR, resection rate, disease free survival, toxicity, and QoL. MRI and PET substudies are ongoing. 877 of 1,100 pts have been recruited, accrual expected to complete in Q4 2013. A pilot study within ST03 randomising HER2 positive pts to ECX ⫾ lapatanib (L) opened Q1 2013 and will assess safety, HER2 positivity rate and feasibility in 40 pts randomised between standard ECX and modified ECX⫹L. Trial sponsored and co-ordinated by the MRC Clinical Trials Unit and funded by Cancer Research UK (CRUK06/025, NCT00450203). Clinical trial information: NCT00450203.

Background: Advanced Oesophago-Gastric Carcinoma (AOGC) has a poor prognosis, and there is no established standard treatment following failure of first or second line chemotherapy (CT). Regorafenib (BAY 734506)(REG) is an oral multi-kinase inhibitor which targets kinases involved in angiogenesis (VEGFR1-3, TIE-2), tumor microenvironment (PDGFR-␤, FGFR), and oncogenesis (RAF, RET and KIT), and has shown activity in other solid tumours. Following promising results in colon cancer and GIST, this study will determine if regorafenib has sufficient activity and safety to warrant further evaluation in a phase III trial as a second or third line therapy for AOGC. Methods: International (Australia & New Zealand (ANZ); Canada (NCIC CTG), Korea) randomised phase II, double-blind, placebocontrolled trial with 2:1 (REG:placebo) randomisation and stratification by: (1) Lines of prior chemotherapy for advanced disease (1 vs. 2). (2) Geographic region. Eligible patients with histological confirmation of OGC, with measurable metastatic or locally advanced disease that is refractory to, or relapsed following, first or second line CT, will receive best supportive care plus 160mg REG or matching placebo orally on days 1-21 of each 28 day treatment cycle until disease progression or prohibitive adverse events. Primary endpoint is progression free survival (PFS). Secondary endpoints: PFS by baseline VEGF, response rate, overall survival, safety, quality of life and exploratory plasma angiogenesis and tissue growth factor biomarkers. 150 patients will be randomized in a 2:1 (REG:PBO) ratio. This will provide 90% power to detect a PFS rate at 2 months in the REG arm ⱖ 66% versus ⬍ 50%. If 16 of 33 (evaluable) REG participants have progressed by 2 months, then the study will be reassessed or stopped. Results: As of January 2013, 19 of 29 planned ANZ sites are open, with 10 patients enrolled. Regulatory approval has been received for 16 sites in Canada and 7 sites in Korea. 4 Korean sites have received ethics approval with recruitment expected to commence in early April 2013. Clinical trial information: ACTRN12612000239864.


282s TPS4158


TPS4159


POWER: An open-label, randomized phase III trial of cisplatin and 5-FU with or without panitumumab (P) for patients (pts) with nonresectable, advanced, or metastatic esophageal squamous cell cancer (ESCC). Presenting Author: Markus Hermann Moehler, Johannes Gutenberg University Mainz, Mainz, Germany

Metiv-HCC: A phase III clinical trial evaluating tivantinib (ARQ 197), a MET inhibitor, versus placebo as second-line in patients (pts) with MET-high inoperable hepatocellular carcinoma (HCC). Presenting Author: Armando Santoro, Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy

Background: More than 50% of pts with esophageal cancer have locally advanced or metastatic disease at the time of initial diagnosis. For this group chemotherapy is increasingly used intending local and distant tumor control, improvement of quality of life (QoL) and longer survival. Previous data suggested that EGFR-targeting antibodies may be safely combined with cisplatin and 5-FU, and in addition may increase the efficacy of the standard cisplatin/5-FU regimen [Lorenzen et al, Ann Oncol2009; 20(10): 1667-1673]. Methods: In this open-label, randomized (1:1), multicenter, multinational phase III trial pts with nonresectable, advanced or metastatic ESCC, not eligible for definitive radiochemotherapy, are included. Pts have measurable or non-measurable disease according to RECIST 1.1 and an ECOG PS 0-1. Previous chemotherapy of ESCC in the metastatic setting, concurrent radiotherapy involving target lesions and previous exposure to EGFR-targeted therapy are excluded. Pts receive either CTX (cisplatin 100 mg/m² on day 1 and 5-FU 1000 mg/m²/d on day 1-4) or CTX ⫹ P (9 mg/kg on day 1). Cycles are repeated every 3 weeks until progression of disease. Tumor assessment is performed every 9 weeks. The primary objective is to demonstrate superiority of CTX ⫹ P over CTX alone in terms of overall survival. Secondary endpoints are progression-free survival, 1-year survival, response rate, safety and tolerability, and QoL. A translational analysis in tumor tissue and serum samples is included. 300 pts are planned to be enrolled for a power of 90% to reject the null hypothesis in which the median overall survival in the control and experimental groups are 6 and 9 months, respectively. 18 pts have been enrolled to date. A Data Monitoring Board will review safety data after 40, 100 and 200 pts. The clinical trial registry number is NCT1627379. Clinical trial information: NCT01627379.

Background: Tivantinibis a selective, non-ATP competitive, oral inhibitor of MET, the tyrosine kinase receptor for hepatocyte growth factor (HGF). MET over-expression is associated with poor prognosis in HCC patients. A phase Ib study (Santoro et al, Br J Cancer, 2013) with tivantinib 360mg BID revealed no worsening of liver function in cirrhotic HCC pts. A randomized, placebo-controlled phase 2 study identified HCC patients with high tumor MET expression at immunohistochemistry (IHC) as the target population for tivantinib in second line (overall survival: 7.2 months on tivantinib, 3.8 months on placebo, HR: 0.38, p⫽0.01), and selected 240mg BID as the appropriate dose for HCC patients (Santoro et al, Lancet Oncol, 2013). Methods: Enrollment forthis phase III clinical trial (ARQ 197-A-U303, NCT01755767) has begun.Eligible pts must present with Child Pugh A; ECOG performance score ⬍1; inoperable RECIST 1.1 measurable disease; adequate bone marrow, liver and kidney functions; no prior liver transplant. Pts must have progressed after or not tolerated one prior line of systemic therapy including sorafenib and their tumor samples must be deemed MET-High by IHC at a central laboratory to be eligible. Approximately 303 pts are randomized 2:1 to receive tivantinib 240mg PO twice daily or placebo. Pts are stratified by vascular invasion, metastases, and alphafetoprotein level, and they are evaluated by CT or MRI scan at 8-week intervals. The primary endpoint is overall survival (OS). Secondary endpoints include progression-free survival and safety. Treatment continues until confirmed disease progression or unacceptable toxicity. Pts discontinued from study treatment will be followed for survival. Participating centers are located in Europe, Australia, New Zealand, and the Americas. This trial is expected to complete enrollment by mid-2015, and an interim analysis is planned when approximately 60% of OS events are reached. Clinical trial information: NCT01755767.

TPS4160

TPS4161^



Open-label, phase I/randomized, phase II trial of the triple angiokinase inhibitor, nintedanib, versus sorafenib in previously untreated patients with advanced hepatocellular carcinoma (HCC). Presenting Author: Daniel H. Palmer, Liverpool Cancer Research UK Centre, University of Liverpool, Liverpool, United Kingdom

Phase IIb randomized trial of Pexa-Vec (pexastimogene devacirepvec; JX-594), a targeted oncolytic vaccinia virus, plus best supportive care (BSC) versus BSC alone in patients with advanced hepatocellular carcinoma who have failed sorafenib treatment (TRAVERSE). Presenting Author: Jeong Heo, Pusan National University Hospital, Busan, South Korea

Background: While sorafenib is established as the standard first-line treatment for patients with advanced HCC, its use can be complicated by the occurrence of drug-related adverse events (AEs). Nintedanib, a potent, oral triple angiokinase inhibitor that targets VEGF, PDGF and FGF signaling (as well as Flt3 and RET), has demonstrated clinical activity in various advanced solid tumors with a relatively low incidence of AEs typically associated with angiogenesis inhibitors (e.g. skin toxicity, hypertension, hemorrhage, and hematologic toxicity) and is currently in phase III for non-small cell lung cancer and ovarian cancer. In the Phase I, dose-finding stage of this ongoing, multicenter, open-label Phase I/II trial (NCT01004003), 200mg twice daily (bid) was established as the maximum tolerated dose of nintedanib in previously untreated patients with advanced HCC (Palmer D, et al. Ann Oncol 2012;23(Suppl 9):ix245[Abs 740P]). Nintedanib had an acceptable liver AE profile; the most common AEs were mild/moderate gastrointestinal toxicities. Methods: The randomized Phase II stage of the trial aims to assess the efficacy, safety, and pharmacokinetics of nintedanib in comparison with sorafenib. Eligible patients have pathologically confirmed, measurable HCC that is not amenable to local therapy, ECOG Performance Status of ⱕ2, Child-Pugh score of 5– 6 (Class A), AST/ALT levels ⱕ2⫻ upper limit of normal, and no prior systemic therapy. Patients are being stratified by macrovascular invasion and/or extrahepatic spread and then randomized 2:1 to receive nintedanib 200mg bid or sorafenib 400mg bid in continuous 28-day cycles until progression or unacceptable toxicity. Overall, 93 patients were randomized between Sept 2011 and Nov 2012. The primary endpoint is time to progression (TTP) by independent review, according to RECIST 1.0. TTP will be estimated in the treated set by Kaplan–Meier methodology with treatment effects compared using a Cox proportional hazards model. Secondary endpoints include overall survival, tumor response, progressionfree survival, safety and pharmacokinetics. Results are due late 2013. Clinical trial information: NCT01004003.

Background: Pexa-Vec is a targeted oncolytic and immunotherapeutic vaccinia virus engineered to express human granulocyte-macrophage colony stimulating factor (GM-CSF). Direct oncolysis plus GM-CSF expression stimulates tumor vascular disruption and anti-tumor immunity (Nature Rev Cancer, 2009). Pexa-Vec was well-tolerated in Phase 1 trials and was shown to replicate in metastatic tumors following intratumoral (IT) or intravenous (IV) administration (Lancet Oncol, 2008 and Nature, 2011). A randomized high vs low dose Phase 2 trial in 30 patients with advanced HCC, demonstrated prolonged survival in the high-dose Pexa-Vec arm (median survival 14.1 mo vs. 6.7 mo; Hazard Ratio 0.39, p⫽0.02) (AASLD Annual Meeting, 2011, LB1). Methods: TRAVERSE is a Phase 2b randomized, open-label, multi-center trial in patients with advanced HCC who have failed sorafenib treatment. Approximately 120 patients will be randomized 2:1 to Pexa-Vec plus BSC versus BSC, respectively. Randomization will be stratified by region (Asian vs. non-Asian); sorafenib intolerant vs refractory; and presence vs absence of extra-hepatic disease. The primary objective is to determine overall survival. Main inclusion criteria are advanced HCC having failed sorafenib (intolerance or radiographic progression during or ⬍ 3 months following last sorafenib), Child-Pugh A-B7 (no ascites), acceptable hematologic function. Assuming a median overall survival of 4.0 months with BSC and a target hazard ratio of 0.57 (corresponding to an experimental arm median survival of 7.0 months), 73 events (deaths) will provide 70% power at 1-sided alpha ⫽ 0.05 to detect a difference in overall survival between the treatment groups using a stratified logrank test. Patients randomized to Pexa-Vec will receive a dose of 109 plaque forming units (pfu) IV on Day 1 followed by five IT treatments between Day 8 and Week 18. Enrollment has begun on this study with clinical trial registry number of NCT01387555. Clinical trial information: NCT01387555.




TPS4163

283s


A randomized controlled trial comparing modified gemcitabine plus oxaliplatin (mGEMOX) to gemcitabine plus cisplatin in the management of unresectable gall bladder cancer. Presenting Author: Atul Sharma, All India Institute of Medical Sciences, New Delhi, India

Regorafenib (REG) in patients with hepatocellular carcinoma (HCC) progressing following sorafenib: An ongoing randomized, double-blind, phase III trial. Presenting Author: Ann-Lii Cheng, National Taiwan University Hospital, Taipei, Taiwan

Background: In a recently conducted study we have shown that combination of gemcitabine and oxaliplatin is superior to 5 fluorouracil and leucoverine or best supportive care. (Sharma A, Dwary AD, Mohanti BK,et al. Best supportive care compared with chemotherapy for unresectable gall bladder cancer:A randomized controlled study. J Clin Oncol. 2010; 28: 45814586.) In another recent publication from UK, gemcitabine and cisplatin combination was found superior to gemcitabine alone in biliary tract cancers (J W Valle, HS Wasan, DD Palmer, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Eng J Med. 2010;362:12731281.).The current study is being planned to see whether the combination of gemcitabine and oxaliplatin is equivalent (equivalence study) to gemcitabine and cisplatin in these patients. Methods: Primary end point of the study is overall survival in subjects receiving mGEMOX or GemCis regimen. Secondary end points are: a) Comparison of progression free survival in 2 groups; b) Response rates in two groups; c) Identification of genes predictive of responses in a subset of patients; d) To evaluate role of PET CT in GBC patients predicting disease activity. Sample size was calculated taking median survival of 9.5 months in our previous study with mGEMOX and 11.7 months with GemCis. For this total of 216 patients are required (108 in each arm); to make for major protocol violation and lost to follow up additional 22 patients in each arm will be enrolled. Thus in total 260 patients (130) in each arm will be recruited. This will have alpha and beta values of 0.05 and 0.20 respectively. So far 103 patients have been enrolled and interim analysis is being planned. Treatment protocol: Cycles will be repeated every 3 weeks. Arm A- mGEMOX. Inj Oxaliplatin 80 mg/m22 hours infusion in Dextrose 5% Day 1 and 8. Inj Gemcitabine 900 mg/m2IV 30 minutes infusion day 1 and 8 maximum of 6 cycles. Arm BGEMCIS. Inj Cisplatin 25 mg/m2PO Days 1 and 8. Inj Gemcitabine 1000 mg/m2IV 30 minutes infusion day1and 8 maximum of 8 cycles. Clinical trial information: CTRI/2010/091/001406.

Background: Sorafenib is the accepted first-line systemic therapy for HCC, but no standard option is available for patients with tumor progression following sorafenib. An open-label phase II study suggested that REG, a multikinase inhibitor, had an acceptable safety profile and showed evidence of antitumor activity in patients with progressive HCC (Bolondi et al. Eur J Cancer 2011; 47 [Suppl 1]: abstract 6.576): disease control was achieved in 26/36 patients (72%) and median time to progression (TTP) was 4.3 months; median overall survival (OS) was 13.8 months. On the basis of these promising data, a phase III trial was designed. Methods: This randomized, double-blind, placebo (PBO)-controlled, multinational study (ClinicalTrials.gov identifier NCT01774344) will assess the efficacy and tolerability of REG vs PBO in patients with HCC that has progressed following sorafenib treatment (target n⫽530). Inclusion criteria include Barcelona Clinic Liver Cancer stage B or C disease, Child–Pugh A liver function, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. Patients who discontinued sorafenib ⱖ8 weeks before study entry or who received other previous systemic therapy for HCC will be excluded. Patients will be randomized in a 2:1 ratio to receive REG 160 mg or matching PBO OD for weeks 1–3 of each 4-week cycle; all patients will also receive best supportive care. Treatment will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Doses of study drug may be delayed or reduced to manage clinically significant drug-related toxicities. The primary endpoint is OS; secondary endpoints are TTP, progression-free survival, tumor response, and safety. Analysis will be according to randomized group, stratified by geographic region (Asia vs rest of world), ECOG PS (0 vs 1), alfa-fetoprotein level (⬍400 vs ⱖ400 ng/ml), extrahepatic disease (yes vs no), and macrovascular invasion (yes vs no). In addition, blood, plasma, and archival tissue will be assessed for pharmacokinetic and biomarker analyses, and healthrelated quality of life and health utility will be measured. Clinical trial information: NCT01774344.


284s LBA4500

Genitourinary (Nonprostate) Cancer Oral Abstract Session, Sat, 1:15 PM-4:15 PM

A phase III trial of personalized chemotherapy based on serum tumor marker decline in poor-prognosis germ-cell tumors: Results of GETUG 13. Presenting Author: Karim Fizazi, Institut Gustave Roussy, University of Paris Sud, Villejuif, France

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Saturday, June 1, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.

4501


Paclitaxel, ifosfamide, and cisplatin (TIP) efficacy for first-line treatment of patients (pts) with intermediate- or poor-risk germ cell tumors (GCT). Presenting Author: Darren Richard Feldman, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Durable progression-free survival (PFS) rates for pts with intermediate- and poor-risk GCT approximate only 75% and 50%, respectively with standard BEP. This multicenter phase II study investigated first-line TIP in this population. Methods: Pts age ⱖ18 with untreated, IGCCCG intermediate- (LDH modified to ⱖ3x upper limit of normal) or poor-risk GCT were eligible. Pts received 4 cycles of TIP every 21 days, consisting of paclitaxel 120mg/m2 days 1-2; ifosfamide 1200mg/m2 days 1-5; and cisplatin 20mg/m2days 1-5, followed by G-CSF and levofloxacin for neutropenic fever prophylaxis. The primary endpoint was the complete response (CR) rate; secondary endpoints included PFS and toxicity. A Simon’s 2-stage design required a CR in ⱖ11/18 pts to proceed to stage 2, where with ⱖ27/41 CRs overall, the regimen would be considered active and worthy of further study. Results: Of 44 men (median age 27) enrolled; 38 had nonseminoma and 6 seminoma; 29 were poor-risk and 15 intermediate-risk. Primary site was testis in 30, mediastinum in 11, and retroperitoneum in 3. 42 pts had elevated markers and 14, 6, and 1 had liver, bone, and brain metastasis, respectively. The trial met its primary endpoint; of 41 evaluable pts, 28 achieved a CR (see Table) and 6 pts (5 with seminoma) achieved a partial response with negative markers (PR-). Two pts relapsed. With a median follow-up of 2.2 years, estimated 3-year PFS was 79% and 3-year overall survival (OS) 98% (see Table). There were no treatment-related deaths. Grade 3/4 toxicities were primarily hematologic and 6 (14%) pts developed neutropenic fever. Conclusions: TIP demonstrates promising efficacy and is well-tolerated in intermediate- and poor-risk GCT pts. A randomized trial of TIP vs. BEP has been initiated to compare efficacy. Clinical trial information: NCT00470366. Outcome

Intermediate-risk Nⴝ15 (14 evaluable for response)

Poor-risk Nⴝ29 (27 evaluable for response)

Total Nⴝ44 (41 evaluable for response)

57 36 93 7

74 4 78 22

68* 15 83 17

87 (56-96) 100

76 (55-88) 97 (76-99)

79 (64-89) 98 (84-100)

Response CR % PR- % Favorable response (CR ⴙ PR-) % Incomplete response % Survival 3-year PFS % (95% CI) 3-year OS % (95% CI)

*Crude CR rate 68%; estimated CR rate 70% (90% CI: 58% – 76%).

4502


A nationwide cohort study of surveillance for stage I seminoma. Presenting Author: Mette Sakso Mortensen, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Background: The standard treatment for stage I seminoma remains a topic for discussion. Survival rates are excellent irrespective of treatment modality (radiotherapy, carboplatin or surveillance). However, late effects might differ between treatment options. Only smaller surveillance studies with limited follow-up have previously been published. We present data from a large nationwide cohort study on surveillance in stage I seminoma patients. Methods: A nationwide and population based clinical database covering germ cell cancer patients diagnosed 1984-2007 was constructed. The database included 4,683 cases. All stage I seminoma patients followed by surveillance were identified. Possible prognostic factors for relapse were collected from patient files and pathology reports. By merging our data with the national patient registry we were able to collect data on late relapses, vital status and cause of death on all patients up to December 2012. Results: 1,822 patients with stage I seminoma were followed on a surveillance program. The median follow-up time was 15.4 years. Ten year cancer specific survival (CSS) was 99.6%. A total of 355 (19.5%) patients had a relapse after a median time of 13.7 months (range 1.2-173.7 months). Within 2-5 years after orchiectomy, 72 patients (4.0 %) had a relapse and 26 patients (1.4 %) had a relapse more than 5 years after orchiectomy. Invasion of blood or lymphatic vessels, tumor size ⬎ 4 cm and serum human chorionic gonadotropin ⬎ 200 IU/L were all predictive factors for relapse in both univariate and multivariate analyses (p⬍0.01). Invasion of rete testis was significant in the univariate analysis but not in the multivariate analyses (p⫽0.53). Conclusions: We present the largest cohort ever published of stage I seminoma patients followed on a surveillance program. The prognosis was excellent with a 10 year CSS of 99.6%. Prognostic factors for relapse were identified. The relapse rate after 5-years of follow-up was 1.4%. Surveillance should be the preferred option of management in stage I seminoma patients. Several international guidelines are now in agreement with this statement.

4503


Characterization of relapse in patients with clinical stage I (CSI) nonseminoma (NS-TC) managed with active surveillance (AS): A large multicenter study. Presenting Author: Christian K. Kollmannsberger, BC Cancer Agency, Vancouver, BC, Canada Background: Large single institution trials have demonstrated that AS for patients with CSI NS-TC is safe and effective. Information on timing and extent of relapse following AS has the potential to guide intensity and duration of imaging on AS. Methods: Retrospective clinical data on CSI patients were obtained from existing large databases, including institutions/ regions which have a standardized policy of centralized management of testicular cancer including AS for patients with CSI NS-TC. In all, 1,034 patients with CSI NS-TC managed with AS were reviewed of whom 886 had no lymphovascular invasion (LVI-), 220 had lymphovascular invasion (LVI⫹) and 28 had unknown lymphovascular status (LVI unknown). Results: A total of 221 relapses occurred with 150/886 (17%) of LVI– pts , 60/120 (50%) LVI⫹ pts and 11/28 (39%) of LVI unknown pts (Table). Median follow-up was 63 months (1-163 months). At last follow up 1,013/1,034 (98%) were alive without disease, 16/1,034 (1.5%) were dead of other causes and 7/1,035 (0.05%) were alive with disease or dead of disease. Relapse was identified by marker elevation and/or abdominal imaging in almost all patients. Few patients relapsed with IGCCCC intermediate (18/221, 8%) or poor risk disease (3/221, 1.4%). Conclusions: AS for CSI NS-TC is safe and effective, using a policy of centralized management with loco-regional delivery of care. Our multinational outcomes compare well to single institutional reports. Relapse other than with IGCCC good risk disease was uncommon and death from disease was rare. Compared to patients with LVI-, relapses in LVI ⫹ CSI patients occur earlier and few relapses are detected past the first year of follow-up. This data may help in the design of follow up schedules tailored towards the relapse risk in CSI NS-TC AS. Characteristics of relapsing LVI- and LVIⴙ CSI NS-TC. Stage at relapse

LVInⴝ 150 LVI ⴙ nⴝ60 LVI unknown Nⴝ11

Timing of relapse

Good risk

Intermediate risk

Poor risk

Stage not available

1-12 mo.

1-24 mo

1-36 mo

> 36 mo

117/150 78% 57/60 95% 10/11 91%

15/150 10% 1/60 2% 1/11 9%

3/150 2% 0

15/150 10% 2/60 3% 0

112/150 75% 56/60 93% 6/11 55%

135/150 90% 58/60 97% 10/11 91%

140/150 93% 59/60 98% 0

10/150 7% 1/60 2% 1/11 9%

0


Genitourinary (Nonprostate) Cancer 4504


Record-3: Phase II randomized trial comparing sequential first-line everolimus (EVE) and second-line sunitinib (SUN) versus first-line SUN and second-line EVE in patients with metastatic renal cell carcinoma (mRCC). Presenting Author: Robert John Motzer, Memorial Sloan-Kettering Cancer Center, New York, NY

4505

285s Oral Abstract Session, Sat, 1:15 PM-4:15 PM

Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with metastatic renal cell carcinoma (mRCC). Presenting Author: Daniel C. Cho, Beth Israel Deaconess Medical Center, Boston, MA

Background: Sequential SUN (tyrosine kinase inhibitor, TKI) until progression of disease (PD) followed by EVE (mTOR inhibitor) is standard therapy for patients with mRCC. This open-label, multicenter, phase II trial compared 1st-line EVE to 1st-line SUN (NCT00903175). Sequential EVE¡SUN was also compared with standard SUN¡EVE. Methods: Patients with mRCC (clear or non-clear cell) naive to prior systemic therapy were randomized 1:1 to either 1st-line EVE 10 mg/day or SUN 50 mg/day (4 weeks on, 2 weeks off) until PD. Patients then crossed over and continued on the alternate drug until PD. Primary objective was to assess PFS noninferiority of 1st-line EVE to 1st-line SUN; defined as an observed hazard ratio (HR)1st EVE/SUN ⱕ1.1. Overall survival (OS), combined 1st-line and 2nd-line PFS, and safety were secondary end points. Results: From10/09 to 6/11, 471 patients enrolled (EVE¡SUN, n ⫽ 238; SUN¡EVE, n ⫽ 233). Median age was 62 years, 85.4% had clear-cell RCC, and MSKCC favorable/intermediate/poor risk was 30/56/14%. Median follow-up was 22.7 months. A total of 53.7% of patients who discontinued 1st-line EVE entered into 2nd-line SUN and 51.6% of patients who discontinued 1st-line SUN entered into 2nd-line EVE. Median PFS (95% CI) was 7.9 (5.6-8.2) months for 1st-line EVE and 10.7 (8.2-11.5) months for 1st-line SUN. HR1st EVE/1st SUN (95% CI) was 1.43 (1.15-1.77). Median OS (95% CI) was 22.4 (19.7-NA) months for EVE¡SUN and 32.0 (20.5-NA) months for SUN¡EVE; HREVE-SUN/SUN-EVE (95% CI) was 1.24 (0.94-1.64). A trend in favor of SUN¡EVE for OS was observed, but will need to be confirmed with final OS analysis. Additional efficacy results for secondary end points are forthcoming. Common treatment-emergent adverse events for 1st-line EVE vs SUN, respectively, were stomatitis (53% vs 57%), fatigue (45% vs 51%), and diarrhea (38% vs 57%). Conclusions: Noninferiority of PFS for 1st-line EVE compared with SUN was not achieved in this randomized phase II trial of mRCC patients. The treatment paradigm remains SUN¡EVE since the sequence achieved optimal clinical benefit. Clinical trial information: NCT00903175.

Background: Human RCC expresses PD-L1 and has been shown to respond to immune-based therapy. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Methods: Pts with mRCC received MPDL3280A administered IV q3w at doses between 3-20 mg/kg in a Phase I expansion study. Pts were treated for up to 1 y. Response was assessed by RECIST v1.1. Results: As of Jan 10, 2013, 53 RCC pts were evaluable for safety and treated at doses of 3 (n⫽2), 10 (n⫽12), 15 (n⫽18) and 20 mg/kg (n⫽21). These pts had a median age of 62 y (range 33-79 y), 100% were PS 0-1 and all had had prior surgery. 83% of pts had received prior systemic therapy; 38% received immunotherapy, 57% received TKIs and 36% received anti-angiogenic therapy. Pts received treatment with MPDL3280A for a median duration of 190 days (range 21-317). The incidence of G3/4 AEs in RCC pts was 43%, regardless of attribution, with hypophosphatemia, fatigue, dyspnea and hyperglycemia (all 4%) being the most common. 13% of G3/4 AEs were attributable to study drug. 1 case of myasthenia gravis was observed in a pt who was retrospectively found to have anti-acetylcholine receptor antibodies prior to starting therapy. No G3-5 pneumonitis or diarrhea was reported. No treatment-related deaths occurred. 39 RCC pts enrolled prior to Jul 1, 2012, were evaluable for efficacy. RECIST responses, including CR, were observed across dose levels, with all responses ongoing at the time of data cutoff. Some RCC pts experienced prolonged SD prior to experiencing RECIST response. The 24-week PFS was 50%. Analysis of biomarker data from mandatory archival tumors demonstrated a correlation between PD-L1 status and efficacy. In addition, response correlated with low IL-17 expression in tumor tissue. Updated data will be presented. Conclusions: MPDL3280A was well tolerated, with no pneumonitis-related deaths. PD-L1–positive status correlates with response to MPDL3280A. Durable responses have been observed in RCC pts treated with MPDL3280A and further study is warranted. Clinical trial information: NCT01375842.

4506

4507^


Phase II efficacy and safety study of nintedanib versus sunitinib in previously untreated renal cell carcinoma (RCC) patients. Presenting Author: Tim Eisen, Cambridge University Health Partners, Addenbrooke’s Hospital, Cambridge, United Kingdom Background: Sunitinib (S) is established as a standard first-line therapy for patients (pts) with advanced RCC. However, treatment can be limited by the occurrence of drug-related adverse events (AEs). This Phase II study assessed the efficacy and safety of nintedanib (N) – a potent, triple angiokinase inhibitor of VEGFR-1–3, PDGFR-␣/␤, and FGFR-1–3, as well as RET and Flt3 – vs S in previously untreated pts with RCC. Methods: Ninety-nine eligible pts (96 of whom were treated) with advanced, unresectable/recurrent clear cell RCC, an ECOG performance status of 0 –1, and no prior systemic therapy were randomized 2:1 to receive N 200 mg twice daily (n⫽64; given in 4-week cycles) or S 50 mg once daily (n⫽32; 4 weeks on, 2 weeks off schedule). Treatment continued until disease progression or unacceptable drug-related AEs. Primary endpoints were progression-free survival at 9 months (PFS-9) and, in N-treated pts only, QTc interval change (baseline to day 15). Secondary endpoints included PFS, objective response rate (ORR; RECIST 1.1), overall survival (OS), time to progression (TTP), time to treatment failure (TTF), and AEs. Results: Baseline characteristics were balanced between the arms. PFS-9 was not statistically significantly different between N- and S-treated pts (43 vs 45%; p⫽0.85). There were also no statistically significant differences between N and S with regard to PFS (median: 8.44 vs 8.38 mo; hazard ratio: 1.16; 95% CI: 0.71–1.89; p⫽0.56), confirmed ORR (18.8 vs 31.3%; p⫽0.19), OS (median: 20.37 vs 21.22 mo; p⫽0.63), TTP (median: 8.48 vs 8.54 mo; p⫽0.52), and TTF (median: 8.41 vs 8.36 mo; p⫽0.46). Grade ⱖ3 AEs occurred in 47% of N-treated pts and 56% of S-treated pts. Common AEs (all grades; N vs S) included diarrhea (61 vs 50%), nausea (38 vs 34%), fatigue (both 25%), and vomiting (16 vs 22%). Dermatologic AEs (8 vs 47%) were less frequent with N than S. There was no increase from baseline in QTc ⬎60 ms on days 1 or 15 in N-treated pts, and there was no relationship between N exposure and QT interval change. Conclusions: N demonstrated similar efficacy to S and had a manageable safety profile, including a lower incidence of dermatologic AEs vs S. In addition, N was not associated with QT prolongation. Clinical trial information: NCT01024920.


ARISER: A randomized double blind phase III study to evaluate adjuvant cG250 treatment versus placebo in patients with high-risk ccRCC—Results and implications for adjuvant clinical trials. Presenting Author: Arie S. Belldegrun, Institute of Urologic Oncology, Department of Urology, UCLA, Los Angeles, CA Background: cG250 (Rencarex) is a chimeric monoclonal antibody that binds to the CAIX cell-surface antigen present on 95% of ccRCC. Its safety and activity in phase II studies provided the rationale to investigate its use as an adjuvant monotherapy in subjects with clinically localized high-risk ccRCC—50% of whom progress to metastatic disease. Methods: We performed an international, prospective, multicenter, phase III trial of the efficacy and safety of adjuvant cG250 vs placebo (randomized 1:1) by assessing disease-free (DFS) and overall survival (OS) in 864 RCC patients after nephrectomy. Inclusion criteria were: 1) T3/T4 N0/M0; 2) any T stage and N⫹/M0; or 3) T1b/T2 N0/M0 high-grade ccRCC. Treatment consisted of a 50 mg loading dose followed by 23-weekly infusions of 20 mg. DFS and CAIX antigen expression were quantified by an independent radiological review and a central pathologist. CAIX score was derived by multiplying the intensity of staining (1–3) by the fraction of positive of cells (0 –1), yielding a range of 0.0 –3.0. Results: Baseline demographics were well balanced across groups. Treatment demonstrated an excellent safety profile. There were 360 confirmed recurrences and 181 deaths during follow up. When compared with the placebo group, cG250-treated subjects did not enjoy a statistically significant DFS (HR⫽0.99, p⫽0.74) or OS advantage (HR⫽1.01, p⫽0.94). Median DFS and OS were over 6 years and never reached irrespective of treatment, respectively. However, on subset analysis, subjects with high CAIX expression (⬎2.0) who received cG250 experienced a statistically significant treatment effect with improved DFS (HR⫽0.55; p⫽0.01). Conclusions: While cG250 appears not to have clinical benefit in the adjuvant treatment for all high-risk patients, cG250-treated patients with a high CAIX score appeared to have a significantly improved DFS. The CAIX score may help in stratifying patients who may benefit from cG250 adjuvant therapy. Notwithstanding this benefit, the surprising median DFS of over 6 years and outstanding OS in high-risk patients represent a significant challenge to adjuvant ccRCC drug development. Clinical trial information: NCT00087022.


286s

Genitourinary (Nonprostate) Cancer

4508


Pazopanib prior to planned nephrectomy in metastatic clear cell renal cancer: A clinical and biomarker study. Presenting Author: Thomas Powles, St. Bartholomew’s Hospital, London, United Kingdom Background: The safety and efficacy of upfront pazopanib, prior to nephrectomy in metastatic clear cell renal cancer (mRCC), has not been prospectively evaluated. The toxicity profile of pazopanib potentially makes it an attractive agent in this setting. Methods: A single arm phase II study (2009-016675-29) evaluated 12-14 weeks of pazopanib prior to planned nephrectomy in 102 untreated patients with mRCC. Patients had MSKCC intermediate (n⫽80) and poor risk disease (n⫽22). The Primary endpoint of the trial was to achieve at least a 75% clinical benefit rate (absence of disease progression) with pazopanib at the time of surgery. Sequential tissue was used for biomarker analysis (exploratory endpoint). Tissue from a previous sunitinib trials with a similar design was included for comparative purposes. Results: Overall 81% of patients obtained clinical benefit prior to surgery. The partial response rate of the primary tumor was 14% by RECIST v1.1. The median reduction in the size of the primary tumor was 14% (range 33% to - 41%). No patients became inoperable due to local progression of disease. A nephrectomy was performed in 66% of patients. The two commonest reasons for not having surgery were patient choice (9%) and progression of disease (16%). There were 2 (3%) post operative surgical death. Delayed wound healing occurred in 5%. Progression during the treatment free interval for surgery was 26%. Median PFS has not been reached. Results from biomarker analysis of sequential tissue revealed therapy resulted in a significant decrease in CD31 (-49%), PDL-1 (-31%) and pS6K (-26%), while FGF-2 (⫹147%), MET (⫹34%) and Ki-67 expression increased with therapy. Increased ki-67 and CD31 correlated with a poor outcome. Conclusions: Nephrectomy after upfront pazopanib can be performed safely in mRCC and obtains control of disease in the majority of patients. Biomarker analysis shows dynamic changes some of which are prognostically significant. Clinical trial information: NCT01512186.

4511

Clinical Science Symposium, Mon, 11:30 AM-1:00 PM

A first-in-human study of the oral selective androgen receptor downregulating drug (SARD) AZD3514 in patients with castration-resistant prostate cancer (CRPC). Presenting Author: Aurelius Gabriel Omlin, The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom Background: AZD3514 is a first in class, orally bio-available drug that inhibits androgen-dependent and –independent androgen receptor (AR) signaling through two distinct mechanisms; inhibition of ligand-driven nuclear AR translocation and down-regulation of AR levels. Methods: A rolling six design was employed initially using a once a day (QD) schedule (A). PK assessments led to a change to twice daily (BD) dosing (B) to increase exposure. PK profiles were studied over 96 hours after a single dose and over 24 hours at start of/following 21 days continuous dosing. PD analyses included PSA and CTC quantification. Results: 49 CRPC patients (pts) have been treated with escalating doses of AZD3514 (A 35 pts, B 14 pts). Starting doses were 100 mg (A) and 1000 mg (B). The AZD3514 formulation was switched from capsules to tablets at 1000mg (QD). 2000mg BD was considered non-tolerable due to multiple grade 2 toxicities (nausea [N], vomiting [V], fatigue). No adverse events (AEs) met the DLT definition. The most frequent drug-related AE’s were N; G1/2 36/49 (73%), G3 2/49 (4%) and V; G1/2 24/49 (49%) & G3 3/49 (6%). N/V were managed with oral anti-emetics. Dose proportional increases in plasma concentrations were observed following a single dose. Geometric mean (%CV) Cmax and AUC at MTD were 9,608 (38.5) ng/mL and 61,734 (40.6) ng.hr/mL, respectively. Compared with single dose continuous dosing led to a mean decrease of 26% in exposure. Maximum PSA and CTC declines are summarized below. Objective soft tissue responses per RECIST1.1 were observed in 2/26 (8%) pts. One pt with abiraterone resistant disease remained on study for 19 months. At 6 and 12 months 21 (43%) and 8 (16%) pts remained on study without evidence of bone or soft tissue progression, respectively. Conclusions: AZD3514 has antitumor activity in patients with advanced CRPC. Clinical trial information: NCT01162395. AZD3514 Dose (mg) 100 QD 250 QD 500 QD 1000 QD 1000 BD 2000 BD a1

N

PSA decline >50%

PSA decline >30%

CTC conversion (N/Eval. pts; %)

CTC decline >30% (N/Eval. pts; %)

5 6a 12 12 9a 5b

0% 0% 17% (2) 25% (3) 25% (2) NA

0% 0% 25% (3) 42% (5) 38% (3) NA

0/1 (0%) 1/5 (20%) 1/5 (20%) 2/6 (33%) 1/3 (33%) 1/2 (50%)

0/1 (0%) 2/5 (40%) 3/5 (60%) 5/6 (83%) 3/3 (100%) 2/2 (100%)

pt. b All pts non evaluable.

LBA4510


Duration of androgen deprivation therapy in high-risk prostate cancer: A randomized trial. Presenting Author: Abdenour Nabid, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

4512


Combination of antiangiogenic therapy and cytotoxic chemotherapy for sarcomatoid renal cell carcinoma. Presenting Author: M Dror Michaelson, Massachusetts General Hospital Cancer Center, Boston, MA Background: Numerous treatment options exist for metastatic renal cell carcinoma (mRCC), but optimal treatment for patients (pts) with sarcomatoid features remains undefined. Sarcomatoid differentiation is a particularly unfavorable prognostic feature in mRCC. Cytotoxic chemotherapy has modest activity, with a response rate of 16% for doxorubicin plus gemcitabine (Gem). Retrospective data has suggested a response rate of 10% for antiangiogenic therapy. We prospectively studied the combination of antiangiogenic therapy, sunitinib (Su), with Gem chemotherapy in this mRCC subpopulation. Methods: Pts with mRCC and sarcomatoid differentiation were enrolled in a phase 2 clinical trial at 3 institutions. Treatment consisted of 21-day cycles of Su, 37.5 mg on a 2 weeks on/1 week off schedule, along with Gem 1000 mg/m2 on days 1 and 8. The primary endpoint was radiographic response rate (RR) by RECIST. Secondary endpoints included time to disease progression (TTP), safety, and overall survival (OS). Results: Among 35 pts treated in total, 7 were classified as MSKCC good risk, 26 as intermediate risk, and 2 as poor risk. There were 10 partial responses and 1 complete response, for a confirmed RR of 30%. An additional 10 pts exhibited stable disease (clinical benefit rate 60%). Among the 10 pts who had progressive disease as their best response, the majority had underlying non-clear cell histology. Median TTP was 3.5 months (range 0.5-12). Eight pts discontinued due to adverse events (AEs). The most common treatment-emergent grade 3 or higher AEs were neutropenia (8 pts), fatigue (5), anemia (2), and hypertension (2). No treatment-related deaths occurred. Median OS was 11 months (range 1-38⫹). Conclusions: To our knowledge, this is the largest prospective trial combining cytotoxic chemotherapy and antiangiogenic therapy in patients with RCC and sarcomatoid features. Our results suggest that combination therapy may be more efficacious than either treatment alone in this subtype of mRCC and supports an ongoing intergroup trial (NCT01164228). Further research is necessary to define prognostic factors, including histologic and molecular biomarkers, for distinct subpopulations within this heterogeneous disease. Clinical trial information: NCT00556049.




Tivozanib in patients treatment-naive for metastatic renal cell carcinoma: A subset analysis of the phase III TIVO-1 study. Presenting Author: Cora N. Sternberg, Department of Medical Oncology, San Camillo-Forlanini Hospital, Rome, Italy Background: Tivozanib (T) is a potent, selective inhibitor of all three VEGF receptors with a long half-life of 4.5–5.1 days. Superior progression-free survival (PFS) and overall response rate (ORR) with T versus sorafenib (S) were demonstrated in a Phase III trial (TIVO-1) in patients (pts) with metastatic renal cell carcinoma (mRCC) (in ITT population, PFS: 11.9 vs 9.1 months HR⫽0.797, 95% CI 0.639 – 0.993; P⫽0.042; ORR: 33% vs 23%, P⫽0.014). Hypertension was more common with T, while lower rates of certain off-target AEs and fewer dose adjustments relative to S were reported (J Clin Oncol 2012;30[suppl]:Abstract 4501). Here we present efficacy and safety analyses for the pre-specified subset of pts who received no prior systemic therapy for mRCC. Methods: In the ITT population (N⫽517), pts were treatment-naïve or had received no more than 1 prior systemic therapy for metastatic disease; pts receiving prior VEGF- or mTOR-targeted therapy were excluded. Pts were randomized 1:1 to T 1.5 mg/d (once daily, 3 weeks on, 1 week off) or S 400 mg/d (twice daily, continuously). Of these, 181 pts (70%) in each treatment arm had not received prior systemic therapy for mRCC. Results: In pts who received no prior systemic therapy for mRCC, demographics were well balanced between the 2 arms. Median PFS was 12.7 for T vs 9.1 months for S (HR⫽0.756, 95% CI 0.580 – 0.985, P⫽0.037). ORR was 34% for T vs 24% for S (P⫽0.038). The most common adverse event (AE; All grades/ Grade ⱖ3) for T was hypertension (T: 40%/25% vs S: 35%/18%), suggesting “on-target” biological activity and was manageable medically, while the most common AE for S was hand-foot syndrome (T: 11%/2% vs S: 52%/16%). Other common AEs were diarrhea (T: 22%/2% vs S: 32%/7%), fatigue (T: 19%/6% vs S: 15%/3%), and weight decrease (T: 18%/1% vs S: 17%/2%). Dose reduction (T: 12% vs S: 42%) and interruption (T: 18% vs S: 35%) rates were lower in the T arm and similar to the ITT population. Conclusions: T demonstrated significant improvement in PFS and ORR compared with S in pts who had received no prior systemic therapy for metastatic RCC. T was generally well tolerated, with low rates of treatmentrelated reduction/interruption in this pre-specified subgroup of pts. Clinical trial information: NCT01030783.

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Survival, safety, and response duration results of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in a phase I trial in patients with previously treated metastatic renal cell carcinoma (mRCC): Long-term patient followup. Presenting Author: Charles G. Drake, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD Background: Programmed death-1 (PD-1) is an immune checkpoint receptor that negatively regulates T-cell activation. PD-L1, a PD-1 ligand, has been associated with poor prognosis in mRCC pts. In a phase I study of nivolumab, a PD-1 receptor blocking antibody, in pts with previously treated mRCC and other solid tumors, an MTD was not reached at 10 mg/kg IV Q2WK. Cohorts of mRCC pts were expanded at the 1 and 10 mg/kg dose levels. Methods: Pts received nivolumab for ⱕ12 cycles (4 doses/cycle) until unacceptable toxicity, progression, or complete response. We report overall survival (OS), updated response data, and long-term safety for the mRCC cohorts from a data analysis in July 2012. Results: 34 pts with mRCC were treated at 1 mg/kg (n⫽18) or 10 mg/kg (n⫽16). 44% of pts had received ⱖ3 prior therapies (74% prior antiangiogenic therapy; 59% prior immunotherapy). Median OS across doses has not yet been reached. Median duration of response was 12.9 months for both doses with 5 of the 10 responses lasting ⱖ1 year. The incidence of grade 3-4 related adverse events for the RCC cohort was 21% and included hypophosphatemia (6%) and respiratory disorders (6%), with no confirmed-drug related deaths or grade 3 pneumonitis. Treatment discontinuation due to drug-related AEs occurred in 18/304 (6%) of patients in the overall treated population. Conclusions: Nivolumab produced durable survival and responses in a subset of heavily pretreated mRCC pts, with an acceptable safety profile, even after long term continuous dosing. Overall survival appears promising for this population of pts. These findings provide the basis for an ongoing randomized phase III trial of nivolumab in mRCC (NCT01668784). Follow-up data through a February 2013 cutoff is being collected. Clinical trial information: NCT00730639. Dose, mg/kg 1 10 1-10 OS ratea 1 Yr 2 Yr 3 Yr a

ORR, n (%)

Stable disease rate >24 weeks, n (%)

PFS rate at 24 weeks, %

5 (28) 5 (31) 10 (29)

4 (22) 5 (31) 9 (27)

50 67 58

% (95% CI) 70 (55-86) 52 (32-72) 52 (32-72)

Pts at risk, n 22 7 1

All doses. OS estimates after 1 year reflect heavy censoring and shorter follow-up for pts enrolling in the later portion of the study.

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A phase II study of intermittent sunitinib (S) in previously untreated patients (pts) with metastatic renal cell carcinoma (mRCC). Presenting Author: Brian I. Rini, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH

A phase II clinical trial examining the impact of neoadjuvant axitinib on primary tumor response in patients with locally advanced clear cell renal cell carcinoma. Presenting Author: Jose A. Karam, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: S as initial treatment in mRCC is limited by balancing acute and chronic toxicity with clinical benefit. Pre-clinical and retrospective clinical data support that extended treatment breaks are feasible without a reduction in efficacy. Methods: Pts with treatment-naïve clear cell mRCC were enrolled on a prospective phase II trial and initially treated with 4 cycles of S (50 mg 4/2). Pts with ⱖ 10% reduction in tumor burden (TB) following 4 cycles had S held, with CT scans approximately every 10 weeks. S was re-initiated for 2 cycles in those pts with an increase in TB by ⱖ 10% and again held with ⱖ 10% TB reduction. This intermittent S dosing continued until RECIST-defined disease progression while on S. The primary objective was feasibility of intermittent S, defined as the proportion of eligible pts who underwent intermittent therapy. The alternative hypothesis was a feasibility of ⬎ 80% vs. a null hypothesis of ⬍ 50% (a⫽0.05; power 80%). Results: Thirty-six pts were enrolled; 70% male, median age 60, 95% PS 0/1 and 32% favorable/65% intermediate by Heng criteria. Twenty pts were eligible for intermittent therapy and all pts (100%) entered the intermittent phase. Pts were not eligible for intermittent S due to PD (n⫽13); toxicity (n⫽1) or w/d of consent (n⫽2) prior to end of cycle #4. Sixteen pts (80%) had ⱖ 10% TB increase off S with a median (range) increase of 1.5 cm (1.1-2.5) compared to the TB immediately prior to stopping S, considering all off periods.Four pts did not have ⱖ 10% TB increase off S (3 pts after the 1st off period; off for 12, 8 and 5 months to date and 1 pt after the 2nd off period; off for 8 months prior to restarting S). Most pts exhibited a stable saw tooth pattern of TB reduction on S and TB increase off S. No pt had RECIST-defined PD while on S, but 2 pts were taken off extended breaks due to gradual TB increase over time, and 1 pt developed new CNS mets during the 2nd off period.The objective response rate was 53%. Toxicity was typical for S and completely resolved during treatment breaks. Conclusions: S dosing with periodic extended time off drug is feasible and associated with reduction in toxicity during the off periods. Clinical efficacy does not appear to be compromised. Clinical trial information: NCT01158222.

Background: Previous studies have shown minimal impact of TKIs on primary renal tumor downsizing. Axitinib is a VEGFR TKI that has been recently approved for use in patients with metastatic clear cell renal cell carcinoma (RCC). In this prospective phase II trial, we sought to investigate the safety and role of axitinib in downsizing tumors in patients with non-metastatic renal cell carcinoma, prior to undergoing surgical resection. Methods: Patients with locally advanced (clinical stage T2-T3b N0 M0) biopsy-proven clear cell RCC were eligible for this phase II clinical trial. The primary outcome was objective response rate (using RECIST) following the administration of axitinib for 12 weeks prior to undergoing radical nephrectomy. Secondary outcomes included safety, tolerability, and feasibility of administration of axitinib in this patient population. Patients were given axitinib 5mg PO BID, and dose titration was allowed. Axitinib was continued until 36 hours prior to surgery. A dedicated radiologist independently reviewed all CT scans to evaluate for response using RECIST. Results: The study goal of enrolling 24 patients has been recently reached. At present, nineteen patients have completed the studies required for assessment of the primary outcome and are hereby reported. Fifteen patients were males, and four were females. Median age was 61 years (range 42-83 years). All patients had biopsy-proven clear cell RCC. All 19 patients continued axitinib for 12 weeks, and underwent surgery as planned without delay. Adverse events of any grade were: arthralgia in 6, hypothyroidism in 14, fatigue in 15, and hypertension in 16 patients. No wound complications occurred after surgery. Nine patients (47%) experienced a partial response by RECIST, and 10 patients had stable disease. There was no progression of disease while on axitinib. Conclusions: Axitinib is well tolerated in the neoadjuvant setting in patients with planned surgery for locally advanced non-metastatic clear cell RCC. The drug showed tumor downsizing activity when given for 12 weeks prior to surgery. Adverse events of any grade were common and easily manageable with routine care. Clinical trial information: NCT01263769.


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Genitourinary (Nonprostate) Cancer Poster Discussion Session (Board #6), Tue, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

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Randomized phase II CTEP study of MK2206 versus everolimus in VEGF inhibitor refractory renal cell carcinoma patients. Presenting Author: Eric Jonasch, The University of Texas MD Anderson Cancer Center, Houston, TX

Gene expression profiling in bladder cancer to identify potential therapeutic targets. Presenting Author: Syed A. Hussain, University of Liverpool, Liverpool, United Kingdom

Background: Up-regulation of the phosphoinositide-3 phosphate kinase (PI3K) pathway is associated with poorer prognosis in pts with advanced RCC. We hypothesized that optimal blockade of AKT in pts refractory to anti-VEGF therapy eliminates key drivers of tumor growth and proangiogenic signaling, and will prolong progression-free survival (PFS). We tested whether MK-2206, a selective allosteric inhibitor of AKT, will yield superior PFS to everolimus in anti-VEGF therapy refractory RCC pts. Methods: Eligible pts with metastatic RCC who progressed on an anti-VEGF agent were randomized (2:1 ratio) to receive MK2206 or everolimus. Up to two prior therapies allowed. Primary endpoint was PFS. The study had 80% power to detect a 67% increase in PFS with MK2206 over everolimus (8.2 vs. 4.9 mo) with a 1-sided log-rank at alpha⫽ 0.10. One interim futility analysis was planned. Secondary endpoints: safety, overall survival, & response rate. Tumor tissue was collected in correlative analyses. Results: A total of 43 patients were accrued; 42 were evaluable for efficacy. Demographics: Male, 77%;White, 81%; median age 62 (range 41-83). MK2206 was held in 3 pts due to grade 3 rash; 1 came off study for rash. No everolimus pt discontinued study drug due to AEs. 30 events had occurred at first futility analysis. The 1-sided log-rank p-value for rejecting null hypothesis was 0.979, exceeding p-value boundary of 0.6413 for stopping trial. Median PFS for MK2206 was 3.65 mo (95%CI 1.77-5.52) and 7.43 mo for everolimus (95%CI 1.84-13.27). Two out of 29 MK2206 pts demonstrated dramatic response with greater than 50% disease regression and PFS of 8 months and 6 months (ongoing). Conclusions: Monotherapy with MK2206 was not superior to everolimus in this randomized, phase II study. However, dramatic response to MK2206 was seen in a subset of patients. Planned translational studies to allow genotypephenotype correlations may help explain this observation. Clinical trial information: NCT01239342.

Background: Characterization of gene expression patterns in bladder cancer (BC) allows the identification of pathways involved in its pathogenesis, and may stimulate the development of novel therapies targeting these pathways. Methods: Between 2004 and 2005, cystoscopic bladder biopsies were obtained from 19 patients and 11 controls. These were subjected to whole transcript-based microarray analysis. Unsupervised hierarchical clustering was used to identify samples with similar expression profiles. Results: Hierarchical clustering defined signatures, which differentiated between cancer and normal, muscle-invasive or non-muscle invasive cancer and normal, g1 and g3. Pathways associated with cell cycle and proliferations were markedly upregulated in muscle-invasive and grade 3 cancers. Genes associated with the classical complement pathway were downregulated in non-muscle invasive cancer. Osteopontin was markedly overexpressed in invasive cancer as compared to normal tissue. Conclusions: This study contributes to a growing body of work on gene expression signatures in BC. The data support an important role for osteopontin in BC, and identify several pathways worthy of further investigation.

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Association of IL8 polymorphisms with overall survival in patients with renal cell carcinoma in COMPARZ (pazopanib versus sunitinib phase III study). Presenting Author: Chun-fang Xu, GlaxoSmithKline, Harlow, United Kingdom Background: Pazopanib and sunitinib are angiogenesis inhibitors approved for treatment of advanced renal cell carcinoma (RCC). COMPARZ, a phase III randomized clinical trial comparing pazopanib vs sunitinib for RCC, demonstrated similar efficacies for the two therapies but safety profiles differed. Our genetic analyses of previous pazopanib clinical trials found that IL8 polymorphisms may be associated with progression-free survival (PFS) and overall survival (OS). We attempted to validate these associations in the COMPARZ study. Methods: Of the 1110 participants in COMPARZ, 724 (65%) provided consent and DNA for pharmacogenetic analyses (pazopanib, N ⫽ 371; sunitinib, N ⫽ 353).Associations of IL8 polymorphisms (rs1126647 and rs4073) with PFS and OS were tested using the Cox proportional hazards model with baseline factors as covariates in a combined analysis of all patients and also separately in pazopanib-treated and sunitinib-treated patients. One-tailed P values were calculated for effects in the same direction as previously observed. Results: For PFS there was no significant association in the combined analysis or in pazopanib-treated patients, but there was a significant association in sunitinib-treated patients (P ⫽ 0.017). For OS there were significant associations in the combined analysis (P ⫽ 0.010) and in sunitinib-treated patients (P ⫽ 0.0043) but not in pazopanib-treated patients (P ⫽ 0.30). Hazard ratios (HRs) for genetic effects were not significantly different between sunitinib- and pazopanib-treated patients (two-tailed P ⫽ 0.23 for genotype-by-treatment interaction). Kaplan-Meier plots suggested a recessive genetic model in the combined data set, with median OS (95% CI) 23.7 months (15.4 –29.1) for rs1126647 TT genotype compared to 35.5 months (30.8 –⬁) for AA or AT genotypes (HR ⫽ 1.66, P ⫽ 0.0007). Similar associations were seen for rs4073. Conclusions: Germline variants in IL8 are associated with survival outcome in patients with RCC who have received angiogenesis inhibitors. These findings may provide additional scientific insights in making treatment decisions and developing alternative therapies.

Genes showing >5 fold increase in expression in MIBC versus normal tissue (FDR p < 0.05). Gene Secreted phosphoprotein 1/osteopontin Anillin, actin binding protein TPX2, microtubule-associated, homolog (Xenopus laevis) Topoisomerase (DNA) II alpha 170kDa Matrix metallopeptidase 1 Gasdermin C N serpin peptidase inhibitor, clade B, member 13 Chloride channel accessory 2 Antigen identified by monoclonal antibody Ki-67 Kinesin family member 23 Serpin peptidase inhibitor, clade B (ovalbumin), member3 Entromere protein F, 350/400ka (mitosin) Family with sequence similarity 83, member A Cyclin E2

Gene ID

P value

Fold change (invasive vs adjacent tissue)

SPP1 ANLN TPX2 TOP2A MMP1 GSDMC SERPINB13 CLCA2 MKI67 KIF23 SERPINB3 CENPF FAM83A CCNE2

0.000278942 0.000100265 0.000281361 0.000327502 4.53E-05 2.47E-06 5.94E-06 0.00335894 0.000992039 0.000252044 0.00367834 0.00190184 3.54E-06 0.000232145

10.9828 8.49928 7.51978 7.07702 6.48753 6.02525 5.98179 5.61433 5.43103 5.32734 5.26492 5.1824 5.16728 5.1512


Identification of predictive biomarkers of overall survival (OS) in patients (pts) with advanced renal cell carcinoma (RCC) treated with interferon alpha (I) with or without bevacizumab (B): Results from CALGB 90206 (Alliance). Presenting Author: Andrew B. Nixon, Duke University Medical Center, Durham, NC Background: CALGB 90206 was a phase III trial of 732 pts with RCC comparing B⫹I versus I alone demonstrating no difference in OS. To date, there are no validated predictive biomarkers for B in RCC. For this reason, baseline plasma samples from CALGB 90206 pts were analyzed to identify and test predictive markers for B⫹I in RCC pts. Methods: Baseline EDTA plasma samples from 424 consenting pts were analyzed using an optimized multiplex ELISA platform for 32 candidate factors related to tumor growth, angiogenesis, and inflammation. The data were randomly split into training (n⫽286) and validation (n⫽138) sets. The proportional hazards model was used to test for treatment-marker interactions of OS. The estimated coefficients from the training set were used to compute a risk score (RS) for each pt in the validation set. The RS classified pts by risk in the validation set. The model was assessed for its predictive accuracy using area under the curve (AUC). Results: A statistically significant 3-way interaction between interleukin-6 (IL-6), hepatocyte growth factor (HGF) and treatment was observed in the training set (p⬍0.0001). The median levels of IL-6 and HGF in the training set were 8.4 pg/ml and 89 pg/ml, respectively. In the validation set, the RS was predictive of OS (p⬍0.001) with the high and low risk groups having a median OS of 10 months and 32 months, respectively. The AUC in the validation set was 0.82 (95% CI⫽0.77-0.88). The median OS (in months) by median levels of IL-6 and HGF stratified by treatment arm in the validation set is presented in the table with associated 95% CI (NR⫽not reached). Conclusions: IL-6 and HGF are predictive for OS in RCC patients treated with B⫹I and a RS based on these factors identified patients who benefitted most from B. If independently validated, this novel RS could guide clinical decisions and pt selection in future RCC trials. Validation set: I Arm (nⴝ67)

Low IL-6 (nⴝ43) High IL-6 (nⴝ24)

Low HGF (nⴝ36)

High HGF (nⴝ31)

27 (19-40) 11 (6-NR)

18 (11-NR) 6 (5-25)

Low HGF (n⫽36) 55 (42-NR) 16 (12-NR)

High HGF (n⫽35) 16 (14-NR) 12 (8-32)

Validation set: BⴙI Arm (nⴝ71) Low IL-6 (nⴝ34) High IL-6 (nⴝ37)




Pdl-1/pdl-3 (programmed death ligand-1/3) tissue expression and response to treatment with IL2 and antiangiogenic therapies. Presenting Author: Alexandra S. Bailey, Beth Israel Deaconess Medical Center, Boston, MA Background: Expression of PDL1 by RCC has been associated with aggressive histology and poor survival. Tissue obtained from the patients enrolled in the IL-2 Select Trial, a prospective, single arm, multicenter CWG study, was analyzed by IHC to determine if PDL1or PDL3 expression predicted for response to initial or subsequent therapy. Methods: Paraffin embedded tumor tissue was stained for PDL1 and PDL3 expression, and results were correlated with RECIST defined response to IL2 treatment. Tumor tissue was considered positive for PDL1 if ⬎5% of the tumor membranes stained for the marker. A cutoff of 10% was used for PDL3. Duration of subsequent VEGFR/mTOR inhibitor therapy was also correlated with tissue PDL1/3 expression. Results: 120 eligible pts were enrolled; 115 had clear cell histology. The overall response rate (ORR) to IL2 was 25% (30/120) with a median OS of 40.6 months. 113 tumors were stained. 18 (16%) were PDL1⫹. ORR was 19% and 50% in the patients PDL1- and PDL1⫹ tumors, respectively (p⫽0.012). 85 (75%) tumors were PDL3⫹. ORR was 10.7% and 29.4% in the PDL3- and PDL3⫹ tumors, respectively (p⫽0.075). In the 17 patients who were positive for both PDL1 and PDL3, ORR was 52.9%. In the 27 pts who were negative for both PDL1 and PDL3, ORR was 11.1%. 69 patients received at least 1 dose of a VEGFR TKI as next therapy following IL2 treatment. 66 tumors were stained. Pts who were PDL1⫹/PDL3⫹ had a shorter duration on VEGFR TKI therapy compared to pts who were PDL1-/PDL3- (see Table). Conclusions: This small, retrospective analysis suggests that PDL1 and PDL3 tissue expression may predict for better response to IL2. PDL1 expression has been suggested as a possible predictor of response to anti-PD1 therapy. The current data suggests that its expression may predict for benefit to other immune therapies. PDL3 (⫹/- PDL1) expression appears to correlate to less benefit from subsequent VEGFR TKI therapy. Funded by NCI SPORE Grant # 5 P50 CA101942-08. PDL1/3 expression PDL1ⴙ/PDL3ⴙ PDL1-/PDL3ⴙ PDL1-/PDL3-

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Median time on VEGFR TKI Tx (mo)

Median time on 1st VEGFR TKI Tx (mo)

9.0 21.3 42.5

4.9 6.9 14.2


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A validated 34-gene signature for assessing risk of recurrence in clear cell renal cell carcinoma. Presenting Author: Kimryn Rathmell, The University of North Carolina at Chapel Hill, Chapel Hill, NC Background: The objective of this study is to create a molecular tool that can be applied widely to clinical specimens using existing transcript signatures for use in clinical risk prediction of clear cell Renal Cell Carcinoma (ccRCC) to improve personalized disease management. Methods: We developed a 34-gene subtype predictor to classify clear cell tumors according to two subtypes, clear cell A (ccA) or B (ccB). The training set consisted of 72 ccRCC microarray-analyzed tumor samples that had previously been classified by unsupervised clustering and logical analysis of data (LAD). The predictor was developed from a panel of genes significantly expressed in ccA and ccB tumors and associated with prognosis. The prognostic value of the algorithm was corroborated in RNA-sequencing data from 379 ccRCC samples from The Cancer Genome Atlas (TCGA) and further validated using the NanoString platform with a cohort of 163 archival fixed samples collected at the University of North Carolina. Results: Risk associated molecular subtypes, ccA and ccB, were classified in TCGA and NanoString cohorts. Subtype classification showed significant prognostic outcomes for overall survival (p⬍.001), cancer-specific survival (p⫽.003), and recurrence-free survival (p⬍.05) and remained significant in multivariate analyses that included age at diagnosis, gender, ethnicity, pathologic stage, and histologic grade. A prognostic model was built for overall and recurrence-free survival for non-metastatic ccRCC patients within the context of subtype and clinical characteristics. Conclusions: The ccA and ccB subtypes significantly added prognostic information to clinical parameters, particularly for non-metastatic ccRCC patients.The subtypes can be used for future analyses involving risk for developing metastatic disease and cancer-specific outcomes. This research was supported with a grant from the American Association for Cancer Research, and the UNC Lineberger Comprehensive Cancer Center Cancer Cell Biology Training Grant.

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Association of IGF1R overexpression (OE) with outcome in invasive urothelial carcinoma (UC) of urinary bladder. Presenting Author: Nilda Gonzalez-Ribbon, Johns Hopkins University, Baltimore, MD

Nomogram to estimate the activity of second-line therapy for advanced urothelial carcinoma (UC). Presenting Author: Guru Sonpavde, University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL

Background: Insulin-like growth factor-1 receptor (IGF1R) is a transmembrane tyrosine kinase receptor involved in cell proliferation and differentiation. IGF1R is overexpressed in several tumors including UC and is currently under investigation as a target of Rx. We here explore IGF1R expression in UC, its association with clinicopathologic parameters and prognostic role. Methods: Fivetissue microarrays (TMA) were constructed from 100 cystectomy specimens performed for invasive UC at our institution (1994 to 2007). Formalin-fixed paraffin-embedded paired tumor and benign samples were spotted 3-4 times each. Membranous IGF1R staining was evaluated using immunohistochemistry (G11, Ventana Medical Systems). A scoring method analogous to that of Her2 expression in breast cancer was used and the highest score was assigned to each tumor. IGF1R was considered overexpressed in cases with score 1. Endpoints of the study included overall survival (OS) and disease-specific survival (DSS). Patients were followed-up for a median of 33.5 months (range 1, 141 months). Results: IGF1R OE was found in 62% of UC. No differences were noted between normal urothelium and UC regarding IGF1R OE (74% vs. 60%; P⫽0.14). IGFR1 OE was more frequent in tumors from African-American patients compared to Caucasians (100% vs. 59%, P⫽0.04). Tumors at stage pT4 overexpressed IGF1R more frequently than tumors at stages pT1-pT3 (71% vs. 29%, P⫽0.005). No association with other analyzed clinicopathologic parameters such as patient’s age or gender, muscularis propria invasion, or lymph node metastasis) was found. OS and diseasespecific survival (DSS) rates were 58% and 69%, respectively. Patients with tumors overexpressing IGF1R had a lower OS and DSS compared to those without IGF1R OE (Mantel-Cox P⫽0.0007 and P⫽0.006, respectively). Using Cox proportional hazards regression, IGF1R OE remained a significant predictor of OS (HR⫽3.49, P⫽0.001) and DSS (HR⫽3.54, P⫽0.007) after adjusting for pathologic stage. Conclusions: OE of IGF1R was found in 62% of UC. High stage tumors overexpressed IGF1R more frequently than low stage tumors. Further, IGF1R OE was a significant independent predictor of OS and DSS in invasive UC.

Background: Prognostic factors may impact on endpoints used in phase II trials of second-line therapy for advanced UC. We aimed to study the impact of prognostic factors (liver metastasis [LM], anemia [Hb⬍10 g/dl], ECOG-performance status [PS] ⱖ1, time from prior chemotherapy [TFPC]) on PFS6 and RR. Methods: Twelve phase II trials evaluating second-line chemotherapy and/or biologics (n⫽748) in patients with progressive disease were pooled. PFS was defined as tumor progression or death from any cause. PFS6 was defined from the date of registration and calculated using the Kaplan-Meier method. RR was defined using RECIST 1.0. A nomogram predicting PFS6 was constructed using the RMS package in R (www.r-project.org). Results: Data regarding progression, Hb, LM, PS and TFPC were available from 570 patients. The mean age was 65.1 years, 45.3% had ECOG-PS ⱖ1, 30.2% had LM, 14.6% had anemia and TFPC was ⬍6 months (mo) in 60.2%. The overall median PFS was 2.7 mo, PFS6 was 22.2% (95% CI: 18.8-25.9) and RR was 17.5% (95% CI: 14.5%20.9%). For every unit increase in risk group, the hazard of progression increased by 41% and the odds of response decreased by 48% (Table). A nomogram was constructed to predict PFS6 on an individual patient level. Conclusions: PFS6 and RR vary as a function of prognostic factors in patients receiving second-line therapy for advanced UC. A nomogram incorporating prognostic factors might facilitate the evaluation of activity across phase II trials enrolling heterogeneous populations and can help to select and stratify patients for phase III evaluation of suitable agents. Parameter No. of risk factorsⴝ0 1 2 3-4 Hb >10 g/dL Hb 1 TFPC6 months

N

6-month PFS % (95% CI)

Response rate (95% CI)

153 205 146 66 487 83 398 172 312 258 343 227

34.6 (26.9-42.4) 22.0 (16.4-28.2) 17.0 (11.3-23.8) 4.9 (1.3-12.3) 24.2 (20.4-28.2) 10.5 (4.9-18.4) 26.6 (22.3-31.2) 11.6 (7.2-17.1) 25.4 (20.5-30.5) 18.5 (13.9-23.6) 16.6 (12.7-21.0) 30.5 (24.5-36.7)

28.8 (21.7-36.6) 18.5 (13.5-24.5) 10.3 (5.9-16.4) 4.6 (1.0-12.7) 18.9 (15.5-22.7) 9.6 (4.3-18.1) 20.6 (16.7-24.9) 10.6 (6.3-16.0) 20.8 (16.5-25.8) 13.6 (9.6-18.4) 11.4 (8.2-15.2) 26.9 (21.2-33.1)


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Treatment patterns and outcomes in “real world” patients (pts) with metastatic urothelial cancer (UC). Presenting Author: Matt D. Galsky, Division of Hematology and Medical Oncology, The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY Background: Most studies reporting outcomes of pts with metastatic UC are derived from clinical trial data, potentially limiting the breadth/generalizability of the findings. To explore patterns of care/outcomes in “real world” pts, we initiated an international retrospective cohort study. Methods: Data were collected via an electronic data capture platform from 23 centers. Eligible pts had UC (at least muscle-invasive) and were initially evaluated from 1/1/2006-1/1/2011. Parameters were subjected to regression analysis to identify prognostic variables. Results: By 12/18/12, 1905 pts were enrolled. Among 1077 with metastatic UC, median age was 67 (IQR 60-75), 80% were male, 87% had bladder primary tumors, and 33% received perioperative chemotherapy. Only 758 (70%) received 1st-line chemotherapy for metastatic UC: cisplatin-based (51%), carboplatinbased (29%), non-platinum single-agent (16%), and non-platinum multiagent (4%). The median survival from date of diagnosis of metastatic UC was 5.2 months (95% CI 4.4-6.5) and 16.1 months (95% CI 15.1-17.5) for pts who did and did not receive 1st-line chemotherapy, respectively [13.9 months (95% CI 12.78-14.98) from start of chemotherapy for latter group]. Among pts receiving 1st-line chemotherapy, univariable analysis revealed gender, primary tumor site, removal of primary, creatinine clearance, LDH, and hgb were not significantly associated with survival whereas smoking status, performance status, perioperative chemotherapy, metastatic sites, study site and chemotherapy regimen were. The multivariable analysis is shown in the Table. Conclusions: The current analysis identifies previously unrecognized prognostic factors in an international cohort of “real world” pts with metastatic UC treated with 1st-line chemotherapy. A large subset of pts with metastatic UC receives no chemotherapy. Prognostic factors for survival in pts receiving 1st-line chemotherapy. Smoking history Perioperative chemotherapy # of visceral metastatic sites ECOG PS

Current vs. never/former No vs. yes 1 vs. 0 ⱖ2 vs. 0 1 vs. 0 ⱖ2 vs. 0

HR

95% CI

P

1.48 0.63 1.76 2.23 1.73 2.98

1.12-1.95 0.46-0.86 1.25-2.47 1.56-3.20 1.29-2.32 2.02-4.40

0.006 0.004 0.001 ⬍0.001 ⬍0.001 ⬍0.001

4526


Randomized phase III trial of neoadjuvant chemotherapy (NAC) with methotrexate, doxorubicin, vinblastine, and cisplatin (MVAC) followed by radical cystectomy (RC) compared with RC alone for muscle-invasive bladder cancer (MIBC): Japan Clinical Oncology Group study, JCOG0209. Presenting Author: Hiroshi Kitamura, School of Medicine, Sapporo Medical University, Sapporo, Japan Background: Cisplatin-based NAC for patients (pts) with MIBC is considered to provide a 5– 8% overall survival (OS) advantage, although several studies failed to prove the survival benefit of NAC. Methods: Eligibility criteria included histologically proven urothelial carcinoma, MIBC (T24aN0M0) within 8 weeks from TURBT, PS 0-1, and age 20-75 years old. Patients were randomized to receive 2 cycles of neoadjuvant MVAC followed by RC (NAC arm) or RC alone (RC arm). The primary endpoint was OS. Secondary endpoints were progression-free survival (PFS), surgeryrelated complications, adverse events during NAC, the percent with no residual tumor in the RC specimens (pT0), and QOL. The sample size was 180 pts in each arm with a one-sided alpha of 5% and a power of 80% to detect a 7% difference in 5-year OS, 45% in the RC arm, and 57% in the NAC arm. Results: From March 2003 to March 2009, 130 pts were randomized to the NAC arm (n⫽64) and RC arm (n⫽66). Fifty-nine patients in the NAC arm and 65 in the RC arm underwent cystectomy. The patient registration was terminated early because of slow accrual. At the 2nd interim analysis conducted after the completion of patient accrual, OS of the NAC arm was better than that of the RC arm, although the difference was not statistically significant (HR, 0.65; multiplicity adjusted 99.99%CI, 0.19-2.18; one-sided log-rank p ⫽ 0.07). Considering the current situation in which NAC with gemcitabine and cisplatin (GC) is widely used in clinical practice, the Data and Safety Monitoring Committee recommended early publication of the results. PFS of the NAC arm was better than that of the RC arm (HR, 0.61; 95% CI, 0.35-1.06, one-sided log-rank p⫽0.04). No differences in perioperative complications, other than lymph leakage, were observed between the arms. In the NAC arm and the RC arm, 34% and 9% of the patients had pT0, respectively (p⬍0.01). In subgroup analyses, OS in almost all subgroups was in favor of NAC. Conclusions: Although NAC with GC is widely used for MIBC, NAC with MVAC can still be considered promising. Clinical trial information: C000000093.

4527^ Poster Discussion Session (Board #16), Tue, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

4528

Preliminary HER2 expression data from NeuACT, the phase II randomized, open-label trial of DN24-02 in patients (pts) with surgically resected HER2ⴙ urothelial cancer (UC) at high risk for recurrence. Presenting Author: Michael F. Press, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA

Gemcitabine, paclitaxel, and doxorubicin as first-line therapy for patients with advanced urothelial carcinoma and renal insufficiency: A phase II study. Presenting Author: Lance C. Pagliaro, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: HER2 overexpression may be a prognostic factor for poor outcomes in pts with high-risk UC. Publications report a wide variability of HER2 expression in UC, with ⱖ2⫹ HER2 expression by immunohistochemistry (IHC) reported in ⬍10% to ⬎50% of cases. DN24-02 is an investigational autologous immunotherapy targeting HER2, based on the same manufacturing platform used for sipuleucel-T. NeuACT (N10-1; NCT01353222) is designed to evaluate whether DN24-02 can prolong survival when given as adjuvant therapy following surgical resection in pts with high risk HER2-expressing UC (Bajorin, et al. ASCO 2012). Here we report preliminary data for HER2 expression on primary tumor and positive lymph node samples, and covariate analyses. Methods: Trial eligibility criteria include surgical resection of a primary UC, with either ⱖpT2 or pN⫹ staging, and HER2 expression ⱖ1⫹ IHC. Surgical specimens are screened for HER2 expression by central pathology laboratory review and HER2 positivity is scored using the Dako HercepTest system. Results: As of December 2012, tumor specimens from 114 pts have been screened. Of these pts, 84 (74%; 95% CI: 65– 82%) had a HER2 expression score ⱖ1⫹ in the primary tumor, with 36 (32%) having a 2⫹ score and 5 (4%) having a 3⫹ score. Thirty-eight pts also had HER2 expression levels evaluated in lymph node samples. Of these 38 pts, 35 (92%; 95% CI: 79 –98%) had a HER2 expression score ⱖ1⫹ in the lymph nodes, with 17 (45%) having a 2⫹ score and 4 (11%) having a 3⫹ score. Gender, primary tumor site, nodal stage and prior neoadjuvant chemotherapy were not significantly correlated with HER2 expression (pⱖ0.10). Conclusions: To date, high frequencies (ⱖ74%) of HER2 expression ⱖ1⫹ in primary tumor and lymph node samples of UC pts have been observed. No baseline variables, including prior neoadjuvant chemotherapy, appear to affect the rate of HER2 expression. Although preliminary, these data are consistent with prior studies that have noted a higher incidence of HER2 expression in UC lymph node tumor vs. primary tumor and suggest that HER2 protein expression is common in high-risk UC. Clinical trial information: NCT01353222.


Background: The role of cisplatin-based chemotherapy for the treatment of locally advanced or metastatic urothelial carcinoma is well established. For patients (pts) who cannot receive cisplatin owing to renal insufficiency, substitution with carboplatin was associated with inferior response rate and overall survival (OS). To address this unmet need, we conducted a phase II study of gemcitabine (Gem), paclitaxel (Tax), and doxorubicin (Adria) in this group. Methods: The primary endpoint was overall response rate (ORR); secondary endpoints were toxicity, OS, and the safety and efficacy of pegfilgrastim 6 mg (G-CSF) given immediately after chemotherapy on Day 1. A Simon 2-stage design was chosen to detect ORR of 40% and to reject ORR of 25%. Eligible pts had metastatic or unresectable urothelial carcinoma, no prior chemotherapy, performance status ⱕ 2, glomerular filtration ⬍ 60 ml/min, and no need for dialysis; all gave informed consent. Brain metastases were excluded, as were clinically significant heart disease, peripheral neuropathy, and liver or bone marrow dysfunction. Treatment consisted of 900 mg/m2 Gem (fixed rate of 10 mg/m2/min), 135 mg/m2 Tax, and 40 mg/m2 Adria administered with same-day GCSF every 14 d to a maximum of 9 cycles. Tumors were evaluated after every 3 cycles. Results: Forty pts were enrolled January 2008 through November 2011, and 39 could be assessed for response. Median age was 72 (range, 51– 89) and 11 pts (28.2%) were women. There were 7 complete and 15 partial responses, for an ORR of 56.4% (95% CI 39.6-72.2). Notable grade 3 and 4 nonhematologic toxicities in the first 2 cycles were dyspnea and mucositis (1 pt each). There were no treatment-related deaths and no toxicity attributed to same-day G-CSF. Median OS was 14.4 mo with median follow-up of 12.6 mo for all pts, 15.6 mo for 10 who were alive. Conclusions: Gem-Tax-Adria is effective as first-line treatment for metastatic or locally advanced urothelial carcinoma, and it can safely be given to pts with renal insufficiency. Same-day G-CSF also appears to be safe and effective in this setting. Phase III study is warranted. Clinical trial information: NCT00478361.




Prognostics factors in previously untreated urothelial cancer patients ineligible for cisplatin-based chemotherapy: An external validation of the Bajorin risk groups. Presenting Author: Sandra Collette, EORTC Headquarters, Brussels, Belgium Background: In patients with urothelial cancer who are unfit for Cisplatin chemotherapy, EORTC phase II/III trial 30986 investigated two carboplatinbased chemotherapy regimens: Gemcitabine/Carboplatin (GC) and Methotrexate/Carboplatin/Vinblastine (M-CAVI). The trial did not show any significant differences in efficacy (response rate, OS, PFS) between the treatments; however the incidence of severe acute toxicity was slightly higher on M-CAVI. We now investigate the prognostic factors for survival. Methods: 238 patients with impaired renal function (Glomerular Filtration Rate (GF) ⬍60 mL/min) or poor performance status (PS 2) were randomized by 29 institutions between GC and M-CAVI. The median follow-up was 4.5 years and, with 218 deaths reported (progression of malignant disease in 72%), the overall survival median was 9.3 months in the GC arm and 8.1 months in the M-CAVI arm. Univariate and multivariate Cox prognostic factor regression models for overall survival were developed on the whole population stratified by treatment arm. Results: In the multivariate analysis, the risk of death significantly increased (p⬍0.10) with WHO-PS 2, hemoglobin ⱕ 12 g/dl (women) or ⱕ 13.6 g/dl (men), the presence of visceral metastases and even more with the presence of liver metastases. The risk of death was not influenced by the site of the primary tumour, white blood cell or platelet count. In addition, the prognostic factors had a stronger effect in the M-CAVI arm than in the GC arm. Conclusions: This prognostic factors analysis confirms the Bajorin classification based on visceral metastases and performance status. However, we were also able to show the importance of hemoglobin and that in the patients with visceral metastases, the subgroup of patients with liver metastases had a significantly worse prognosis than the patients with only other visceral metastasis. Clinical trial information: NCT00014274.

4531


Phase II study of gemcitabine, oxaliplatin, and paclitaxel (GOT) on a 2-weekly schedule in patients (pts) with refractory germ cell tumor (rGCT): Final results. Presenting Author: Sarmad Sadeghi, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA Background: Modern therapy (Tx) for GCC has transformed the disease but challenges remain in managing rGCT. Methods: 30 men with GCC progression ⱕ4 weeks after a standard (7), salvage (17), or stem cell (6) regimen were enrolled in the trial. PS⬍⫽2, Age⬎16, PD by RECIST/markers (Tm) criteria. Growing teratoma syndrome excluded. Regimen: paclitaxel 170mg/m2/3h; gemcitabine 800mg/m2/80min; oxaliplatin 100mg/m2/90min, increased to 125mg/m2 in cycle 2 if no major toxicity. Mg2⫹ and Ca2⫹infused before oxaliplatin. The regimen was designed to maximize Oxaliplatin density with full dosing of pts with recovering marrow and dose escalation for pts with limited toxicity in cycle 1. Retreatment if ANC ⱖ1000 or 700 with monocytosis, platelets ⬎75K. Pts with normalized Tm had 3 further cycles. Primary endpoint: Response (RR); 2nd: OS, PFS, toxicity. Results: Median GOT cycles 6 [114].Dose escalation in 9 pts correlated with improved OS (p⫽0.03). Tm normalized in 23.3%. 5 pts (4 PR, 1 SD) became NED after definitive surgery. No link between ethnicity and RR or OS. Conclusions: 2-weekly GOT for rGCC produced high rates of Tm and RECIST response and rendered 5 pts resectable. Dose escalation was associated with better OS and will be explored with GCSF in a trial extension. The median OS of 18.3 mos compares favorably with 6-13.5 mos in other series (Oechsle K Eur Urol 60: 850, 2011). Clinical trial information: NCT00183820. Pt characteristics (Nⴝ30) Median age Ethnicity white / Hispanic / Asian Primary testis / mediastinal Seminoma / chorio / YST / emb / teratocarcinoma / undiff / mixed NSGCT KPS > 90% FU LDH AFP ␤hCG Prior lines of Tx Prior surgery primary / metastasis Endpoint RR CR / PR / uPR / SD / PD OS Probability of survival at 2 Y PFS Time to progression Probability of nonPD at 1 Y Toxicity Neutropenia G 3-4 Febrile Death GI G2-3 Neuropathy G 3, 4 G 1-2

32 Y 43 / 47 / 10 % 28 / 2 1 / 3 / 3 / 1 / 5 / 1 / 16 66% 40.9 mos [4.6-71.8] 178 [109-4504] 26.7 [2-363002] 2.6 [0.5-247040] 2 [1-7] 20 / 13 31% (17-50) 2 / 7 / 2 / 11 / 5 18.3 mos (12-71.8) 45⫾10 % 6.5 mos (3.2-27.5) 10.8 mos (3.2-71.8) 47⫹9%

17 7 1 pneumonia 12 4, 1 19

4530

291s


Phase II study of neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC) chemotherapy in patients with muscle-invasive urothelial cancer (MI-UC): Pathologic and radiologic response, serum tumor markers, and DNA excision repair pathway biomarkers in relation to disease-free survival (DFS). Presenting Author: Angela Q. Qu, Dana-Farber Cancer Institute, Boston, MA Background: Neoadjuvant (NA) ddMVAC in patients (pts) with MI-UC is associated with significant pathologic response (PaR) and radiologic response (RaR). We examined the frequency of PaR and RaR as well as the level of serum and tissue biomarkers in correlation with DFS. Methods: Pts treated on phase II prospective study of NA ddMVAC (4 cycles) in MI-UC were evaluated for RaR (at least ⬎50% decrease in the primary tumor and nodes after chemotherapy, with delayed enhancement of residual disease) and PaR (p⬍T1N0M0). Elevated serum tumor markers (CA125, C19-9 and ßHCG) at baseline and Day 1 of each cycle were documented. Expression level of baseline DNA ERCC1 protein in tumor biopsy tissues was determined by immunohistochemistry based on H-score ⬍0.1 (negative) vs. ⬎0.1 (positive). Fisher’s Exact test was used to evaluate association with response. Post-surgery DFS was estimated by the Kaplan-Meier method and compared between response and biomarker groups using the logrank test. Results: Of 39 pts (cT2:42%, cT3:42%, cT4:16%, and cN1:45%), 49% (90% CI 35-63) experienced PaR, and 62% (90% CI 47-75) achieved RaR after ddMVAC chemotherapy. Pts who achieved PaR experienced a DFS advantage, with 18-month DFS of 78% (95% CI 47-92) vs. 48% (95% CI 18-74) in those who did not (p⫽0.146). Those achieving RaR had a significantly longer DFS (p⫽0.006), with 18-month DFS of 87% (95% CI 57-97) vs. 29% (95% CI 5-60) in those who did not. Among 10 pts with any elevated serum tumor marker at baseline, only 2 pts showed normalization, both without a PaR. ERCC1(⫹) tumors were not associated with PaR, pT0 or RaR. DFS by ERCC1status was inconclusive due to limited sample size. 18-month DFS was 91% (95% CI 51-99) in ERCC1(⫹) tumors vs. 63% (95% CI 29-85) in ERCC1(-) tumors. Conclusions: ddMVAC achieves significant PaR and RaR in MI-UC pts that translates into a post-surgery DFS advantage. ERCC1(⫹) was not associated with response. More effective biomarkers of platinum response are needed to select pts most likely to benefit from NA therapy. Clinical trial information: NCT00808639.

4532


Survival and toxicity in patients with disseminated germ-cell cancer above 40 years of age. Presenting Author: Frederik Birkebæk Thomsen, Urology Research Unit, Department of Urology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark Background: The aim was to analyze treatment related toxicity and survival in patients aged 40 years or above (40⫹) treated with standard chemotherapy for germ-cell cancer (GCC). Methods: The study population comprised 135 40⫹ patients with disseminated GCC treated between 1984 – 2011 with either 3 or 4 cycles bleomycin, etoposide and cisplatin (BEP). A control-group of 135 patients aged 18-35 years was randomly selected matched on year of BEP treatment. All patients were followed until death or October 1st2011. Cumulated doses of BEP as well as bone-marrow toxicity, renal- and lung functions were recorded before, during and after termination of treatment. The expected mortality was calculated by extracting survival data for each patient matched on the date and age at the time of diagnosis. The cause of death was categorized as GCC, other malignancy or other. Results: The cumulated doses of BEP were comparable between the two groups and, generally, BEP was equally well tolerated. 40⫹ patients had increased cancer specific mortality, HR ⫽ 4.8 (P ⫽ 0.005). Especially patients with disease progression after first line chemotherapy had increased mortality (P ⫽ 0.015). The year of treatment (P ⫽ 0.32), histology (P ⫽ 0.30), CCI (P ⫽ 0.99), tobacco use (P ⫽ 0.16), alcohol consumption (P ⫽ 0.21), prophylactic G-CSF (P ⫽ 0.61), reduced doses of bleomycin (P ⫽ 0.11) and decreased renal function (P ⫽ 0.18) were not significantly associated with GCC mortality. However, patients with impaired lung function (⬍80% of expected) prior to treatment had an increased risk of GCC mortality (FVC (P ⫽ 0.03), DLCO (P ⫽ 0.01) and FEV1(P ⫽ 0.05)). Moreover, the 5-year overall survival in the 40⫹ group was 82.5% compared to the expected 5-year survival of the background population of 96.2% (P ⬍0.001) and the estimated 5-year survival of 97.0% in the control-group (P ⬍0.001). Conclusions: Reduced treatment intensity, or treatment related toxicity could not explain the increased mortality in 40⫹ GCC patients compared to a younger control-group. The 40⫹ group has a significantly lower response rate to BEP and a significantly higher mortality in case of disease progression. The worse prognosis could be related to tumor biology or increased co-morbidity.

G: grade; Y: years, mos: months. Range in []; 95% CI in ().


292s 4533


Germ cell cancer (GCC): Long-term survival after treatment with bleomycin (B), etoposide (E), and cisplatin (P) in a large cohort. Presenting Author: Maria Gry Gundgaard, Survivorship, Danish Cancer Society, Copenhagen, Denmark Background: In 1997 the International Germ Cell Cancer Collaborative Group presented a classification dividing patients into a good, intermediate, and poor prognostic group for metastatic GCC with 5-year survival information. However, only a minor part of these patients were treated with today’s standard treatment. We present the first nationwide and population based study of overall survival (OS) and disease specific survival (DSS) in a large cohort of GCC patients treated with BEP. Methods: A nationwide and population based clinical database covering GCC patients diagnosed 1984-2007 was constructed, including 4,683 GCC cases. Through merging with national administrative registers, information on vital status and cause of death for all patients until November 30, 2012, was obtained. Results: The 5-year OS for the whole database cohort was 96%. A total of 1,584 patients were treated with BEP (1,099 patients with primary metastatic disease, 485 patients relapsed from stage I). Until 2001, the standard treatment was 4 cycles of BEP, after 2001 patients with good prognosis had 3 cycles of BEP. Overall survival (OS) and disease specific survival (DSS) with 95% confidence intervals (95% CI) (Table), median observation time was 13.8 years. Conclusions: This cohort study showed improved OS for GCC patients across all prognostic groups since 1997, in particular regarding the poor prognostic group. The present result is based on a large number of cases established in a population based fashion, with long follow up time and unbiased information covering all cohort members including detailed clinical information and vital status of all patients. Seminoma (nⴝ360) Histology Prognostic group (%) 5-year OS (%) (95% CI) 5-year DSS (%) (95% CI)

4535

Non-seminoma (nⴝ1,224)

Good

Intermediate

Good

Intermediate

Poor

95 95 (92-97) 97 (95-98)

5 82 (58-93) 85 (61-95)

66 96 (94-97) 98 (97-99)

20 89 (85-93) 90 (86-93)

14 67 (59-74) 71 (63-77)


A randomized trial of 72-hour infusional bleomycin in BEP (cisplatin, etoposide, and bleomycin) versus conventional weekly bleomycin in patients with metastatic IGCCCG good prognosis disease. Presenting Author: Sarah Vinnicombe, University of Dundee, Dundee, United Kingdom Background: Bleomycin is an integral part of combination chemotherapy in germ cell tumours. Pulmonary symptoms often dictate drug cessation and death occurs in 1-2% of patients. Circumstantial evidence suggests that continuous infusion may be less toxic. Methods: We conducted a randomized phase 3 study to see whether infusional bleomycin was associated with less pulmonary toxicity. Patients were stratified for smoking, renal dysfunction and age and were randomized to receive either conventional BEP with weekly bleomycin (3,0000 units /week iv over 30min) or the same doses but administered as a 90,000 unit infusion on day 1 over 72 hours. The primary endpoint was CT proven lung toxicity, secondary endpoints included PFS and changes in lung function testing. CT scans and lung function testing were conducted after 1 cycle, end of treatment and 1 year post treatment. Sample size of 210 was calculated to detect a difference of 16% Bleomycin damage with 80% power at the 5% level of significance using 2-sided test. Results: The median follow-up was 2.5 years. At day 21 of the treatment, 52% patients in the infusional arm had grade 1 or above toxicity compared to 55% in the conventional. At the end of treatment the results were 84% vs. 60% and at one year it was 65% vs. 59%. Repeated measures mixed effects model shows no significant difference in percentage of grade 1 and above toxicity between the two arms (Difference⫽1.63, P⫽0.09, 95% CI: -0.28, 3.54). However, there was a significantly higher level of grade 2 and above toxicity in patients in the infusion arm (difference⫽0.8; 95% CI 0.11 to 1.49). Toxicity level was the highest at the end of treatment and in older patients (Age⬎30). Lung function testing between the two arms failed to show any differences. Two-years PFS rate was 93% in both arms (hazard ratio infusion vs conventional was 0.91; 95% CI 0.33 to 2.52). There was an association between toxicity after 1 cycle and subsequent toxicity at end of treatment and at 1 year (p⫽0.003). Conclusions: Infusional bleomycin has no advantage over standard administration of bleomycin. Clinical trial information: 08648791.

4534


Phase I/II study of paclitaxel plus ifosfamide (TI) followed by high-dose paclitaxel, ifosfamide, and carboplatin (TIC) with autologous stem cell transplant (ASCT) for salvage treatment of germ cell tumors (GCT). Presenting Author: Xiaoyu Jia, Memorial Sloan-Kettering Cancer Center, New York, NY Background: High-dose chemotherapy (HDCT) can achieve durable remissions in 30-60% of GCT patients (pts) requiring salvage treatment. This Phase I/II study investigated safety and efficacy of a novel high-dose regimen (TI-TIC) in this population. Methods: Pts age ⱖ18 with GCT and progression after ⱖ1 cisplatin-based regimen were eligible. TI-TIC consists of 1-2 cycles of conventional-dose paclitaxel plus ifosfamide (TI) q14-21 days followed by 3 cycles of high-dose TIC with ASCT q21-28 days. TI dosing was constant. In Phase I, high-dose TIC was administered in 1 of 5 cohorts (I: 6, 8 or 10g/m2; T: 200 or 250mg/m2; C: AUC⫽21 or 24) using a standard 3⫹3 dose escalation design to determine the maximal tolerated dose (MTD). In Phase II, Simon’s 2-stage optimal design was used to estimate the complete response (CR) rate at MTD. Results: Of 26 pts (25 male; median age 31; 21 nonseminoma, 5 seminoma) enrolled, 23 received ⱖ1 cycle of high-dose TIC. Primary sites included testis (n⫽15), mediastinum (n⫽6), other (5). In Phase I, 0/18 pts had dose-limiting toxicity (DLT) during TIC cycle 1, making cohort 5 (T 250mg/m2, I 10g/m2, C AUC⫽24) the MTD. Toxicities were similar to those reported with TI-CE (Feldman JCO 2010) with little variation across cohorts. However, 2/18 pts in Phase I (1 in cohort 4, 1 in cohort 5) developed grade 3 acute renal insufficiency after cycles 1 and 2 (cycle 3 not given). Both later developed chronic renal insufficiency with 1 pt requiring dialysis 10 months after TI-TIC. A third pt treated in Phase II developed a similar acute and then chronic renal insufficiency pattern with TIC cycles 1 and 2. In Phase II, 7/11 evaluable pts (64%, 90% one-sided CI 40%-100%) achieved a CR, 1 had a partial response with negative markers, and 3 had incomplete responses. Although the CR rate was sufficient to move to the second Simon’s stage, renal toxicity led to premature trial closure. Conclusions: Although there was preliminary evidence of efficacy, high dose TI-TIC was associated with acute and chronic renal insufficiency. TI-CE remains the standard high dose regimen for salvage treatment of GCT at MSKCC. Clinical trial information: NCT00423852.

4536


Stomach cancer risk following radiotherapy for testicular cancer. Presenting Author: Lindsay M Morton, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, MD Background: Testicular cancer (TC) is a highly curable malignancy occurring most commonly among men aged 15-34 years. Survivors are at increased risk for adverse late effects of therapy. Previous studies have reported more than 4-fold risks of stomach cancer after TC, although the potential role of radiotherapy and chemotherapy for TC in these associations is unclear. Methods: We evaluated stomach cancer risk in an international cohort of 23,982 men diagnosed with TC during 1959-1987. Using detailed radiotherapy records, doses to the stomach tumor location were estimated for 92 stomach cancer patients and 180 individually matched controls. Chemotherapy drugs and doses also were recorded. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. Results: Fifty-seven percent of patients with stomach cancer were diagnosed with TC before age 40 years, 65% had seminoma, 95% had stage I or II disease, and 37% were diagnosed with stomach cancer ⱖ20 years after TC diagnosis. Patients who received radiotherapy [87 (95%) cases, 151 (84%) controls] had a 5.9-fold (95%CI 1.6-21.3) increased risk of stomach cancer compared with patients who did not receive radiotherapy. Risk increased with increasing radiation dose to the stomach (P-trend⬍0.001), with ORs of 3.6 (95%CI 1.3-10.6), 4.4 (1.2-16.4) and 13.3 (2.5-70.0) after 20-39.9 Gy, 40-49.9 Gy, and ⱖ50 Gy radiation to the stomach, respectively, compared with ⬍10 Gy. Radiation-related stomach cancer risk did not vary by calendar year of treatment, age at exposure, or TC histology. The OR for having received any chemotherapy was 1.3 (14 cases, 23 controls, 95% CI 0.6-2.8). Stomach cancer risk was not significantly elevated among patients given cisplatin-based chemotherapy (7 cases, 10 controls, OR⫽1.7, 95% CI 0.6-5.1). Conclusions: Patients administered radiotherapy for TC in the past are at increased risk of developing stomach cancer, particularly those who received ⱖ20 Gy to the stomach. The study results warrant consideration in radiation risk assessment and long-term follow-up. Future studies should further investigate a possible role for chemotherapy in stomach cancer risk.




Low-dose versus standard-dose gemcitabine infusion and cisplatin for patients with advanced bladder cancer: A randomized phase II trial: An update. Presenting Author: Rasha Mohamed Haggag, Department of Medical Oncology and Hematology, Faculty of Medicine, Zagazig University, Zagazig, Egypt Background: Bladder carcinoma is still one of the foremost oncologic problems in Egypt. In previous single-arm and double-arm phase II studies, prolonged infusion of low dose gemcitabine and cisplatin proved to be an effective treatment for such patients with advanced disease. Methods: To compare efficacy and safety of both prolonged infusion and standard gemcitabine-cisplatin combination, we updated the data and duplicated the number of patients of our previously published phase II randomized study to 120 untreated patients with stage III/IV bladder cancer. Patients were randomized to receive either gemcitabine (250 mg/m2) 6-hour infusion on days 1 and 8, and cisplatin (70 mg/ m2) on day 2 every 21-day cycle (Arm1) or gemcitabine (1,250 mg/ m2) 30-min infusion on days 1 and 8, and cisplatin (70 mg/ m2) on day 2 every 21-day cycle (Arm 2). Results: The 92 males and 28 females had a median age of 62 years (range 40-85 years). A total of 87 patients had transitional cell, 28 had squamous cell, and 5 had undifferentiated cell carcinoma. Among the 105 evaluable patients (52patients in arm1 and 53patients in arm 2), complete response rate was achieved in 13.5% (7/52 patients of arm 1) and 5.7% (3/53 patients of arm 2). Eighteen patients in arm 1 (34.6%) and 17 patients (32.1%) in arm 2 had partial response on therapy. Thus the overall response rate of patients in arm1 and arm 2 was 48% (25/52 patients) and 37.7% (20/53patients), respectively (p ⫽ 0.26). No significant difference in median time to disease progression (26 months versus 24 months, p ⫽0.4), median survival (12 months versus 16 months, p ⫽0.8), and 1-year survival (49.9 % versus 54.7%, p ⫽ 0.8) was detected between arms 1 and 2, respectively. No treatment- related deaths occurred. Main hematologic and nonhematologic toxicities were similar in both arms with no statistically significant differences. Conclusions: In the treatment of advanced bladder cancer, gemcitabine in low dose and prolonged infusion in combination with cisplatin is not inferior to high-dose short infusion gemcitabine and cisplatin in terms of overall survival, time to disease progression, and response rates with favorable toxicity profile and less financial costs.

4539


Impact of response to prior chemotherapy (RTPC) on outcomes in secondline therapy for advanced urothelial carcinoma (UC): Implications for trial design. Presenting Author: Gregory Russell Pond, McMaster University, Hamilton, ON, Canada Background: Performance status (PS), hemoglobin (Hb), liver metastasis (LM), and time from prior chemotherapy (TFPC) are significant prognostic factors in second-line therapy for advanced UC. Setting of prior chemotherapy, i.e., metastatic or perioperative, has not appeared significant. However, the impact of prior chemosensitivity is unclear, which may confound trial interpretation. Hence, we examined the prognostic impact of RTPC, when prior therapy was given for metastatic disease. Methods: Six phase II trials evaluating second-line chemotherapy and/or biologics (n⫽504) were pooled. Patients who received prior therapy for metastatic disease were eligible for analysis if data regarding Hb, LM, PS, and TFPC were available. Response by RECIST to first-line therapy was recorded. Progression-Free Survival (PFS) and overall survival (OS) were calculated from the date of registration using the Kaplan-Meier method. Results: 275 pts were evaluable for analysis. Patients received gemcitabine-paclitaxel, cyclophosphamide-paclitaxel, pazopanib, docetaxel plus vandetanib/ placebo or vinflunine (2 trials). Those with prior response (n⫽111) had a median (95% CI) OS of 8.0 (6.8-9.4) months (mo) and PFS of 3.0 (2.6-4.0), compared with OS and PFS of 5.9 (5.0-6.6) mo and 2.6 (2.0-2.8) for those without prior response (n⫽164). Multivariable analysis did not reveal an independent impact of RTPC on PFS or OS (Table). Conclusions: RTPC in patients receiving prior chemotherapy for metastatic disease did not confer an independent prognostic impact with second-line therapy for advanced UC. Patients who received prior chemotherapy in peri-operative or metastatic settings may be enrolled in the same secondline trial stratified for PS, anemia, LM and TFPC. Progression-free survival

Liver disease ECOG PS Anemia >3 months from chemo Prior response (yes/no)

Overall survival


P value


P value

1.46 (1.09-1.95) 1.23 (0.93-1.61) 1.48 (1.03-2.11) 0.79 (0.59-1.05) 1.05 (0.78-1.42)

0.012 0.14 0.032 0.11 0.73

1.33 (0.98-1.81) 1.73 (1.29-2.32) 1.65 (1.15-2.38) 0.75 (0.55-1.03) 0.77 (0.56-1.05)

0.068 ⬍0.001 0.007 0.078 0.099

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A STAT3- and p63-dependent transcriptional network to define a lethal basal subset of human bladder cancers. Presenting Author: Colin P.N. Dinney, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Muscle-invasive bladder cancers (MIBCs) are a heterogeneous group of tumors that display widely variable clinical outcomes and responses to conventional chemotherapy. Methods: We used whole genome mRNA expression profiling and unsupervised hierarchical cluster analyses on a cohort of 73 flash frozen primary tumors to identify 3 distinct subsets of muscle-invasive bladder cancer (MIBC). We confirmed the existence of these 3 subsets in a second cohort of 57 formalin-fixed, paraffin-embedded (FFPE) MIBCs and in 2 other public datasets. Analysis of primary tumors and mechanistic studies in human bladder cancer cell lines identified tumors that respond to FGFR inhibitors or chemotherapy. Results: The first subset was driven by an active ⬙basal⬙ EGFR-STAT3-p63 transcriptional network, and was associated with poor clinical outcomes. High miR-200c expression stratified the survival of these basal tumors. The second subset was characterized by active p53 pathway activation, and tumors and cell lines with these features were resistant to cis-platinum based chemotherapy. The third subset expressed ⬙luminal⬙ markers and active estrogen receptor (ER) and PPAR␥ signaling, and luminal cell lines were sensitive to fibroblast growth factor receptor (FGFR) inhibition. Conclusions: Molecular subtyping of MIBCs can be used to identify lethal cancers and enrich for tumors that will respond to FGFR inhibitors or conventional chemotherapy.

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Introduction of a tobacco-screening initiative for those at risk for bladder cancer in a high volume urology clinic. Presenting Author: Jeffrey C. Bassett, Vanderbilt University Medical Center, Nashville, TN Background: Tobacco use is causal or contributory in 50% of bladder cancer diagnoses. Continued use after diagnosis may negatively impact recurrence, progression, and mortality. Despite its relevance, tobacco screening was infrequently occurring in a regional urology clinic. We hypothesized that the clinic was fertile ground for a tobacco-screening initiative given the number of referrals for bladder cancer, hematuria, and other tobaccorelated urologic conditions. Methods: An EMR-based tobacco-screening prompt was designed using the same informatics architecture and clinical reporting system used in primary care. The prompt was introduced for all new patient encounters beginning January 2010. We prospectively collected the proportion of patients asked about tobacco use, advised to quit, and assisted with smoking cessation. Results: For the two years ending December 2011, 4,617 patients were seen in urologic consultation; 31% (n ⫽ 1,444) were referred for tobacco-related urologic diagnoses, 36% (n ⫽ 518) of whom were referred for bladder cancer or hematuria. The tobacco-screening prompt was used 57% (n ⫽ 2,626) of the time. Attending physicians utilized the template in 17% of their encounters, resident physicians in 71%, and nurse practitioners in 97% (p ⬍ 0.001). 49% (n ⫽ 255) of those referred for bladder cancer or hematuria were screened for tobacco use. Active smokers comprised 21% (n ⫽ 558) of screened patients. Relative to former and never smokers, active smokers were more likely referred for bladder cancer or hematuria (p ⫽ 0.005). 40% (n ⫽ 225) of active smokers desired to quit. Those counseled by an attending physician were more likely ready to quit and trended toward a more intensive cessation program (p ⫽ 0.004 and p ⫽ 0.07, respectively). Conclusions: Our data suggest that urology clinics may be important sites for tobacco-screening initiatives, particularly for those with tobacco-related urologic diagnoses. Screening patients referred for bladder cancer or hematuria is likely high yield due to the increased proportion of active smokers. Given the disparate utilization of the prompt, identification of provider-level facilitators and barriers to tobacco screening is worthy of study.


294s 4541

Genitourinary (Nonprostate) Cancer General Poster Session (Board #26B), Mon, 8:00 AM-11:45 AM

Expression of PD-L1 in primary urothelial carcinoma (UC). Presenting Author: Jingsong Zhang, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL

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Development of a genomic-clinical classifier for predicting progression after radical cystectomy in patients with muscle invasive bladder cancer. Presenting Author: Anirban Pradip Mitra, University of Southern California, Los Angeles, CA

Background: Engagement of programmed cell death-1 (PD-1), expressed on CD8⫹ T cells, with it ligand PD-L1(B7H1), expressed on tumor cells, results in T cell suppression and tumor protection. Antibodies against PD-1 or PD-L1 have reported impressive anti-tumor activities in phase I/II trials and are being tested in the phase 3 setting. Exploratory analysis indicated that expression of PD-L1 could be a predictive marker for response. Of note, urothelial carcinoma (UC) was not included in the early phase anti-PD1 or anti-PD-L1 studies. To explore anti-PD-L1 as a new treatment for this lethal disease, we assessed PD-L1 expression in UC. Methods: The relative mRNA abundance of PD-L1 mRNA in UC was studied in the Oncomine Bittner Multi-cancer dataset, which included a total of 1911 tumor samples. PD-L1 immunohistochemistry (IHC) was performed with rabbit monoclonal antibody against human PD-L1 on tissue microarrays with 83 formalin fixed paraffin embedded T1, T2 and T3 UC. IHC slides were reviewed by a genitourinary pathologist. A positive staining is defined when ⱖ 5% of cancer cells had positive PD-L1 membrane and/or cytoplasmic staining. The IHC slides were scanned with the Aperio ScanScope XT and the immunopositivity of PD-L1 was quantitatively scored using commercial algorithms from the Aperio Toolbox and TissueStudio. The 1⫹, 2⫹, and 3⫹ score of each core was based on the dominant IHC staining intensity. Results: In the Bittner multi-cancer dataset, the log2 median mRNA intensities of PD-L1 in prostate cancer, clear cell renal cell carcinoma, colon cancer, UC of the bladder, ureter and squamous cell carcinoma of the bladder were 0.245, 0.528, 0.61, 0.81, 0.802, and 1.202 respectively. The overall PD-L1 IHC staining positivity was 45% in 83 primary UC samples. All six 3⫹ PD-L1 staining cores were grade 3 urothelial carcinomas and each core had more than 60% of cancer cells with 3⫹ PD-L1 membrane staining. Grade 3 cores also had the highest percentage of 2⫹ and 3⫹ PD-L1 positivity. No association was observed between T staging and PD-L1 staining intensity. Conclusions: PD-L1 is expressed in primary UC. We have obtained additional UC samples to correlate its expression with survival and its expression pattern with the pattern of tumor infiltrating lymphocytes.

Background: The mainstay of muscle-invasive bladder cancer treatment is surgical resection with/without multi-agent chemotherapy. Management decisions are based on a small number of clinical and pathologic parameters with poor prognostic and predictive power. There is an urgent need for enhanced biomarkers to guide therapy of this lethal disease. Here we have developed a genomic signature of bladder cancer progression using whole transcriptome profiling technology. Methods: 251 FFPE bladder cancer specimens were obtained from patients undergoing radical cystectomy at the University of Southern California (1998-2004). All patients had pT2-T4a,N0 urothelial carcinoma in the absence of pre-operative chemotherapy. Median follow-up was 5 years. RNA expression levels were measured with 1.4 million feature oligonucleotide microarrays. Patients were divided into a training set (2/3 of cohort) to develop a genomic classifier for risk of progression (defined as any type of bladder cancer recurrence), and a validation set (1/3 of cohort). In parallel, multivariable analysis was used to develop a clinical classifier using typical clinical and pathologic variables. Finally, a genomic-clinical classifier was built combining the genomic classifier with clinical variables using logistic regression. The receiver-operator characteristic (ROC) area under the curve (AUC) metric was used to evaluate each classifier in the validation set. Results: The genomic classifier consisted of 89 features corresponding to 80 genes that were combined in a k-nearest neighbor model (KNN89). KNN89 showed an AUC of 0.77 in ROC analysis on the validation set. The best clinical classifier showed an AUC of 0.72. The genomic-clinical classifier demonstrated an AUC of 0.81. Multivariable analysis incorporating all clinical parameters and KNN89 further revealed that KNN89 was the only significant predictor of bladder cancer progression (p⫽0.0077). Conclusions: We have developed a combined genomic-clinical classifier that shows improved performance over clinical models alone for prediction of progression after radical cystectomy. External validation of this classifier is ongoing.

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Preclinical and correlative studies of cabozantinib (XL184) in urothelial cancer (UC). Presenting Author: Andrea Borghese Apolo, National Cancer Institute, Bethesda, MD Background: Mounting evidence supports Met as a therapeutic target in urothelial cancer (UC). Activated Met can promote angiogenesis and tumor growth by upregulating VEGF and may play a role in UC pathogenesis. Cabozantinib inhibits VEGFR2 and Met pathways. In this study, we assessed shed Met (sMet) levels in the urine and serum of UC patients (pts) and cabozantinib’s effects on HGF-driven UC cell growth and invasion. Methods: sMet levels in serum and urine samples from 31 pts with UC (23 metastatic, 8 muscle-invasive) were correlated with stage, presence of visceral metastases and urinary source. The effects of cabozantinib on 4 human UC-derived cell lines were studied in vitro. Intact RT4, TCC-SUP, T24M2 and T24M3 cells at 80% confluence were serum deprived 16 h, then left untreated or treated with hepatocyte growth factor (HGF) and/or cabozantinib prior to analysis of Met, phospho- (p)Met, pAkt, Akt, pMAPK and MAPK by immunoassay or immunoblotting. Cabozantinib effects on basal and HGF-induced UC cell invasion, proliferation and soft agar growth were measured. Results: Median serum Met levels were modestly higher in pts with metastatic versus muscle-invasive disease. Urinary Met levels were clearly higher in pts with visceral metastasis (P⫽0.0111) and in urine from ileal conduits and neobladders compared to normally voided urine, regardless of stage (P⫽0.0489). Met content in UC cell lines was low in RT4 and higher in T24M2, T24M3 and TCC-SUP. Basal pMet content was universally low, increased significantly by HGF and this was reversed by cabozantinib. HGF-driven increases in pAkt/Akt and pMAPK/MAPK in all 4 cell lines were reversed by cabozantinib, as were HGF-enhanced UC cell invasion, proliferation and anchorage independent growth. Conclusions: Median urinary sMet is significantly higher in pts with visceral metastasis and in specimens from ileal conduits and neobladders relative to normally voided urine. UC cell Met content in culture increased with disease grade; HGF stimulated activation of Met and known effectors, and enhanced invasion, growth rate and anchorage-independent growth; cabozantinib effectively reversed these HGF-driven effects. These data support evaluation of cabozantinib in pts with metastatic UC.


Does chemotherapy improve survival in muscle-invasive bladder cancer (MIBC)? A systematic review and meta-analysis (MA) of randomized controlled trials (RCT). Presenting Author: Angelina Tjokrowidjaja, Sydney Medical School, University of Sydney, Sydney, Australia Background: There is strong evidence that neoadjuvant chemotherapy improves survival in MIBC but its uptake in clinical practice is variable. The benefits of adjuvant chemotherapy are controversial, especially with the recent presentation of 3 RCTs not included in previous MA.We sought to summarise the effects of chemotherapy, both neoadjuvant and adjuvant, on survival in MIBC. Methods: We included published summary data from recent MA and RCTs. Eligible RCTs compared the addition of chemotherapy, neoadjuvant or adjuvant, to local treatment versus local treatment alone. We searched CENTRAL, PubMed, MEDLINE, proceedings of ASCO and clinicaltrials.gov from 2004 to August 2012.The primary outcome was overall survival (OS). Disease-free survival (DFS) and adverse events (AE) were secondary outcomes. Pooled hazard ratios (HR), confidence intervals (CI) and p-values (p) were estimated with fixed effects model. Heterogeneity and subgroup effects were assessed with p-values for interaction. Results: We included 21 RCTs (n⫽3986), 12 of neoadjuvant (n⫽3047) and 9 adjuvant chemotherapy (n⫽939).The addition of chemotherapy significantly improved OS (HR 0.86, 95% CI 0.79 to 0.93, p⫽0.0004). Separate analyses of neoadjuvant therapy and adjuvant therapy yielded significant results in both subgroups (HR 0.89, 95% CI 0.81 to 0.98, p⫽0.02; HR 0.75, 95% CI 0.63 to 0.90, p⫽0.002; respectively; p-value for interaction 0.11). There were larger benefits in DFS (HR 0.77, 95% CI 0.71 to 0.84, p⬍0.000001), which were also noted with the addition of neoadjuvant and adjuvant therapy (HR 0.80 95% CI 0.73 to 0.88, p⬍0.00001; HR 0.67 95% CI 0.55 to 0.81, p⬍0.0001; respectively; p-value for interaction 0.10). The most common AE of grade 3 or 4 were haematological, gastrointestinal and renal impairment with median frequencies of 33%, 15% and 2% respectively in neoadjuvant; and 15%, 21% and 27% in adjuvant trials. Conclusions: Meta-analysis of available randomized trials indicates that chemotherapy, both adjuvant and neoadjuvant, improves survival in MIBC. A direct comparison of these two strategies in a large scale randomised trial is needed to determine which is optimal.




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Investigation of a novel irreversible pan-HER inhibitor combined with chemotherapy in bladder cancer models. Presenting Author: Petros Grivas, University of Michigan, Ann Arbor, MI

Association between pioglitazone (PZD) therapy and bladder cancer (BC): A meta-analysis of epidemiologic evidence. Presenting Author: Alexei Shimanovsky, University of Connecticut, Farmington, CT

Background: Human Epidermal Receptors (HER) play an important role in bladder cancer (BCa) progression and may mediate chemotherapy resistance. Dacomitinib (Dac) is a novel, potent, irreversible pan-HER inhibitor with activity in several solid tumors, currently in phase III trials in NSCLC. We showed that Dac has single agent anti-tumor activity in human BCa models in vitro and in vivo, inducing apoptosis and G1 arrest. We hypothesized that Dac has additive effects with Gemcitabine (G) and Cisplatin (C) in BCa xenografts. Methods: UM-UC-6 (UC6) or UM-UC-9 (UC9) xenografts were established in age-matched NOD/SCID mice. A week after injection, mice had small tumors, were randomized and treated with i. G 50mg/kg ⫹ C 2mg/kg via 3 weekly intra-peritoneal injections (IPI) ⫹ daily p.o. buffer for 3 weeks; ii. Dac 6mg/kg p.o. daily for 3 weeks ⫹ 3 weekly IPI (saline); iii. GC (same dose/schedule) ⫹ Dac starting 1 day after GC (based on cell cycle effect and kinetics); iv. no treatment (control). Mice were monitored daily, weighed weekly, sacrificed at 4 weeks and tumors were weighed. 3 tumors/group were stained for EGFR, HER2, Ki67, E-cadherin, ALDH, p-EGFR, p-ERK, p-Akt. 3rd GC dose in UC6 model was given at 50% due to weight loss; all GC doses were given at 50% in UC9 model. Mann-Whitney test with multiple comparison adjustments was used for analysis. Results: Dac- and GC⫹Dac-treated mice had no significant weight loss. UC6 tumor weights were significantly lower in Dac and GC⫹Dac vs control (p⬍0.0001) or GC (p⬍0.0001), corresponding to decreased p-ERK %cell expression and staining intensity. GC and control had similar tumor weights (p⫽0.19). 5 Dac and 3 GC⫹Dac UC6-injected mice had no tumor at 4 weeks. UC9 tumor weights were significantly lower in Dac (p⫽0.002, 6x reduction) or GC (p⫽0.0006; 7x reduction) vs control. GC⫹Dac had significantly lower tumor weights vs GC (p⫽0.005), Dac (p⫽0.06) or control (p⬍0.0001; 17x reduction). Conclusions: Dac had dramatic singe-agent activity in UC6 xenograft that was GC-resistant. Dac⫹GC was superior to GC in UC9 xenograft, supporting clinical evaluation. Further investigation of Dac anti-tumor activity and predictive biomarker discovery in additional bladder cancer models is pursued.

Background: There is evidence suggesting that PZD use may be a risk factor for BC, yet these reports are controversial. The aim of this meta-analysis is to review available data and evaluate the association between PZD and BC. Methods: Two independent reviewers conducted a systematic search of the Cochrane Library, OvidSP and PubMed for articles published January 1970 to April 2012. MeSH search terms included PZD, Actos, thiazolidinediones, diabetes mellitus (DM), and BC. Only studies reporting an effect measure for the association between PZD and BC were included. Subgroup analyses by study design and country were performed. Analysis was done using a random effect model after a preliminary review showed evidence of study heterogeneity. This was then assessed using the Cochrane’s Q and I2 statistics. Publication bias was evaluated using the Begg’s and Egger’s tests, and funnel plots. All analyses were performed using REVMAN 5.1. Results: A total of 6 studies (3 cohort and 3 case control) met the inclusion criteria. The overall pooled risk ratio (RR) for the association between PZD and BC was 1.12 (95% CI 1.09, 1.15; P ⬍0.001). The summary RR for cohort and case control studies were 1.13(95% CI 1.07, 1.19; P ⬍0.001) and 1.11(95% CI 1.07, 1.15; P ⬍0.001), respectively. The subgroup analysis showed a significant association with BC in the USA and Europe, but not in Asia (RR 0.98, 95% CI 0.71, 1.34; P ⫽ 0.88). The association of PZD and BC was more sensitive for treatment duration (⬎12 month). Conclusions: Our study analyzed 1,214,071 patients, demonstrating a weak association between PZD and BC. The results were significant with increase in treatment duration, which corresponds to previous studies. This meta-analysis has limitations. Not all studies reported known variables associated with BC, such as smoking or occupational exposure. They did not address patient BMI, time from DM diagnosis or previous drug therapy. These parameters reflect severity of disease and level of insulin-resistance. Future studies should evaluate markers of insulin-resistance with PZD use and correlate with BC. Understanding the link between PZD and BC in the context of DM may allow physicians to determine a more accurate risk of PZD use.

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Preliminary safety, product parameters, and immune response assessments from a phase II randomized, open-label trial of DN24-02, an autologous cellular immunotherapy (ACI), in patients (pts) with surgically resected HER2ⴙ urothelial cancer (UC) at high risk for recurrence. Presenting Author: Dean F. Bajorin, Memorial Sloan-Kettering Cancer Center, New York, NY Background: DN24-02 is a HER2-targeted ACI, consisting of antigen presenting cells (APC) cultured with BA7072, a recombinant HER2derived antigen (HER500) linked to GM-CSF; DN24-02 is based on the same manufacturing platform as sipuleucel-T, approved for asymptomatic/ minimally symptomatic metastatic castrate resistant prostate cancer. NeuACT (N10E1; NCT01353222) is an open-label, randomized phase 2 trial comparing adjuvant DN24E02 to surveillance in HER2⫹ UC pts at high risk of relapse following cystectomy or nephroureterectomy. The primary endpoint is overall survival. Here we report preliminary evaluation of adverse events (AE), product potency, and immune response. Methods: Pts randomized to DN24-02 underwent leukapheresis followed by infusion of DN24-02 (total of 3 infusions with 2 wk intervals). AEs were assessed at each visit. Product potency was assessed for each infusion by measuring CD54 upregulation on APCs, a marker of APC activation. Antigen-specific immune responses were evaluated by ELISA to HER500 and BA7072. Results: As of November 2012, 13 pts had received ⱖ1 DN24-02 infusion. The most commonly reported AEs within 1 day after DN24-02 infusion were mild–moderate chills (54%), nausea (31%) and fatigue (23%). Ten pts completed all DN24-02 infusions and were assessed for product potency. Increased median APC activation at infusions 2 and 3 compared with infusion 1 was indicative of an immunological prime-boost effect; this effect was also seen in the 7/10 pts with prior neoadjuvant chemotherapy. Median anti-BA7072 and anti-HER500 titers (IgM) were 128- and 256-fold higher at week 6 vs baseline, respectively. The emergence of IgG indicated a memory antibody phenotype. Conclusions: Preliminary data indicate that DN24-02 product potency (CD54 upregulation) is comparable to sipuleucel-T. DN24-02 appears to be well tolerated in UC. Favorable immune responses were observed, including in pts with prior neoadjuvant chemotherapy. Updated results, including preliminary T-cell immune response data, will be presented. Clinical trial information: NCT01353222.


A novel phase I trial design featuring a two-dimensional dose-finding algorithm optimizing the dose of gemcitabine and doxorubicin with bortezomib in metastatic urothelial carcinoma (UC). Presenting Author: Arlene O. Siefker-Radtke, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Preclinical studies suggested that bortezomib (B) enhanced the activity of gemcitabine and doxorubicin (GA) in UC; thus we sought to define possible combinations of bortezomib with this doublet. We employed a novel phase I trial design systematically exploring doses in 2 dimensions. The method estimates an isotoxic curve allowing not only a combination with approximately equal (with respect to single component MTD) contributions of the two components to be found, but also combinations emphasizing one component or the other. Methods: Since 11/06, 74 patients with previously treated metastatic cancer were enrolled (70 UC, 3 prostate, 1 renal). GA was treated as a single component and given in a fixed ratio to a maximum of 900 and 50 mg/m2, and B to a maximal dose of 1.6 mg/m2 IV, with dosing every 14 days. After determining the MTD along the diagonal, we then decreased the dose of B, increasing GA, and vice versa, exploring doses along an isotoxic curve aiming for ⱕ 30% dose limiting toxicity (DLT) in cycle 1. The objective response rate (ORR) includes PR or CR, and excludes SD. Results: The MTD along the diagonal for GAB was 756, 42, and 1.4 mg/m2, respectively. Doses maximizing the GA (900, 50) required reduction of B to 1.2 mg/m2. Likewise, doses maximizing B (1.6) required reduction of GA to 559 and 33 mg/m2. The most common DLT were thrombocytopenia 14%, neutropenic fever 5%, and mucositis 1%. There was minimal activity at the on-diagonal MTD with an ORR 1/10. Of the tolerable doses along the isotoxic curve, the greatest activity was seen when maximizing B (1.5-1.6 mg/m2, ORR 7/12 (58%)). The ORR when maximizing GA was 4/10. The most frequent ⱖ G3 toxicities include: thrombocytopenia (26%), neutropenia (26%), anemia (24%), fatigue (8%), and neutropenic fever or infection (12%). Treatment was tolerable in poor renal function; 36 patients (49%) had a GFR ⬍ 50 ml/min. Conclusions: The combination of GAB has promising activity at doses maximizing proteosome inhibition, despite relatively low doses of GA. Traditional phase 1 design dosing to the MTD ⬙along the diagonal⬙ would have lead to the incorrect conclusion that there was minimal activity. Clinical trial information: NCT00479128.


296s 4549

Genitourinary (Nonprostate) Cancer General Poster Session (Board #29A), Mon, 8:00 AM-11:45 AM

4550


Investigating serum ␤-HCG as an independent prognostic factor in patients (pts) receiving chemotherapy (Ct) for transitional cell carcinoma (TCC) of the urothelial tract. Presenting Author: Simon J. Crabb, University of Southampton, Faculty of Medicine, Southampton, United Kingdom

Phase I/II study of biweekly pemetrexed plus cisplatin in patients with locally advanced, nonresectable or metastatic urothelial cancer: Safety and efficacy results from phase II. Presenting Author: Ana Lopez Martin, Hospital Universitario Severo Ochoa, Madrid, Spain

Background: Serum human chorionic gonadotrophin ␤ subunit (␤-HCG) has prognostic value in TCC but has not been investigated in pts receiving Ct for this disease. Furthermore prior studies lacked statistical power to test independence from other prognostic variables. Methods: A single institution retrospective clinical database was constructed of pts receiving Ct between 2005 and 2011 for cancer of the urothelial tract. Eligible pts had pure or a component of TCC. Prognostic variables were tested by univariate Kaplan Meier analyses. Statistically significant variables were then assessed by multivariate cox regression analysis. A prospectively defined ␤-HCG cutpoint of ⬍ versus ⱖ 2 iu/L, either prior to (␤-HCGp), or on completion of (␤-HCGc) Ct was used. Results: 235 pts were eligible (72% male, 55% ⱕ70 years, 83% bladder primary). Initial Ct was perioperative (CtPeri) in 46% (7% adjuvant, 39% neoadjuvant). 63% had first line palliative Ct for metastatic disease (CtMet). For CtPeri, ECOG performance status (PS), haemoglobin (Hb), CtPeri regimen and T stage were statistically significant prognostic factors in univariate analyses for overall survival (OS), as were ␤-HCGp (median OS (mOS) 8.50 v. 1.86 years, p⬍0.001) and ␤-HCGc (mOS 4.27 v. 0.66 years, p⫽0.003). ␤-HCGp and ␤-HCGc after CtPeri were also prognostic for relapse free survival and in multivariable analysis remained statistically significant as a prognostic factor for OS (␤-HCGp: hazard ratio (HR) 3.13, p⫽0.001; ␤-HCGc: HR 4.26, p⫽0.007). In pts treated with CtMet, PS, alkaline phosphatase, prior CtPeri, visceral metastases, CtMet regimen and ␤-HCGc (mOS 1.70 v. 1.07 years, p⫽0.005) were prognostic in univariate analyses for OS. ␤-HCGc after CtMet was also prognostic for progression free survival and in multivariable analysis remained statistically significant as a prognostic factor for OS (HR 3.47, p⬍0.001). Conclusions: ␤-HCG, and specifically its post-Ct level, is an independent prognostic factor for TCC treated with Ct in both curative and palliative settings. Prospective evaluation is warranted for incorporation into treatment selection strategies.

Background: Pemetrexed (P) plus cisplatin (C) combination is effective against several malignant tumors. Single-agent P has shown antitumor activity in advanced urothelial cancer; we performed a phase I/II study to define the maximum tolerated dose of biweekly P plus C combination. Here, we report the final results of the phase II study. Methods: Eligible patients (pts) had locally advanced or metastatic transitional cell carcinoma of the urothelium not suitable for curative therapy, performance status (PS) 0-2, estimated life expectancy of at least 12 weeks, and adequate organ function. P and C were administered on days 1 and 15 of each 28-day cycle, up to a maximum of 6 cycles. Pts received the recommended dose from phase I, with P at 400 mg/m2 plus C at 50 mg/m2 (folic acid and vitamin B12 supplementation were also administered). Primary objective was overall response rate (ORR) according to RECIST 1.0. Results: Thirty-eight pts were recruited, 32 (84.2%) pts had bladder cancer with a mean diagnosis time of 1 (range 0-7) year and 30 (78.9%) had metastatic disease; 19 (50%) pts had visceral metastasis and 2 (5.3%) pts had a PS 2. Only 2 pts did receive adjuvant systemic therapy. Median number of cycles was 3 (range 0-7). Twelve (31.6%) pts discontinued the study treatment due to toxicity. The most common treatmentrelated AEs (⬎ 20%) were asthenia (n⫽27 pts), nausea and vomiting (n⫽21, respectively), diarrhea (n⫽18), anorexia (n⫽17), mucosal inflammation (n⫽14), and constipation (n⫽8). Most treatment-related AEs were of mild or moderate severity. Neutropenia (n⫽5) and asthenia (n⫽3) were the most frequent Grade 3 or 4 treatment-related AEs. Serious related AEs were observed in 8 (21.1%) pts. ORR was 39.5% (95% CI 24.0-56.6): 2 (5.3%) pts achieved complete response and 13 (34.2%) pts, partial response. Median progression free survival was 6.7 months, and median overall survival was 10.5 months. Conclusions: In this study, biweekly P (400 mg/m2) plus C (50 mg/m2) combination showed anti-tumor activity in pts with advanced urothelial cancer, with an acceptable safety profile. Clinical trial information: NCT00374868.

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Patterns of chemotherapy and survival in elderly patients with advanced bladder cancer: A large Medicare database study. Presenting Author: Guoqing J. Chen, Michael E. DeBakey VA Medical Center/Baylor College of Medicine, Houston, TX

The impact of clinically significant discrepancies from primary pathological review of transurethral bladder resection specimens upon repeat review at a tertiary care center. Presenting Author: Lamont J. Barlow, Department of Urology, Columbia University Medical Center, New York, NY

Background: The frequency of employment of cisplatin-based chemotherapy in elderly patients (ⱖ66 years) presenting with advanced (unresectable or metastatic) bladder cancer is unclear. We examined the use of and overall survival (OS) with chemotherapy regimens employed in elderly patients with newly diagnosed advanced bladder cancer (ABC). Methods: SEER-Medicare linked data were used to identify incident ABC patients presenting with the following stages of bladder cancer: T4bN0M0; Any TN1–N3M0; Any T, Any N, M1 between 2004 and 2007, with claims data until 2009. Outpatient and inpatient Medicare claims data were queried for receipt and type of chemotherapy used. The descriptive analyses were performed to examine associations between chemotherapy regimen, clinical characteristics and OS. Results: A total of 1,031 patients with ABC met inclusion criteria. The median age was 74 years, 69.8% were men. 4.6% (n⫽47) were T4bN0M0, 55.3% (n⫽570) were anyT,N1-3M0 and 40.1% (n⫽414) were any T, any N, M1. Overall, 20.5% (n⫽211) received cisplatin, 26.1% (n⫽269) received carboplatin, 5% (n⫽52) received no platinum and 48.4% (n⫽499) received no chemotherapy. There were no differences in regimen according to gender, race, stage and age. The median OS for cisplatin, carboplatin, no platinum and no chemotherapy groups were 1.67, 1.41, 1.5 and 1.41 years, respectively (F⫽5.36, p⬍0.001). Patients with Any TN1–N3M0; Any T, Any N, M1 receiving cisplatin had better OS compared to carboplatin. T4bN0M0 patients receiving carboplatin exhibited better OS relative to those receiving cisplatin, but this finding is limited by the small number of patients. Conclusions: Among patients presenting with ABC in the Medicare database aged ⱖ66 years, only 20.5% received cisplatin and 48.4% received no chemotherapy. Those with distant and nodal metastasis displayed better OS with cisplatin. Further analysis will control for baseline prognostic factors and comorbidities. Drug development in the ABC population, especially the elderly, should focus on chemotherapy-ineligible and cisplatin-ineligible patients.

Background: Internal review of outside pathology slides is a common practice among urologic oncologists at tertiary care facilities, and discrepancies have a potential to directly affect the choice of treatment. While repeat prostate biopsy review has been extensively studied, there is little data available on the impact of repeat reviews of bladder biopsies. The purpose of the current study is to perform a standardized comparison of original and internal pathology reviews of identical bladder specimens to characterize the impact of repeat review on treatment decisions. Methods: Using the Columbia Urologic Oncology Database, a retrospective analysis of 91 consecutive patients who underwent bladder resections at outside institutions from 2008-2012 with secondary referral to a single urologist and internal review at our institution was conducted. Characteristics of both original pathology reports and internal reviews were collected and compared by blinded reviewers. A discrepancy in one of the following characteristics was considered treatment-altering: presence of muscularis in specimen or tumor involvement in muscularis. Additional clinicallysignificant discrepancies including presence of secondary histology, carcinoma in situ, lymphovascular invasion, micropapillary features, tumor stage, and overall accumulative discrepancy rate were also analyzed. Results: Median time from original procedure to internal review was 34 days (range: 9-368). 56/91 (62%) patients had at least one of the predefined clinically-significant discrepancies. 27/91 (30%) patients had at least one treatment-altering discrepancy, including 25 with discrepant muscle in specimen and 11 with discrepant muscle invasion. Regarding tumor stage, 8 patients were upstaged, 71 were unchanged, and 12 were downstaged on internal review. Conclusions: Repeat pathologic review of primary bladder specimens at a tertiary care center has the potential to alter clinical care for the majority of patients. Further studies are needed to determine if these discrepancies and the decisions they influence have a significant impact on patient outcomes.




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One course of adjuvant BEP in clinical stage I, nonseminoma: Mature and expanded results from the SWENOTECA group. Presenting Author: Torgrim Tandstad, Department of Oncology, St. Olavs University Hospital, Trondheim, Norway

Aggressive surgical management of germ cell tumors with somatic-type malignancy: Pathologic features, prognostic factors, and survival outcomes. Presenting Author: Kevin R Rice, Indiana University Department of Urology and Simon Cancer Center, Indianapolis, IN

Background: The SWENOTECA group has since 1998 offered patients with clinical stage I (CSI) nonseminoma (NSGCT) treatment based on a risk-adapted approach. Patients with lymphovascular invasion (VASC⫹) were recommended one course of adjuvant chemotherapy (ACT) with bleomycin, etoposide and cisplatin (BEP). Patients without lymphovascular invasion (VASC-) had the choice between one course of adjuvant BEP or active surveillance. Methods: From 1998-2010, 491 patients with CSI NSGCT received one course of adjuvant BEP. Following histopathological evaluation 247 patients were classified as VASC⫹, 239 as VASC- and five patients had uncertain VASC status. All patients were included into a prospective, community-based, multicenter SWENOTECA management program. Initial results from patients treated during 1998-2005 have earlier been reported. We now report the mature data, expanded with patients treated during 2005-2010. Results: The median follow-up was 8.0 years. Eleven relapses were observed. After one course of adjuvant BEP 2.3% of patients relapsed. In regard to VASC status 3.4% of VASC⫹ and 1.3% of VASC- patients relapsed. The latest relapse was detected 3.3 years after ACT. Ten patients have died, only one due to testicular cancer. The 5 and 10-year overall survival rates were 98.9% and 96.8%, respectively. The 5 and 10-year disease-specific survival rates were 100% and 99.6% respectively. Conclusions: One course of adjuvant BEP reduces the risk of relapse in CSI NSGCT with over 90%. These mature results confirm our earlier results on one course of adjuvant BEP. There is no evidence of late relapses, or chemotherapy-resistance in relapses following ACT. To detect relapses, a follow-up of five years is sufficient.

Background: Germ cell tumors (GCT) with somatic-type malignancy (SM) are rare occurring in approximately 3-8% of GCT cases. Prognostic factors and optimal management remain poorly-defined. Methods: The Indiana University (IU) testis cancer database was queried from 1979 to 2011 for patients demonstrating atypical histology at orchiectomy or subsequent resection of metastatic disease. Patients with transformation to PNET only were excluded due to distinct management. Chart review, pathologic review, and survival analysis were performed. Results: 122 patients met study inclusion criteria. Primary tumor site was testis in 112, retroperitoneum in 8, groin in 1, and pineal gland in 1. The most common SM histologies were sarcoma (71) and carcinoma (32). At GCT diagnosis, 24, 44, 45 patients had stage I, II, and III disease, respectively. Stage was unknown in 9. Median time from GCT diagnosis to SM was 13 months (Range, 0-397). This interval was longest for carcinomas (94.5 months) and sarcomatoid yolk sac tumors (113 months). Only 11 of 83 patients (13.3%) receiving cisplatin-based chemotherapy for measurable disease demonstrated an initial complete response. First resection at IU was reoperative in 45 patients (36.9%). 69 patients (56.6%) required extirpation of abdominal viscera/vascular structures or distant metastases. At a median follow-up of 71 months, the 5-year cancer specific survival (CSS) was 63%. Predictors of poorer CSS included SM diagnosed at late relapse (p ⫽ 0.014), referral to IU for reoperative RPLND (p ⫽ 0.022), and tumor grade (p ⫽ 0.043). SM histology subtype, stage, risk category, and number of resections for SM were not predictive of CSS. Conclusions: GCT with SM is associated with poorer CSS than traditional GCT. Established prognostic factors for GCT lose their predictive value in the setting of SM. SM can occur at any point in the course of GCT, but has a propensity for delayed presentation with later onset being associated with poorer CSS. Aggressive and serial surgical resections are often necessary to optimize CSS. Tumor grade is an important prognostic factor, particularly in sarcoma cases.

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Association between ERCC1 and XPA expression and polymorphisms and the response to cisplatin in patients with non-seminomatous testicular germ cell tumors. Presenting Author: Julia Mendoza, Instituto Nacional de Cancerología, Mexico City, Mexico

Expression profiling of peripheral blood (PB) enriched for circulating tumor cells (CTCs) in testicular germ cell tumors (TGCTs). Presenting Author: Michal Mego, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia

Background: Cisplatin-based chemotherapy cures over 80% of testicular germ cell tumors (TGCTs); nucleotide-excision repair (NER) modifies the sensitivity to cisplatin. In this work we explored the association between NER-proteins and their polymorphisms (SNPs) with cisplatin-sensitivity (CPS) and overall survival (OS) of patients with advanced non-seminomatous (ns)-TGCTs treated with bleomycin-etoposide-cisplatin (BEP). Methods: ERCC1, XPA-expression and gammaH2AX-presence, were tested in cisplatin-treated cancer cell lines. ERCC1 and XPA-expression were also analyzed in ns-TGCTs by qPCR. Immunohistochemistry was performed to detect ERCC1 protein in ns-TGCTs specimens. The SNPs were genotyped by PCR-RFLPs technique. Results: High basal ERCC1-expression was observed in non-CPS cancer cell lines; ERCC1-expression augmented further, as well as gammaH2AX, after cisplatin-treatment. Basal ERCC1 expression increases in the non-CPS patients in Mexican and Peruvian populations compared to CPS patients (p⬍0.001; p⫽0.002). XPAexpression levels weren’t different. These polymorphisms weren’t associated with CPS or OS. ERCC1-positive immunostaining was observed in 30/108 patients (27.8%). From 76 patients that were CPS, 59 (77.6%) were ERCC1-negative, compared with 17 (22.4%) that were ERCC1-positive (p⫽0.05). 5-year OS probability was smaller for those patients ERCC1positive and non-CPS (15.38%) than tumor ERCC1-negative and CPS (89.3%) (p⬍0.001). Using the Cox Model, adjusted on the prognosis groups, the hazard ratio (HR) of death in patients with ERCC1-negative and non-CPS was ⬎14.43 and in patients ERCC1-positive and non-CPS the HR was ⬎11.86 (p⬍0.001). Conclusions: High-levels of ERCC1-expression and ERCC1-protein are associated with non-CPS, suggesting the use of ERCC1 as a potential indicator of response to cisplatin-based chemotherapy and the prognosis in patients with ns-TGCTs. Moreover, it’s important to identify patients potentially non-CPS in order to diminish the toxicity of cisplatin and improved quality of life avoiding adverse effects due to this agent. Work supported by CONACYT 83959 and PAPIIT IN213311-3.

Background: CTCs are prognostic in several types of tumors and are easily accessible for repeat examination. TGCTs represent a model for the cure of cancer. Nonetheless, a small proportion of patients develop disease recurrence. We investigated expression profiling of PB enriched for CTCs in TGCTs aimed to identify expression signature associated with treatment resistance. Methods: This prospective study included 30 patients (pt) treated with first line (27 pt) or salvage (3 pt) chemotherapy. CD45peripheral mononuclear cells (PBMCs) were isolated from 10mL of PB on day 1 and on day 22 of first cycle of chemotherapy. Isolated PBMC were depleted of cells of hematopoietic origin (CD45⫹) using RossetteSep kit negative selection with anti-CD45 antibody. CD45-depleted PBMC represent compartment enriched for CTCs, as showed previously. RNA was extracted from CD45-PBMCs and the expression profiles were obtained using Roche NimbleGen microarrays. Data analysis was processed in R using a limma package followed by GO analysis and MetaCore pathway analysis. Results: Six patients achieved unfavorable response to chemotherapy (other than CR or PR with negative serum markers). We identified 1,506 and 211 genes that were expressed at significantly different levels (FDR⬍0.05) on day 1 and day 22 of chemotherapy, respectively, with 108 overlapping genes. Cluster analysis using principal component analysis showed, that 5 of 6 samples from patients with unfavourable response to chemotherapy form clearly defined cluster opposed to samples from patients with favourable response. Based on pretreatment expression profiling using MetaCore pathway analysis software, we further identified 758 genes, belonging to several critical functional groups such as immune response, signal transduction, cell proliferation, cell cycle progression, or apoptosis, to be significantly differentially expressed in patients with favourable vs. unfavourable response. Conclusions: Our data suggests that expression profiling of PB enriched for CTCs in TGCTs is feasible, and show great promise in identifying new therapeutic targets and gene expression signature associated with treatment resistance.


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A retrospective analysis of patients with poor-risk germ cell tumor (PRGCT) treated at Indiana University from 2000 to 2010. Presenting Author: Nabil Adra, Indiana University, Indianapolis, IN Background: PRGCT represents 14% of germ cell tumors, with 2-year PFS of 50%. PRGCT is defined by primary mediastinal non-seminomatous germ cell tumor (PMNSGCT), non-pulmonary visceral metastasis (NPVM), AFP ⬎ 10,000 or hCG ⬎ 50,000. This analysis attempts to identify subsets of patients with more or less favorable outcomes among the poor risk groups. Methods: Retrospective analysis of all patients with testicular cancer seen at Indiana University (IU) from 2000-2010. 291 patients with PRGCT identified of whom 79 received initial therapy at IU. We analyzed the following variables: primary site testis/retroperitoneal (T/RP) vs. PMNSGCT, pulmonary vs. NPVM, and the amplitude of serum tumor markers. We identified groups of patients according to the level of tumor marker elevation with cutoff points of AFP 20,000 and hCG 200,000. Results: Mean age 29, mean AFP 8,283, mean hCG 185,667. 24% had PMNSGCT, 48% NPVM, 11% AFP⬎20,000, and 25% hCG⬎200,000. When hCG was analyzed as a continuous variable, every 10,000 unit increase in hCG caused the hazard of progression to increase by 1% (p value 0.01). Patients with NPVM had significantly worse PFS. NPVM with elevated hCG had worse outcome than NPVM with normal hCG. This did not correlate as well with AFP. PFS was worse with NPVM than elevated pre-chemotherapy tumor markers. Multiple different criteria for poor risk disease carried significantly worse impact on PFS and OS when compared to having a single criterion for poor risk disease. Conclusions: Our data indicate that patients with NPVM or more than one criteria for PRGCT have a worse outcome compared to other PRGCT subgroups. AFP < 20,000 vs AFP > 20,000 hCG < 200,000 vs hCG > 200,000 No NPVM vs NPVM PMNSGCT vs T/RP No NPVM with AFP20,000 NPVM with hCG200,000 Single criterion vsMultiple criteria for poor-risk disease

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2 y PFS

5 y PFS

5 y OS

P value

61% vs 57% 63% vs 52% 65% vs 54% 67% vs 58% 68% vs 50%

56% vs 57% 57% vs 52% 61% vs 50% 59% vs 55% 63% vs 50%

79% vs 83% 80% vs 79% 83% vs 75% 66% vs 84% 85% vs 75%

PFS 0.98; OS 0.80 PFS 0.28; OS 0.50 PFS 0.05; OS 0.18 PFS 0.36; OS 0.34 PFS 0.17; OS 0.49

62% vs 39%

55% vs 39%

75% vs 75%

PFS 0.11; OS 0.47

71% vs 47%

71% vs 37%

84% vs 73%

PFS 0.003; OS 0.07


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Two cycles of carboplatin as adjuvant therapy in stage I seminoma: 8-year experience by the Hellenic Co-operative Oncology Group (HECOG). Presenting Author: Konstantinos Koutsoukos, Deptartment of Clinical Therapeutics, University of Athens, Athens, Greece Background: Adjuvant chemotherapy is used in stage I testicular seminoma. We have reported a risk-adapted strategy of 2 cycles of cisplatin/etoposide (EP) in 64 patients with age ⬍ 34 and/or tumor diameter ⬎ 4cm) (Bamias et al, Urology 2007), resulting in no relapses over a median follow up of 5 years. Following the establishment of adjuvant carboplatin as a standard, we adopted this treatment for all patients with stage I seminoma. We report our 8-year experience and compare these results with our previous EP strategy. Methods: Patients with stage I seminoma, treated with 2 cycles of carboplatin AUC 6 and a minimum follow up of 1 year after chemotherapy were selected. All patients consented for the use of their medical information and the analysis was approved by the centers involved. Survival functions were presented using Kaplan-Meier curves. The log-rank test was used to test for survival differences across different categories. Results: 137 patients (Median age: 34; Age⬍34: 49%, tumor diameter⬎4cm: 42%; rete testis invasion: 24%), treated between 11/2003-12/2011 were selected. During a median follow up of 4 years, there were 5 relapses (5-y relapse rate [RR]: 97% [SE: 2%]): retroperitoneal lymph nodes (n⫽4) and isolated brain (n⫽1). All patients with relapse had tumor diameter ⬎ 4cm and/or age ⬍ 34. No relapse was associated with rete testis invasion. Patients with at least 1 of the above risk factors (n⫽94) had a significantly higher relapse rate compared with a similar population (n⫽64) treated with 2 cycles of adjuvant EP: 5-y RR was 95% (SE: 2%) vs.100% (SE 0%), (p⫽0.033). All relapsed patients were treated with BEP chemotherapy and are currently alive with no evidence of relapse. Neutropenia and nausea/ vomiting were less frequent with carboplatin than with EP (11% vs. 36% and 15% vs. 65%). Conclusions: Our analysis confirms the association of age and tumor diameter with relapse in stage I seminoma treated with adjuvant carboplatin. Although adjuvant carboplatin in patients with age⬍34 and/or tumor diameter⬎ 4 cm is associated with higher RR than EP, the prognosis of these patients is excellent with salvage chemotherapy and, therefore, the use of less toxic treatment is justified.

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First-salvage treatment in patients with recurrent or refractory advanced germ-cell cancer after cisplatin-based chemotherapy: A database of the German Testicular Cancer Study Group. Presenting Author: Karin Oechsle, University Medical Center Hamburg-Eppendorf, Department of Oncology, Hematology and BMT with section of Pneumology, Hamburg, Germany

Comparing diagnosis, management, and outcomes of synchronous versus metacrhonus brain metastases from testicular germ cell tumors (TGCT): Multinstitutional experience from the Spanish Germ Cell Cancer Group (SGCCG). Presenting Author: Jorge Aparicio, Department of Medical Oncology, La Fe University Hospital, Valencia, Spain

Background: About 20-30% of patients (pts) with advanced germ-cell cancer (GCC) relapse after cisplatin-based chemotherapy. This database evaluates first salvage treatment and the prognostic categories at first relapse according to the International Prognostic Factors Study Group (⫽ IPFSG; JCO 2010). Methods: A total of 144 pts (78% nonseminoma) with relapsed or refractory GCC undergoing 1st salvage treatment with either conventional (CD-CX) or high-dose chemotherapy with autologous stem cell support (HD-CX) from 16 German centers were retrospectively analysed. Results: Subgroups according to the IPFSG prognostic categories, were: very low risk in 9/144 (6%), low risk in 26/144 (18%), intermediate risk in 78/144 (54%), high risk in 27/144 (19%), and very high risk in 4/144 pts (3%). 1st salvage treatment consisted of HD-CX in 96 (67%) and CD-CX in 48 pts (33%). Treatment response was CR/PR- in 60%, PR⫹/SD in 33%, and PD in 7%. After a median follow-up (mFU) of 21 months (mos) (range, 0 – 193), 53% of all pts had relapsed and 30% had died resulting in a median progression-free survival (PFS) of 7 mos (95%CI 0-16) and overall survival (OS) of 47 mos (95%CI 21-73). At subsequent relapses, 25/48 pts (52%) received HD-CX as ⬎ 2nd-salvage treatment. For the total cohort, PFS rate after 2 years was 35%, and OS rate after 5 years was 53%. Stratification according to IPFSG prognostic categories significantly correlated with PFS (p⫽0.001) and OS (p⫽0.004) after 1st salvage treatment. Even among high-risk and very high risk (n⫽31, mFU 12 mos) a PFS of 37 % at 2 years and an OS of 60 % at 2 years was observed, after 1st or 2nd salvage treatment, which might be due to patient selection and short follow-up. Conclusions: IPFSG prognostic categories highly correlated with observed PFS and OS after first salvage treatment in this cohort of pts with refractory or relapsed GCC. First salvage treatment with CD- or HD-CX resulted in overall 5 year-OS rates of about 50% across all prognostic categories. Even pts with high and very high risk achieved 2 year-OS rates of about 60% with salvage HD-CX at first or subsequent relapses.

Background: Metastases of testicular germ cell tumors (TGCT) to brain are a rare event. Prognostic is poor and there is little evidence on optimal management of these patients. Methods: A retrospective review of case records of germ cell tumor patients within the Spanish Germ Cell Cancer Group from 1994 to 2012 was conducted. Results: Thirty-tree cases of testicular germ cell tumors from 17 institutions were reported. Nineteen patients (57%) presented with brain metastases at primary diagnosis (group 1: synchronous), thirteen (40%) developed brain metastases at relapse (group 2: metachronous) and only one patient developed brain metastasis during cisplatin based-chemotherapy (3%) (excluded from the analysis). Main demographics and comparison between series are shown on table. Median serum BHCG levels at initial diagnosis were higher in group 1(279.083 versus 175.873), whereas those of AFP were higher in group 2(1320 versus 4181). The most common histology in the primary tumor was choriocarcinoma for group; versus embryonal carcinoma for group 2. Patients had neurological symptoms at diagnosis of brain metastases (63% synchronic/93% metachronus). Performance status was also poor (PS 2-3: 52,6%group 1-62,2% group 2). Four patients (21%) in group 1 had a solitary brain lesion vs seven (54%) on group 2. Median time since last dose of cisplatin to development of brain metastases on group 2 was 6 months (3-22).Median overall survival was 16 months (95% CI 5,3-26,6): group 1: 16 (95% CI 13,9-18);23 group 2 (95% CI 0-165). We have not found significant differences in survival between both groups. Overall 37,5% of patients achieved long-term survival (38,9% in group 1 versus 38,5% in group 2). Patients achieving complete response of brain metastases had a better survival (log rank p:0,003). Conclusions: Long term survival can be achieved in approximately 1/3 of patients with brain metastases. Chemotherapy remains the cornerstone of treatment. Selection bias because of the retrospective nature of review should make us be careful with the conclusions.




Smoking history and disease outcomes in patients with malignant germ cell tumors. Presenting Author: Elizabeth O’Donnell, Dana-Farber Cancer Institute, Boston, MA Background: In 2011, of 8260 cases of Germ Cell Tumor (GCT) in the US, about 350 (4%) died of disease. The impact of smoking on disease outcomes of relapse and death is unknown. Methods: Retrospective review of 891 GCT pts treated at Dana-Farber Cancer Institute (DFCI) between 1997 and 2010 was conducted. Inclusion criteria were men age⬎18 yrs treated for GCT with a quantified smoking history in an electronic medical record. The outcomes of interest were relapse after first-line chemotherapy and death from the disease. A Chi-square or Fisher’s exact test assessed the association of the disease outcomes and the smoking history (heavy smoker vs. less), and a Wilcoxon test for ordered categories assessed the association of the outcomes with the IGCCCG risk groups (good, intermediate, and poor), stratified by histology (seminoma vs non-seminoma (NS)). Results: 327 men with metastatic disease were identified. Median age was 31.5 years. 47(14%) had a history of smoking ⬎10 pack-years (pyrs). Of the 256 NSGCT pts with metastases at time of chemotherapy, pts who smoked ⬎10 pyrs constituted 27% of the 64 relapses vs. 11% of the 192 non-relapses (Odds Ratio (OR) 2.9, p⫽0.003). Of the 71 metastatic seminoma pts, 40% of the 10 relapses had smoked ⬎10 pyrs compared with 8% of the 61 pts who did not relapse (OR 7.5, p⫽0.01). Smoking ⬎10 pyrs was associated with (i) higher IGCCCG risk at time of metastatic disease [24% of poor-risk pts had a ⬎10 pyr history compared with 12% who had good-risk or 19% who had intermediate-risk (p⫽0.01)] and (ii) higher staging at initial diagnosis, 23% of poor-risk pts were heavy smokers compared with 9% who were CS1 and 12% good-risk (p⫽0.002). Of the 50 pts who died of metastatic disease, 36% had smoked ⬎10 pyrs compared to 9% who were cured, Pts who smoked ⬎10 pyrs had significantly increased odds of death compared to those who smoked 0-10 pyrs (OR⫽5.5, p ⬍0.0001). 3 out of 30 pts who smoked ⬎10 pyrs received suboptimal bleomycin, and only 1 relapsed. Conclusions: Greater than 10 pack-year smoking history is a modifiable risk factor associated with a higher IGCCCG risk at diagnosis of metastatic disease, higher risk of relapse after 1st-line chemotherapy and higher risk of death from germ cell tumor.

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A phase I/II trial of BNC105P with everolimus in metastatic renal cell carcinoma (mRCC) patients: Updated phase I results of the Disruptor-1 trial. Presenting Author: John Sarantopoulos, Institute for Drug Development, University of Texas Health Science Center, San Antonio, TX Background: BNC105P is an inhibitor of tubulin polymerization. In vivo exposure to BNC105P leads to selective damage of tumor vasculature in both primary and metastatic lesions, causing disruption of blood flow to tumors, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Up regulation of the mTOR pathway has been identified as a cellular response to hypoxic stress. The combined use of BNC105P with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to VEGFR-directed tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. The phase I component enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6, 16 mg/m2; IV infusion Days 1 & 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during Cycle 1. Biomarker samples (pre- and post-dose during Cycle 1) were analyzed for 70 plasma analytes including VEGF, PDGF and other markers associated with angiogenesis and vascular responses. Results: Updated results from the completed phase I component confirm the BNC105P / everolimus combination was well tolerated. No DLTs (drug-related, during cycle 1) were observed in any of the phase I subjects. Toxicities on study deemed to be drug-related (either single agent or combination) included single Grade 3 events of anemia and pericardial effusion. Grade 2 events of fatigue, anemia and oral mucositis were also observed. Eight of the 12 phase I subjects achieved disease stabilization. Across all subjects a median of 6 cycles (range: 1-24) was administered, with removal from study predominantly due to disease progression. PK analysis confirmed no drug-drug interaction. The randomized phase II component of the study continues and will compare everolimus given concomitantly with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: Full dose BNC105P (16 mg/m2) can be combined with full dose everolimus (10 mg) and is being further evaluated in a randomized phase II study. Clinical trial information: NCT01034631.

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Testosterone (T), luteinizing hormone (LH), and follicle stimulating hormone (FSH) levels in testicular cancer survivors (TCSs) 11 and 19 years after orchiectomy. Presenting Author: Mette Sprauten, OUS, The Norwegian Radium Hospital, Oslo, Norway Background: Hypogonadism, i.e., low T-, high LH- and/or FSH-levels, is frequently observed in TCSs and is associated with cardiovascular disease, osteoporosis and reduced quality of life. Little is known about the impact of aging on hypogonadism in TCSs. Methods: T, LH, and FSH levels were retrieved twice from 874 TCSs median 11 (S11) and 19 (S19) years after orchiectomy and categorized based on cut-offs calculated from 570 healthy controls (C), separately for each decadal age group. Treatment was categorized into surgery (S), radiotherapy (RT) or cisplatin-based chemotherapy (CT). Impact of treatment and aging on T, LH and FSH levels was assessed by comparing proportions of TCSs grouped into the C quartiles by ordinal logistic regression and expressed with odds ratios (OR) and 95% confidence interval (CI). Results: TCSs had lower T and higher LH and FSH levels than C at S11 and S19 (p⬍0.05, except for LH after S at S11) (Table).Approximately 50% of TCSs had T levels in the lowestquartile at S11 and S19. The proportion of TCSs with T below the 2.5% cut-off threshold for C increased from S11 to S19, for the S (9.7 - 12.5%), RT (9.4 - 16.3%) and CT group (12.5- 19.9%). Conclusions: TCSs had lower T and higher LH and FSH levels than C of similar age indicating an impact of treatment. Importantly, proportions of TCSs in the highest LH quartile and below the 2.5% cut-off for T-level increased from S11 to S19, indicating an accelerated hormonal aging. Continued follow-up of hormone levels is important. S11

S19

4564

TCSs: nⴝ874

S: nⴝ176, (100%)

RT: nⴝ362, (100%)

CT: nⴝ336, (100%)

T in lowest quartile OR(95%CI) LH in highest quartile OR(95%CI) FSH in highest quartile OR(95%CI) T in lowest quartile OR(95%CI) LH in highest quartile OR(95%CI) FSH in highest quartile OR(95%CI)

80 (46) 2.6 (1.9- 3.5) 58 (33) 1.2 (0.9- 1.6) 146 (83) 15.6 (10.1 – 24.0) 81 (46) 2.5 (1.8- 3.4) 90 (51) 3.2 (2.3- 4.4) 149 (85) 17.4 (11.1 – 27.1)

190 (53) 3.3 (2.6- 4.3) 150 (41) 2.0 (1.6- 2.5) 293 (81) 13.5 (9.8- 18.5) 201 (56) 3.9 (3.0- 5.0) 207 (57) 4.0 (3.1- 5.2) 296 (82) 14.4 (10.4 – 19.7)

184 (55) 3.6 (2.8 - 4.7) 173 (52) 2.7 (2.1- 3.4) 292 (87) 21.1 (14.7- 30.4) 193 (57) 3.8 (3.0- 5.0) 200 (60) 4.5 (3.5- 5.9) 293 (87) 21.4 (14.8 – 30.7)


Rates of dose adjustment in patients treated with tivozanib versus sorafenib in the phase III TIVO-1 study. Presenting Author: Thomas E. Hutson, Texas Oncology–Baylor Charles A. Sammons Cancer Center, Dallas, TX Background: Tivozanib hydrochloride (tivozanib) is a potent, selective, tyrosine kinase inhibitor of all three vascular endothelial growth factor receptors, with a long half-life. Superior progression-free survival (PFS) and overall response rate (ORR) with tivozanib versus sorafenib were demonstrated in a phase III trial (TIVO-1) in patients with advanced renal cell carcinoma (PFS: 11.9 vs 9.1 months in ITT population, 12.7 vs 9.1 months in patients who received no prior systemic treatment for mRCC; ORR: 33% vs 23% in ITT population). Hypertension was more common with tivozanib, while lower rates of certain off-target adverse events (AEs) relative to sorafenib were reported (J Clin Oncol 2012; 30[suppl]:Abstract 4501). Here we present detailed dose adjustment data. Methods: In total, 517 patients were enrolled and randomized 1:1 to tivozanib 1.5 mg/d (once daily 3 weeks on, 1 week off) or sorafenib 400 mg/d (twice daily, continuously). Treatment duration and AEs leading to discontinuation and dose adjustment were assessed in these patients. Results: Median duration of treatment with tivozanib was 12.7 months vs 9.5 months with sorafenib; fewer patients in the tivozanib arm experienced drug reduction or dose interruption due to AEs (see Table). Treatment-related AEs, as defined by the investigator, led to drug discontinuation in 3.9% of tivozanib patients and 5.4% sorafenib patients. Conclusions: Lower rates of dose adjustment due to related AEs were observed in patients with metastatic RCC who received tivozanib compared to sorafenib. Clinical trial information: NCT01030783. Related AEs leading to dose reduction or dose interruption. Adverse event, all/grade 3–4 Dose reductions Related AEs leading to dose reduction Related AEs occurring in >1.5% of patients Hand-foot syndrome Diarrhea Combined hypertension1 Lipase increase Dose interruptions Related AEs Related AEs leading to dose interruption in >1.5% of patients Diarrhea Combined hypertension1 Hand-foot syndrome Rash erythematous Asthenia 1Combined

Tivozanib (nⴝ259) %

Sorafenib (nⴝ257) %

11/8

37/17

2/2 1/1 2/2 ⬍1/⬍1

17/2 5/4 4/3 3/3

14/10

33/27

2/1 6/5 2/⬍1 0/0 1/⬍1

3/3 3/2 18/15 2/⬍1 2/⬍1

hypertension includes hypertension and hypertensive crisis.


300s 4565


Outcome of metastatic sarcomatoid renal cell carcinoma (sRCC): Results from the International mRCC Database Consortium. Presenting Author: Namita Chittoria, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH Background: Sarcomatoid differentiation in metastatic RCC (sRCC) is associated with poor prognosis. Robust data regarding outcome in the targeted therapy era is lacking. Methods: Clinical features, prognostic factors, and treatment outcomes in mRCC patients with and without sarcomatoid histology treated with targeted therapy were retrospectively analyzed and compared. Results: 2,286 patients were identified (nonsRCC(n⫽2,056); sRCC(n⫽230)). sRCC patients had significantly worse Heng prognostic group distribution compared to non-sRCC (11% vs 19% favorable risk, 49% vs 57% intermediate risk, and 40% vs 24% poor risk; p⬍0.0001). Time from original diagnosis to relapse (excluding synchronous metastatic disease) in the sRCC patients was 18.8 months compared to 42.9 months in non-sRCC group; p⬍0.0001. There was no significant difference in the incidence of CNS metastases (6-8%) or underlying clear cell histology (87-88%). Greater than 93% of patients received VEGF inhibitors as first line therapy; 21% achieved an objective response in the sRCC group as compared to 26% in the non-sRCC group with significantly more sRCC patients (43% vs. 21%) having primary refractory disease (p⬍0.0001, for both). sRCC patients had significantly less use of secondline (p⫽0.018) and third-line (p⫽0.0004) systemic therapy. The median PFS / OS was 4.5 months / 10.4 months in sRCC patients and 7.8 months / 22.5 months in non-sRCC patients (p⬍0.0001 for both). Sarcomatoid histology was associated with a significantly worse PFS and OS after adjusting for the individual Heng risk factors in multivariable analysis (HR 1.5, p⬍0.0001 for both). Conclusions: Patients with sRCC have worse baseline prognostic criteria, a shorter time to relapse and worse clinical outcome to targeted therapy compared to patients with non-sRCC. Additional insight into the biology of sRCC is needed to develop alternative therapeutics.

4567


Validation of an inverse association between programmed death ligand 1 (PDL1) and genes in the vascular endothelial growth factor (VEGF) pathway in primary clear cell renal cell (ccRCC). Presenting Author: Richard Wayne Joseph, Mayo Clinic, Jacksonville, FL Background: Trials combining anti-PDL1 and anti-VEGF therapies for clear cell renal cell carcinoma (ccRCC) are underway; however the relationship between the expression of PDL1 and genes in the VEGF pathway is poorly understood. Using the Affymetrix platform, we observed an inverse association between the expression of PDL1 and key genes in the VEGF pathway. Herein, we validate this inverse association using an independent set of 100 primary ccRCC tumors. Methods: From our registry database we sampled 100 ccRCC tumors with varying PDL1 protein expression (0%100%) determined by immunohistochemistry (IHC). We extracted RNA from FFPE slides and performed RT-PCR to quantify gene expression of PDL1, VEGF, VEGFR1, and VEGFR2. All genes were normalized to the POLR2a gene. We evaluated the association of PDL1 protein expression and VEGF gene expression using Spearman rank correlation. In addition, we employed a linear mixed effects model to compare the fold-change in expression of VEGF genes between PDL1 low (0-5%, n⫽68) and PDL1 high (⬎5%, n⫽32) tumors. Results: As expected, PDL1 protein expression positively correlates with PDL1 geneexpression (corr⫽0.42, p⬍0.001). Validating our array data, PDL1 protein expression inversely correlates with expression of key VEGF genes: VEGF (corr⫽-0.23, p⫽0.01), VEGFR1 (corr⫽-0.34, p⬍0.001), and VEGFR2 (corr⫽-0.23, p⫽0.01). In our dichotomized analysis, we noted significantly higher expression of VEGF genes in the PDL1 low compared to the PDL1 high group: VEGF (fold change⫽1.82, p⬍0.001), VEGFR1 (FC⫽2.63, p⬍0.001), and VEGFR2 (FC⫽2.13, p⫽0.001). Conclusions: We independently validate an inverse association between the expression of PDL1 and key genes in the VEGF pathway in primary ccRCC. If validated further in larger studies, the existence of an immune evasive and an angiogenic phenotype within ccRCC could inform current clinical trials targeting these two pathways. Ultimately, whether VEGF signaling affects PDL1 expression, or whether angiogenic or immune evasive phenotypes predict response to anti-PDL1, anti-VEGF, or a combination of the two therapies remains unclear.

4566


Genome-wide methylation profiling to identify potential epigenetic biomarkers associated with response to sunitinib in metastatic renal cell cancer (mRCC) patients (pts). Presenting Author: Jenny J. Kim, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD Background: There exists a significant heterogeneity in the clinical response to sunitinib among pts treated for mRCC and, thus, a biomarker which would predict pts’ response up front would be an invaluable tool in the clinical management of these pts. In this regard, whole genome methylation array was performed between 2 extreme groups: sunitinib responders (RES) and non-responders (NRES) to identify differentially methylated genes between these subsets of pts. Methods: mRCC pts who received sunitinib therapy with available frozen nephrectomy tissues (stored at -80°C) and clinical data were identified. RES were identified as pts with progression free survival (PFS) of ⬎ or ⫽11 months (mos) and NRES as those with PFS ⬍ or ⫽ 3 mos. After DNA extraction and quality assurance according to standard protocol, whole genome methylation array was performed using Infinium Humanmethylation450 BeadChip Kit - Illumina. Data normalization was achieved by subset-quantile within array normalization (PMID: 22703947). Differentially methylated regions were identified using logit transformed Beta values, using an F-test after shrinking variance via empirical Bayes (PMID: 21118553). Results: Total of 13 pts who received sunitinib therapy with available frozen nephrectomy tissues were identified. Of the 13, 5 pts qualified for each RES and NRES cohort as described in methods section. All pts in RES group had clear cell subtype. Two pts of the NRES group were of non-clear cell subtype. The QC plots showed that all arrays were successful. For RES vs. NRES, one genomic location, DENND2D, was significantly hypermethylated in the RES group with a false discovery rate (FDR) of ⬍10%. DENND2D has been identified as a tumor suppressor-like gene in non-small cell lung cancer and melanoma cell lines in the recent past. Conclusions: In this study, DENND2D was significantly hypermethylated in sunitinib RES compared to NRES among mRCC pts. Data analysis with a less stringent FDR is also being pursued. Technical validation as well as clinical validation of DENND2D utilizing a larger pt cohort are ongoing.

4568


VHL-mutant renal cell carcinomas contain cancer cells with mesenchymal phenotypes. Presenting Author: Craig Gedye, Ontario Cancer Institute, Toronto, ON, Canada Background: To study “cancer stem cells” it is imperative to account for all stromal cell populations within the tumour. The existence of “cancer stem cells” in clear cell renal cell carcinoma (ccRCC) has not been examined in ex vivo patient samples. Methods: We established a multiplex flow cytometry (FC) antibody panel in ccRCC, which reliably identified stromal lineages including CD45⫹ immune, CD31⫹/CD144⫹ endothelial and fibroblast-marker-positive subpopulations, thus allowing isolation of ⬙lineage-negative⬙ tumor cells. To verify the identity of tumour-derived populations as either cancer cells or normal stromal cells, we took advantage of the fact that mutations in VHL occur early during ccRCC tumorigenesis and are found in two-thirds of patients. Results: We sequenced 18 patient tumor samples, 12 of which had VHL exome mutations. Targeted re-sequencing of FC sorted subpopulations from these patients’ samples revealed that while CD45⫹ immune cells and CD31⫹/CD144⫹ endothelial cells were genetically normal, a population of VHL-mutant fibroblast-marker positive cells was consistently identified in every patient’s tumour. Immunohistochemistry showed that fibroblast marker-positive VHL-mutant cells do not have the large “clear cell” morphology typical of the majority of the cancer cells in these tumours. When purified and cultured, these fibroblast marker-positive VHL-mutant cells proliferate extensively under mesenchymal culture conditions, but displayed different morphologies to lineagenegative VHL-mutant tumor cells. Functional characterization of these FC sorted cell subpopulations is ongoing, including proliferation, migration, invasion, differentiation and treatment resistance. Conclusions: The phenotype and preliminary functional characterization of these VHL-mutant fibroblast-marker positive cells suggests a mesenchymal differentiation program in ccRCC, with implications for the ontogeny, biology and clinical management of VHL-mutant renal cancer.




4570

301s


Association of hyperbilirubinemia in pazopanib- or sunitinib-treated patients in COMPARZ with UGT1A1 polymorphisms. Presenting Author: Toby Johnson, GlaxoSmithKline, Uxbridge, United Kingdom

Pharmacogenetics as predictor of sunitinib and mTOR inhibitors toxicity in patients with metastatic renal cell carcinoma (mRCC). Presenting Author: Yuksel Urun, Dana-Farber Cancer Institute, Boston, MA

Background: A phase III randomized clinical trial (COMPARZ) comparing pazopanib vs sunitinib for treatment of advanced renal cell carcinoma demonstrated similar efficacies but different safety profiles for the two therapies. Elevations in serum total bilirubin have been observed in patients receiving either therapy. UGT1A1 polymorphisms are associated with elevated bilirubin in the general population (Gilbert’s syndrome). This study investigated the association between functional UGT1A1 polymorphisms and on-therapy serum total bilirubin in the COMPARZ study. Methods: Patients homozygous or compound heterozygous for UGT1A1 *28, *37, and *6 alleles were predicted to have reduced UGT1A1 function. Logistic regression adjusted for ancestry principal components was used to compare patients with on-therapy hyperbilirubinemia (ⱖ1.5 ⫻ upper limit of normal [ULN]; pazopanib, N ⫽ 62; sunitinib, N ⫽ 34) against patients exposed to treatment and with maximum on-therapy bilirubin ⱕ1 ⫻ ULN (pazopanib, N ⫽ 213; sunitinib, N ⫽ 215), excluding patients with maximum on-therapy bilirubin between 1 and 1.5 ⫻ ULN (pazopanib, N ⫽ 96; sunitinib, N ⫽ 104). Results: Patients with predicted reduced UGT1A1 function had higher baseline bilirubin and also were more likely to experience hyperbilirubinemia when receiving either pazopanib (P ⫽ 6.9⫻10– 8) or sunitinib (P ⫽ 1.8⫻10–3). After adjusting for baseline bilirubin, patients with predicted reduced UGT1A1 function remained more likely to experience hyperbilirubinemia when receiving pazopanib (P ⫽ 0.015) or sunitinib (P ⫽ 0.026), with odds ratio (95% CI) 3.53 (1.28 –9.76) and 4.41 (1.23–15.75), respectively. Conclusions: The data suggest that some instances of hyperbilirubinemia in patients treated with pazopanib or sunitinib may be benign manifestations of Gilbert’s syndrome. Bilirubin fractionation or, if not available, UGT1A1 genotyping, would enable further characterization of liver safety risk and help in making treatment decisions.

Background: Single nucleotide polymorphisms (SNPs) in major pharmacokinetics (PK) and pharmacodynamics (PD) pathways of targeted agents may affect the incidence of drug toxicities. Methods: Germline DNA was extracted fromwhole blood or normal kidney parenchyma frommRCC pts of European ancestry in two cohorts: those treated with VEGF-targeted therapy (sunitinib) (n⫽159) or with an mTOR inhibitor (everolimus or temsirolimus) (n⫽62). Ten SNPs in 6 candidate genes: CYP3A4 (rs2242480, rs4646437, rs2246709), CYP3A5 (rs15524), ABCB1 (rs2032582, rs1045642), VEGFR2 (rs2305948), NR1I3 (rs2307424, rs2307418), FLT3 (rs1933437) were genotyped using Sequenom iPlex Gold platform. Logistic regression model tested the association of genotype variants with adverse events of 1) grade 3/4 (G3/4) toxicity and G3/4 hypertension (for sunitinib cohort) and 2) grade 3/4 toxicity and all grade pneumonitis (for mTOR inhibitors cohort), adjusted for clinical factors associated with toxicity outcomes. Results: In the sunitinib cohort, median treatment duration was 7.7 months (IQR⫽3-15.5), 83 (52%) pts had grade 3/4 toxicities and 22 (14%) had grade 3/4 hypertension. Rare variant (AG) of CYP3A4 rs464637 was associated with the reduced risk of grade 3/4 toxicities (4 events/17 cases) vs. wild-type (GG, 73 events/134 cases), (Odds Ratio (OR) ⫽ 0.27, 95%CI: 0.08-0.88, p⫽0.03). No association between SNPs and hypertension was observed. In the mTOR inhibitor cohort, median treatment duration was 3.4 months (IQR⫽1.4-6), 21(34%) pts had G3/4 toxicities and 27 (43%) had all grade pneumonitis. No association between SNPs and G3/4 toxicities was observed. Rare homozygote (GG) of FLT3 SNP rs1933437 was associated with increased risk of all grade pneumonitis (7 events/ 9 cases) vs. wild-type (AA, 4 events/12 cases), however, given the very small variant group size, further investigation is required to verify the association. Conclusions: The minor allele of SNP rs464637 in the gene CYP3A4 may influence sunitinib toxicity. Further validation is needed to determine if the marker could be used for in targeted therapy dosing strategies and direct patient care. (IQR⫽Interquartile Range).

4571

4572



A phase II trial assessing pazopanib (paz) as third-line therapy for metastatic renal cell carcinoma (mRCC): Clinical outcome and temporal analysis of molecular profile. Presenting Author: Sumanta Kumar Pal, City of Hope, Duarte, CA

Prognostic significance of bone metastases (BM) and bisphosphonate (BIS) therapy in patients with metastatic renal cell carcinoma (mRCC) treated with molecularly targeted agents (MTAs). Presenting Author: Rana R. McKay, Dana-Farber Cancer Institute, Boston, MA

Background: Paz, an oral vascular endothelial growth factor (VEGF) receptor inhibitor, was assessed in a phase III study conducted in patients (pts) with mRCC who were cytokine-refractory or treatment-naïve (Sternberg et al J Clin Oncol 2010). Clinical outcomes with paz have been associated with a molecular profile (Tran et al Lancet Oncol 2012). The activity of paz in the 3rd-line setting and temporal changes in molecular profile during paz therapy are poorly understood. Methods: Eligibility was limited to pts with 2 prior lines of therapy (including at least 1 VEGF-directed therapy), ECOG PS 0-2, and clear cell histology. Pts received paz 800 mg/daily on a 28d cycle, and were assessed for response by RECIST 1.1 every 2 cycles. A Simon MinMax 2-stage design was employed, with 80% power of declaring an encouraging overall response rate (ORR) of 23% (type I error⫽10%). Molecular profiles were assessed on a Luminex platform using the Human Cytokine 30-plex Cytokine Immunoassay (Invitrogen) at baseline, 6 mos and 12 mos. Results: 28 pts (20M, 8F) were enrolled, with a median age of 63 (range, 45-86). All patients received at least 2 lines of prior therapy, and 6 pts (21%) had received 2 prior lines of VEGF-directed therapy. In the pre-specified intent-to-treat analysis, 12/28 pts (43%) had a confirmed response (1 CR, 11 PR), with 1 additional unconfirmed PR. 8 pts (29%) had SD as a best response. Median PFS for the cohort was 17.4 mos (95% CI 14.7-NR). No grade 4 treatment-related toxicities were observed. The most common grade 3 toxicities were hypertension (46%) and proteinuria (14%). At baseline, IL-6 was marginally lower in patients who achieved PR/CR (responders) as compared to those who did not (non-responders; P⫽0.06). Amongst patients still on therapy at 6 months and 12 months, responders had lower levels of HGF, IL-2R, IL-6, IL-8, and VEGF (P⬍0.05 for each) at both time intervals. Conclusions: Paz demonstrated an ORR of 43%, representing the highest ORR observed to date in a 3rd-line trial in mRCC. At 6 and 12 months, differences in molecular profile emerged between responders and non-responders, potentially underscoring mechanisms of drug resistance. Clinical trial information: NCT01157091.

Background: BM are frequently present in patients with mRCC. BM cause significant morbidity and are associated with high rates of skeletal related events (SREs). The purpose of this retrospective analysis was to assess the impact of BM and BIS use on outcomes including progression-free survival (PFS) and overall survival (OS) in patients with mRCC. Methods: We conducted a pooled analysis of patients with mRCC treated from 20032011 on phase III (NCT00083899, NCT00065468, NCT00678392) and phase II trials (NCT00054886, NCT00077974, NCT00083889, NCT00338884, NCT00137423). Statistical analyses were performed using Cox regression and the Kaplan-Meier method. Results: We identified 2,749 patients treated with sunitinib (n⫽1,059), sorafenib (n⫽335), axitinib (n⫽359), temsirolimus (TEM) (n⫽208), TEM ⫹ interferon-alfa (IFN) (n⫽208), or IFN (n⫽560). Most patients were male (71%), had baseline ECOG PS of 0 (47%) or 1 (51%), clear cell histology (91%), and prior nephrectomy (84%). 285 patients (10.4%) received treatment with BIS (zoledronic acid n⫽233, pamidronate n⫽57, unspecified n⫽1). No patients received denosumab. Of the 2,504 patients with data regarding site of metastasis at diagnosis, 31.9% (n⫽781) had BM. The rate of SREs in patients with BM compared to patients without BM was 6.4% versus 1.4% (p⬍0.0001). Presence of BM was associated with shorter PFS (5.1 vs. 6.7 months (mo), HR 1.195, 95% CI 1.076-1.328, p⬍0.0008) and OS (13.2 vs. 20.2 mo, HR 1.292, 95% CI 1.145-1.456, p⬍0.0001) when compared to those without BM. In patients with BM, the use of BIS was not associated with improved PFS (5.1 vs. 4.9 mo, HR 0.867, 95% CI 0.704-1.067, p⫽0.1785) or OS (13.3 vs. 13.1 mo, HR 0.904, 95% CI 0.722-1.132, p⫽0.3801) when compared to patients who did not receive BIS. In patients with BM stratified by type of first-line MTA (TKI, mTOR inhibitor, or IFN-based), use of BIS was not associated with improved PFS or OS. Conclusions: In this analysis, we confirm that the presence of BM is an adverse risk factor for shorter PFS and OS in patients with mRCC treated with MTAs. Treatment with BIS did not have a positive impact on survival in this cohort.


302s

Genitourinary (Nonprostate) Cancer

4573


Effective monotherapy despite intratumor heterogeneity: Clonal convergence within the PI3K pathway and sensitivity to mTOR inhibitors in patients with advanced renal cell carcinoma (RCC). Presenting Author: Martin Henner Voss, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Rapalogs, inhibitors of mTOR, are approved for treatment of advanced RCC. Recent reports of clonal heterogeneity challenge the concept of targeted monotherapy and the development of genomic biomarkers. Still, a subset of patients (pts) derives extended benefit from single agent rapalogs. This study analyzed such outliers so as to explore the genomic background of rapalog sensitivity in the setting of clonal heterogeneity. Methods: Cases were chosen based on time to treatment failure ⬎ 20 mos and tissue availability. DNA was extracted from spatially separate areas in primary tumors, metastases and the germline. Custom target capture and ultra-deep sequencing identified small indels, single base pair substitutions and copy number changes across all exons of 230 target genes. Results: 4 pts contributed 13 specimens (11 primary tumor samples, 2 metastases); mean exon coverage was 443X. Genomic alterations with activating effect on PI3K pathway signaling were seen in 11 of 13 specimens (Table). Clonal heterogeneity was present in all pts. For 2 pts, different mechanisms activated the pathway in separate sites, in 1 pt through separate genes. Conclusions: Pathway-activating genomic events across all sites explain rapalog benefit in 3 of 4 pts. Different disease sites in the same pt can harbor separate mechanisms activating the targeted pathway. This suggests that clonal convergence within the PI3K pathway can create an oncogenomic landscape sensitive to rapalogs despite branching clonal evolution. It supports the notion of sampling ⬎1 disease site during future biomarker development. 1

2

3

4

4575

P1 P2 P3 P1 P2 P3 M1 P1 P2 P3 P4 P1 M1

4574


Pazopanib (P) and bevacizumab (B) in patients with metastatic renal cell carcinoma (mRCC) or other advanced refractory tumors: Phase I combination study final analysis. Presenting Author: Sylvie Negrier, Léon-Bérard Cancer Centre, Lyon, France Background: Since previous experiments of B with VEGFR tyrosine kinase inhibitors showed overlapping and limiting toxicities, a dose-finding study was designed to explore the safety and feasibility of the combination of a recent VEGFR inhibitor P with B in mRCC treatment-naive patients (pts) or in pts with other advanced refractory solid tumors. Methods: This double center trial was conducted with 3⫹3⫹3 escalation doses of P ⫹ B. The maximum tolerated dose (MTD) was the highest dosage not expected to cause a dose limiting toxicity (DLT) in more than 2/3, 3/6 or finally 3/9 pts, during the first 8 weeks of treatment. After preliminary DLT results, an approved by IDSMB extension cohort was enrolled and treated at MTD level.The effect of B on steady-state pharmacokinetic (PK) of P was also investigated by comparing PK at day 1 (D1) and D15 (day of B infusion). Results: 25 pts were enrolled with mRCC (n⫽7) or other advanced refractory solid tumors (n⫽18). Median age is 62 (41-79), 14 pts are male. At DL2 (n⫽10) 3 nephrectomized and 2 non-nephrectomized pts experienced DLT, as presented in the Table. In the 6-non-nephrectomized-pt extension cohort at DL1, 3 additional DLT were observed. Mean P AUC at D1 was higher than previously described in phase I P monotherapy (Clin Cancer Res 2009;15:4220). Mean P AUC at steady-state (D15) at both P dose levels was also significantly higher, though without being influenced by B infusion. Conclusions: The MTD of the P ⫹ B combination is respectively 400 mg/d and 7.5mg/kg (DL1) in all patients. Final PK analysis showed that there is no influence of B on P PK and that P AUC is higher than previously reported. Clinical trial information: NCT01202032.

Mutations

Copy no. alteration

Functional (Fct) effect

N

P

DLT

TSC1 frameshift TSC1 frameshift TSC1 nonsense TSC1 frameshift TSC1 frameshift TSC1 frameshift TSC1 frameshift mTOR missense mTOR missense mTOR missense TSC1 nonsense -

Heterozygous deleletion (Het del) TSC1 Het del TSC1 Het del TSC1 Het del TSC1 Het del TSC1 Het del TSC1 Het del TSC1 Het del TSC1 -

Fct loss TSC1 Fct loss TSC1 Fct loss TSC1 Fct loss TSC1 Fct loss TSC1 Fct loss TSC1 Fct loss TSC1 Fct gain mTOR Fct gain mTOR Fct gain mTOR Fct loss TSC1 -

9 6

DL1 7.5 mg/kg (extension cohort at DL1)

400 mg

10

DL2

600 mg

No DLT 3 DLT: 2 grade 3 MAHA*, 1 grade 3 AST/ALT 5 DLT: 1 grade 3 AST/ALT#, 1 grade 3 pulmonary embolism# 2 (1⫹1#) grade 3 reversible MAHA, 1 grade 3 AST/ALT, grade 2 hyperbilirubinemia


Dose level (DL)

B

7.5 mg/kg

* Microangiopathic hemolytic anemia. # Nephrectomized pt.

4576


Adoptive immunotherapy with autologous cytotoxic T lymphocytes (CTLs) pulsed ex vivo with patient-derived tumor cells in heavily pretreated, advanced renal cell carcinoma (aRCC) patients: A feasibility study. Presenting Author: Camillo Porta, IRCCS San Matteo University Hospital Foundation, Pavia, Italy

Randomized phase II study of first-line everolimus plus bevacizumab (EⴙB) versus interferon ␣-2a plus bevacizumab (IⴙB) in patients (pts) with metastatic renal cell carcinoma (mRCC): Record-2 final overall survival (OS) and safety results. Presenting Author: Alain Ravaud, Hôpital SaintAndré CHU, Bordeaux, France

Background: Immunotherapy still remains the only treatment which proved able to induce long-lasting complete responses in aRCC. The aim of the present study was to evaluate the feasibility and safety of adoptive immunotherapy with ex vivo-generated autologous CTLs pulsed with patient-derived tumor cells in heavily pre-treated subjects with aRCC. Methods: This study was performed in accordance with local regulations on the production of cell derivatives; local Ethical Committee approval was obtained on a named patient basis, after obtaining each patient’s informed consent. CTLs were generated stimulating CD8-enriched lymphocytes with dendritic cells (DCs) pulsed with fresh autologous tumor cells in the presence of IL-12 and IL-7; these specific anti-tumor CTLs were expanded and then reinfused after a lymphodepleting chemotherapy with CTX and fludarabine, followed by s.c. administration of low-dose IL-2. Disease status was assessed after every two re-infusions. Eight patients were enrolled, 6 with a clear cell RCC, 1 with a papillary RCC, and 1 with a mixed, papillary and collecting ducts, RCC. All patients have been previously treated with a median of 5 prior treatment lines; the median time between diagnosis of aRCC and tumor biopsy was 55 months (15-185). Results: Six of the 8 enrolled patients have produced suitable tumor cell lines, and 5 of them had been already re-infused with tumor-specific CTLs. All patients received at least 2 CTL infusions (range: 2-5⫹); mean of totally infused CTLs was 10.7 x 109(range: 4-26.6). All CTLs infusions were well tolerated, with no evidence of autoimmune reactions. In terms of antitumor activity, one patient achieved a partial response, 3 had a slowly progressing disease, and one patient is still not evaluable; furthermore, in 3 patients disease-related symptoms improved. Conclusions: Our preliminary results suggest that immunotherapy with autologous CTLs pulsed ex-vivo with patient-derived tumor cells is feasible and safe in heavily pre-treated aRCC patients. Signs of activity were recorded, suggesting the need to further expand this cohort of patients.

Background: RECORD-2 (NCT00719264) primary analysis demonstrated similar median progression-free survival (PFS) for pts with mRCC treated with E⫹B and I⫹B (Dec 2011 cut-off). The primary objective was not met; median PFS in E⫹B/I⫹B was 9.3/10.0 mo (HRIFN/EVE, 0.91; 95% CI, 0.69-1.19; P⫽0.485) and probability of success (PoS) of a subsequent phase III trial was 5.1%. Here we present final OS and safety/exposure results (Aug 2012 cut-off). Methods: Untreated pts with clear cell mRCC and previous nephrectomy were randomized 1:1 to B 10 mg/kg every 2 weeks and either E 10 mg/day or I (9 MIU 3 times/week). The primary objective was treatment effect on PFS per central review based on an estimation of PoS (ⱖ50%) of a subsequent phase III study. Secondary objectives included OS and safety. Results: In E⫹B (n⫽182) and I⫹B (n⫽183) arms, median age was 60/60 years and 76/72% of pts were men, respectively. In both arms, most pts (93%) were of favorable/intermediate MSKCC risk. Median follow-up was 33 mo. In E⫹B and I⫹B arms, 51/52% of pts died, respectively. Median OS (95% CI) was 27.1 mo (19.9-35.3) in the E⫹B arm and 27.1 mo (20.4-30.8) in the I⫹B arm. After discontinuing study treatment, 64/60% of pts in E⫹B and I⫹B arms, respectively, received antineoplastic therapy. Median exposure duration in E⫹B and I⫹B arms was 8.5/8.3 mo, respectively; AEs resulted in treatment discontinuation for 23/25% of pts, respectively. The most frequent AEs (%) were stomatitis (63), proteinuria (50), diarrhea (40), hypertension (38), and epistaxis (35) in the E⫹B arm and decreased appetite (45), fatigue (42), proteinuria (38), asthenia (35), and pyrexia (35) in the I⫹B arm. The most frequent grade 3/4 AEs (%) were proteinuria (24), stomatitis (11), and anemia (11) for E⫹B and fatigue (17), asthenia (14), and proteinuria (10) for I⫹B. Conclusions: OS of E⫹B and I⫹B was similar. OS results are consistent with PFS primary analysis. First-line treatment with mTOR inhibitor-based therapy did not impair chance of survival relative to standard therapy. No new safety issues were identified and E⫹B remained generally well tolerated. Clinical trial information: NCT00719264.




Multiplexed tissue protein assay as a predictor of response to targeted therapy in advanced renal cell carcinoma. Presenting Author: Ulka N. Vaishampayan, Wayne State University, Detroit, MI Background: A number of prognostic biomarkers have been explored in advanced renal cancer, but to date none have been useful in therapeutic outcome prediction. Methods: Following regulatory approval, formalin-fixed paraffin embedded (FFPE) pre-therapy (sunitinib and/or mTOR inhibitors) tissue samples and clinical data on kidney cancer patients (pts) were obtained. The FFPE tissue was analyzed using layered immunohistochemistry which allows analysis of multiple biomarkers using a single tissue section. Multiplexed panels of protein biomarkers were used to probe tissue sections for proteins along the PI3K/AKT/mTOR and/or the VEGFR/PDGFR signaling pathways. Expression of biomarkers in tumor tissue was scored and predictive scores which correlated with the pt’s clinical outcome status generated. Results: Tissue samples of 51 pts treated with sunitinib (S)were analyzed. A predictive score was generated by combining the scores assigned to VEGFR1 and VEGFR2 and multiplying the sum with the score of VEGFA. A predictive score equal to or above 24, was associated with response or stable disease (SD) at 12 weeks. Patients with a score ⬍24 were predicted to have progression (PD) on S. Using this scoring method, 27 of the 33 responders tested and 15 of the 18 non responders were accurately identified. The accuracy of the test was noted to be 82.6% and sensitivity and specificity were 81.8% and 83.3% respectively. Tissue samples of 33 pts treated with mTOR inhibitor were analyzed using the same technique. Three biomarkers in the mTOR pathway (pmTOR (Ser 2448), p4EBP1 (Ser 65), p4EBP1 (Thr 37-46)) were used to create a predictive score. Eight of 12 OR/SD pts (sensitivity 67%) and 17 of 21 PD pts (specificity 76%) were accurately predicted using a score cut-off of 6 for an accuracy of 71.5%. Statistical modeling, results of ongoing validation testing, and score correlation with time to progression will be presented. Conclusions: These results indicate that an assay based on multiplexed protein analysis of tumor tissue is capable of providing clinically applicable information to help guide therapy. Funding source: Supported in part by NCI BRIDGE Grant 5R44CA123994-06 and by NCI SBIR Contract No. HHSN261201000135C.

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Treatment response and survival outcome of patients with late relapse (LR) from renal cell carcinoma (RCC) in the era of targeted therapy. Presenting Author: Nils Kroeger, Tom Baker Cancer Centre, Calgary, AB, Canada Background: A small subset of localized RCC patients will experience disease recurrence ⱖ5 years after nephrectomy. Clinical outcome of patients with LR has not been well characterized. Methods: Patients with mRCC treated with targeted therapy were retrospectively characterized according to time to relapse. Replase was defined as diagnosis of recurrent metastatic disease ⬎3 months after initial diagnosis. Patients with synchronous metastatic disease at presentation were excluded. Patients were classified as Early Relapsers (ER) if they recurred within 5 years while Late Relapsers (LR) recurred after 5 years. Demographics and outcomes were compared. Results: 1210 mRCC patients were identified; 903 (74.6%) with relapse within the first 5 years, 200 (16.5%) within ⬎5-10 years, and 107 (8.8%) after 10 years (range 10-35 years). Baseline characteristics are presented in the Table. Overall response rates to targeted therapy were better in LR vs. ER (35% vs. 24%; p⫽0.009). LR patients had significant longer progression free- (10.7 vs. 8.5 months; log rank p⫽0.004) and overall survival (34.0 vs. 27.3 months; log rank p⫽0.003). Conclusions: One quarter of patients that eventually developed metastatic disease treated with targeted therapy relapsed over 5 years from initial diagnosis. The proportion of patients that relapse after five years is substantial. mRCC patients presenting with LR have more favorable prognostic features, treatment response, and overall survival. Baseline characteristics. Characteristic Age of metastatic disease (mean yrs) Heng prognostic score Favorable Intermediate Poor >1 organ metastatic site Yes No Brain metastases Yes No Clear cell histology Yes No Sarcomatoid histology Yes No Furhman grade 1 2 3 4

4580

Early relapser (5yrs) Nⴝ307

59 231 (31%) 422 (56%) 94 (13%)

62 119 (46%) 125 (49%) 12 (5%)

0.0007 ⬍0.0001

634 (70%) 269 (30%)

250 (81%) 57 (19%)

0.0001

68 (8%) 830 (92%)

22 (7%) 285 (93%)

0.8152

750 (86%) 120 (14%)

261 (93%) 19 (7%)

0.0018

66 (8%) 741 (92%)

4 (2%) 229 (98%)

0.0005

22 (3%) 225 (32%) 317 (44%) 135 (19%)

19 (12%) 77 (48%) 56 (35%) 7 (4%)

⬍0.0001

P value


Impact of cytoreductive nephrectomy on disease-specific survival (DSS) in the cytokine and targeted therapy eras: Age- and TNM-stage matched analysis of SEER data. Presenting Author: Rebecca A. Nelson, City of Hope, Duarte, CA

Association analysis of polymorphisms in genes related to sunitinib pharmacokinetics. Presenting Author: Meta Diekstra, Leiden University Medical Center, Department of Clinical Pharmacy and Toxicology, Leiden, Netherlands

Background: The role of cytoreductive nephrectomy (CN) for patients with mRCC was well-defined in the cytokine era. However, its role is controversial in the era of targeted therapies. Methods: The Survival, Epidemiology, and End Results (SEER) Database was queried to compare the relative benefit of CN in the cytokine era (defined as 1992-2004) as compared to the targeted therapy era (defined as 2005-2009). Patients with mRCC and clear cell, papillary or chromophobe histology were identified, and divided into cohorts with and without CN. Within each category, patients diagnosed during the cytokine era were matched by age and TNM stage to patients diagnosed during the targeted therapy era. Associations between clinicopathologic characteristics and DSS were explored through univariate and multivariate analyses. Results: Amongst matched pts who had received CN (n⫽2,218), no significant differences in age, gender, race, histology (clear cell v non-clear cell), T-stage, or N-stage were observed. Median DSS was superior in those patients diagnosed during the targeted therapy era as compared to the cytokine era (22 mos v 17 mos, P⬍0.0001). On multivariate analysis including the aforementioned clinicopathologic variables and DSS, diagnosis during the targeted therapy era was an independent predictor of improved survival amongst patients who had received CN (HR 0.78, 95%CI 0.70-0.87; P⬍0.0001). Amongst matched pts who had not received CN (n⫽4,214), there were no differences in clinicopathologic characteristics. Median DSS was similar in patients diagnosed during the targeted therapy era as compared to the cytokine era within this group (4 mos for each; P⫽NS). Conclusions: Patients who received CN during the targeted therapy era had a superior DSS as compared to patients who received the procedure during the cytokine era. In contrast, patients who had not received CN had a similar DSS across both time periods. While prospective trials mature (i.e., CARMENA and EORTC 30073), these data support the continued use of CN in the context of targeted agents.

Background: Sunitinib is approved as systemic therapy for mRCC, GIST and pNET. Interpatient variability in the pharmacokinetics (PK) of sunitinib is high, which may have serious consequences for efficacy and toxicity of the drug. The objective of this study was to evaluate whether polymorphisms in candidate genes involved in sunitinib metabolism are related to the PK of sunitinib and its active metabolite SU12662. Methods: In this multicenter study, steady state sunitinib plasma concentrations and genotypes were prospectively obtained from 115 patients. Single nucleotide polymorphisms (SNPs) and haplotypes in 8 genes encoding CYP1A1, CYP3A4, CYP3A5, ABCB1, ABCG2, NR1I2, NR1I3, and PORwere evaluated as covariates in a population pharmacokinetic model describing both sunitinib and SU12662 PK using NONMEM. First, candidate genotypes/haplotypes were individually tested for a potential association with sunitinib or SU12662 clearance. Next, potential significant SNPs (p⬍0.05) were simultaneously included in a multivariate model and tested by backward elimination with a significance threshold of p⬍0.0005. Results: Four out of 37 screened genotypes (from 14 different SNPs) were related to sunitinib clearance (CYP3A4*22 CC and CT, CYP3A5*3 GG, and ABCB1 (2677 TT)). CYP3A5*3 AG genotype was associated with clearance of SU12662. In the multivariate analysis, none of the SNPs reached the predefined significance threshold of p⬍0.0005. Nevertheless, CYP3A4*22T allele carriers showed a 22.5% decreased clearance of sunitinib (p⬍0.01). Conclusions: Our data suggest that individual SNPs or haplotypes in CYP1A1, CYP3A4, CYP3A5, ABCB1, ABCG2, NR1I2, NR1I3 and POR are not clearly associated with sunitinib or SU12662 clearance. Several (environmental) factors may also influence the PK of sunitinib. Interestingly, the recently identified CYP3A4*22 SNP potentially has an impact on drug exposure. Replication studies in larger groups of patients are needed to verify the role of CYP3A4*22 for sunitinib clearance.


304s 4581


Novel stratification of the recurrence risk following surgical extirpation of clear cell renal cell carcinoma using tissue biomarkers in the mammalian target of rapamycin pathway. Presenting Author: Laura-Maria Krabbe, The University of Texas Southwestern Medical Center, Dallas, TX Background: Aberrant activation of the mammalian target of rapamycin (mTOR) pathway promotes invasiveness and metastatic potential in a variety of malignancies. The aim of the present study was to evaluate the association of altered expression of mTOR pathway components with recurrence outcome in non-metastatic clear cell renal cell carcinoma (ccRCC) patients. Methods: Immunohistochemistry for phos-S6, phosmTOR, mTOR, phos-AKT, HIF-1␣, RAPTOR, PTEN, PI3K, and phos4EBP1 was performed on tissue microarrays of patients treated for non-metastatic kidney cancer between 1997-2010. Patients were defined as having a low (⬍) or high risk (ⱖ) of nomogram predicted recurrence (2001 MSKCC RCC post-op) using an 8% cutoff. The relationship between individual marker expression, as well as combined marker score (low, intermediate and high defined as ⱕ 3, 4-5, ⬎5 altered biomarkers; respectively) with the actual and predicted relapse rates was assessed. Results: The study included 419 non- metastatic ccRCC patients (pT1-T2 79.5%, pT3-T4 20.5%, Fuhrman nuclear grade 1-2 in 69%, 3-4 in 31%). 219 and 200 patients had low (⬍8%) and high (ⱖ8%) nomogrampredicted 5-year risk of recurrence respectively. With a median follow-up of 2.2 years, recurrences were detected in 5 (2.3%) of the predicted low risk and 30 (15%) of the predicted high risk patients. mTOR pathway biomarker profiles were not predictive for patients at low predicted risk of recurrences. For patients at high predicted risk of recurrence, low, intermediate and high combined marker scores were found in 84 (42%), 79 (39.5%), and 37 (18.5%), respectively. The actual rates of recurrence were noted for 8.3% of low, 13.9% of intermediate and 32.4% of high combined marker score in a statistically significant distribution (p⫽0.027). Conclusions: The cumulative number of aberrantly expressed mTOR biomarkers correlates with a higher rate of recurrence. The combined marker score may help further stratify patients with high nomogram predicted risk of recurrence. Our data supports prospective evaluation of these biomarkers to augment current clinico-pathologic predictors of outcomes in ccRCC.

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Overcoming sunitinib-induced resistance by dose escalation in renal cell carcinoma: Evidence in animal models and patients. Presenting Author: Roberto Pili, Roswell Park Cancer Institute, Buffalo, NY Background: Sunitinib is considered a first-line therapeutic option for patients with advanced clear cell renal cell carcinoma (ccRCC). However, despite the clinical efficacy, eventually tumors develop resistance and progress. Thus, we have tested the hypothesis whether sunitinib doseescalation could overcome initial drug resistance. Methods: Human patientderived ccRCC xenografts were implanted in SCID mice and were randomly assigned into two groups (sunitinib and vehicle). Mice were treated with sunitinib 5 days/week with a dose-escalation schema starting from 40 mg/kg to 60 mg/kg and 80 mg/kg. Tumor volumes and body weights were assessed weekly. Tumor tissues and blood were collected prior to dose increments. In selected patients treated with 50 mg sunitinib and presenting minimal toxicities, dose was escalated to 62.5 and 75 mg at the time of tumor progression. Results: Our preclinical results show that patient-derived tumors (RP-01 and RP-02), although initially responsive to sunitinib 40 mg/kg, eventually became resistant to treatment. Following dose increase to 60 mg/kg, we observed again tumor response but eventually the tumors became resistant. A similar effect was noticed when we further escalated sunitinib to 80 mg/kg. Immunohistochemistry analysis shows decreased tumor vascularization during response to sunitinib, but then hypervascularization at the time of resistance. Associated increase in expression of the methyltransferase EZH2, the histone marks H3K27me3, H3k4me2 and H3K9me2 in tumors resistant to sunitinib was observed. Analysis of sunitinib and VEGF/VEFGR2 blood and tumor levels will be reported. In parallel, our clinical experience shows that intra-patient sunitinib dose-escalation was safe and clinical benefit was observed. Details on tumor responses and toxicities will be reported. Conclusions: Overall, our results suggest that sunitinib-induced resistance may be overcome in part by increasing the dose of the VEGF receptor tyrosine kinase inhibitor in mouse models and ccRCC patients, and highlights the potential role of epigenetic changes associated with sunitinib resistance.

4584


Contrasting vascular response to sunitinib as measured by DCE-CT, DCE-MRI, and DCE-US in renal cell carcinoma (RCC) patients (pts). Presenting Author: John M. Hudson, Imaging Research, Sunnybrook Research Institute, Toronto, ON, Canada

Phase II trial of vandetanib in Von Hippel-Lindau-associated renal cell carcinoma. Presenting Author: Lambros Stamatakis, Urologic Oncology Branch, National Cancer Institute at the National Institutes of Health, Bethesda, MD

Background: Imaging (DCE-MRI, DCE-CT, DCE-US) provides information about the integrity and hemodynamics of the tumor microvasculature. Methods: 34 treatment (Rx) naive pts with RCC and abdominal tumor suitable for imaging received sunitinib 50 mg on a standard 4/2 schedule. DCE-US, DCE-CT, and DCE-MRI were done at baseline, during the first course and after 2wks off Rx. Imaging parameters included vessel permeability (Ktrans), extracellular volume fraction (ve) and Ktrans/ve⫽Kep (by DCE-MRI), permeability surface product (PS) by DCE-CT, blood volume (BV), by DCE-CT and DCE-US and blood perfusion (by DCE-US). A morphology parameter (MP) was developed that relates flow kinetics of the microbubble contrast agent to tumor vascular morphology by DCE-US. Results: Several imaging parameters predicted for progression free survival (PFS) in responding pts (N⫽26). Baseline imaging parameters correlated with PFS: Ktrans by DCE-MR (Spearman r⫽ 0.53, p⫽0.01, N⫽24), BV by DCE-CT (r⫽0.48, p⫽0.02, N⫽25) and disorganized vessel morphology (large MP) by DCE-US (r⫽ - 0.45, p⫽0.02, N⫽24). Changes from baseline imaging parameters correlated with PFS: BV by DCE-US at 2 wks (r⫽ -0.46, p⫽0.02, N⫽24), Kep by DCE-MR at 2 wks (r⫽ -0.45, p⫽0.03, N⫽24) and MP at 1wk (r⫽0.67, p⫽0.02, N⫽12). There was a correlation between imaging methods: BV measured by DCE-CT correlated with BV by DCE-US (r⫽0.46, p⫽0.03, N⫽23) and Kep by DCE-MR (r⫽0.59, p⫽0.003, N⫽22); Permeability measured by DCE-MR (Ktrans) and DCE-CT (PS) correlated at 2wks (r⫽0.56, p⫽0.01, N⫽21). A combination of baseline US and MR parameters identified responders and nonresponders with a sensitivity of 83% and specificity of 90%. Conclusions: This is the first study to contrast DCE-US, DCE-CT and DCE-MRI imaging in pts receiving antiangiogenic therapy. Baseline parameters for all three methods can predict for PFS. Changes from baseline in DCE-US and DCE-MRI parameters also predict for PFS. There is a correlation between imaging methods in parameters that measure BV and permeability. A novel DCE-US parameter was developed (MP) that quantifies the degree of tumor vascular disorganization. Baseline values in MP and changes during Rx correlate with PFS. Clinical trial information: OCT1205.

Background: Germline mutations in the von Hippel Lindau (VHL) gene are associated with the development of bilateral multifocal clear-cell renal cell carcinoma (RCC). VHL patients with localized disease are surgically managed, with nephron sparing resection recommended once tumors reach 3 cm. Patients typically undergo multiple surgeries with significant cumulative morbidity. In this phase 2 trial of vandetanib, a dual VEGFR2/ EGFR inhibitor, a systemic approach to these tumors was explored. Methods: Patients with VHL-associated RCC were treated with 300 mg vandetanib daily until disease progression or unacceptable toxicity. Cross sectional imaging was performed at baseline and every 12 weeks. The primary endpoint was overall renal tumor response assessed by RECIST. Results: A total of 34 subjects were enrolled, with a mean age of 47 years (range 28 – 72). The median number of targeted lesions per subject was 2 (range 1 – 6) and the mean tumor diameter was 2.3 cm (range 1.2 – 4.0). Twenty-seven (80%) subjects had baseline imaging and at least one follow-up study to allow response evaluation. Median time on study was 6.1 months (range 1.0 – 23.3). Thirteen (38%) subjects demonstrated overall reduction in tumor burden with a median reduction of 6% (range 4-54%). One (3%) subject had a PR by RECIST and 26 (77%) had stable disease as their best response. Eleven (32%) subjects were taken off study due to growth of at least one lesion that met criteria for surgical resection or disease progression. Nine (27%) subjects required dose reductions due to toxicity. Although the majority of adverse events encountered on trial were grade 2 or less, 9 (27%) subjects were taken off trial due to drug-related toxicities and 9 (27%) withdrew due to intolerable side effects. Rash (71%), and QTc prolongation (41%) were the most common adverse events noted. Conclusions: In the largest phase II study of a systemic agent for VHL-related RCC, vandetanib demonstrated anti-tumor activity. Despite a reasonable safety profile, poor tolerability necessitated drug withdrawal in a significant proportion of patients. Newer agents that selectively target the VEGF receptors may offer a more tolerable alternative and might optimize clinical benefits in this population. Clinical trial information: NCT0056695.




Continuation of sunitinib following RECIST progression on first-line sunitinib. Presenting Author: Mauricio Emmanuel Burotto Pichun, National Cancer Institute, National Institutes of Health, Bethesda, MD Background: In the last seven years the FDA and the EMA have approved seven agents for treatment of RCC. Five of these target the VEGF pathway. Methods: We conducted a detailed analysis of data from the sunitinib registration trial examining the growth and regression rate constants and the stability of the growth rate as measures of effectiveness and to understand development of resistance. Results: Sufficient data was available for the analysis of 350/374 patients enrolled. Statistically valid data was obtained in 321(91.7%). The median regression rate constant was 0.0048 days-1, and in 59 patients no evidence of growth was recorded while on study, only regression. The median growth rate was 0.00082 days-1 and this rate was stable a median of 267 days, remaining stable beyond 300 days in 172 patients, beyond 600 days in 95 patients, and beyond 900 days in 49 pts. A suggestion of a possible increase of the growth rate while sunitinib was administered could be discerned in only 15/321 pts. With a median growth rate 0.00082 days-1 the estimated time to progression were sunitinib discontinued and then re-started would have been a minimum of 7.3 months. Thus a meaningful outcome could be achieved provided continued sunitinib is tolerable. Finally with an estimated 47%, 27% and 13% of tumor still sensitive to sunitinib 100, 200 and 300 days after starting therapy, shrinkage with a new TKI in patients who discontinue sunitinib before day 300 for toxicity may not be a sign of non-cross resistance, but of residual sensitive tumor. Conclusions: Prolonged stability of the growth rate of RCC on sunitinib is consistent with intrinsic and not acquired resistance. Baring toxicity, continued sunitinib beyond RECIST criteria for progression may provide a beneficial outcome and can be considered a treatment alternative in selected patients. Randomized trials to assess the value of VEGF TKI’s in patients whose disease has “progressed” on sunitinib should consider including an arm that continues sunitinib to test this hypothesis.

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First-, second-, third-line therapy for metastatic renal cell carcinoma (mRCC): Benchmarks for trials design from the International mRCC Database Consortium (IMDC). Presenting Author: Daniel Yick Chin Heng, Tom Baker Cancer Centre, Calgary, AB, Canada Background: Limited data exists on outcomes for mRCC patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counseling and clinical trial design. Methods: Outcomes of mRCC patients from the IMDC treated with 1, 2, or 3⫹ lines of targeted therapy (TT) were compared and adjusted by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) benchmarks were calculated using different population inclusion criteria. OS and PFS are calculated from the line of therapy under consideration unless otherwise specified. Results: 2,705 patients were treated with TT of which 1,533 (57%) received only 1st-line TT, 734 (27%) received 2 lines of TT, and 438 (16%) received 3⫹ lines of TT. The median OS of patients that received 1, 2 or 3⫹ lines of TT starting from initial TT was 14.9, 21.0, and 39.2 months, respectively (p⬍0.0001). On multivariable analysis adjusting for baseline Heng prognostic factors, the use of 2nd-line and 3rd-line therapy were each independently associated with better OS (HR⫽0.738 and 0.626, respectively, both p⬍0.0001). Survival benchmarks derived from patients in the IMDC using selected inclusion criteria as seen in contemporary mRCC clinical trials are shown below. Conclusions: Patients that are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing new clinical trials. Population (data from IMDC) All patients 1st line therapy in intermediate/poor risk patients with diagnosis to treatment interval < 1 year (ADAPT (AGS003) trialdesign) 1st line therapy in patients with prior nephrectomy (TIVO-1 (Tivozanib) trial design) 2nd line therapy (INTORSECT trial design) 3rd line therapy (all patients) 3rd line therapy in patients with 1 prior VEGF and 1 prior mTOR inhibitor (GOLD (dovitinib) study)

4587


305s

TPS4588^

PFS (mon) (95% CI)

OS (mon) (95%CI)

7.2 (6.7-7.7) n⫽2,659 5.6 (5.3-6.1) n⫽1,174

20.9 (19.6-22.5) n⫽2,705 14.7 (13.3-16.5) n⫽1,189

8.2 (7.8-8.6) n⫽2,080 3.9 (3.6-4.3) n⫽1,151 4.0 (3.4-4.5) n⫽425 4.4 (3.3-5.2) n⫽140

24.8 (23.1-27.3) n⫽2,117 13.0 (12.2-14.7) n⫽1,157 12.1 (10.7-13.9) n⫽455 18.0 (11.8-24.0) n⫽147


Phase II study of dovitinib in first line metastatic or (nonresectable primary) adrenocortical carcinoma (ACC): SOGUG study 2011-03. Presenting Author: Jesús García-Donas, Centro Integral Oncológico Clara Campal, Madrid, Spain

The Borealis-2 clinical trial: A randomized phase II study of OGX-427 plus docetaxel versus docetaxel alone in relapsed/refractory metastatic urothelial cancer. Presenting Author: Jonathan E. Rosenberg, Memorial SloanKettering Cancer Center, New York, NY

Background: Dovitinib is a novel targeted therapy that inhibits the fribroblast growth factor receptor (FGFR). Preclinical studies have pointed to a major role of this pathway in adrenocortical carcinoma (ACC) thus we aimed to test its clinical efficacy in this tumor. Methods: A phase II proof of concept trial was designed. Since this is an extremely infrequent disease sample size calculation was done taking as a basis the first stage of a two-stage Gehan model. Thus 15 patients needed to be included to show a treatment efficacy of at least 15% (probability of Type I error ␣ ⫽ 0.05, power [1 – ␤] ⫽ 0.8). Main inclusion criteria was advanced non-resectable ACC, histologically confirmed, with no prior therapy other than mitotane. Primary endpoint was response rate (RR) by RECIST 1.1 assessed by an independent radiologist. Secondary endpoints included clinical benefit (RR plus stable disease), progression free (PFS) and overall survival (OS). Dovitinib was administered at 500mg daily dose 5 days on 2 days off for 6 months. Continuation of therapy was permitted at physician criteria. Results: From January 2012 to August 2012, 17 patients (5 male and 12 female) have been included in 7 institutions. Median age was 53 years (range 26-72); ECOG was 0-1 in 15 patients, 2 in one patient and N/A in one patient. 77 cycles, defined as one month on treatment, have been administered with dose reductions in 6 (7.8%). Grade 3-4 adverse events deemed as related to the drug were: rash (6%), asthenia (12%), diarrhea (6%), GGT elevation (18%), nausea (6%), hypertriglyceridemia (6%), hypertension (6%), hyperkalemia (6%). 13 patients withdrew treatment because of disease progression and 4 remain on dovitinib. No toxic death was reported. After a median follow-up of 5, 2 months (range 2,27 – 9,7) no objective response has been observed. Median PFS was 1,8 months (CI 95% [ 1,35 -2,25]), median OS has not been reached and clinical benefit has been achieved in 35% of patients with long lasting stable disease (⬎6 months) in 23%. Conclusions: Though no objective response was observed, a significant number of long lasting stabilizations have been achieved with an acceptable toxicity. These encouraging results merit further study. Clinical trial information: NCT01514526.

Background: Heat shock protein 27 (Hsp27) is over-expressed in many cancers including bladder, lung, prostate, and breast. Increased Hsp27 has been associated with inhibition of chemotherapy-induced apoptosis, increased tumor cytoprotection, and development of treatment resistance. OGX-427 is an antisense oligonucleotide designed to bind Hsp27 mRNA, inhibiting production of the Hsp27 protein. Inhibition of Hsp27 has been shown to increase apoptosis, inhibit tumor growth, and sensitize tumor cells to chemotherapy in a variety of malignancies, including urothelial cancer. Results of preclinical and phase 1 studies suggest that addition of OGX-427 to chemotherapy is well tolerated and may improve treatment efficacy. BOREALIS-2 is a randomized, multicenter, phase 2 study of OGX-427 in combination with docetaxel (DOC) vs. DOC alone in locally advanced/metastatic bladder cancer patients who received at least one line of prior platinum-based therapy. The primary objective is to evaluate overall survival. Secondary objectives include comparisons of safety and tolerability, disease response, and serum levels of Hsp27 and other pathway-related proteins. Associations between clinical outcomes, levels of Hsp27 and other proteins, and circulating tumor cells will be evaluated. Methods: Patients (N⫽200) are randomized in a 1:1 ratio following stratification (time from prior systemic chemotherapy; Bellmunt criteria). Up to 2 prior systemic therapies are allowed. Treatment-arm patients receive three loading doses of OGX-427 (600 mg) followed by up to ten 21-day treatment cycles (OGX-427 1000 mg on Days 1, 8, and 15 and DOC 75 mg/M2 IV on Day 1). Control-arm patients receive DOC 75 mg/M2 IV on Day 1 of each cycle. Treatment may continue until disease progression, unacceptable toxicity, completion of 10 cycles, or patient withdrawal. Patients who discontinue DOC due to toxicity after ⱖ2 cycles and do not have disease progression may receive maintenance therapy with OGX-427. One interim futility analysis will be performed. The trial will not be stopped early based on efficacy. Clinical trial information: NCT01780545.


306s TPS4589


TPS4590


A phase II study of cabozantinib (XL184) in patients with advanced/ metastatic urothelial carcinoma. Presenting Author: Andrea Borghese Apolo, National Cancer Institute, Bethesda, MD

ASPEN: A randomized phase II trial of everolimus versus sunitinib in patients with metastatic non-clear cell renal cell carcinoma. Presenting Author: Andrew J. Armstrong, Duke Cancer Institute, Durham, NC

Background: Accumulating evidence supports MET as a therapeutic target in urothelial carcinoma. Activated MET can promote angiogenesis and tumor growth by upregulating VEGF and may play a role in urothelial carcinoma pathogenesis. Cabozantinib inhibits primarily VEGFR2 and MET pathways. Cabozantinib has been approved by the FDA for the treatment of progressive metastatic medullary thyroid cancer, is in Phase 3 trials for metastatic castration-resistant prostate cancer and has demonstrated clinical activity in multiple solid tumors. We previously reported that shed MET levels in serum and urine of patients with urothelial carcinoma correlate with stage, presence of visceral metastases and urinary source and that cabozantinib is effective in reversing HGF-driven urothelial carcinoma cell growth and invasion. These data support the evaluation of cabozantinib in patients with metastatic urothelial carcinoma. Methods: This is a phase II study of oral cabozantinib 60mg daily given continuously in 28-day cycles. There are three study cohorts: [1] metastatic urothelial carcinoma [2] bone only metastatic urothelial carcinoma [3] metastatic non-urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis. A maximum of 55 subjects will be enrolled. Up to 45 patients will be accrued to cohort 1.The remainder will be enrolled on exploratory cohorts 2 & 3. A two-stage single-arm phase II design will be employed. The primary objective is to determine the objective response rate in patients with metastatic urothelial carcinoma who have progressed on prior chemotherapy. Secondary objectives include progression free survival, safety and toxicity, and overall survival. Exploratory objectives include tumor tissue Met expression, shed MET levels in serum and urine, immune subsets, genetic biomarkers, molecular markers of angiogenesis and circulating tumor cells, correlation with clinical response parameters. Finally we will explore treatment evaluation with FDG and NaF PET/CT compared to standard imaging. This study is supported by the Cancer Therapy Evaluation Program (CTEP). NCT01688999 Clinical trial information: NCT01688999.

Background: Currently no level 1 evidence exists to guide therapeutic decisions in patients with metastatic non-clear cell renal cell carcinoma. Case series and retrospective analyses suggest that strategies targeting either the VEGF or mTOR/TORC1 pathways have clinical activity in papillary, chromophobe, or poorly differentiated histologic subtypes. Methods: We are conducting an international, randomized phase 2 trial of patients with metastatic non-clear cell RCC; either papillary, chromophobe, or undifferentiated histology; any Motzer risk group; and who have had no prior systemic therapy. All patients contribute tissue to an international biorepository for correlative genomic, genetic, and protein biomarker studies, along with companion longitudinal plasma and urine angiome studies. Patients are randomized to either everolimus or sunitinib (1:1) at FDA approved dosing until progression. The primary endpoint is progression free survival. Trial status: Seventy-three out of a planned 108 subjects have been enrolled at the time of abstract submission: median age 64, 59 white, 10 black, 4 unknown race, and includes 42 papillary and 31 chromophobe/undifferentiated histologies, 49 men and 22 women. Accrual is anticipated to be completed by December 2013. Accrual distribution by country is currently 43 (USA), 27 (UK), and 3 (Canada). The first DSMB meeting was conducted after 40 subjects completed at least 6 months of therapy and concluded that there were no unexpected safety signals and that the study should proceed. Tissue (primary, some metastatic, urine, plasma, whole blood) has been collected on all patients to date through the Duke Center for Human Genetics Biorepository. Clinical trial information: NCT01108445.

TPS4591

TPS4592


Phase III randomized sequential open-label study to evaluate the efficacy and safety of sorafenib followed by pazopanib versus pazopanib followed by sorafenib in the treatment of advanced/metastatic renal cell carcinoma (SWITCH-2 study). Presenting Author: Juergen Gschwend, Department of Urology, Rechts der Isar Medical Center, Technische Universität München, Munich, Germany Background: Sorafenib (SO) and pazopanib (PA) are both effective treatments for metastatic RCC (mRCC). For optimal treatment of mRCC patients (pts) it is essential to compare efficacy and safety of different sequential 1st and 2nd line treatments. The primary endpoint of this study is to evaluate if total PFS of SO followed by PA is non-inferior to PA followed by SO. Secondary objectives include time to progression during second-line treatment; time to first-line treatment failure in each arm, and PFS in firstand second-line treatment; overall survival; disease control rate in first- and second-line, safety and tolerability, and health-related quality of life. Also, a comprehensive translational research programme is integrated. Methods: Major inclusion criteria: pts with metastatic/advanced RCC not suitable for cytokines and for whom study medication constitutes first-line therapy; 18-85 years, ECOG PS 0 or 1, MSKCC score low or intermediate; at least one measurable lesion (RECIST 1.1). 544 pts will be randomized to the sequence SO¡PA or PA¡SO. Treatment under each drug continues until progression or intolerable toxicity. Between 1st and 2ndline therapy will be a treatment-free period of 1-4 wks. SO and PA are given in their registered doses. Pts undergo CT/MRI after every second cycle, i.e. after every 8 wks. The experimental arm will be considered to be non-inferior as long as the lower limit of the HR 95 % confidence interval (one-sided) excludes a median total PFS lower than 13.1 mos (⫽non inferiority margin). 383 events need to be observed to have 80% power to reject the null hypothesis of inferiority (HR ⱖ1.225) when the true HR⫽0.95. Recruitment started in June 2012. Study centers are in Germany, The Netherlands, and Austria. Clinical trial information: NCT01613846.


A phase III comparative study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus everolimus in patients (pts) with advanced or metastatic renal cell carcinoma (mRCC) previously treated with antiangiogenic therapy. Presenting Author: Robert John Motzer, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Standard approved treatments for pts with mRCC include interleukin-2 as well as therapies that target the vascular endothelial growth factor (eg, sunitinib, pazopanib) or mammalian target of rapamycin (eg, temsirolimus, everolimus) pathways. However, most pts may develop resistance, and overall survival (OS) improvement has only been shown in one phase 3 trial in poor-risk pts. Everolimus demonstrated a 3-month improvement in median progression-free survival (PFS) vs placebo, with no OS improvement (Motzer RJ, et al. Lancet. 2008;372:449-56). A phase 1 study of the fully human programmed death-1 (PD-1) receptor blocking monoclonal antibody nivolumab showed encouraging antitumor activity with previously treated mRCC (objective response rate [ORR], 29% (10/34); stable disease at ⱖ24 weeks [wks], 27% [9/34]). PD-1 is an immune checkpoint receptor that negatively regulates T-cell activation and PD-1 overexpression by tumor infiltrating lymphocytes has been associated with poor prognosis in multiple tumor types. Therefore, an ongoing, randomized, open-label, global phase 3 trial was developed to evaluate the clinical benefit of nivolumab in mRCC pts previously treated with antiangiogenic therapy. Methods: Approximately 822 pts with advanced or metastatic clear-cell mRCC who have received ⱕ2 prior anti-angiogenic therapies and ⱕ3 total prior systemic regimens will be randomized 1:1 to receive nivolumab 3 mg/kg IV every 2 wks (Arm A) or everolimus 10 mg PO daily (Arm B). Pts will be stratified by region, MSKCC risk group, and number of prior anti-angiogenic therapy regimens. Tumor response will be assessed using RECIST 1.1 every 8 wks following randomization for the first year and then every 12 wks until disease progression or treatment discontinuation, whichever occurs later. The primary endpoint is OS. Secondary endpoints include PFS, ORR, OR duration, adverse events, OS in PD ligand 1 (PD-L1) positive or negative subgroups, and patient-reported outcomes. The trial is open and enrolling pts. Clinical trial information: NCT01668784.


Genitourinary (Nonprostate) Cancer TPS4593


TPS4594

307s


A phase I study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) in combination with sunitinib, pazopanib, or ipilimumab in patients (pts) with metastatic renal cell carcinoma (mRCC). Presenting Author: Asim Amin, Levine Cancer Institute, Charlotte, NC

A phase II multicenter study of the efficacy and safety of sunitinib given on an individualized schedule as first-line therapy for metastatic renal cell cancer. Presenting Author: Georg A. Bjarnason, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada

Background: Vascular endothelial growth factor receptor-tyrosine kinase inhibitors are established therapies for mRCC. However, sunitinib and pazopanib rarely elicit durable responses. Programmed death-1 receptor (PD-1) is an immune checkpoint modulator that suppresses T-cell activation by interacting with its ligands (PD-L1/2) on antigen presenting cells and some tumor cells. Nivolumab, a PD-1 receptor blocking antibody, has shown durable responses in previously treated pts with mRCC in Phase 1 and 2 trials. Ipilimumab is an immune checkpoint inhibitor (anti-CTLA-4 antibody) already approved for the treatment of advanced melanoma. We describe an ongoing Phase 1 dose-escalation and expansion study evaluating combination of nivolumab with sunitinib, pazopanib or ipilimumab in pts with mRCC. Methods: Patients with histologically confirmed mRCC are treated on 4 parallel arms: nivolumab 2.0 or 5.0 mg/kg ⫹ sunitinib standard dosing (Arm S), nivolumab 2.0 or 5.0 mg/kg ⫹ pazopanib standard dosing (Arm P), nivolumab 3 mg/kg ⫹ ipilimumab 1 mg/kg as induction (Arm I-1), and nivolumab 1 mg/kg ⫹ ipilimumab 3 mg/kg as induction (Arm I-3) with nivolumab 3 mg/kg maintenance for both arms. Arms S and P are being conducted in 2 phases: nivolumab dose-escalation phase for previously treated pts (ⱕ18 pts/arm) and then dose-expansion phase for treatment-naïve pts (20 pts/arm) if the maximum tolerated dose is ⱖ5 mg/kg. Arms I-1 and I-3 are fixed-dose cohorts (20 pts/arm) including both treatment-naïve and previously treated pts. Most of the study population consists of pts with clear-cell histology; non-clear cell mRCC pts are allowed in the dose-escalation cohorts of Arms S and P. The primary objectives are to assess safety and tolerability, and to determine the recommended Phase 2 dose in pts with mRCC. The secondary objective is to assess preliminary antitumor activity (objective response rate and response duration per RECIST 1.1). Exploratory objectives are to evaluate overall survival, pharmacodynamics, and predictive biomarkers for the combinations, and pharmacokinetics and immunogenicity of nivolumab. Clinical trial information: NCT01472081.

Background: Retrospective reviews have shown poorer than expected response rate (RR), progression free survival (PFS) and overall survival (OS) in Sunitinib treated (Rx) Renal Cell Cancer (RCC) patients (pts) who experience minimal toxicity. This study is based on an individualized (individ) Rx strategy where dose/schedule modifications (DSM) were done to maximize dose and minimize time off Rx in 172 pts (Bjarnason ASCO-GU 2011). Pts started on 50mg 28 days (d) on/14d off. DSM were done to keep toxicity (fatigue, skin, GI, hematology) at ⱕ grade-2. DSM-1 was 50mg 14d/7d with individ increases in d on Rx based on toxicity. DSM-2 was 50mg 7d/7d with individ increases in d on Rx. DSM-3 was 37.5mg continuously with individ 7d breaks. DSM-4 was 25mg continuously with individ 7d breaks.In pts with clear cell histology PFS was inferior (5.8 mo) on the standard 50mg 28d/14d schedule vs. DSM schedules (⬎14 months, p⫽0.0002) These data, confirmed in 185 pts at MD Anderson (Jonasch KCA 2012), suggest that pts with minimal toxicity after 28d on Rx may benefit from dose escalation. Methods: A prospective phase II study has opened in 11 centers in Canada. DSM are done as described above. Pts with minimal toxicity after 28d are escalated to 62.5 mg and then 75 mg on a 14d /7d schedule. We expect to dose escalate 25% of pts and maintain another 40% of pts on a 50 mg dose that would otherwise have been dose reduced. The primary objective is the PFS associated with this strategy. Secondary objectives include dose intensity, RR, OS, toxicity, and quality of life. Samples for Sunitinib pharmacokinetics are obtained during the first course and again when the ideal sunitinib schedule has been established. Samples for biomarker and DNA correlative studies are collected. Based on the standard arm of the EFFECT trial (identical eligibility criteria), we assume a median PFS of 8.5 months in pts Rx using standard dosing. We expect pts treated with the indiv dosing will have a median PFS of 14 months. With alpha⫽0.05, a two-sided, single-arm non-parametric survival test would have over 90% power to detect this difference with a total of 110 pts on study. Study enrollment began in July 2012 with 25 pts currently on study. Clinical trial information: NCT01499121.

TPS4595


Phase II randomized study of dalantercept in combination with axitinib compared to axitinib alone as second-line treatment in patients with metastatic renal cell carcinoma. Presenting Author: Michael B. Atkins, Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC Background: The treatment of metastatic renal cell cancer (mRCC) with therapies targeting the vascular endothelial growth factor (VEGF) pathway delays disease progression; however, overcoming tumor resistance to these agents remains a therapeutic challenge. Activin receptor-like kinase 1(ALK1) is a type 1 receptor in the TGF-ß superfamily and is selectively expressed on activated endothelial cells. While VEGF drives the proliferative stage of angiogenesis, ALK1 is primarily involved in the maturation phase. Dalantercept is a human ALK1-Fc receptor fusion protein that binds to bone morphogenetic proteins (BMP) 9 and 10 (ligands for ALK1) and acts as a ligand trap. Preclinically, dalantercept showed delayed tumor growth in solid tumor models, including RCC models alone and in combination with sunitinib. In RCC models, the addition of dalantercept to sunitinib enhanced the reduction in tumor blood flow compared to sunitinib alone. Dalantercept showed anti-tumor activity in a completed phase 1 study in 37 pts. with advanced solid tumors. Based on this promising data, we hypothesize that ALK1 inhibition may be synergistic with axitinib, a VEGFR tyrosine kinase inhibitor (TKI), in pts. with mRCC. Methods: A two-part, multi-center, open label phase 2 study to evaluate safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of dalantercept plus axitinib as second line therapy is ongoing. In Part 1, dose escalation using a 3⫹3 design will assess the safety and PK of dalantercept SC every 3 weeks plus axitinib 5 mg PO BID until disease progression or unacceptable toxicity. Once the maximum tolerated dose (MTD) has been determined, up to 20 pts. may be enrolled in an expansion cohort to establish safety for the recommended dose for Part 2. Part 2 will include 112 pts. randomized 1:1 to dalantercept plus axitinib vs. axitinib alone. Key eligibility criteria are one prior TKI in the first-line setting, ECOG 600 patients in the control arm of the stampede trial (NCT00268476). Presenting Author: Noel W Clarke, Department of Urology, The Christie NHS Foundation Trust, Manchester, United Kingdom

A prognostic model for predicting overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA) after docetaxel. Presenting Author: Kim N. Chi, British Columbia Cancer Agency, Vancouver, BC, Canada

Background: STAMPEDE (www.stampedetrial.org) recruits men with newlydiagnosed or rapidly relapsing prostate cancer (PCa) that is metastatic (M1) or high-risk locally advanced, all commencing long-term androgen ablation therapy (AAT) for the first time. This is now the largest therapeutic RCT in PCa. We report survival outcomes for newly-diagnosed M1 control arm men in order to inform future trials in this setting. Methods: Newly-diagnosed men with M1 disease in the trial’s control arm (standard of care: AAT alone for at least 2yr), diagnosed up to 6 months prior to randomisation, were identified from trial records in Dec-2012. We report overall survival (OS) and failure-free survival (FFS) from randomisation by primary disease characteristics. Results: 3703 men were recruited to STAMPEDE Oct-2005 to Dec-2012, including a control arm cohort of 630 M1 men with newly-diagnosed disease. This cohort has median age at randomisation 66yr (quartiles 60-71), median PSA 105 (quartiles 34-379) IU/l; metastases to bone only (B) 393 (62%), soft tissue only (ST) 78 (13%) or bone and soft tissue (B⫹ST) 159 (25%). ST was mainly lymph nodes. Median time from diagnosis to randomisation is 69 days (max 180 days). Median duration of AAT prior to randomisation is 46 days (max 105 days). There were 129 deaths, of which 111 were from PCa. Median OS from randomisation is 42 months, with 2-yr OS 74% (95%CI 68, 78) in this cohort; B 77% (95%CI 71, 83), ST 85% (95%CI 70, 93), B⫹ST 57% (95%CI 45, 68). Median FFS is 12 months, driven by rising PSA; 2-yr FFS 32% (95%CI 27-37). Median time from FFS event to death was 22 months. Additional data on relapse therapies will be presented. Conclusions: Survival, and particularly FFS, remains relatively poor for men presenting with M1 disease starting long-term AAT, despite potential access when castration-resistant (CRPC) to docetaxel and other newer therapies. Better first-line therapy is required; STAMPEDE will report many comparisons in the future. Different M1 patterns may vary prognostically. Men with M1 disease will now spend most time in a state of CRPC, which has important implications for clinicians and trialists. Clinical trial information: NCT00268476.

Background: COU-AA-301 was a multinational, randomized, controlled, phase III trial comparing AA ⫹ prednisone (P) (n ⫽ 797) versus placebo ⫹ P (n ⫽ 398) in mCRPC pts post-docetaxel. Using data from that trial, we developed a prognostic model for predicting OS in pts treated with AA post-chemotherapy, with a focus on readily assessable clinical parameters. Methods: The analyses used data from pts treated with AA in the COU-AA301 trial for whom relevant baseline data were available (n ⫽ 729). Baseline variables were assessed for association with OS through a univariate Cox proportional hazards regression model. High/low values for accepted normal ranges were used for laboratory parameters. The Cox proportional hazards regression was used with a stepwise procedure to identify independent prognostic factors for OS. The model was subject to sensitivity analyses and the C-index was utilized as a measure of model accuracy. Results: The following risk factors were associated with a poor prognosis: ECOG performance status (only pts with scores of ⱕ 2 were eligible for this trial) of 2 (HR ⫽ 2.19, p ⬍ 0.0001), presence of liver metastases (HR ⫽ 2.00, p ⬍ 0.0001), time from start of initial LHRH agonist therapy to start of AA treatment ⱕ 36 months (HR ⫽ 1.30, p ⫽ 0.0078), low albumin (HR ⫽ 1.54, p ⬍ 0.0001), high ALP (HR ⫽ 1.38, p ⫽ 0.0016), and high LDH (HR ⫽ 2.31, p ⬍ 0.0001). Patients were categorized into 3 risk groups (good prognosis, n ⫽ 369; intermediate prognosis, n ⫽ 321; poor prognosis, n ⫽ 107) based on total number of risk factors and median OS calculated for each group (table). The C-index was 0.74 (95% CI: 0.68, 0.80). Conclusions: This prognostic model uses readily available clinical parameters to conveniently assess risk for mCRPC pts previously treated with docetaxel and initiating treatment with AA ⫹ P. If validated, the model will be useful in clinical practice and clinical trials. Clinical trial information: NCT00638690. Number of risk factors

Median OS, mos (95% CI)

HR (95% CI)

0 or 1 (good) 2 or 3 (intermediate) 4 to 6 (poor)

21.3 (19.4, 27.1) 13.9 (11.7, 14.8) 6.1 (4.8, 7.2)

2.30a (1.89, 2.81) 6.19a (4.76, 8.05)

a

5014


Versus patients with good prognosis.

5015


Effect of corticosteroid (CS) use at baseline (CUB) on overall survival (OS) in patients (pts) receiving abiraterone acetate (AA): Results from a randomized study (COU-AA-301) in metastatic castration-resistant prostate cancer (mCRPC) post-docetaxel (D). Presenting Author: Robert B. Montgomery, University of Washington, Seattle, WA

Evolving patterns of metastatic disease in castration-resistant prostate cancer (CRPC) reported in clinical trials from 1990 to 2011. Presenting Author: Stephanie Doctor, Division of Hematology and Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY

Background: CS have been used to mitigate mineralocorticoid-related effects and restore sensitivity to AA (Attard et al., J Clin Oncol. 2008). Prednisone (P) was also used as an active comparator in the COU-AA-301 (de Bono et al., N Engl J Med. 2011) and COU-AA-302 (Ryan et al., N Engl J Med. 2013) AA pivotal studies. CUB has also been reported to adversely influence OS in the AFFIRM study, which may reflect an influence on disease biology or unrecognized factors that are not a part of clinically based prognostic models (Scher et al., Ann Oncol. 2012). This post hoc exploratory analysis investigated whether CUB is a prognostic factor for OS in mCRPC post-D pts treated with AA ⫹ P or P alone. Methods: COU-AA301 is a randomized double-blind study of AA (1 g) ⫹ P (5 mg po BID) vs placebo ⫹ P in mCRPC post-D. The primary endpoint was OS. All pts had received CS with D therapy. CUB included P (n ⫽ 272), dexamethasone (n ⫽ 107), and others (n ⫽ 110). 797 pts were not on CUB. Median times were estimated by the product-limit method; Cox model was used to obtain the hazard ratio (HR) and associated confidence interval (CI). Results: Pts with CUB had worse baseline disease characteristics (including adverse ECOG PS, Gleason score, analgesic score, and LDH) (all p ⬍ 0.05). Pts receiving CUB had inferior OS; AA ⫹ P improved OS independent of CUB. (Table). CUB was an independent prognostic factor in multivariate analysis (p ⫽ 0.03; HR 1.22 [95% CI: 1.02-1.45]) that was associated with lower baseline androgen levels (p ⬍ 0.0001). In a stepwise selection model, CUB was not an independent prognostic factor. Conclusions: In this study, CUB was not a strong independent prognostic factor in mCRPC post-D pts treated with AA ⫹ P or P alone. CUB was associated with worse baseline disease characteristics and inferior OS in this study, in which all pts subsequently received CS. Clinical trial information: NCT00638690.

Background: Bone remains the most common site of metastasis in CRPC. With new therapies extending survival in metastatic CRPC (mCRPC), we hypothesized that the incidence of non-osseous metastases is increasing over time. In this study, we evaluated the pattern of metastatic disease in mCRPC as reported in baseline characteristics of prospective clinical trials over 2 decades. Methods: We identified all therapeutic studies in patients with mCRPC in Pubmed and ASCO abstracts from 1990-2011. Inclusion criteria included phase 2 or 3 clinical trials in mCRPC with available baseline demographic data and no exclusion of specific site of metastatic disease (except brain). ASCO abstracts were limited to presentations in which data were available online. For each study, demographic data and study-reported sites of non-osseous metastatic disease were recorded (lymph node, visceral, soft tissue, liver). For each type of metastasis, weighted least squares linear regression models were used to evaluate temporal trends. Results: We identified a total of 290 eligible studies (270 phase II and 20 phase III) involving 19,110 patients. Of these, 127 studies reported data on non-osseous metastases and prior chemotherapy. There was a significant trend over time (p⫽0.001) of increasing proportions of patients with non-osseous metastasis in both chemotherapy- naïve and treated groups (1.4% per year increase). Increased lymph node, visceral, and soft tissue metastases were seen over the study period. However, the proportion of patients with liver metastasis remained relatively stable Conclusions: In this study, we noted an increasing trend of non-osseous metastatic disease in patients with mCRPC over 20 years. This included lymph node, visceral and soft tissue metastatic disease, and this trend was observed in both chemotherapy-naïve and treated patients. Longer survival and new therapies may be changing the clinical presentation of patients with mCRPC.

No CUB

Median OS, mos

AA ⫹ P n ⫽ 537 17.3

P n ⫽ 260 13.4

CUB HR (95% CI) p value 0.76 (0.63-0.92) 0.0044

AA ⫹ P n ⫽260 12.7

P n ⫽ 138 9.3

HR (95% CI) p value 0.79 (0.62-1.00) 0.0502


312s 5016

Genitourinary (Prostate) Cancer Poster Discussion Session (Board #8), Sat, 8:00 AM-12:00 PM and 12:00 PM-1:00 PM

A randomized phase II study evaluating the optimal sequencing of sipuleucel-T and androgen deprivation therapy (ADT) in biochemically recurrent prostate cancer (BRPC): Immune results. Presenting Author: Emmanuel S. Antonarakis, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD Background: ADT is a standard treatment for men with BRPC after failure of local therapy, and has immunomodulatory effects. Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic/minimally symptomatic metastatic castrate resistant prostate cancer. The STAND trial (NCT01431391) aimed to evaluate optimal sequencing of sipuleucel-T and ADT in men with BRPC at high risk for metastases (ie PSA doubling time ⱕ12 mo). Methods: Men were randomized (1:1) to Arm 1: sipuleucel-T followed by ADT (2 wks after 3rd infusion); or Arm 2: ADT (3 mo lead in) followed by sipuleucel-T. All men had 3 doses of sipuleucel-T and 12 mo of ADT (45 mg leuprolide SQ at 6 mo intervals). The primary endpoint is cellular immune response (ELISPOT to PA2024 [PAPGMCSF]). Secondary endpoints are humoral and cytokine responses, product parameters and safety. Results: 68 men were randomized. Preliminary data show higher levels of serum cytokines in Arm 2 vs Arm 1, with a pattern suggesting a mixed TH1/TH2 cellular immune response; elevations were seen in TH1 (IFN␥, IL 12), TH2 (IL 4, 5, 10, 13) and TH17 (IL 17) subsets (all P⬍.05). The increase in TH1 cytokines was consistent with a trend toward higher PA2024-specific ELISPOT responses 2 wk after the 3rd sipuleucel-T infusion in Arm 2 vs Arm 1 (40.5 vs 12.8 spots; P⫽.086), suggesting increased T cell activation in Arm 2. Antigen-specific humoral responses were induced in both arms with no differences yet observed between arms. Sipuleucel-T product parameters were roughly equivalent in both arms with APC activation data indicating a robust prime-boost effect. Conclusions: While confirmation is required, these preliminary data suggest that tumor-specific T cell responses and broad based immune responses are augmented when sipuleucel-T is given after rather than before ADT initiation. These data are consistent with preclinical studies showing that ADT enhances T cell activity, and provide preliminary evidence that combining ADT with sipuleucel-T may augment adaptive immunity. Further follow up will determine whether augmented immune responses correlate with clinical parameters (eg PSA recurrence). Clinical trial information: NCT01431391.

5018


Prostate-specific membrane antigen antibody drug conjugate (PSMA ADC): A phase I trial in metastatic castration-resistant prostate cancer (mCRPC) previously treated with a taxane. Presenting Author: Daniel Peter Petrylak, Yale University Medical Center, New Haven, CT Background: The abundant expression of prostate specific membrane antigen (PSMA) on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC is a fully human antibody to PSMA linked to the microtubule disrupting agent monomethyl auristatin E (MMAE). It binds PSMA and is internalized within the cancer cell where cleavage by lysosomal enzymes release free MMAE, causing cell cycle arrest and apoptosis. A phase 1 dose escalation study of PSMA ADC in taxanerefractory mCRPC has been completed. Methods: Patients with progressive mCRPC following taxane-containing chemotherapy and ECOG status of 0 or 1 were eligible. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Safety, pharmacokinetics, PSA, circulating tumor cells (CTC), immunogenicity and clinical progression were assessed. Serum PSMA ADC and total anti-PSMA ADC antibodies were measured by ELISA, and free MMAE was measured by LC/MS/MS.The dosing cohorts ranged from 0.4 mg/kg to 2.8 mg/kg. Subjects who benefitted from PSMA ADC were eligible for treatment in an extension study. Results: 52 subjects were dosed in 9 dose levels. All subjects received prior docetaxel, 6 also received cabazitaxel and 3 subjects also received paclitaxel. PSMA ADC was generally well tolerated with the most commonly seen adverse events being anorexia and fatigue. 16 patients reported peripheral neuropathies, including 3 with grade 3. Dose limiting toxicities (DLT) seen at 2.8 mg/kg were neutropenia (one death) and reversible elevations in liver function tests (LFTs). Antitumor activity was manifested as reductions either in PSA or in CTCs in approximately 50% of patients at ⱖ 1.8 mg/kg PSMA ADC. Exposure to PSMA ADC increased with dose and was ~1,000-fold greater than MMAE exposure. There was no accumulation. Conclusion: PSMA ADC in this study was generally well tolerated in subjects with progressive mCRPC, previously treated with taxane. Antitumor activity was seen at doses ⱖ 1.8 mg/kg. DLTs were neutropenia and reversible LFT abnormalities. The maximum tolerated dose was determined to be 2.5 mg/kg. A phase 2 trial of PSMA ADC in taxane refractory mCRPC has been initiated at 2.5 mg/kg. Clinical trial information: NCT01414283.

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Sulforaphane treatment in men with recurrent prostate cancer. Presenting Author: Joshi J. Alumkal, Oregon Health & Science University Knight Cancer Institute, Portland, OR Background: Diets high in cruciferous vegetables are strongly associated with lower prostate cancer risk. Sulforaphane is a constituent of these foods postulated to harbor the anti-neoplastic activity based on pre-clinical evidence in multiple tumor models. Our own work demonstrates that sulforaphane inhibits HDAC function and suppresses AR signaling in prostate cancer cells (Gibbs, et al PNAS 2009). However, the anti-tumor efficacy and safety of sulforaphane in men with prostate cancer was unknown. Methods: In this single arm study, we treated patients with biochemical (PSA)-recurrence of prostate cancer with 200 ␮mol of sulforaphane extracts for up to 20 weeks. The primary endpoint was PSA response rate (⬎50% decline in PSA). Other efficacy endpoints included: maximal PSA decline and percent change in PSA from baseline to end of study. We also analyzed PSA doubling time changes using a mixed effects model. Genotyping for GSTM1 that contributes to sulforaphane metabolism, sulforaphane pharmacokinetics (PK), and pharmacodynamic (PD) measurements of HDAC inhibition in mononuclear cells (MCs) were also performed. Results: Twenty patients were enrolled, and 16/20 (80%) completed the pre-planned 20 weeks of treatment. One patient experienced a PSA decline ⬎50%. Thirty-five percent of patients had lesser PSA declines (3% to 20%), and 15% of patients had a final PSA lower than baseline. There was a significant reduction in PSA doubling time (6 months pre-study vs. 9.4 months on-study, p⫽.013). Of note, testosterone levels remained non-castrate in all subjects. PK analysis demonstrated that GSTM1 null genotype correlated with longer sulforaphane T1/2 (half-life) (2.6 hours for GSTM1 null vs. 2.1 hours for GSTM1 intact, p⫽0.04). Sulforaphane treatment also increased histone acetylation in PD assays in MCs. Finally, no grade three adverse events were seen, and only one patient discontinued study treatment for toxicity (grade one GI discomfort). Conclusions: Treatment with 200 ␮mol per day of sulforaphane is feasible, safe, and inhibits HDAC function. This combined with the preliminary observation of PSA modulation, which may indicate biologic activity, provides the basis for dose escalation studies of sulforaphane in men with prostate cancer. Clinical trial information: NCT01228084.

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Randomized phase II study with window-design to evaluate anti-tumor activity of the survivin antisense oligonucleotide (ASO) ly2181308 in combination with docetaxel for first-line treatment of castrate-resistant prostate cancer (CRPC). Presenting Author: Pawel J. Wiechno, Department of Urology, Institute of Oncology, Warsaw, Poland Background: In prostate cancer, expression of survivin, a protein that inhibits apoptosis, is associated with resistance to taxanes and poor outcome. LY2181308 reduces survivin expression and consequently is expected to improve activity of taxanes, such as docetaxel. A randomized phase II study was conducted to assess the activity of the combination. Methods: Adult patients (pts) with CRPC, ECOG performance status ⬍2, and no bone or CNSmetastases were randomized 1:2 to standard docetaxel/ prednisone every 21 days (Arm A) or standard therapy combined with LY2181308 given as a 3-hr IV infusion (Arm B). Analysis was planned and performed after 130 pts progressed or died. This assessment provided a 70% chance of detecting a difference in progression-free survival (PFS) at the 10% significance level. Initially, LY2181308 was given as a loading dose (3 consecutive days) and then as a weekly 3-hr IV maintenance dose. Arm B also included a window treatment with LY2181308 monotherapy equivalent to a 21-day cycle of docetaxel before starting combined treatment. The primary endpoint was PFS. Results: This study enrolled 154 pts. The median PFS for Arm B was 8.64 (90% CI, 7.39 –10.45) months vs. 9.00 (90% CI, 7.00 –10.09) months in Arm A, showing no statistical difference (log rank p⫽0.755). The median overall survival (OS) for Arm B was 27.04 (90% CI, 19.94 –33.41) months vs. 29.04 (90% CI, 20.11– 39.26) months for Arm A (log-rank p⫽ 0.838). The PSA responses (⬎50% reduction in PSA) were similar: 56.9% for Arm A and 56.1% in Arm B (p⫽0.856). Most pts had no pain or mild pain at baseline and during the active period. Pts treated in Arm B had a higher frequency of serious and nonserious adverse events (AEs) than those in Arm A. The observed AE and pharmacokinetic (PK) profiles were consistent with the known safety and PK profiles of LY2181308 and docetaxel. Conclusions: The addition of LY2181308 to a standard docetaxel/prednisone regimen showed no improvement in PFS, PSA response, and OS in first line CRPC pts. The safety profile of docetaxel and LY2181308 is predictable and consistent with the known safety profiles. Clinical trial information: NCT00642018.


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A phase I study of the safety and pharmacokinetics of DSTP3086S, an anti-STEAP1 antibody-drug conjugate (ADC), in patients (pts) with metastatic castration-resistant prostate cancer (CRPC). Presenting Author: Daniel Costin Danila, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY

Safety of radium-223 dichloride (Ra-223) with docetaxel (D) in patients with bone metastases from castration-resistant prostate cancer (CRPC): A phase I Prostate Cancer Clinical Trials Consortium Study. Presenting Author: Michael J. Morris, Memorial Sloan-Kettering Cancer Center, New York, NY

Background: Six-transmembrane epithelial antigen of the prostate-1 (STEAP1) protein is a cell-surface antigen overexpressed in human epithelial prostate cancers. The ADC DSTP3086S contains the humanized IgG1 anti-STEAP1 monoclonal antibody linked to the potent anti-mitotic agent MMAE. Methods: This study evaluated safety, pharmacokinetics, and pharmacodynamic activity of intravenous DSTP3086S (0.3-2.8 mg/kg) given every 3 weeks (q3w) to pts with CRPC. A traditional 3⫹3 design was used to determine maximum-tolerated dose, followed by cohort expansion at the recommended Phase II dose (RP2D). Clinical activity was evaluated per PCWG criteria. Dose escalation results are presented. Results: Twentyeight pts were enrolled with a median age of 67 (43-76), all ECOG PS 0-1, and with a median of 7 prior systemic regimens (including a median of 4 hormonal and 3 non-hormonal regimens). Pts received a median of 3 doses (range 1-10) of DSTP3086S. Reversible Grade 3 transaminitis DLTs occurred in one pt each in the 2.25 mg/kg and 2.8 mg/kg cohorts. Serious AEs (SAE) related to study drug (3 total) included one DVT (Grade 3) in the 1.5 mg/kg cohort, as well as one GI hemorrhage (Grade 3) and one sepsis event (Grade 5) in the 2.25 mg/kg cohort. The most common related AEs across all doses were fatigue (36%), nausea (32%), constipation (25%), decreased appetite and diarrhea (each 21%), and musculoskeletal pain and vomiting (each 18%). Exposure for total antibody, free MMAE, and conjugated MMAE was dose proportional. Approximately 60% of the tumor samples assessed showed high STEAP1 expression. CTC reductions were most robust at 2.8 mg/kg; 4/4 patients with unfavorable CTCs at baseline (median of 99, range: 21-205) exhibited CTC conversions from unfavorable to favorable (⬍5) after a single dose of DSTP3086S. CTC conversions were also observed at lower doses. PSA decreases of ⱖ 50% were observed in 1 pt at 2.25 mg/kg, and 2 pts at 2.8 mg/kg who also had PCWG2 radiologic responses. Conclusions: DSTP3086S at the RP2D of 2.8 mg/kg q3w has a tolerable safety profile and shows evidence of anti-tumor activity. Enrollment in the expansion cohort is ongoing.

Background: Ra-223, a first-in-class ␣-emitting pharmaceutical, targets bone metastases (mets) with high-energy ␣-particles of very short range (⬍ 100 ␮m). D is an approved chemotherapy with demonstrated survival benefit for patients progressing after castrating hormone therapy. We are exploring the hypothesis that simultaneously targeting the tumor and the bone is clinically superior to targeting either alone. We therefore conducted a phase I study of Ra-223 ⫹ D in patients with CRPC and bone mets to establish the safety of the combination. Methods: Eligible patients had confirmedsymptomaticCRPC with ⱖ 2 bone mets and were candidates for treatment with D. Dose escalation followed a 3 ⫹ 3 design, with no intrapatient dose escalation or overlapping of cohorts. Patients were to receive 2 combined doses of Ra-223 q6wk ⫹ D q3wk (cohort 1: Ra-223/D ⫽ 25 kBq/kg /75 mg/m2; cohort 2: Ra-223/D ⫽ 25 kBq/kg /60 mg/m2; and cohort 3: Ra-223/D ⫽ 50 kBq/kg /60 mg/m2). Dose-limiting toxicity was assessed 6 weeks after first Ra-223 ⫹ D injection. Long-term safety data were collected every 3 months after end of study treatment for up to 1 year after start of study treatment. Results: 17 patients were treated, 7 each in cohorts 1 and 3 (1 patient in each cohort discontinued early and was replaced), and 3 in cohort 2. There was no discontinuation or delay of Ra-223 due to adverse events, and so far no reports of long-term toxicity during follow-up. 4 cases of febrile neutropenia occurred during study treatment (12 wk): 3 occurred in cohort 1 (1 was 7 days after first Ra-223 ⫹ D, and 2 were in the same subject, both occurring 1 wk after first and second doses of D alone [wk 4 and 10]); 1 occurred in cohort 3, 1 week after second Ra-223 ⫹ D (wk 7). Other safety data were as expected based on Ra-223 and D monotherapy data. Conclusions: The phase IIa regimen of Ra-223 ⫹ D utilizes a regimen of D 60 mg/m2 q3wk ⫻ 10 ⫹ Ra-223 50 kBq/kg q6wk ⫻ 5. The regimen is currently being explored in a randomized 2:1 open-label expanded safety cohort comparing Ra-223 ⫹ D versus D 75 mg/ m2 alone (standard dose). Clinical trial information: NCT01106352.

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Mortality at 120 days following prostatic biopsy: Analysis of data in the PLCO study. Presenting Author: Mathieu Boniol, International Prevention Research Institute, Lyon, France Background: With the widespread use of PSA testing for prostate cancer screening in population, more prostate biopsy are being performed and seem set to increase in number. The safety of this diagnostic procedure needs to be ascertained. Only one study evaluated the mortality following prostate biopsy (Gallina et al, Int J Cancer 2008;123:647-52) and reported an increase of 2 deaths per 1,000 biopsies. Our objective was to re-evaluate the risk of death following prostate biopsy in a large, wellconducted randomised trial – the Prostate, Lung, Colorectal and Ovary (PLCO) Study. Methods: We extracted data from the PLCO study on all men participating in the study with a follow-up until 31/12/2009. All biopsies performed since randomisation were included. Cause of death was defined by ICD9 classification. Results: Among 12,300 prostate biopsies, 36 deaths occurred within120 days: 17/8390 in the intervention arm and 19/3910 in the control group. Only 17 deaths had neoplasm listed as the underlying cause of death. Thirty-two deaths out of 9,124 (0.35%) occurred in the positive biopsy group compared to 4 out of 3,176 (0.13%) in the negative biopsy group. In this latest group, this represents 1.3 deaths per 1,000 biopsies. Deaths occurred in all age groups from 55-69 to 70-74, and there was no difference identified in age between study arms (p⫽0.45) nor between those with a prostate cancer diagnosis and those not (p⫽0.73). Conclusions: The mortality rate at 120 days following prostate biopsy of 1.3 deaths per 1,000 biopsies, in a population free of cancer, is a serious concern for the computation of benefit risk associated with PSA testing. This figure is in line with the risk reported by Gallina et al (2008) and is now based on a properly monitored population. This prostatic biopsy mortality would occur earlier than any benefit from a screening program and could reverse any potential gain from screening such as recorded in ERSPC study.


Prospective evaluation of testosterone (T) recovery and PSA relapse following 18 months of androgen deprivation (ADT) after prostatectomy (RP): Results from the TAX-3501 trial. Presenting Author: Michael Thomas Schweizer, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD Background: Surgical adjuvant trials in men with prostate cancer (PCa) employing progression free (PFS) and overall survival (OS) endpoints require large sample sizes and long-term follow-up, challenging planned study completion. Recent adjuvant trials are designed to evaluate PSA progression as the primary study endpoint. Since PSA is T-responsive, a thorough understanding of T recovery kinetics after ADT is needed. Methods: TAX-3501 was a randomized phase III adjuvant study post-RP in men with high-risk PCa (n⫽228) comparing 18 months of hormonal therapy with (CHT) or without (HT) docetaxel either immediately (I) or deferred (D). We analyzed the T recovery data in 108 patients treated with HT who had at least one post-treatment T value. Results: After a median post-treatment follow-up of 676 days (d) (interquartile range 478-847 d) 90 (83%) and 64 (59%) of men had T recovery to ⬎150 ng/dL and to baseline respectively. No significant differences in T recovery between groups were observed (Table). The median time to T recovery from the last day of treatment to ⬎150 ng/dL was 306 d (95% CI, 294-345 d) and to baseline was 487 d (95% CI, 457-546 d). The baseline T recovery in the combined docetaxel [i.e. I(CHT)⫹D(CHT)] and HT arms [i.e. I(HT)⫹D(HT)] was not significantly different at 458 d (95% CI, 336-529 d) and 535 d (95% CI, 457-749 d) respectively (HR 1.4, P⫽0.18). After a median total follow-up of 3.4 years(IQR 2.3–3.8 years) 39/228 (17%) patients had PSA progression, metastatic progression occurred in 1 patient. Conclusions: Prospective analyses of T kinetics in TAX-3501 indicate that recovery is prolonged after 18 months of HT and PSA relapses occur late. Given that PSA is androgen responsive, concomitant post-HT T monitoring is critical for understanding PSA relapse rates after HT. Further, since the correlation of PSA relapse with PFS and OS in the adjuvant setting remains poorly defined, metastasis-free survival may be a more reliable and meaningful clinical endpoint. Clinical trial information: NCT00283062. Group

Recover T >150 ng/dL No Yes (%)

Recover to baseline T No Yes (%)

I(CHT) I(HT) D(CHT) D(HT) Total

5 3 5 5 18

12 17 8 7 44

32 (86) 43 (93) 9 (64) 6 (55) 90 (83)

25 (68) 29 (63) 6 (43) 4 (36) 64 (59)


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Genitourinary (Prostate) Cancer Poster Discussion Session (Board #16), Sat, 8:00 AM-12:00 PM and 12:00 PM-1:00 PM

Impact of prostate cancer national guidelines on brachytherapy monotherapy practice patterns. Presenting Author: Yolanda Diana Tseng, Harvard Radiation Oncology Program, Boston, MA

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Treatment of prostate cancer with intermittent versus continuous androgen deprivation: A recommendation based on systematic review and metaanalysis of randomized trials. Presenting Author: Saroj Niraula, Division of Medical Oncology and Hematology, CancerCare Manitoba and University of Manitoba, Winnipeg, MB, Canada

Background: In 1999, the American Brachytherapy Society (ABS) recommended brachytherapy monotherapy (BT) be limited to low-risk prostate cancer, in part because a high-impact 1998 publication suggested that intermediate or high-risk disease had worse outcomes with BT than with external beam radiation (EBRT) or radical prostatectomy (RP). We studied temporal patterns of BT use before and after the 1999 ABS published guidelines as compared with 4 other treatment options. Methods: A retrospective analysis was performed of all men with T1c-T3cN0M0 prostate cancer treated definitively in the United States from 1990 to 2011 in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry. Logistic regression was used to estimate adjusted odds ratios (AOR) comparing BT use with other treatment groups between the 1990-1998 and 1999-2011 periods, controlling for age, disease characteristics, and clinic site type. Results: 8128 men received BT (n⫽1117), BT⫹EBRT (n⫽313), EBRT alone (n⫽596), EBRT⫹androgen deprivation therapy (ADT, n⫽613), or RP (n⫽5489) for modified D’Amico low (n⫽3506), intermediate (n⫽2938) or high-risk (n⫽1684) disease. By t-tests, BT patients were younger than either EBRT or EBRT⫹ADT patients (both p⬍0.001), older than RP patients (p⬍0.001), and had lower risk disease than men in any of the four treatment groups (all Cochran-MantelHaenszel chi-square p⬍0.001). BT comprised 6.1% and 16.6% of all treatments in 1990-1998 and 1999-2011, respectively (Pearson p⬍0.01). The odds of BT use remained increased after adjusting for potential confounders (AOR 4.50, p⬍0.001). Increased BT use was seen only among low (AOR 5.06, p⬍0.001) and intermediate-risk patients (AOR 4.59, p⬍0.001). Among men with low or intermediate-risk disease, BT use increased compared with EBRT (AORLOW 10.00; AORINT 12.66, both p⬍0.001), EBRT⫹ADT (AORLOW 2.90, p⫽0.0037; AORINT 2.15, p⫽0.0041) and RP (AORLOW 4.76; AORINT5.10, both p⬍0.001). Conclusions: Despite national guidelines to the contrary, brachytherapy monotherapy for intermediate-risk prostate cancer increased over time relative to other treatments. Further studies are needed to identify factors that contribute to this evidence-practice gap.

Background: Despite announcement of results from major randomized controlled trials(RCTs), uncertainty exists regarding benefits and/or harms of intermittent androgen deprivation (IAD) compared to continuous androgen deprivation (CAD) for treatment of prostate cancer. Based on a systematic review of evidence, our aim was to formulate a recommendation for either IAD or CAD to treat relapsing, locally-advanced or metastatic prostate cancer. Methods: We searched literature published till September 2012 from MEDLINE, EMBASE, the Cochrane Library and major conference proceedings. We included RCTs comparing IAD and CAD if they reported overall survival(OS) or biochemical/radiological time to disease progression(TTP). Revman 5.1 software was used for meta-analysis. Results: Nine stringently quality-rated studies with 5,508 patients met our criteria.OS was an endpoint in 7 studies. There were no significant differences in time-to-event outcomes between the groups in any studies. Pooled hazard ratio (HR) for OS was 1.02 (95% CI, 0.94 -1.11) for IAD compared to CAD and HR for TTP was 0.96 (95 % CI, 0.76-1.20). More prostate-cancer related deaths with IAD tended to be balanced by more non-prostate cancer related deaths with CAD. Overall quality-of-life scores did not differ significantly (except one study demonstrating supremacy of IAD) but superiority of IAD for sexual function, physical activity and general well-being was observed in most trials. Median cost savings were estimated to be 48% (approximately US $ 5,685/patient/year). Conclusions: There is fair evidence (Level-I) to recommend use of IAD instead of CAD for the treatment of men with relapsing, locally-advanced or metastatic prostate cancer who achieve a good initial response to androgen deprivation (USPSTF Grade-B Recommendation). This recommendation is based on (i) evidence against superiority of either strategy for time-to-event outcomes and (ii) substantial decrease in exposure to androgen deprivation, with saving of cost, inconvenience and potential toxicity.

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An exploratory analysis of bone scan lesion area (BSLA), circulating tumor cell (CTC) change, pain reduction, and overall survival (OS) in patients (pts) with castration-resistant prostate cancer (CRPC) treated with cabozantinib (cabo): Updated results of a phase II nonrandomized expansion (NRE) cohort. Presenting Author: Howard I. Scher, Memorial Sloan-Kettering Cancer Center, New York, NY Background: The results of 144 pts with metastatic CRPC treated in a phase II NRE cohort with daily cabo 100 mg and 40 mg starting doses have been previously reported. Substantial rates of bone scan improvement, reductions in CTC counts and pain relief were observed. To better understand the implication of these effects, the association with OS was explored. Methods: Relevant baseline variables (LDH, BSLA, visceral disease, pain, hemoglobin, CTCs) and post-treatment changes at week 6: ⱖ30% reduction in BSLA using computeraided assessment, CTC conversion (⬎5 vs. 4 or less/7.5 ml of blood), and pain intensity (7 day averaged worst pain score; BPI scale; using an IVR system) were associated with OS in 144 CRPC pts with bone metastasis who progressed within 6 months of docetaxel (D) treatment (ⱖ225 mg/m2) in either bone or soft tissue. Median OS was compared between responders and non-responders for each of the above outcomes categories using a Cox proportional hazard model. The findings were examined further after adjusting for significant baseline covariates selected from a stepwise Cox regression model. Results: See Table. Conclusions: Recognizing the limitations of associating response with survival, this retrospective analysis of decreases in BSLA, CTC conversions and reductions in pain intensity support further study in ongoing phase III trials. Clinical trial information: NCT00940225. Baseline characteristics, Nⴝ144. Median age 66 Prior therapies, % ⱖ2 prior lines therapy including docetaxel 73 Cabazitaxel 24 Abiraterone 43 Progression 8, % Gleason APC activation3,4

1 Prior to sip-T. 2 Docetaxel stop date missing for 3 pts. 3 Median (Q1,Q3). 4 Cumulative. 5 Ratio of CD54 molecules post- vs pre-incubation with PAP-GM-CSF.

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The association between pre-treatment serum 25-hydroxyvitamin D and survival in stage IV prostate cancer. Presenting Author: Pankaj G. Vashi, Cancer Treatment Centers of America, Zion, IL Background: Emerging evidence in the literature suggests a positive association between serum 25-hydroxyvitamin D [25(OH)D], a standard indicator of vitamin D status, and survival in certain types of cancer. We investigated this relationship in newly diagnosed stage IV prostate cancer patients. Methods: A case series of 54 newly diagnosed stage IV prostate cancer patients underwent a baseline serum 25(OH)D evaluation prior to receiving any treatment at our institution between Jan 2008 and Dec 2010. We defined vitamin D insufficiency as serum 25(OH)D levels of ⬍⫽32 ng/ml. Patient survival was defined as the time between date of first patient visit and date of death from any cause/date of last contact. Cox regression was used to evaluate the prognostic significance of serum 25(OH)D after adjusting for age, prostate specific antigen (PSA) and functional status. Results: Mean age at diagnosis was 59.6 years. During a median follow-up of 23.6 months, 16 deaths occurred. The mean serum 25(OH)D was 30.1 ng/ml, among whom 38 (70.4%) were insufficient in vitamin D (⬍⫽32 ng/ml). Mean overall survival was 49.4 months (95% CI: 38.1-60.7). Mean survival was 32.6 months and 62.4 months for patients in ⬍⫽32 ng/ml and ⬎32 ng/ml groups respectively (p ⫽ 0.02). On univariate analysis, patients with levels ⬎32 ng/ml had a significantly lower risk of mortality compared to those with levels ⬍⫽32 ng/ml (HR⫽0.19; 95% CI: 0.04-0.87; p⫽0.03). On multivariate analysis controlling for age, performance status and PSA, patients with levels ⬎32 ng/ml demonstrated significantly lower mortality (HR⫽0.13; 95% CI: 0.02-1.0; p⫽0.05) compared to those with levels ⬍⫽32 ng/ml. Conclusions: Higher circulating levels of serum 25(OH)D were positively associated with survival in patients with metastatic prostate cancer. While these results need to be confirmed in prospective clinical trials, our study adds to the growing body of literature on the prognostic role of serum vitamin D in cancer. Given the high prevalence of vitamin D insufficiency in prostate cancer and the fact that this insufficiency is easily correctable by supplementation, we recommend early vitamin D assessment and intervention for a potential impact on patient survival.

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Impact of concomitant bone-targeted therapies (BTT) on outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients (pts) without prior chemotherapy (ctx) treated with abiraterone acetate (AA) or prednisone (P). Presenting Author: Fred Saad, University of Montreal, Montreal, QC, Canada Background: BTT can delay symptomatic progression in cancer pts with bone metastases. In a post hoc analysis, we assessed the impact of concomitant BTT on outcomes in a recent large, multinational study in mCRPC pts without prior ctx. Methods: COU-AA-302 was a phase III trial in asymptomatic/mildly symptomatic pts with progressive mCRPC and no prior ctx. 1,088 pts were stratified by ECOG performance status (ECOG-PS, 0 vs 1) and randomized 1:1 to AA 1 g or placebo QD, plus prednisone 5 mg BID. Radiographic progression-free survival (rPFS) and overall survival (OS) were primary end points; secondary end points were times to opiate use, ctx, ECOG-PS deterioration, and PSA progression. The effect of concomitant use of BTT on all end points was assessed retrospectively using a stratified Cox regression model with factors for treatment, concomitant BTT, interaction of treatment and BTT, and baseline covariates. All data were obtained from a prespecified interim analysis at 55% OS events. Results: Median follow-up at the time of analysis was 27.1 mos. Among intent-to-treat (ITT) pts, 184/546 AA and 169/542 P pts received concomitant BTT for treatment of bone metastases, either zoledronic acid (n ⫽ 330), other bisphosphonates (n ⫽ 16), denosumab (n ⫽ 22), and/or other BTT (n ⫽ 5). In these pts, concomitant BTT use was associated with improved OS, time to opiate use for cancer pain, and time to ECOG-PS deterioration (Table). Results were similar in a sensitivity analysis including only ITT pts with bone metastases at baseline. Conclusions: In this post hoc, exploratory analysis, concomitant BTT use was associated with delayed symptomatic progression in asymptomatic/mildly symptomatic mCRPC pts. This potential clinical benefit should be investigated in prospective studies. Clinical trial information: NCT00887198. End point

Hazard ratioa (95% CI)

P value

rPFS OS Time to opiate use Time to ctx Time to ECOG-PS deterioration Time to PSA progression

0.855 (0.718-1.018) 0.754 (0.604-0.940) 0.801 (0.651-0.985) 0.916 (0.762-1.100) 0.750 (0.643-0.874) 0.878 (0.750-1.028)

0.079 0.012 0.036 0.348 ⬍ 0.001 0.105

a

BTT vs no BTT.




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Pain analyses from the phase III randomized ALSYMPCA study with radium-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients with bone metastases. Presenting Author: Sten Nilsson, Karolinska University Hospital, Stockholm, Sweden

A randomized phase II study of cediranib (CED) alone versus CED plus dasatinib (DAS) in patients (pts) with castration-resistant prostate cancer (CRPC). Presenting Author: Anna Spreafico, Princess Margaret Cancer Center, Toronto, ON, Canada

Background: Bone metastases (mets), present in ⬎ 90% of patients (pts) with CRPC, may cause severe pain. In a phase 2 dose-response study with a single injection of Ra-223, pain response was seen in up to 71% of CRPC pts with painful bone mets (Nilsson 2012). In the phase 3 ALSYMPCA study, which included 921 CRPC pts with bone mets randomized 2:1 to receive 6 injections of Ra-223 (50 kBq/kg IV) q4wk or matching placebo (Ra-223, n ⫽ 614; placebo, n ⫽ 307), Ra-223 significantly improved overall survival vs placebo (median 14.9 vs 11.3 mo; HR ⫽ 0.695) and was well tolerated. Post hoc analyses of pain parameters in ALSYMPCA are presented. Methods: The Cox proportional hazards model was used to analyze time to initial opioid use and time to EBRT. Pts with no opioid use at baseline were included in the pain analyses. All pts were included in the analysis for the prespecified endpoint time to EBRT. Concomitant opioid use was recorded from first study drug injection to 12 weeks after last injection. Pain-related QOL was analyzed based on the sum of 4 questions within FACT-P prostate cancer subscale (PCS) (Cella 2009) using ANCOVA. Results: Baseline pain characteristics were similar between the treatment groups (approximately 55% of pts had moderate to severe pain and opioid use based on WHO ladder for cancer pain). Time to EBRT was significantly longer with Ra-223 vs placebo (HR ⫽ 0.670; 95% CI, 0.525-0.854). Despite a longer observation time, fewer Ra-223 pts (50%) than placebo pts (62%) reported bone pain as an AE. At baseline, 269 Ra-223 pts and 139 placebo pts did not use opioids. Median time to initial opioid use was significantly longer in the Ra-223 group, with a risk reduction of 38%, compared to placebo (HR ⫽ 0.621; 95% CI, 0.4560.846). Fewer Ra-223 pts (36%) than placebo pts (50%) required opioids for pain relief. The QOL pain score indicated reduced pain for Ra-223 pts relative to placebo pts at week 16 (P ⫽ 0.001). Ra-223 pts had significant pain reduction relative to baseline at weeks 16 (P ⬍ 0.001 ) and 24 (P ⫽ 0.001). Conclusions: These results provide consistent evidence that, in addition to prolonging survival, Ra-223 reduces pain and opioid use in CRPC pts with bone mets. Clinical trial information: NCT00699751.

Background: Activation of the Vascular Endothelial Growth Factor Receptor (VEGFR) and the oncogenic Src pathway has been implicated in the development of CRPC in preclinical models. CED and DAS are multi-kinase inhibitors targeting VEGFR and Src respectively. Phase II studies of CED (Karakunnel et al ASCO 2009) and DAS (Yu et al Urology 2011) in CRPC have shown single agent activity. Methods: Docetaxel-preteated CRPC pts were randomized to arm A: CED alone (20 mg/day) vs arm B: CED (20 mg/day) plus DAS (100 mg/day) given orally on 4-week cycles. Primary endpoint was 12 week progression-free survival (PFS) as per the Prostate Cancer Clinical Trials Working Group (PCWG2). Patient reported outcomes were evaluated using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and Present Pain Intensity (PPI) scales. Correlative studies of bone turnover markers (BTM), including bone alkaline phosphate (BAP) and serum beta-C telopeptide (B-CTx) were serially assayed. Results: 22 patients, 11 per arm, were enrolled. Baseline demographics were similar in both arms. Median number of cycles ⫽ 4 in arm A (range 1-12) and 2 in arm B (range 1-9). Twelve-week PFS was 73 % in arm A vs 18 % in arm B (p ⫽ 0.03). Median PFS in months (arm A vs B) was: 5.2 vs 2.6 (95% CI: 1.9-6.5 vs 1.4-not reached). Most common grade 3 toxicities were hypertension, anemia and thrombocytopenia in arm A and hypertension, diarrhea and fatigue in arm B. One treatment-related death (retroperitoneal hemorrhage) was seen in arm A. FACT-P and PPI scores did not significantly change in either arm. No correlation between BTM and PFS was seen in both arms A and B. Conclusions: Although limited by small numbers, this randomized study showed that the combination of VEGFR and Src targeted therapy did not result in improved efficacy and may be associated with a worse outcome than VEGFR targeted therapy alone in pts with CRPC. Clinical trial information: NCT01260688.

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Use of bone scans during initial prostate cancer (CaP) workup, downstream procedures, and associated Medicare costs. Presenting Author: Aaron David Falchook, The University of North Carolina at Chapel Hill, Chapel Hill, NC Background: Bone scans are not recommended in the routine workup for patients with apparent low and intermediate risk CaP. We quantified the use of bone scans in low and intermediate risk patients, uses of other imaging and procedures after the bone scan, and costs to Medicare. Methods: Patients in the Surveillance Epidemiology and End Results (SEER)-Medicare database diagnosed with CaP from 2004 to 2007 were included. PSA, Gleason score and clinical T stage were used to define D’Amico risk categories. Patients with metastatic disease were included because the decision to order a staging bone scan for patients with apparent low and intermediate risk cancers occurs before knowledge about metastasis. We report use of bone scans from the date of diagnosis to the earlier of treatment or 12 months. In patients who received bone scans, we report use of X-ray, CT, MRI, and bone biopsy following bone scan to the earlier of treatment or 12 months. Cost was estimated using Medicare reimbursement rates. Results: 28% and 47% of patients with apparent lowand intermediate-risk prostate cancer received a bone scan (Table); ⬍1% of these patients were found to have metastatic disease after work-up. A high proportion of patients had other imaging studies or biopsies after bone scan. For low and intermediate risk patients, the combined cost to Medicare of bone scan, X-ray, and bone biopsy as part of initial workup is estimated at $11,000,000 per year. The cost from CT and MRI after bone scan costs Medicare approximately $15,400,000 per year. Conclusions: Overuse of bone scans is common in workup of apparent low and intermediate risk CaP, even with an almost 0% risk of metastatic disease. X-rays, bone biopsies, and perhaps additional scans such as CT and MRI may result from bone scan findings, which are mostly false positives for these patients. These unnecessary procedures are costly to Medicare. Apparent risk group Total number of patients Percentage receiving bone scan Percentage with metastatic disease

Low

Intermediate

High

11,443 28 0.1

16,512 47 0.7

19,821 62 12.1

Percentage receiving scans and procedures after bone scan X-ray 20.8 19.6 CT 43.4 42.3 MRI 8.5 7.5 Bone biopsy 0.4 1.0

14.8 39.4 7.3 5.0


Phase II trial of intravenous carboplatin (C), oral everolimus (E), and prednisone (P) in docetaxel-pretreated (DP) metastatic castrate-resistant prostate cancer (mCRPC): A Prostate Cancer Clinical Trials Consortium study. Presenting Author: Muthu Kumaran Veeraputhiran, Karmanos Cancer Institute, Wayne State University, Detroit, MI Background: A phase II clinical trial was conducted of the combination of C and E due to the synergy noted. Methods: The primary endpoint was time to progression (TTP). Intravenous C at a target AUC of 5 on day 1, and oral E 5mg once daily and P 5mg twice daily were administered in 21 day cycles. PSA was assessed every 21 days and radiologic response was assessed every 3 cycles. Secondary endpoints included overall survival (OS), the correlation of TTP with phosphorylated (p) mTOR, pAKT, p70S6, and circulating tumor cells (CTC). A 1-stage study design assumed: a reference median TTP ⫽ 1.5 months; 1-sided alpha ⫽ 0.15; and power ⫽ 0.90, requiring 26 patients (pts). Results: 26 pts enrolled; median age 69 years (range 54-86) ;8 African American and 18 Caucasians. Median pretherapy PSA was 190 ng/ml (range 13 - 2174). 18 pts (69%) each had bone pain and Gleason score ⬎ 8. 125 cycles have been administered; median 3 cycles (range 1 - 16). Predominant grade 3 or 4 toxicities were thrombocytopenia in 8 pts, pulmonary embolism in 2 and neutropenia in 3. No treatment related deaths occurred. 4 (15%) had a ⬎ 30% PSA decline and 1 had a ⬎90% PSA decline. 8/19 pts had stable disease but no objective responses in MD. The median TTP and OS were 2.5 months (90% CI: 1.8 4.3), and 12.5 months (90% CI: 6.7 - 16.1), respectively. Median area under curves were 5.9 (range, 4.3 – 11.0) and 4.5 (range, 4.1 – 7.1) mg/mL*min with C given alone and in combination with E, respectively. E did not influence pharmacokinetics of C. Median baseline CTC (n⫽18) was 30 (range 0-2372). 5/18 pts had favorable CTC (CTC⬍5/7.5 mL) pretherapy. Patients with TTP ⬎18 weeks had reduction in post-therapy CTC with a median decrease of 63% (range 11%-100%). Lack of IHC staining for pAKT was noted in 2/2 pts on therapy for ⬎ 30 weeks vs increased expression was noted in 8/8 pts on therapy for ⬍ 9 weeks. Testing for TSC1 mutation is planned and will be reported. Conclusions: The combination was tolerable but revealed modest clinical efficacy. Biomarker evaluations such as pAKT may help identify a subset likely to benefit from mTOR inhibitor strategy in mCRPC. Clinical trial information: NCT01051570.


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Genitourinary (Prostate) Cancer General Poster Session (Board #36A), Mon, 8:00 AM-11:45 AM

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NCIC CTG, IND-205: A phase II study of PX-866 in patients with recurrent or metastatic castration-resistant prostate cancer (CRPC). Presenting Author: Sebastien J. Hotte, Juravinski Cancer Centre, Hamilton, ON, Canada

Value of cell cycle progression (CCP) score to predict biochemical recurrence and definitive post-surgical pathology. Presenting Author: Thorsten Schlomm, Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Background: PX-866 is an irreversible, pan-isoform inhibitor of Class I PI-3K. Mutations in PIK3CA and loss of PTEN activity lead to activation of AKT signaling; alterations in these genes occur frequently in prostate cancers while activation of the PI-3K/AKT signaling pathway is implicated in prostate cancer progression and treatment resistance. Hence, novel inhibitors of the pathway such as PX-866 are of interest. Methods: In this multicenter, two-stage, phase II study, docetaxel-naïve CRPC pts received PX-866, 8mg daily on a 6-week cycle. Primary endpoint was lack of progression at 12 weeks (PCWG2 criteria). Secondary endpoints included PSA and objective response rates and change in circulating tumor cells (CTC) during treatment. If ⱕ5 of the first 20 pts were progression free at 12 weeks, the study would stop. Otherwise, 40 pts would be accrued and PX-866 deemed worthy of further study if ⱖ16 pts were progression free at 12 weeks. Results: 43 pts were accrued after the criteria to progress to stage 2 were met. Median age was 70, ECOG PS was 0/1/2 in 27/15/1 pts, 23 pts had measurable disease, 24 patients had CTC ⱖ5. Median number of cycles was 2 (range 1– 8). Most common adverse events (AE) were diarrhea (27 pts), nausea (25), fatigue (15), vomiting (13), anorexia (15) and grade 1 hypomagnesemia (11); 7 pts discontinued because of toxicity (3 GI, 3 LFTs, 1 fatigue). Grade 3 AEs were diarrhea (5 pts), AST/ALT elevation (4), fatigue (3). 11 patients were progression free at 12 weeks. 16 of the 24 pts with measurable disease were evaluable for response; there were no objective responses but 10 pts had stable disease (2.6-13.9m). One pt had a confirmed PSA response. CTC favorable conversion (from 5 at baseline to ⬍5) was observed in 6/24 evaluable patients (25%). Correlative studies are ongoing. Conclusions: PX-866 is well tolerated and showed modest activity in CRPC but did not meet a priori benchmarks for further development as a single agent in unselected patients. As androgen receptor inhibition promotes PI3K activity in PTEN-loss PC models, the addition of PX-866 in pts whose PSA is rising on abiraterone may reverse resistance and phase B of the study is underway to test this hypothesis clinically. Clinical trial information: NCT01331083.

Background: Prostate cancer (PCA) has a highly variable natural history and better tools are needed to more appropriately match treatment to a patient’s risk of progression. A prognostic mRNA expression signature composed of genes involved in cell cycle progression (CCP) has been previously developed. Here, we tested the utility of this signature to predict biochemical recurrence (BCR) and definitive post-surgical pathological stage. Methods: The eligible patient population was treated for PCA by radical prostatectomy at a single high volume center (2005-2006). We randomly selected 390 patients for the study. From each patient we prepared a ‘simulated biopsy’ by removing a tissue cylinder (0.6mm) from the post-surgical FFPE block containing the largest tumor foci. 249 patients remained eligible for analysis after excluding patients for either insufficient tumor in the biopsy, poor quality molecular data, or receiving neoadjuvant therapy. The median follow-up time for patients who did not recur was 60.8 months. 46 patients experienced BCR. CCP scores were generated as in previous studies. Cox PH models and logistic regression were used to evaluate CCP associations with outcome. Results: The CCP signature was a highly significant univariate predictor of BCR (HR⫽2.03; 95%CI: 1.48-2.79; p⫽3.1x10-5). After adjusting for clinical parameters including biopsy Gleason and PSA, the hazard ratio for CCP score remained significant (HR⫽1.6; 95%CI: 1.15-2.24; p⫽0.0068). In a multivariate model including PSA, biopsy Gleason, and clinical stage, CCP score was also an independent predictor of pathological stage (pT2 vs. pT3, p⫽0.029). In this analysis, PSA was the most predictive variable, but CCP score and clinical stage also provided important and non-redundant information. Conclusions: The CCP score has predicted PCA outcomes in multiple patient cohorts and different clinical settings. In this study, we have extended the demonstrated clinical utility to a modern patient cohort from Europe, and for the first time, provided evidence that the score can be used to predict definitive post-surgical tumor stage. The CCP expression score is an emerging and important component in evaluating PCA prognosis.

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The impact of technology diffusion on treatment for prostate cancer. Presenting Author: Florian Rudolf Schroeck, University of Michigan, Department of Urology, Ann Arbor, MI

Automated quantum dots ISH assay for detection of ERG rearrangement and PTEN deletion in prostate cancer. Presenting Author: Lei Tang, Ventana Medical Systems, Inc., Oro Valley, AZ

Background: Robotic prostatectomy and intensity modulated radiotherapy (IMRT) hold the promise of improving cancer control and minimizing side-effects for patients with prostate cancer, but are associated with significant upfront investments. Many worry that the perceived advantages of these new technologies and the need to recoup start-up costs could shift decision making in favor of local therapy in lieu of expectant management. In this context, we examined the association of market-level technology penetration with receipt of local therapy. Methods: We used the Surveillance Epidemiology and End Results (SEER) - Medicare linked database to identify all patients with loco-regional prostate cancer who were treated or managed expectantly from 2003 to 2007 (n⫽59,241). We measured technology penetration as the number of providers performing robotic prostatectomy or IMRT per population in a market (hospital referral region). We then performed multinomial logistic regression to examine the association of technology penetration with receipt of prostatectomy, radiotherapy, or no local therapy. Results: For each 1,000 patients diagnosed with prostate cancer, 171 underwent prostatectomy, 493 radiotherapy, and 336 had no local therapy. Markets with high robotic prostatectomy penetration had higher use of prostatectomy (175 vs. 141 per 1,000 men, p⫽0.004) but decreased use of radiotherapy (584 vs. 613 per 1,000 men, p⫽0.046), resulting in a stable rate of local therapy (Table). High versus low IMRT penetration did not significantly impact use of prostatectomy and radiotherapy (Table). Conclusions: Increased penetration of robotic surgical technology was associated with more use of prostatectomy and less use of radiotherapy. However, increased penetration of both robotic prostatectomy and IMRT did not change the overall rate of local therapy. Our findings allay concerns that new technology spurs additional local therapy of prostate cancer.

Background: ERG rearrangement and PTEN deletion are the two most common genomic events in prostate cancer. Overexpression of the ERG protein caused by rearrangement of the ERG gene has been frequently associated with more aggressive prostate cancers and a poor prognosis. PTEN genomic deletion and absence of PTEN expression are associated with unfavorable clinical outcome. To detect ERG rearrangement and PTEN deletion simultaneously, we developed a four-color multiplex ISH assay using non-organic quantum dots (QD). The photo-stability and narrow emission spectra of QDs makes them desirable for ultrasensitive and multiplexing ISH applications. The automated QD ISH assay allows adequate delivery of QDs to nuclear targets and reproducible detection of ERG and PTEN gene targets. Methods: DNA probes specific for ERG 5’, ERG 3’, PTEN and CEN 10 were labeled with different haptens, digoxigenin (DIG), dinitrophenyl (DNP), thiazole sulfonamide (TS), or nitropyrazole (NP). QDs with 565, 655, 605 and 525nm wavelengths were conjugated to the anti- DIG, DNP, TS or NP antibodies, respectively. The multiplex QD ISH assay was fully automated on the VENTANA BenchMark ULTRA. FFPE prostate tissue slides were hybridized with the labeled probes. The probes were then detected by the QD-conjugated antibodies and visualized under fluorescent microscope. Results: We performed the multiplex QD ISH assay on 386 slides with tissue sections from 10 prostate specimens on 13 BenchMark ULTRA instruments. The 10 cases consisted of either benign prostate tissues or prostate cancer, positive or negative for ERG rearrangement and/or PTEN deletion. 350 (91%) of the slides were successfully stained for all 4 molecular targets. The expected ERG and PTEN status were detected with high reproducibility. Conclusions: We developed an automated QD based multiplex ISH assay to simultaneously detect ERG rearrangement and PTEN deletion in prostate cancer. The assay is highly sensitive and reproducible. It enables investigation of potential clinical use of ERG and PTEN as predictive or prognostic markers. In addition, the same technology is expected to enable multiplex in situ detection of other molecular biomarkers using standard clinical specimens.

Adjusted number of patients treated per 1,000 diagnosed. Type of treatment

Robotic prostatectomy penetration

Surgery Radiation No local therapy

Low 141 613 246

High 175 584 241

p 0.004 0.046 0.540

IMRT penetration Low 154 596 250

High 154 606 240

p 0.995 0.571 0.263




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ASP9521, a novel, selective, orally bioavailable AKR1C3 (type 5, 17ßhydroxysteroid dehydrogenase) inhibitor: In vitro and in vivo characterization. Presenting Author: Aya Kikuchi, Astellas Pharma US, Inc., Ibaraki, Japan

A randomized phase II trial of sipuleucel-T with concurrent or sequential abiraterone acetate (AA) plus prednisone (P) in metastatic castrateresistant prostate cancer (mCRPC). Presenting Author: Eric Jay Small, University of California, San Francisco, San Francisco, CA

Background: Aldo– keto reductase 1C3 (AKR1C3), also known as type 5, 17␤-hydroxysteroid dehydrogenase, is reported to be highly expressed in human normal prostate and prostate cancer (PC) and the expression increases along with increasing malignancy or grade of PC. Since AKR1C3 converts the adrenal androgen, androstenedione (AD) into testosterone (T), combination with a GnRH analogue and AKR1C3 inhibitor would be expected to provide total androgen blockade in the treatment of castrationresistant prostate cancer (CRPC). We obtained a lead compound having a non-steroidal scaffold by high throughput screening (HTS) approaches for targeting enzyme activity of AKR1C3. After optimization of the lead compound, we found ASP9521 as a potent, selective, and orally bioavailable AKR1C3 inhibitor. Methods: The inhibitory effect of ASP9521 on enzymatic conversion from AD to T by AKR1C3 was evaluated in vitro, and in CWR22R xenograft models. Effect of PSA production and proliferation on LNCaP cells stably expressing AKR1C3 was examined. Pharmacokinetics in various animals were also investigated. Results: ASP9521 showed potent inhibitory effect on enzymatic conversion from AD to T by both human AKR1C3 and cynomolgus monkey homologues in a concentrationdependent manner, with IC50 values of 11 and 49 nmol/L, respectively ASP9521 suppressed both AD-dependent PSA production and cell proliferation in LNCaP cells exogenously expressing AKR1C3 in vitro. The bioavailability of ASP9521after oral administration of 1mg/kg were 30% and 78% in rat and dog, respectively. Furthermore, ASP9521 single oral administration of 3 mg/kg suppressed AD-induced intratumoral T production in CWR22R xenografted castrate nude mice, and this inhibitory effect was maintained for 24 h. In addition, ASP9521 was rapidly eliminated from plasma after oral administration while its intratumoral concentration remained high in tumors expressing AKR1C3. Conclusions: These preclinical in vitro and in vivo data are consistent with a potent inhibition of 17␤-hydroxysteroid dehydrogenase. The results suggest that ASP9521 should be investigated further to elucidate its role as treatment for PC.

Background: Sipuleucel-T and AA ⫹ P are FDA-approved for asymptomatic/ minimally symptomatic mCRPC. Suppression of the androgen axis can be immunostimulatory and AA suppresses circulating androgen levels; AA plus sipuleucel-T may therefore be synergistic. However P used with AA, which may be immunosuppressive, has not been studied with concurrent sipuleucelET and could impair sipuleucel-T production and/or immunologic response. P11-3 (NCT01487863) is the 1st study to evaluate the combination of sipuleucel-T and AA ⫹ P Methods: Patients (pts) with asymptomatic/minimally symptomatic mCRPC were randomized (1:1) to sipuleucel-T (3 infusions at approx 2-wk intervals) with up to 26 wks of AA ⫹ P (AA 1000mg QD ⫹ P 5mg BID) starting 1 day after the 1st sipuleucel-T infusion (concurrent, arm A) or at 10 wks following the 1st sipuleucel-T infusion (sequential, arm B). Endpoints included the effect of AA ⫹ P on product (sipuleucel-T) characteristics eg antigen presenting cell (APC) activation, measured as CD54 upregulation (primary endpoint), APC (measured as CD54⫹ cells) and total nucleated cell (TNC) counts, as well as safety and immunologic responses. Results: 31 pts in arm A and 32 pts in arm B completed sipuleucel-T treatment by the interim analysis (Nov 2012). Baseline characteristics were similar in the 2 arms. 60/63 pts received all 3 infusions of sipuleucel-T. No significant differences in median cumulative APC activation, APC count or TNC count were seen between the arms. Increased CD54 upregulation with the 2nd and 3rd treatments were indicative of a prime boost effect in both arms. Similar profiles of antigen-specific humoral and cellular immune responses were generated with no difference in magnitude of response between the arms (p⬎0.05). The incidence of adverse events (AEs) and serious AEs was similar in both arms. Conclusions: These data suggest sipuleucel-T can be successfully manufactured during concurrent AA ⫹ P. Product potency and prime boost effect were similar to sipuleucel-T alone. Immune responses and AEs were similar in both arms. It is not known if sipuleucel-T will provide similar efficacy with concurrent or sequential AA ⫹ P. Clinical trial information: NCT01487863.

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The ELDORADO study: A phase II randomised study of concurrent weekly docetaxel, IMRT, and ltadt in patients with high-risk prostate cancer. Presenting Author: Derek Wilke, Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada Background: Treatment intensification is warranted for ‘high risk’ prostate cancer. Docetaxel (DO) and radiotherapy (IMRT) may cause dose-limiting GI or GU toxicity. Treating the whole pelvis last (WP-L) versus the whole pelvic lymphatics first (WP-F) could reduce the number of dose delays or omissions of DO. Methods: We performed a double-blind, randomized trial, in patients with ‘high risk’ non-metastatic prostate cancer who had any one of the following: 1) ⱖ T2c TNM category, 2) Gleason score ⱖ 8, or PSA ⬎ 20 and ⬍ 50 ␮g/L, OR have a greater than 50% risk of recurrence after radical prostatectomy (RP), as predicted by the Kattan nomogram, with no evidence of metastatic disease. Patients receive long-term androgen deprivation therapy (LTADT), and after 4 months of neoadjuvant ADT, receive IMRT and concurrent DO 20 mg/m2 x 8 weekly infusions. Patients were randomized to receive WP-F followed by a boost to the prostate/ prostate bed, or to have WP-L. The primary outcome was to compare the number of DO dose reductions, delays or omissions due to GI or GU toxicity, between arms. Target sample size was 86 patients (pts). Results: 98 pts were registered, 88 were randomized, 2 withdrew consent, leaving 42 pts randomized to WP-F, and 44 pts to WP-L. The trial was closed to accrual Feb 2, 2012. Twenty-five pts had previous RP (29%). Seven pts (16.6%) allocated to WP-F had chemotherapy dose reductions/delays versus 3 pts (6.8%) allocated to WP-L , which was not statistically significant (p⫽0.19). Overall 80.2% of pts received all 8 weekly doses of DO and IMRT (WP-F vs. WP-L: 78.6% vs.81.8%, p⫽0.9). Actuarial overall survival at 4 years is 96 % (WP-F vs. WP-L: 94% vs.97%, p⫽0.6). Biochemical relapse-free survival at 4 years is 96.7% (WP-F vs. WP-L: 98% vs.97%, p⫽0.92). Two patients have needed surgical intervention for Grade ⬎ 3 GU toxicity. Cumulative treatment-related grade 3 or 4 GI or GU toxicity was 36%. When patients were last seen, only 2/84 (2.3%) patients had ongoing grade 3 GI or GU toxicity at a median follow up of 2.7 years Conclusions: Concurrent use of DO and IMRT is feasible with reasonable toxicity. Sequence inversion does not enhance chemotherapy delivery. Clinical trial information: NCT00452556.


A phase I/II study of cabazitaxel (Cbz) combined with abiraterone acetate (AA) and prednisone (P) in patients (pts) with metastatic castrationresistant prostate cancer (mCRPC) whose disease has progressed after docetaxel (D) chemotherapy: Preliminary results. Presenting Author: Christophe Massard, Institut Gustave Roussy, Villejuif, France Background: Both Cbz and AA have demonstrated significantly improved survival in randomized Ph 3 studies in pts with mCRPC and progressive disease after D treatment. Cbz and AA have established non-overlapping adverse event (AE) profiles. A Ph 1/2 study was initiated to investigate the combination of Cbz ⫹ AA for the treatment of mCRPC (NCT01511536). Methods: Pts with progressive mCRPC after D were enrolled. The primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz ⫹ AA (Ph 1), and the PSA response rate (RR) with this combination (Ph 2). Secondary endpoints included AEs, pharmacokinetics (PK) and efficacy. All pts received oral AA 1000 mg QD and P 5 mg BID. In Ph 1, pts received 1 of 2 dose levels (DL) of Cbz (20 and 25 mg/m2 IV Q3W) according to a 3⫹3 design. A 2-cycle DLT observation period was used. Here, we report results of Ph 1. Results: Ten pts were enrolled in Ph 1; 9 were evaluable: 3 at DL1 and 6 at DL2 completed 2 cycles without DLTs (total number of cycles ⫽ 46). In general, AEs were Grade (Gr) 1/2; the most frequent all-Gr AEs by pt cycle were asthenia (39%), diarrhea (37%; Gr 3 in 1 pt), back pain (26%), nausea (20%), constipation (20%), anemia (17%), decreased appetite (17%) and fatigue (15%; Gr 3 in 2 pts). In the safety population, 0/3 pts at DL1 and 2/7 pts at DL2 experienced Gr 3– 4 neutropenia. The MTD was established at the full approved doses of both drugs (Cbz 25 mg/m2/AA 1000 mg). In 6 pts evaluable for PK (DL1 and DL2), median Cbz clearance (coefficient of variation %) was similar at cycle 1 (Cbz alone: 28.9 L/h/m2 [11%]) and cycle 2 (Cbz ⫹ AA coadministration: 28.6 L/h/m2 [42%]). In 9 evaluable pts, 55% PSA RR was observed. Conclusions: In this Ph 1 study, Cbz in combination with AA appeared to have a manageable safety profile. Gr 3– 4 neutropenia was observed in 2 of 10 patients. Daily AA treatment did not affect Cbz clearance; Cbz exposure was comparable to previous studies of Cbz ⫹ P treatment. The Ph 2 portion is ongoing at the established MTD. Detailed safety, PK and preliminary efficacy data (Ph 1) will be presented. Clinical trial information: NCT01511536.


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Clinical outcome (CO) evaluation of very old (> 80 years) castration resistant prostate cancer (CRPC) patients (pts) treated with docetaxel (DOC): Preliminary results of an Italian multicenter retrospective study (DELPHI study). Presenting Author: Francesca Maines, Medical Oncology Department, Trento, Italy Background: Since prostate cancer is mainly diagnosed in pts over 65 yrs of age, castration resistance is usually observed in older pts. In the case of very old pts (ⱖ 80 years), fear of high toxicity degree limit chemotherapy use due to both pts frailty and several comorbidities occurrence. Moreover, if treated these pts usually receive an adapted chemotherapy, often with a weekly schedule, which in TAX327 trial failed to show survival advantage compared to mitoxantrone. The present retrospective study is aimed to assess CO in this very elderly CRPC population. Methods: In this multicentric retrospective study, after Ethical Committee approval, we have reviewed the clinical records of all ⱖ 80 yrs CRPC pts from participating institutions, treated with DOC in clinical practice, recording the pre and post-DOC clinical history, the DOC treatment details and outcomes. Results: To date we collected a consecutive series of 81 pts from 17 Italian hospitals. The median age was 82 yrs (range 80-90). The median baseline PSA was 107 ng/ml (range 3-1597); 81% of the pts had bone metastases, while nodal, lung and liver metastases were observed in 37%, 6%, and 6% of the pts, respectively. Median Cumulative Illness Rating Scale score was 3 (range 0-11), median Activity Daily Living index score was 0 (range 0-5), median Instrumental Activities of Daily Living score was 0 (range 0-5). The DOC was administered on 3-week or weekly schedule basis (41%/59%). A PSA reduction ⬎ 50% and an objective response were observed in 74% and 11% of the pts, respectively. Grade 3-4 toxicities were: neutropenia (11%) , fatigue (8%), diarrhea (1%), renal (2%), and febrile neutropenia (1%). The median PFS and OS were 7 mos and 22 mos, while the 1-year PFS and OS rates were 17.3% and 43.9%, respectively. Conclusions: This data suggests that DOC treatment, both on 3-week or weekly schedule, is able to produce good survival outcomes, comparable to pivotal trials (18 mos), also in highly selected very older (ⱖ 80 yrs) CRPC pts.

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Detecting lower in addition to the highest Gleason score prostate cancer on core biopsy and the risk of prostate cancer-specific mortality. Presenting Author: Ayal A. Aizer, Harvard Radiation Oncology Program, Boston, MA Background: We evaluated the risk of prostate cancer-specific mortality (PCSM) following definitive treatment in men with at least one prostate biopsy core with a Gleason score (GS) lower than the highest GS identified. This pattern termed “ComboGS” in a concurrent submission was shown to be associated with a significant reduction in the odds of upgrading at radical prostatectomy (RP). Methods: In this validation cohort 666 men with localized or locally advanced prostate cancer, men were diagnosed via a transrectal, ultrasound-guided needle prostate biopsy (median 6, IQR 5-6 cores) and treated definitively between 1989-2000 with either RP or radiation (RT) or RT and hormones (HT) at a regional radiation oncology center. Patients could be referred into this center from 6 community based hospitals in Southeastern Massachusetts and Rhode Island. Community based pathologists from these 6 health care facilities assigned the biopsy GS used for the analyses in this study. Multivariable competing risks regression was performed (Table) to assess the impact of ComboGS on the risk of PCSM adjusting for age, established PC prognostic factors, and treatment. Results: After a median follow up of 4.6 years (IQR 2.5-6.7 years), 168 men (25.2%) died, 41 (24.4%) of PC. ComboGS was associated with a decreased risk of PCSM (Adjusted Hazard Ratio (AHR) 0.40, 95% Confidence Interval (CI) 0.19-0.85, p⫽.017). Estimates of PCSM were significantly lower in men with versus without ComboGS when the highest GS was ⱖ7 (p⬍.001) but not 6 or less (p⫽.71). Specifically these 5-year estimates were 14.4% and 4.8% versus 1.9% and 2.7% respectively. Conclusions: In addition to lower odds of upgrading at RP, using an independent data set the ComboGS assessed by community based pathologists serving 6 hospitals was found to also be associated with a decreased risk of PCSM. Clinical factor

AHR [95% CI]

p

Present Absent

0.40[0.19, 0.85] 1.0

.017 -

RT RP RT⫹HT

0.94[0.34, 2.65] 1.21[0.23, 6.43] 1.0 2.63[1.71, 4.06]

.91 .82 ⬍.001

8-10 7 6 or less

10.73[3.57, 32.31] 3.59[1.27, 10.16] 1.0

⬍.001 .016 -

T3-4 T2 T1c

0.67[0.17, 2.68] 1.12[0.51, 2.46] 1.0 1.04[0.98, 1.10]

.57 .78 .22

ComboGS Treatment

PSA(log) Gleason score

Tumor stage

Age

5052


First-in-human phase I study of EZN-4176, a locked nucleic acid antisense oligonucleotide (LNA-ASO) to androgen receptor (AR) mRNA in patients with castration-resistant prostate cancer (CRPC). Presenting Author: Diletta Bianchini, The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom Background: EZN-4176 is a third generationLNA-ASO that binds the ligand binding domain of AR mRNA resulting in full length AR mRNA degradation and decreased AR protein expression. Methods: Patients (pts) (performance status ECOGⱕ1) with progressing CRPC were eligible; prior abiraterone and enzalutamide treatment were allowed. EZN-4176 was administered as a weekly (QW) one-hour intravenous infusion. The starting dose was 0.5 mg/Kg with a 4-week dose-limiting toxicity (DLT) period. After determination of the DLT and the maximum tolerated dose (MTD) for weekly administration, a fortnightly schedule (Q2W) was initiated; a 3⫹3 modified Fibonacci dose escalation design was pursued. PD studies evaluated AR expression in tissue utilizing antibodies to the amino and carboxy-termini of the AR. Results: 22 pts were enrolled (median age 70.6 years, range 59 – 84 years). One pt was treated with the Q2W schedule. Two DLTs (G3/G4 ALT/AST elevation) occurred at 10 mg/Kg, which was therefore identified as the MTD for the weekly schedule. Multiple pts treated at 6.5 and 10 mg/Kg (5/9 pts, 55%) developed ⱖG2 ALT and/or AST elevation after the first cycle requiring dose reduction and treatment delay. The most frequent adverse events (AEs) all-grades were fatigue (21/22 pts, 95.4%), nausea (10/22 pts, 45.4%), constipation (8/22 pts, 36.3%), AST (8/22 pts, 36.3%) and ALT (10/22 pts, 45.4%) elevation. The most frequent G3/4 AEs were AST (4/22 pts, 18.1%) and ALT (5/22 pts, 22.7%) elevation. Maximum PSA and circulating tumor cells (CTCs) declines are summarized below. There were no objective soft tissue responses. PD studies did not document any knockdown of AR expression Conclusions: EZN-4176 has limited antitumour activity in CRPC at its MTD for weekly administration. Safety, PK, PD and efficacy data will be presented. Clinical trial information: NCT01337518.

EZN-4176 dose (mg/Kg QW) 0.5 1 2 4 6.5 10 10 *

N

PSA decline > 50%

PSA decline > 30%

CTC conversion from baseline >5 to 30% (N/Eval. pts) 0/0 0/0 0/1 0/3 1/1 (100%) 1/3 (33%) 0/0

5053^


Open-label, multicenter study of sipuleucel-T in men with metastatic castrate-resistant prostate cancer (mCRPC) previously treated with sipuleucel-T: Evaluation of antigen presenting cell (APC) activation and ELISPOT data. Presenting Author: Tomasz M. Beer, Oregon Health & Science University Knight Cancer Institute, Portland, OR Background: P10-1 (NCT01338012) is a study of sipuleucel-T, an autologous cellular immunotherapy, in men with mCRPC previously treated with sipuleucel-T in PROTECT (NCT00779402). This preliminary analysis of P10-1 evaluates APC activation (a measure of product potency) and immune responses in men retreated with sipuleucelET. Methods: Men who received ⱖ1 infusion of sipuleucel-T in PROTECT and progressed to mCRPC were retreated with 3 infusions of sipuleucel-T. APC activation was assessed by CD54 upregulation. T cell responses to prostatic acid phosphatase (PAP) and PA2024 (PAP-GM-CSF) antigens were assessed by IFN␥ELISPOT assay. Results: As of October 23, 2012, 7 men were enrolled and received ⱖ1 infusion. Median time between the third PROTECT infusion and first P10-1 infusion was 9.2 (range: 7.8 –10.0) years. APC activation was greater at the first P10-1 treatment vs the last PROTECT treatment (Table). PA2024 and PAP ELISPOT responses were present prior to retreatment, indicating long-term memory (Table 1); based on other studies of sipuleucel-T, ELISPOT responses are not generally present prior to the first treatment (Beer. Clin Cancer Res 2011; Sheikh. Cancer Immunol Immunother 2013). Conclusions: This is the first trial to report the feasibility of sipuleucel-T retreatment following treatment in an earlier stage of prostate cancer. These data indicate the presence of existing immunological memory to the immunizing antigen several years after initial treatment. In addition, retreatment with sipuleucel-T appeared to boost product potency compared with prior treatment. Clinical trial information: NCT01338012. CD54 upregulation and IFN-␥ ELISPOT response by infusion. PROTECT infusions (treatment)

CD54 upregulation, median (range) IFN-␥ ELISPOT/ 300,000 PBMC, median (range)

P10-1 infusions (retreatment)

1 (Day 0)

2 (Wk 2)

Final (Wk 4)

1 (Day 0)

2 (Wk 2)

Final (Wk 4)

Post-final (Wk 6)

PA2024

6.2 (4.2–10.5) –

14.7 (8.4–20.9) –

13.2 (6.4–19.0) –

PAP

–

–

–

19.8 (11.7–26.2) 18 (0–386) 21 (0–308)

20.5 (7.8–31.2) 187 (0–946) 67 (0–1076)

22.5 (15.8–26.6) 70 (1–776) 45 (0–720)

34 (3–1176) 32 (0–1517)

–

* EZN-4176 Q2W, **30 days after treatment discontinuation.




Profile study: Genetic prostate cancer risk stratification for targeted screening. Presenting Author: Elena Castro, The Institute of Cancer Research, The Royal Marsden NHS Foundation Trust, London, United Kingdom Background: Prostate cancer (PC) screening is controversial and better approaches are needed, including a better assessment of individualized PC risk. Several studies have identified a number of common single nucleotide polymorphisms (SNPs) that confer a cumulative risk of PC. We have explored the potential role of genetic markers in identifying men who should be selectively targeted for screening in a population with increased risk of PC due to family history (FH) of the disease. Methods: PROFILE has been developed as a pilot study. The primary aim is to determine the feasibility of targeted PC screening using prostatic biopsy (PB) and its association with specific genetic profiles in men with FH. Secondary aims are to evaluate the role of PSA and Diffusion Weighted MRI (DW-MRI) as screening tools in this population. From December 2010 men aged 40-69 with FH of PC were invited into the study until 100 men were enrolled. Blood samples were provided for PSA and DNA extraction. The cumulative SNP risk scores for each patient were calculated by summing 59 risk alleles for each locus using the weighted effect as estimated in previous studies (log-additive model). DW-MRI was performed in 50 patients. All participants were asked to undergo a 10 core PB regardless of baseline PSA. Those who declined PB have been excluded from this analysis. Data on side effects and cancer worry were also collected. Results: 35% of invited men entered the study. Median age was 53 yrs (40-69) and median PSA was 1.15. Ninety men accepted to undergo a PB as primary PC screening. Twenty-two tumours were found and 45% of them were clinically significant [Median age 64yrs (47-69), median PSA 5.4 (0.91-9.3)]. The predictive performance of DW-MRI, PSA, genetic model and genetic model plus PSA measured by AUC were: 0.85, 0.73, 0.57 and 0.74, respectively. The genetic model performed better in men with PSA⬍3(AUC 0.63). No severe side effect or adverse psychosocial variables were noted. Conclusions: Our results indicate that PB is acceptable as a means of PC screening in men with FH of PC. Overall, DW-MRI and PSA were more predictive of PC than the genetic risk score. As more SNPs are found, a larger study is warranted to evaluate their role in the PC screening algorithm.

5056


Clinicopathologic features and clinical outcomes associated with Gleason upgrading from biopsy to radical prostatectomy. Presenting Author: Sun Mi Yoo, Dana-Farber Cancer Institute, Boston, MA Background: Gleason score stratifies patients into prognostic categories and is critical in guiding treatment. Previous series indicate that ~25% of patients with low-grade (Gleason ⱕ6) disease on biopsy are upgraded to higher grade disease upon radical prostatectomy (RP). We sought to characterize the clinical and pathologic variables associated with upgrading and investigate its clinical implications. Methods: 1,469 prostate cancer patients underwent prostate biopsy and RP, were seen at DanaFarber Cancer Institute/Brigham and Women’s Hospital (DFCI/BWH), and had tissue specimens reviewed by DFCI/BWH genitourinary pathologists between 1999-2011. Associations between Gleason upgrading and clinical and pathologic variables were assessed using Wilcoxon’s nonparametric test and Fisher’s exact tests. Log rank test was used to assess association between upgrading and time to biochemical recurrence (BCR). Results: Of 1,469 patients, 958 (65%) had biopsy Gleason 6 and 511 (35%) had biopsy Gleason 7. Among individuals with biopsy Gleason 6, 336 (35%) were upgraded to Gleason ⱖ7 upon RP (275 3⫹4 and 49 4⫹3) while 622 (65%) remained Gleason 6 at RP. Variables associated with increased risk of upgrading: greater PSA at diagnosis (p⫽1x10-4); age ⬎58 (OR⫽1.62, p ⬍ 1x10-4); ⬎1/3 positive biopsy cores (OR⫽2.1 for 33-50% compared to ⱕ33%, p ⬍ 1x10-4). In this study the number of cores biopsied was not associated with upgrading. Gleason upgrading was also associated with extraprostatic tissue involvement (OR⫽1.69, p⫽0.005). Patients upgraded from biopsy Gleason ⱕ6 to Gleason 7 on RP had a longer time to BCR than those with Gleason 7 on both biopsy and RP, but a shorter time to BCR than those who remained Gleason 6 on RP (adjusted hazard ratio 0.69, 95% CI 0.49-0.98, p⫽0.03). Conclusions: Gleason upgrading from low-grade to higher grade disease is associated with a higher PSA at diagnosis, older age at diagnosis, and a greater number of positive biopsy cores. Clinically, prostate cancers upgraded from Gleason ⱕ6 to Gleason 7 appear to behave differently than those who are not upgraded. These results could have implications in determining ideal candidates for active surveillance.

5055

321s


Interim safety analysis of a compassionate-use program (CUP) and earlyaccess program (EAP) providing cabazitaxel (Cbz) plus prednisone (P) to patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel. Presenting Author: Zafar I. Malik, Clatterbridge Cancer Centre, Merseyside, United Kingdom Background: Cbz ⫹ P provides a significant survival benefit vs mitoxantrone ⫹ P in pts with mCRPC (Phase III TROPIC study [NCT00417079]; hazard ratio 0.70; p ⬍ 0.0001). These findings supported the initiation of ongoing Sanofi-funded CUP and EAP (NCT01254279) to provide access to Cbz prior to commercialization and to collect real-life safety data. Methods: Expected enrollment is ~1600 pts with mCRPC from 250 centers worldwide. Pts receive Cbz (25 mg/m2 Q3W) ⫹ P (10 mg oral QD) until progressive disease (PD), death, unacceptable toxicity, physician/pt decision or Cbz commercial availability. Pts are followed until 30 days after last dose. Granulocyte colony-stimulating factor (G-CSF) use is recommended as per ASCO guidance. Results: Interim baseline and safety data from the first 1301 pts treated in 37 countries are now available. Mean age was 68 yrs (22% were ⱖ 75 yrs). All pts had an ECOG performance status ⱕ 2. Median time from initial prostate cancer diagnosis was 57.6 months and 60% of pts had ⱖ 2 metastatic sites; the most common were bone (91%) and lymph nodes (regional 30%, distant 27%). In total, 17% had PD whilst on docetaxel. The median number of Cbz cycles was 6 (range 1–22); median relative dose intensity was 99%. Overall, 837 pts (64%) received G-CSF (n ⫽ 123 curative [C], n ⫽ 765 prophylactic [P] and n ⫽ 99 [C ⫹ P]). Of 1142 pts (88%) who discontinued Cbz ⫹ P, the most common reasons were PD (44%), adverse event (AE; 27%), physician decision (13%) and commercial availability of Cbz (7%). Grade 3– 4 AEs possibly related to Cbz ⫹ P occurred in 43% of pts; the most frequent were clinical neutropenia (18%), febrile neutropenia (FN; 7%) and diarrhea (4%). Of 80 pts (6%) with AEs leading to death, the AE was related to Cbz ⫹ P in 39 pts (3%). Conclusions: These results provide valuable data on Cbz ⫹ P treatment in routine clinical practice, confirming the safety results of clinical trials and showing that treatment with Cbz ⫹ P is associated with a manageable safety profile. The incidence of FN seems slightly lower than in TROPIC, owing to more frequent use of G-CSF prophylaxis in the CUP and EAP. Clinical trial information: NCT01254279.

5057


Use of serum markers in prediction of survival in the trapeze factorial trial evaluating docetaxel with zoledronic acid, strontium-89, or both in castraterefractory prostate cancer (CRPC) metastatic to bone. Presenting Author: Vivek K Wadhwa, Cancer Research UK Clinical Trials Unit, School of Cancer Sciences, Birmingham, United Kingdom Background: There is emerging interest in the use of bone turnover markers in CRPC to compliment current modalities and aid therapeutic management decisions. We report the preliminary results of investigation into the clinical utility of P1NP, total alkaline phosphatase (ALP) and PSA as parameters of survival in a representative sample of patients from TRAPEZE. Methods: Baseline and post treatment (cycle six or end of treatment if sooner) samples were taken from 120 patients equally distributed across the trial arms of TRAPEZE. Absolute and percentage change in the markers were investigated in relation to overall survival (OS) using the Cox Regression model. Results: Of the 120 patients, 38(32%) failed to complete 6 cycles. No relationship was observed between P1NP and OS using either absolute or percentage change (p⫽0.59, p⫽0.64). Absolute change in log PSA was significantly related to OS (HR⫽1.22 (95%CI 1.01, 1.48), p⬍0.05, respectively) however percentage change in log PSA did not reach statistical significance (HR⫽1.006 (95%CI 0.99, 1.01), p⫽0.095). Absolute change in ALP was found to be inversely related to OS (HR⫽0.999 (95%CI 0.998, 0.999), p⬍0.001) but percentage change in ALP was not significant (p⫽0.89). When the PSA and ALP models were applied to the entire trial set (757 patients) the predictive value of both absolute and percentage change in log PSA remained highly significant (HR⫽1.23, p⬍0.001 & HR⫽1.01, p⬍0.001). In addition the significance of absolute change in ALP also remained (HR⫽0.999, p⬍0.05). Conclusions: Changes in P1NP were not related to OS in CRPC patients metastatic to bone. Absolute change in ALP was inversely related to OS and both absolute and percentage changes in log PSA were also related to OS in this sub-study. When applied to the entire TRAPEZE patient group all remained statistically significant. The utility of changes in ALP and PSA, as prospective markers for studies in CRPC patients metastatic to bone, merit further evaluation.


322s 5058


Novel predictive markers of PSA response to abiraterone acetate in men with metastatic castration-resistant-prostate-cancer (mCRPC). Presenting Author: Raya Leibowitz-Amit, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada Background: Abiraterone acetate (AA) prolongs survival in men with mCRPC pre- and post- chemotherapy. To date, clinical predictive biomarkers of response remain poorly characterized. The aim of this retrospective study was to identify and analyze predictors of response to AA in men with mCRPC. Methods: All men receiving AA at the Princess Margaret Cancer Centre between November 2009 and December 2012 were reviewed. PSA response rate (RR) was defined according to PCWG2 criteria and assessed 12 weeks after AA start. Potential predictive factors were analyzed using uni- and multivariable logistic regression models. Results: In total, 70 patients were evaluable for response: 34 men were chemotherapy naive and had a PSA RR of 44% (95% CI 27-62%); 36 men had prior chemotherapy and had a PSA RR of 33% (95% CI 17-50%). In univariable analysis, pre-treatment lactate dehydrogenase (LDH) level ⬎220 U/L (ULN) and a neutrophil-to-lymphocyte ratio (NLR) ⬎5 were both significantly associated with a lack of PSA response. On multivariable analysis, NLR⬎5 remained significantly associated with lack of a PSA response (Table 1A). Men were then stratified into three groups according to these two variables. These groups were significantly associated with RRs (Table 1B). PSA RR was not found to be associated with the Gleason score, initial stage, time from initial diagnosis to mCRPC or to AA initiation, prior ketoconazole or docetaxel treatment, pre-treatment alkaline phosphate or PSA doubling time. Conclusions: A pretreatment NLR⬎5 and an LDH⬎ULN were both strongly associated with a lack of PSA response to AA. These factors may be key in stratifying men into different response groups to AA. Variable 5 < NLR ULN < LDH Patient groups 0 1

2

5060

Univariable analysis Odds ratio (OR) for response CI %95 P value 0.10 0.33

0.48-0.02 0.92-0.12

Description ULN, ⬎LDH 5⬎NLR ULN ⬎ LDH or 5⬍and NLR ULN ⬍LDH 5⬎and NLR ULN, ⬍LDH 5⬍NLR

Multivariable analysis OR for response CI %95 P value

No. of pts 19

0.004 0.034 No. of responders 12

0.11 0.40 (%) RR (CI %95) (87-39) 63

34

14

(60-25) 42

17

1

(18-0) 6

0.55-0.02 0.007 0.13-1.21 0.1 Response OR (CI %95) Group 2 vs 0: 0.04 (0.004-0.34) Group 2 vs 1: 0.09 (0.01-0.75)


Hb (p value)


Interim safety results of a global early access protocol (EAP) of abiraterone acetate (AA) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) progressing after taxane-based chemotherapy. Presenting Author: Daniel J. George, Duke Cancer Institute, Durham, NC Background: The COU-AA-301 phase 3 trial showed significantly longer overall survival for AA ⫹ prednisone (P) than P alone in mCRPC pts refractory to docetaxel. This global EAP was conducted in the same setting to collect additional safety data. Methods: Open-label EAP in pts with mCRPC who progressed after 1 - 2 chemotherapy regimens (ⱖ 1 taxane), resided in areas where AA was unavailable and were ineligible for ongoing clinical trials of AA. Pts received AA (1000 mg PO/d) plus P (5 mg bid) in 28 d cycles until disease progression. Only serious or clinically important adverse events (AEs) were to be reported by investigators. First interim results (clinical cut-off date: December 31, 2011), reported as part of regulatory submissions, are presented. Results: 1079 pts from 15 countries were included: N. America (47%), Europe (29%), Australia (13%), Latin America (7%), and Asia (3%). Median age: 70 years (range: 47 – 93); 89% of pts were White. Median treatment exposure, incl. pts still on treatment (285 pts), was ⬇ 3 months. 620 pts (58%) received ⱖ 4 treatment cycles, 58 pts (5%) received ⱖ 8 cycles. 441 pts (41%) reported serious or clinically important AEs, which were treatment-related in 154 pts (14%). Most common grade 3-4 AEs: 1ALP (6%), anemia (3%), hypertension (3%), back pain (2%), and fatigue (2%). Grade 3-4 AEs of special interest were infrequent: LFT abnormalities (8%), hypertension (3%), cardiac disorders (2%), hypokalemia (⬍ 1%), fluid retention/edema (⬍ 1%), osteoporotic fractures (⬍ 1%). Main reason for discontinuation (795 pts): disease progression, in 335 pts (31%). 253 pts (23%) discontinued after marketing authorization. Discontinuations due to treatment-emergent AEs, death, or withdrawal of consent were ⬍ 6% each. Conclusions: The safety profile observed in these EAP interim results was consistent with that in the COU-AA-301 randomized, placebo controlled trial conducted in the same clinical setting. No new safety signals with AA plus P were detected in this expanded patient population, which included pts from Latin America and Asia, i.e. regions that did not participate in COU-AA-301. Clinical trial information: NCT01217697.

p value⫽0.012

Hematologic safety of Ra-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients with bone metastases from the phase III ALSYMPCA trial. Presenting Author: Chris Parker, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom Background: In the updated analysis of the ALSYMPCA study, Ra-223 significantly improved median survival by 3.6 mo vs placebo (Pbo) in 921 CRPC patients (pts) with bone mets (HR ⫽ 0.695; 95% CI, 0.581-0.832; p ⫽ 0.00007) and had a highly favorable safety profile (Parker et al. ASCO 2012). The hematologic safety profile and results from a post hoc analysis assessing prognostic factors for changes in hematologic parameters in ALSYMPCA pts are presented. Methods: Pts were randomized 2:1 to 6 injections (inj) of Ra-223 (50 kBq/kg IV) q4wk or matching Pbo and stratified by prior docetaxel (D) use, total alkaline phosphatase (tALP), and current bisphosphonate use.Multivariate regression analysis was performed to explore the relationship of 6 baseline factors (Table) with maximum % change of hematologic parameters from baseline up to 24 wk on treatment (tx). Results: The updated analysis included 901 pts (safety population; Ra-223, n ⫽ 600; Pbo, n ⫽ 301). Overall grade 3/4 AEs were similar between Ra-223 and Pbo groups, with neutropenia in 2% and 1%, thrombocytopenia in 6% and 2%, and anemia in 13% and 13% of Ra-223 and Pbo groups, respectively. Tx with Ra-223, prior D use, extent of disease (EOD) ⬎ 6 bone mets, and tALP ⱖ 220 U/L, but not current bisphosphonate use, were associated with decreases from baseline in hemoglobin (Hb), neutrophils, or platelets; prior EBRT to bone for pain was associated with an increase. The significance of the relationship between baseline factors and changes in hematologic parameters is summarized in the Table. Conclusions: Overall, there was a low risk for hematologic AEs with Ra-223 tx in CRPC pts with bone mets. The strongest prognostic factors for decreases in neutrophils and platelets were Ra-223 tx and prior D use. Baseline tALP ⱖ 220 U/L was a strong predictor of decrease in Hb. Clinical trial information: NCT00699751. Variable

5059

Neutrophils (p value)

Platelets (p value)

Study tx (Ra-223/Pbo) 0.037* ⬍ 0.0001* ⬍ 0.0001* Current use of bisphosphonates (Y/N) 0.055 0.479 0.408 Prior use of D (Y/N) 0.069 0.007* ⬍ 0.0001* EOD > 6 mets including superscan (Y/N) 0.010* 0.321 0.006* Prior EBRT to bone for pain (Y/N) 0.001* 0.019* 0.089 tALP (< 220 U/L/> 220 U//L) ⬍ 0.0001* 0.629 0.023*

5061


A pilot phase II study of digoxin in patients with recurrent prostate cancer as evident by a rising PSA. Presenting Author: Jianqing Lin, Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA Background: Hypoxia-inducible factor 1␣ (HIF-1␣) is a novel cancer drug target and inhibitors of hypoxia-response pathway are being developed. Digoxin and other cardiac glycosides were found to inhibit prostate cancer (PCa) growth via the inhibition of HIF-1␣ synthesis in mouse model. Epidemiologic data showed that use of digoxin in men was associated with a significant lower risk of development of PCa. We hypothesized that therapeutic dose of digoxin could inhibit human PCa growth and disease progression. Methods: Open label, non-placebo pilot study. Non-metastatic, biochemically relapsed PCa patients (pts) with prostate specific antigen doubling time (PSADT) of 3 -24 months and no hormonal therapy within the past 6 months were enrolled. All pts had testosterone ⬎ 50 ng/dL at baseline. Digoxin was taken daily with dose titration to therapeutic level (0.8 – 2 mg/dl) and pts had routine follow-up that include cardiac monitoring with EKG. The primary endpoint was to evaluate the proportion of patients at 6 month post-treatment that had a PSADT ⬎ 200% from the baseline. Results: Fifteen pts were enrolled into the study with 13 pts finishing the planned 6 months of treatment. Twenty percent (3/15) of the pts had PSA decrease ⬎25% from baseline. At 6 months, 7 of 15 (47%) pts had PSADT ⬎ 200% of the baseline PSADT and were continued on study for an additional 24 weeks of treatment. Mean duration of digoxin treatment was 34.5 weeks. Digoxin was well tolerated with possible relation of one grade 3 back pain and one grade 2 hyperglycemia. No pts came off study due to cardiac reasons. Pre-and post-treatment PSA kinetics, vascular endothelial growth factors and other cytokines levels are being determined. Conclusions: Digoxin was well tolerated and showed a prolongation in the PSDAT in 47% of the patients. Digoxin may have biologic activity in men with androgen-dependent PCa but further controlled studies are required to confirm the results. Clinical trial information: NCT01162135.

*p ⬍ 0.05.




5063

323s


A phase I dose-escalation trial of AEZS-108 in taxane- and castrationresistant prostate cancer (CRPC). Presenting Author: Jacek K. Pinski, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA

Prognostic factors of survival in patients with metastatic castration resistant prostate cancer (mCRPC) treated with cabazitaxel: Sequencing might matter. Presenting Author: Antoine Angelergues, Department of Medical Oncology, Georges Pompidou European Hospital, Paris, France

Background: The receptor for luteinizing hormone releasing hormone (LHRH-R) is highly expressed on CRPC cells and is a potential therapeutic target. AEZS-108 is an LHRH-cytotoxic hybrid that covalently couples an LHRH agonist with doxorubicin. We report the completed Phase I trial of AEZS-108 in men with taxane-resistant CRPC. We explored visualization of AEZS-108 internalization into circulating tumor cells (CTCs) exploiting the auto-fluorescence of doxorubicin and also tested LHRH-R expression on CTCs. Methods: This was a dose escalation Phase I trial in men with taxane-resistant CRPC to confirm the dose established in a phase I trial in women. Standard 3⫹3 design was used with planned expansion at the MTD to ensure 6 patients received 2⫹ courses without DLT. Eligibility criteria included progression of disease despite prior LHRH agonist and taxane therapy. Patients received AEZS-108 every 21 days until progression or unacceptable toxicity. The primary endpoint was safety. CTCs were captured with a novel slot microfilter and identified by PSA and DAPI staining. AEZS-108 internalization was visualized by fluorescence microscopy. Results: Eighteen men with a median of 2 prior chemotherapy regimens (range 1-5) and a median PSA of 106.4 ng/mL (range 8.4-1624.0) enrolled from November 2010 to August 2012. The dose was escalated from 160 mg/m2 to 210 mg/m2 then to 267 mg/m2. There were 2 DLTs in the 7 men receiving 267 mg/m2 (grade 4 neutropenia), prompting de-escalation to 210 mg/m2 where 1 of 8 men experienced a DLT (grade 4 neutropenic fever), establishing 210 mg/m2 as the MTD. Significant non-hematologic toxicities included a case of grade 3 nausea. No cardiotoxicity was seen on serial evaluation and 6 patients completed 6 cycles. Internalization of AEZS-108 was consistently visualized in CTCs 1-3 hours after dosing. Maximal PSA response was stable or decreased in 8 of 18 men. Conclusions: The MTD of AEZS-108 in men with taxane-resistant CRPC is 210 mg/m2, which is below the MTD reported in women with refractory endometrial, ovarian and breast cancer. The activity of AEZS108 was promising in this heavily pretreated population. The Phase II portion is currently accruing. Clinical trial information: NCT01240629.

Background: Recently, several new drugs have demonstrated an overall survival (OS) benefit in patients (pts) with mCRPC. Their use must be optimized to maximize patient outcomes. We evaluated prognostic factors of OS in mCRPC pts treated with cabazitaxel (C), a new taxane developed to overcome docetaxel (D) resistance. Methods: Records of 125 consecutive mCRPC pts (median 67 yrs) treated with C (after D) were retrospectively collected in 9 centers (France, n⫽8; Turkey, n⫽1). Baseline characteristics, disease history, PSA response, OS and radiological and/or clinical progression-free survival (PFS) were collected. The influence of selected variables on OS was analyzed by multivariate logistic regression. Results: At C initiation, 83.3% of pts were ECOG 0-1, 50.8% had an initial Gleason score of 8-10, 62.9% had pain and 84.8% had radiological or clinical progression. Median duration of response to first-line androgen deprivation therapy was 20 months (mo) and 22% received ⱖ2 prior D lines. New hormonal agents (abiraterone or enzalutamide) were given before C in 33% of pts and after C in 16%. Median number of C cycles received was 6 (range 2-14). A PSA decrease of ⱖ50% and ⱖ30% was reached in 41.3% and 48.8% of patients treated with C. Median OS from first C cycle was 13.3 mo and median clinical and/or radiological PFS was 6.5 mo. In multivariate analysis, OS was significantly reduced in pts with ECOG 2 (HR: 6.05), alkaline phosphatase ⱖ1.5 ULN (HR: 2.64), lymph node involvement (HR: 1.89). Conversely, OS was significantly prolonged in pts with ⱖ2 prior D lines (HR: 0.35), prior curative therapy (HR: 0.55), a PSA decrease ⱖ30% with C (HR: 0.21) and in pts treated with abiraterone/enzalutamide after C (HR: 0.37). Median OS from the first D dose was 65 mo in pts treated with abiraterone or enzalutamide after C versus 39 mo in pts receiving these agents before C. Conclusions: Patients with ⱖ 2 prior D lines, PSA response ⱖ30% with C and treated with new hormonal agents after C experienced a prolonged OS. Conversely, intake of new hormonal agents before C rather than after was associated with a reduced OS from the first D dose. Prospective randomized trials are needed to confirm these results.

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Effects on androgen receptor nuclear import by docetaxel, cabazitaxel, abiraterone, and enzalutamide: Potential mechanism for cross-resistance in castration-resistant prostate cancer (CRPC). Presenting Author: Robert J. van Soest, Erasmus MC, Rotterdam, Netherlands

Outcomes in patients with liver or lung metastatic castration-resistant prostate cancer (mCRPC) treated with the androgen receptor inhibitor enzalutamide: Results from the phase III AFFIRM trial. Presenting Author: Yohann Loriot, Institut Gustave Roussy, Villejuif, France

Background: Recent reports have suggested that paclitaxel and docetaxel, which exert their therapeutic activity primarily through inhibition of microtubule function and mitosis, also impair androgen receptor (AR) signaling. AR signaling is the key therapeutic target for the newly available agents abiraterone and enzalutamide. A recent study suggested impaired efficacy of docetaxel when given after progression on abiraterone in patients with CRPC. To identify potential mechanisms of cross-resistance, we investigated whether and to what extent AR nuclear translocation is affected by docetaxel, cabazitaxel, abiraterone and enzalutamide. Methods: Hep3B cells stably expressing GFP labeled AR were used for AR translocation studies. Cells were seeded on a cover slip in steroid-stripped medium (DCC) and treated with docetaxel (1 ␮M), cabazitaxel (1 ␮M), abiraterone (6 ␮M) and enzalutamide (1 ␮M). The anthracenedione mitoxantrone (100 nM) that does not target the microtubule cytoskeleton was used as a control cytotoxic agent. Following incubation for 48 hours, the synthetic androgen R1881 was added to study dynamics of AR nuclear import by time-lapse confocal microscopy. Results: Docetaxel and cabazitaxel inhibited R1881 induced AR nuclear translocation with 21% and 34% respectively compared to control, while mitoxantrone did not affect AR transport. Abiraterone inhibited AR translocation with 58% and enzalutamide completely blocked AR translocation. Conclusions: These data point towards a role for microtubules in AR nuclear transport and an additional mechanism of taxane activity in CRPC. Docetaxel, cabazitaxel, abiraterone and enzalutamide all interfere with AR nuclear transport, which is a crucial step in AR signaling. Our findings identify and provide insight in a potential mechanism of clinical cross-resistance between the two taxanes currently registered for treatment in CRPC and the novel agents abiraterone and enzalutamide. Further investigations are warranted in order to define if this potential cross-resistance impacts the most suitable treatment sequence for these drugs in CRPC.

Background: Enzalutamide (ENZA) inhibits multiple steps in the androgen receptor signaling pathway (Tran et al, Science. 2009;324:787). The phase III AFFIRM trial demonstrated that ENZA increased median overall survival (OS) by 4.8 months (P ⬍0.001, HR 0.63) vs placebo (PBO) in post-docetaxel mCRPC patients (pts) (Scher et al, NEJM 2012; 367: 1187). Here we assess the effect of ENZA on outcomes in pts with liver or lung metastases in the AFFIRM trial. Methods: The AFFIRM trial was a phase III multinational, randomized, double-blind study in post-docetaxel mCRPC pts. Randomization was 2:1 to ENZA 160 mg/day or PBO, stratified by baseline ECOG and mean pain score. The primary endpoint was overall survival (OS). Radiographic progression-free survival (rPFS) was a key secondary endpoint. PSA response defined as a decline of ⱖ50% compared to baseline, and soft tissue objective response per RECIST 1.1 were also assessed and reported here. Results: Pts with liver mCRPC comprised 11.5% (92/800) of ENZA pts and 8.5% (34/399) of PBO pts. Pts with lung mCRPC comprised 15.3% (122/800) of ENZA pts and 14.8% (59/399) of PBO pts. The median OS for patients with liver and/or lung mCRPC in the AFFIRM trial was 11.4 months (ENZA: 13.4 months; PBO: 9.5 months). Improved outcomes with ENZA treatment were observed in both liver and lung mCRPC pts. Conclusions: In the phase III AFFIRM trial, pts with lung mCRPC had higher median OS than pts with liver mCRPC. ENZA resulted in higher response rates in both liver and lung mCRPC pts. OS and rPFS were also improved in both pt groups treated with ENZA. Clinical trial information: NCT00974311. Liver mCRPC ENZA (n ⴝ 92) OS (months) rPFS (months) PSA response (%) Objective response (%)

Lung mCRPC PBO (n ⴝ 34)

9.0 5.7 (4.2 , 9.5) (6.4 , 10.7) HR ⫽ 0.697 (95% CI, 0.436, 1.114) 2.9 (2.8 , 4.9) 2.8 (2.7 , 3.2) HR ⫽ 0.645 (95% CI, 0.413, 1.008) 35.1 (24.4 , 47.1) 4.8 (0.1 , 23.8) 14.9 (8.2 , 24.2) 3.3 (0.1 , 17.2)

ENZA (n ⴝ 122)

PBO (n ⴝ 59)

16.5 (12.5 , NM)

10.4 (8.1 , NM)

HR ⫽ 0.760 (95% CI, 0.493, 1.172) 5.6 (5.3 , 8.2) 2.8 (2.7 , 2.9) HR ⫽ 0.427 (95% CI, 0.298, 0.612) 52.8 (42.9 , 62.5) 4.3 (0.5 , 14.5) 29.3 (20.6 , 39.3) 4.9 (0.6 , 16.5)


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Results from a phase I study of enzalutamide in combination with docetaxel in men with prostate cancer. Presenting Author: Mark T. Fleming, Virginia Oncology Associates, Norfolk, VA Background: Enzalutamide (ENZA) is a novel androgen receptor (AR) inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC) who had received prior docetaxel (DOC). DOC also prolongs survival in mCRPC and also appears to have anti-tumor effects mediated through the androgen-receptor axis, providing a compelling rationale for combining the two agents. CYP3A4 plays a role in DOC clearance and is induced by ENZA. We therefore conducted a phase I study to explore the PK and safety profiles of this combination. Methods: This study (NCT01565928) evaluated the safety and pharmacokinetics (PK) of DOC co-administered with ENZA in men with mCRPC on androgen deprivation therapy. Pts received DOC (75 mg/m2) by 1-h infusion every 3 weeks with corticosteroids. ENZA (160 mg/d) was started 24 h after the first DOC infusion. Plasma PK samples were collected for 24 h after Cycle (C) 1 and C2 DOC infusions to enable within-subject comparisons of DOC PK ⫾ ENZA. A sample size of 18 pts able to receive ⱖ 2 full doses of DOC was specified for PK analyses. Results: Twenty-two pts were enrolled, 4 did not receive 2 full doses of DOC. As of 21 Sept 2012, preliminary PK and C1 and C2 safety data were available from 15 pts. The median age was 65 (range 46-80 yrs); 11 had ECOG performance status 1 (vs 0). Prior primary therapy included surgery (n⫽2), radiation (n⫽4) or both (n⫽5); median PSA was 44.7ng/mL (1.9-585). ANC⬍1000/mm3 was reported in 14 pts (1 febrile neutropenia), other adverse events in ⱖ4 pts included fatigue (11), dyspnea (6), alopecia (5), peripheral neuropathy (5), anemia (4) and dysgueusia (4). No seizures were reported. Preliminary PK data (n⫽15) show similar DOC exposure (within 20%) for DOC in combination with ENZA vs. DOC alone.Final PK and updated tolerability and efficacy data beyond Cycle 2 will be presented. Conclusions: In mCRPC pts, ENZA does not appear to affect tolerability of DOC or have a clinically meaningful impact on DOC PK. Clinical trial information: NCT01565928.

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Efficacy and safety of radium-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients with bone metastases who did or did not receive prior docetaxel (D) in the phase III ALSYMPCA trial. Presenting Author: Nicholas J. Vogelzang, Comprehensive Cancer Centers of Nevada, Las Vegas, NV Background: Ra-223, a first-in-class ␣-emitter, significantly improved median overall survival (OS) by 3.6 mo vs placebo (Pbo) in CRPC patients (pts) with bone metastases (mets) receiving best standard of care (BSoC) in the ALSYMPCA study (HR ⫽ 0.695; 95% CI, 0.581-0.832; p ⫽ 0.00007), and had a highly favorable safety profile in the updated ALSYMPCA analysis (Parker et al. ASCO 2012). This predefined subgroup analysis assessed efficacy and safety of Ra-223 in pts who did or did not receive prior D (pD). Methods: Eligible pts had progressive, symptomatic CRPC with ⱖ 2 bone mets; had no known visceral mets; were receiving BSoC; and had received pD, or were unfit for or declined D (npD). Pts were randomized 2:1 to 6 injections of Ra-223 (50 kBq/kg IV) q4wk or matching Pbo and stratified by prior D use, baseline alkaline phosphatase level, and current bisphosphonate use. Survival data were compared using a log-rank test. Results: 395/921 (43%) randomized pts had npD (Ra-223, n ⫽ 262; Pbo, n ⫽ 133); 526/921 (57%) received pD (Ra-223, n ⫽ 352; Pbo, n ⫽ 174). Median ages were 74 y (npD) and 69 y (pD). In pts with npD, median OS was 16.1 mo in the Ra-223 group vs 11.5 mo in the Pbo group (HR ⫽ 0.745; 95% CI, 0.562-0.987; p ⫽ 0.039). In pts with pD, median OS was 14.4 mo vs 11.3 mo in the Ra-223 and Pbo groups, respectively (HR ⫽ 0.710; 95% CI, 0.565-0.891; p ⫽ 0.003). Overall, there was a low incidence of myelosuppression. Incidences of neutropenia and thrombocytopenia were higher in pts with pD vs pts with npD. Conclusions: Ra-223 significantly prolonged OS and had a highly favorable safety profile in CRPC pts with bone mets, regardless of whether they had pD or npD. pD pts had a slightly increased rate of grade 3 and 4 bone marrow suppression with Ra-223. Clinical trial information: NCT00699751. No prior D Prior D No. (%) of patients with grade 3 or 4 AEs* Hematologic Anemia Neutropenia Thrombocytopenia Nonhematologic Diarrhea Nausea Vomiting Constipation†

Ra-223 n ⫽ 253

Pbo n ⫽ 130

Ra-223 n ⫽ 347

Pbo n ⫽ 171

27 (11) 2 (1) 7 (3)

15 (12) 1 (1) 1 (1)

50 (14) 11 (3) 31 (9)

24 (14) 1 (1) 5 (3)

7 (3) 2 (1) 1 (0.4) 3 (1)

1 (1) 2 (2) 2 (2) 3 (2)

2 (1) 8 (2) 9 (3) 3 (1)

4 (2) 3 (2) 5 (3) 1 (1)

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Factors impacting decision by African American and underserved populations to choose active surveillance in early-stage prostate cancer. Presenting Author: Theresa Wicklin Gillespie, Emory University, Depts of Surgery and Hematology & Medical Oncology, Atlanta, GA Background: African-American (AA) men have the highest rates of prostate cancer (PCa) incidence and mortality in the U.S. Screening for PCa with prostate specific antigen (PSA) has allowed detection of early stage disease, but side effects of radical prostatectomy and radiation raise concerns about unfavorable risk:benefit ratios of PSA screening and subsequent therapy. Active surveillance (AS) is an option for early-stage PCa (ESPC), but only 10% of men eligible for AS choose this approach. The 2011 NIH State-of-the-Science Conference promoted the need to enhance decision-making (DM) about AS. In 2012, the U.S. Preventive Services Task Force recommended against PSA screening, while encouraging patient DM. Our study examined DM needs by men (N⫽204; 68% AA; screening PSA within normal limits) and their significant others (SO) (N⫽181; 65% AA) regarding AS and other ESPC options. Methods: This multi-center, mixed methods study (N⫽402; 51% rural) included 5 sites nationwide. Subjects completed quantitative questionnaires prior to focus groups (FG); 54 FG were held, with separate groups for men and SO. Results: After adjusting for education, comorbidities, insurance, age, health literacy, distance to treatment center, willingness to travel, income and numeracy score, AA men were significantly more likely to be influenced by convenience (OR: 2.84, 95% CI: 1.42-5.65) compared to Caucasians. Rural residence, however, did not affect DM. In qualitative analysis, numerous themes were identified relevant to choice of AS: physician treatment discussions being limited to their own specialty; confusion due to conflicting sources of information; convenience; worry about untreated cancer remaining and treatment toxicities; and lack of awareness of AS as an option. SO tended to value cure over avoiding side effects. Conclusions: While the impact of new PCa screening guidelines is uncertain, for AS to become a viable treatment option, providers will need to discuss along with other therapeutic alternatives. SO are influential in DM and may be less enthusiastic about AS than men. For AA men, AS may be a particularly attractive option given the relative influence of convenience in DM.

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Risk of missing advanced stage or high grade tumors during active surveillance (AS) even in favorable-risk prostate cancer (PC). Presenting Author: Jeri Kim, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Owing to tumor heterogeneity, no standard selection criteria exist among prospective AS cohorts. Generally, men with low-stage, -volume, and -grade PC and low prostate-specific antigen (PSA) are eligible. In our prospective single-institution AS trial, men with early-stage PC were stratified: Gr I (favorable risk), II (pt’s choice), or III [competing comorbidities prevent local therapy (Tx)]. We report our experience with Gr I. Methods: Eligibility for Gr I: Gleason score (GS) ⱕ6, 1 positive (pos) core (⬍3 mm), and PSA ⬍4 ng/mL or GS 7 (3⫹4), 1 pos core (⬍2 mm), and PSA ⬍4 ng/mL. Monitoring q6mo included PSA, testosterone, and digital rectal exam. All pts had repeat biopsy (re-BX) at 1 y and then on predetermined BX scheme. Later, re-BX was required within 6 mo of study entry per an 11-core BX scheme (also used during AS). Definitive Tx was offered to pts who met reclassification based on clinical, BX (upgrading, 1 in pos core BX, and/or 1 tumor length), and/or radiographic progression. Imaging studies [bone/CT scans, endorectal MRI (eMRI)] were at physician’s discretion. Results: From 2/2006 to 2/2012, 585 pts enrolled; 191 met Gr I criteria (41 before, 150 after re-BX requirement). Median age was 64 y (range, 36 – 83); 82% were white, 8% African-American, 8% Hispanic, 2% Asian; 4% had cT1a/cT1b, 84% cT1c, and 12% cT2 disease. Most (189/191) had GS 6 [1 had GS 5, and 1, GS 7 (3⫹4)]. Median PSA was 3.3 (range, 0.2–10). With median follow-up of 36.2 mo (95% CI: 30.6 – 41.7), 32/191 (17%) were reclassified [20/41 (49%) before and 12/150 (8%) after re-BX requirement]. Of 32 reclassified, 17 were due to GS: 11 to GS 7 (3⫹4), 4 to GS 7 (4⫹3), and 2 to GS 8 (4⫹4). Ten of the 32 reclassified chose Tx [4 radical prostatectomy (RP); 4 radiation; 2 cryotherapy]. RP showed a pT2N0 GS9 (4⫹5) apical tumor in 1 at 5 y, a pT3aN0 GS7 (4⫹3) tumor in 1 at 3 y, a pT2N0 GS7 (4⫹3) tumor in 1 at 1 y, and a T2N0 GS 7 (3⫹4) tumor in 1 at 2 y. Conclusions: Restrictive selection criteria and re-BX at study entry improve clinical risk classification; however, other improvements, including imaging and markers of disease progression could enhance pt selection for AS.

* Safety population. † No grade 4.




Final results of a phase II study of neoadjuvant metformin in prostatic carcinoma. Presenting Author: Anthony Michael Joshua, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada Background: Metformin is an inhibitor of the complex 1 in the respiratory chain, and is widely used in diabetes due to its effect on reducing insulin resistance. It has also been recently described to have effects via AMPK on inhibiting the mTOR kinase. Significant preclinical and epidemiological studies suggest its role in chemoprevention. These actions provide significant rationale to evaluate its utility in prostate cancer. Methods: Men were required to have histologically confirmed prostate cancer involving at least 20% of at least 1 unfragmented biopsy core. Exclusion criteria included patients who were found to be on treatment with any drug used for the treatment of any form of diabetes, or patients that began treatment for any form of diabetes during the course of the study. Pts were treated with up to 500mg tid of metformin. The primary objectives were to demonstrate safety and tolerability of neoadjuvant metformin administration in men with prostate cancer and to document changes in phospho-AKT signalling indices. Results: 24 patients were enrolled with 21 patients evaluable; median age was 64 yrs (range, 45-70 yrs). Baseline characteristics included median PSA 6 ng/mL (range, 3.22-36.11ng/mL). Median duration of drug treatment was 41 days (range 18-81). No grade 3 adverse events were reported during treatment or radical prostatectomy that were related to metformin. Significant pre-and post changes were noted in serum IGF1 (p⫽0.02), fasting glucose (p⫽0.03), BMI (p⬍0.01) and waist/hip ratio (p⬍0.01). There was a trend for a PSA reduction (p⫽0.08). There were no correlations between any metabolic, morphometric or cancerrelated serum indices. On a per patient analyses, metformin reduced a computerised relative ki67 proliferation index by an average of 29% (absolute difference of 1.4%) compared to the baseline biopsy (p⫽0.006). P-4eBP1 staining was also reduced as assessed by H-score (p⬍0.01) consistent with the ability of metformin to inhibit mTOR. Conclusions: Neoadjuvant metformin is well tolerated prior to radical prostatectomy and shows promising effects on proliferation and signaling indices. Further research is needed to define the clinical utility of metformin in prostate cancer. Clinical trial information: NCT00881725.

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Quantifying copy number variations in cell-free DNA for potential clinical utility from a large prostate cancer cohort. Presenting Author: Ekkehard Schütz, Chronix Biomedical, Göttingen, Germany Background: Prostate cancer (PrCa) is the most frequent non-dermatological malignancy in the male population. Genomic instability resulting in copy number variation (CNV) is a hallmark of malignant transformation. CNV traces from tumors in cell-free DNA (cfDNA) of prostate cancer patients may be identified through massive parallel sequencing (MPS) of serum DNA. These CNV traces may be biomarkers of cancer with clinical applications for screening and follow-up. Methods: DNA was extracted from serum of 205 PrCa patients (Gleason 2 to10), 207 age matched male controls (HC), 10 men with benign hyperplasia (BPH) and 10 with prostatitis (PiS). DNA was amplified using random primers, tagged with a unique molecular identifier per sample, sequenced on a SOLiD system and aligned to the human genome (Build 37). Hits were counted in sliding 100kbp intervals and normalized. Using a random-resampling procedure, genomic regions showing copy number variations in cfDNA that distinguish PrCa from HC were selected. A model using 20 cfDNA regions was cross-validated and used as cfDNA biomarker. Receiver operator characteristics (ROC) curves were calculated for assessment of diagnostic performance by means of area under the curve (AUC). Results: To assess whether CNVs in cfDNA are indicative of PrCa, the number of regions with significant CNV deviation was counted in a first subset of 82 PrCa. Using only the number of regions as measure resulted in an AUC of 0.81 (0.7 – 0.9, p⬍0.001). Therefore, all samples were used to select regions (n⫽80) in random resampling (50/50). These regions were used to define a highly significant 20-regions model using five rounds of 10-fold cross-validation (AUC: 0.85⫾0.7; p⬍ 10-7). This final model discriminated between PrCa and HC with an AUC of 0.92 (0.87 – 0.95) reaching a calculated accuracy of 83%. Both BPH and PiS could be distinguished from PrCa using the cfDNA CNV biomarker with a predicted accuracy of 90%. Conclusions: MPS revealed that only a limited number of chromosomal regions showing CNVs are necessary to achieve statistical separation between prostate cancer and controls. This technique may prove to be clinically useful for screening and follow up of men with prostate cancer.

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Association of SPARC expression with metastatic progression and prostate cancer-specific mortality after radical prostatectomy. Presenting Author: Claudio Jeldres, Virginia Mason Medical Center, Seattle, WA Background: We assessed the expression of the glycoprotein SPARC (secreted protein, acidic, rich in cysteine) in patients with prostate cancer (PCa) treated with radical prostatectomy (RP) and studied its association with adverse clinico-pathological features at RP and long-term clinical outcomes, such as metastatic progression after surgery and cancer-specific death. Methods: Tissues from 78 patients with PCa were used to quantify SPARC expression using tissue microarray (TMA) and immunohistochemistry techniques (IHC). Anti-SPARC mouse monoclonal antibody were use to target the protein and for each patients 4 samples of tissue were used for cytoplasmic staining. Staining of each core was reviewed by an uropathologist who assigned a score (score 0-3) to each core and a global score also assigned to each patient (score 0-3). Analyses of the data relied in cross tables, T-test analyses, survival plots and Cox regression models. Results: Higher expression of SPARC protein was recorded in patients who develop metastases during follow-up after RP (p⫽0.025) and in patients who died of PCa after RP (p⫽0.002). Median follow-up of the cohort was 9.3 years after RP. At 5 years, 95.5%, 92.0% and 89.3% of patients were metastases-free for SPARC expression score 1, 2 and 3 respectively. For the same categories, 10 years after RP, 82.2%, 77.0% and 69.9% were metastases-free (Log-rank tests all pⱕ0.05). Similarly, patients with high SPARC expression had worse cancer-specific survival at 5 and 10 years after RP compared to those with low SPARC expression (Log-rank tests all pⱕ0.01 when score 1 was compared to score 2 or score 3). Finally, advanced stage at RP (T3-T4) [p⫽0.04] and high Gleason sum (8-10) [p⫽0.02] were also associated with higher expression of SPARC. Conclusions: High SPARC expression was associated with worse outcomes in men with prostate cancer treated with radical prostatectomy. Men who developed metastatic disease and men who succumbed to prostate cancer had higher levels of SPARC at radical prostatectomy than their counterpart. SPARC may have an important role in the progression of the disease and may eventually help clinician to better ascertain the risk of progression of the disease.

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Post-treatment alterations in 18F-dihydrotestosterone (FDHT) and FDG PET/CT in metastatic castration-resistant prostate cancer (mCRPC) treated with cabozantinib. Presenting Author: Josef J. Fox, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Cabo is a multitargeted kinase inhibitor that has demonstrated complete and partial responses in mCRPC as assessed byTc-99 MDP bone scintigraphy. FDG and FDHT PET/CT demonstrate glucose metabolism and androgen receptor binding, respectively. We are exploring these tracers as response biomarkers in mCRPC treated with cabo. Methods: Patients (pts) treated with cabo were scanned with FDHT and FDG PET at baseline and after 6, 12, and 24 weeks (wks) of treatment. 5 index lesions were selected at baseline for each PET modality. The hottest slices from each were averaged (SUVmaxavg) and measured on post-treatment scans. The concordance of the post-treatment alterations of the two tracers (rise vs. decline) was examined, as were PSA alterations. Results: All 16 pts had FDG avid and 15 had FDHT avid disease. Baseline median FDHTmaxavg was 10.84 (3.52 – 18.52) and FDGmaxavg was 6.26 (2.74 – 14.7). Post-treatment alterations are described (Table). Conclusions: Most pts with mCRPC demonstrate diminution of FDHT uptake after 6 and 12 wks of treatment with cabo. These declines are matched by FDG 50-60% of the time, and correlate with PSA declines even less frequently. The etiology of the extent and degree of FDHT declines, and lack of concordance with posttreatment PSA changes, warrant further investigation, and correlation with other imaging modalities and clinical outcomes. Clinical trial information: NCT00588185. 6 wks, FDG nⴝ16, FDHT nⴝ15 #Pts with decline in FDHTmaxavg #Pts with decline in FDGmaxavg #Pts with rise in FDHTmaxavg #Pts with rise in FDGmaxavg Median % change FDHTmaxavg (range) Median % change FDGmaxavg (range) Pts with new lesions on FDHT PET Pts with new lesions on FDG PET Median % change in PSA (range) Concordance of FDG and FDHT alterations (both rise or both decline) Concordance of FDHT and PSA alterations (both rise or both decline) Concordance of FDG and PSA alterations (both rise or both decline)

12 wks, nⴝ10

24 wks, nⴝ5 5 4 5 1

-62% (-87 – 39) 1% (-72 – 123) 2 8 42% (-86 – 439) 8/15 (53%)

10 6 0 3 (1 no change) -60% (-85 – -32) -17% (-65 – 35) 2 3 19% (-84 – 348) 6/10 (60%)

-34% (-84 – -20) -24% (-59 – 4) 2 2 146% (-47 – 355) 3/5 (60%)

4/15 (27%)

4/10 (40%)

2/5 (40%)

9/16 (56%)

8/10 (80%)

3/5 (60%)

14 8 1 8


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Use of [-2]proPSA and prostate health index (phi) to improve the diagnostic accuracy of prostate cancer compared to t-PSA and %f-PSA in young men (< 65 years old). Presenting Author: Martin Boegemann, Department of Urology, University of Muenster, Muenster, Germany Background: Although prostate-specific antigen (tPSA) screening reduced prostate cancer (PCa) mortality recent recommendations do not endorse PSA-screening due to overdiagnosis and overtreatment and the resulting harm afflicted to patients. Screening studies showed the maximum benefit in young men ⬍ 65 years of age. tPSA and percent free PSA (%fPSA) lack specifity in the diagnosis of PCa. [-2]proPSA and the prostate health index (phi) improved this diagnostic specifity. Markers to diagnose clinicaly relevant cancers in young men are needed. Methods: The clinical performance of [-2]proPSA and phi was evaluated in a multicenter study. A total of 1362 patients scheduled for initial or repeated prostate biopsy (668 with, 694 without PCa, each ⱖ 10 core biopsies) were recruited in 4 different sites based on PSA level 1.6 – 8.0 ng/mL WHO-calibrated (2-10 ng/mL classically calibrated). Serum samples taken prior to digital rectal examination (DRE) were measured for the concentration of tPSA, fPSA and [-2]proPSA with Beckman Coulter immunoassays on Access 2 or DxI800 instruments. Phi was calculated as [-2]proPSA/fPSA*公tPSA. Results: In univariate analysis [-2]proPSA/fPSA (%[-2]proPSA) and phi were the best predictors of PCa detection in patients at initial biopsy (AUC: 0,72 and 0,73) and repeated biopsy (AUC: 0,74 and 0,74). Analysis of the data for men ⱕ 65 years of age (n⫽593) showed that %[-2]proPSA and phi significantly improved PCa dectection (AUC: 0,72 and 0,73) as compared with tPSA (AUC: 0,54) or %fPSA (AUC: 0,62). In the detection of significant PCa (based on PRIAS criteria) %[-2]proPSA and phi demonstrated the best performance in the whole cohort and in young men (ⱕ 65) years as well (AUC 0,68 and 0,73). Conclusions: This multicenter study showed that [-2]proPSA and phi have a superior clinical performance in detecting PCa in the PSA range of 2-10 ng/mL compared with tPSA and %fPSA at initial and repeated biopsies. This superiority is maintained for the detection of PCa in young men (ⱕ 65 years of age).

5076


Safety, efficacy, and health-related quality of life (HRQoL) of the investigational single agent orteronel (ortl) in nonmetastatic castration-resistant prostate cancer (nmCRPC). Presenting Author: Maha Hussain, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI Background: Ortl is a selective, non-steroidal, oral 17,20-lyase inhibitor. Due to its lower inhibition of 17␣-hydroxylase vs 17,20-lyase, ortl may allow steroid-free dosing. Ortl 300 mg BID was studied in nmCRPC patients (pts). Methods: Pts with nmCRPC, PSA ⱖ2 ng/mL (PSA ⱖ8 ng/mL if doubling time ⬎8 mo), and testosterone (T) ⬍50 ng/dL received ortl 300 mg BID until PSA progression, development of metastases (mets), or unacceptable toxicity. Primary endpoint: the percentage of pts with PSA ⱕ0.2 ng/mL at 3 mo. Secondary endpoints included safety, PSA kinetics, time to mets, and PFS (PSA progression, mets, or death), endocrine and bone markers, bone mineral density (BMD), HRQoL, cardiac and lipid assessments. Results: 38 pts enrolled: median PSA 11.7 ng/mL (range 2.6 – 67.8), T 8.5 ng/dL (1.4 –17.3), and ACTH 20 ng/L (n⫽32; 0 – 47). Median therapy duration was 12.4 mo (0.7–27.8); 55% of pts were treated ⬎12 mo. 6 had dose reduction, 12 discontinued due to adverse events (AEs), including 2 for possible adrenal insufficiency. Gr 3 hypertension occurred in 7 pts (18%); various ⱖGr 3 AEs occurred in another 14 pts; 10 pts (26%) had serious AEs. At 3 mo, median T declined 89% to 0.78 ng/dL; median ACTH increased 171%; median cortisol declined 21%, but remained within normal range. 97% of pts had PSA declines; median PSA declined 83%. 18% had PSA ⱕ0.2ng/mL at 3 mo; 32% achieved PSA ⱕ0.2ng/mL as best response. Median time to PSA progression was 13.8 mo. Median PFS was 13.8 mo. Kaplan-Meier estimates of 1 and 2 y mets-free rates were 94% and 69%, respectively; 8 pts developed mets on study. The patient-reported Aging Male Symptoms Scale showed no decrease in overall scores, psychological, somatic, or sexual domains in 37, 34, 25, and 19 pts assessed at visits 2, 4, 7, and 13, respectively. Serum lipids, cardiac assessments, HbA1C, or bone-specific enzymes (Ntelopeptide, or BMD) were not adversely affected. Conclusions: In pts with nmCRPC, long-term steroid-free ortl was feasible, with clinical activity as reflected by sustained marked declines in PSA and T, and had manageable toxicities, with no adverse effects on HRQoL, cardiac, bone or lipid profiles. Clinical trial information: NCT01046916.

5075


Efficacy of docetaxel chemotherapy in metastatic prostate cancer (mPC) patients (pts) experiencing early castration resistance (CR). Presenting Author: Olivier Huillard, Institut Gustave Roussy, Villejuif, France Background: mPC pts experiencing a short period of sensitivity to initial androgen deprivation therapy (ADT) have an unfavourable prognosis and lower probability of response to 2nd-line endocrine therapy suggestive of androgen receptor (AR) pathway-independent mechanisms of resistance. Recent studies have shown that docetaxel may kill PC cells through AR targeting. We thus investigated whether docetaxel may have efficacy in pts with early CR. Methods: Two independent prospective databases (Institut Gustave Roussy and Institut Jean Godinot) of mCRPC pts were analyzed. Early CR was defined as progression within the first year of ADT. The primary endpoint was time to progression (TTP) on docetaxel. Secondary criteria were clinical benefit (decrease in 2 points on a 0-to-10-pain-scale or in dose or type of pain medication), PSA response (decrease ⬎ 50% in PSA serum level) and overall survival (OS). Pts with early CR were compared to pts with sensitivity to initial ADT ⬎ 1 year (t-test for quantitative data, ␹-2 test or Fischer’s exact test for qualitative data, Logrank test for TTP and OS). Results: 188 pts were selected for analysis. A higher frequency of unfavourable prognostic factors in pts with early CR as compared with others pts was observed with a median PSA serum level of 81 ng/dl (4-8000) vs 35 ng/dl (4-4260) (p⫽5.10-5), presence of visceral metastasis in 11% vs 2% of pts (p⫽0.01) and Gleason score ⱖ 8 in 63% vs 41% of pts respectively (p⫽0.001). Clinical benefit and PSA response on docetaxel were observed in 84% vs 89% of pts (p⫽0.45) and 67% vs 81% of pts (p⫽0.10) respectively. Median TTP was 6.1 months (95%CI⫽6-7.5) vs 7.8 months (95%CI⫽7-8.3) (p⫽0.04). Median OS was 22.4 months (95%CI⫽17.1–28.6) vs 36.1 months (95%CI⫽26.3– 42.4) (p⫽0.002). Conclusions: mPC pts experiencing early CR have more unfavourable baseline prognostic factors, shorter TTP on docetaxel and shorter OS as compared with pts experiencing time to CR ⬎ 1 year. However, similar clinical and biological benefits from docetaxel chemotherapy were observed in this subset of pts. Since they have lower probability of response to second-line endocrine therapy, docetaxel appears as the best option after progression on initial ADT.

5077


Evaluating the hypothalamic-pituitary-adrenal axis (HPAA) in men receiving ketoconazole for castrate resistant prostate cancer (CRPC). Presenting Author: Rahul Raj Aggarwal, University of California, San Francisco, San Francisco, CA Background: Serum adrenal androgen (AA) levels may be prognostic for survival in men with CRPC treated with androgen synthesis inhibitors (ASIs) including ketoconazole (keto) and abiraterone. We hypothesize that upregulation of the HPAA and adrenocorticotropic hormone (ACTH) may contribute to therapeutic resistance on ASIs. The current study explores the relationship between ACTH, AA, testosterone (T) and estradiol (E) among CRPC patients (pts) treated with ASI ⫹ corticosteroids. Methods: Phase II study of keto (400 mg TID) ⫹ hydrocortisone (HC) (30 mg/day) in pts with CRPC. Pts who achieved ⱖ 30% PSA decline from baseline at week 12 continued keto/HC until progression, at which point HC was replaced by dexamethasone (dex). Serum hormone (H) levels were measured (in AM) at baseline and every 4 weeks using standard assays. Statistical tests include Spearman’s rank test for correlation between baseline H levels; Wilcoxon matched pairs for baseline vs. week 4 distribution; and Fisher’s exact test for associations between H levels (dichotomized at median) with PSA decline. Results: Of 30 pts enrolled and 24 evaluable for PSA response, 13 pts (54%) achieved ⱖ 30% PSA decline at 12 weeks. Baseline ACTH was positively correlated with DHEA (r ⫽ 0.40; p ⫽ 0.04) and cortisol (r ⫽ 0.52; p ⫽ 0.007). Change from baseline to week 4 in H levels is shown in table. There was a significant increase in pts achieving a PSA decline of ⬎ 30% if there was a decrease in E at week 4 vs. no decrease (83% vs. 18%; p ⫽ 0.003). Baseline and changes in other H levels were not associated with PSA outcome at week 12. Conclusions: ACTH is positively correlated with DHEA and cortisol in CRPC pts. Declines in E may serve as an additional predictive marker of benefit for ASI therapy. These observations require prospective validation. Analyses exploring changes in ACTH at disease progression and impact of substituting dex for HC are ongoing. Clinical trial information: NCT01036594. Serum hormone ACTH (pcg/mL) T (ng/dL) E (pg/mL) DHEA (ng/dL) DHEA-S (mcg/dL) Androstenedione (ng/dL) Cortisol (mcg/dL)

# Evaluable

Median change (range)

P value

22 23 23 23 22 21 21

4 (-105,72) 2 (⬍ -26,47) -1 (⬍ -17,18) -36 (-318,64) -52 (-196,0) -13 (⬍-67,36) 4 (-21,28)

0.13 0.16 0.38 0.01 0.0001 0.06 0.52




Ejaculation frequency and prostate cancer: A large, prospective study with 16 years of follow-up. Presenting Author: Jennifer R Rider, Harvard School of Public Health, Boston, MA Background: A prospective study in the Health Professionals Follow-up Study (HPFS) cohort published in 2001 found significantly lower risks of prostate cancer (PCa) among men with more frequent ejaculation. Because associations were stronger among men at older ages, which could be indicative of reverse causation (i.e., men ejaculating less because of symptoms associated with PCa) and few advanced cases were included, we conducted an updated study with an additional 8 years of follow up. Methods: We included 31,929 men aged 46-81 years from the HPFS who answered ejaculation frequency questions on the 1992 questionnaire. We assessed average frequency per month at three time points: age 20-29, age 40-49, and in 1991 (the year prior to the questionnaire). These data were also combined to estimate average lifetime frequency. Using follow up through January 31, 2008, we used Cox proportional hazards models to estimate relative risks (RR) and 95% confidence intervals (95% CI) for total PCa risk, as well as risk of advanced, lethal, and high-grade (Gleason 8-10) disease. As sensitivity analyses, we also examined associations within a subgroup of highly screened men and a subgroup of men without erectile dysfunction at baseline. Results: During 16 years of follow up, 3403 men were diagnosed with PCa; 455 were advanced, 360 were high grade, and 304 were lethal. Three percent of men reported a lifetime average frequency of ⬎21 times per month while 34% reported 4-7 times per month. Compared to a frequency of 4-7 times per month, multivariate RRs for total PCa for men with ⬎21 ejaculations per month were 0.81 (95% CI: 0.71-0.91) for ages 20-29; 0.76 (95% CI: 0.66-0.88) for ages 40-49; 0.68 (95% CI: 0.53-0.86) in 1991; and 0.57 (95% CI: 0.430.75) for lifetime average frequency. RRs for advanced PCa were of similar magnitudes at ages 20-29 years and 40-49 years but not statistically significant. Results were similar when we included only highly screened men or men without a history of erectile dysfunction. Conclusions: With extended follow up, ejaculation frequency continues to be strongly inversely associated with risk of total PCa. These findings are unlikely to be attributable to underlying disease or screening frequency.

5079

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Denosumab and zoledronic acid treatment in patients with genitourinary cancers and bone metastases. Presenting Author: Luis Costa, Hospital de Santa Maria and Instituto de Medicina Molecular, Lisbon, Portugal Background: Phase III trial results showed that denosumab is superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) in patients with cancer and metastatic bone disease (Lipton et al; 2012, Eur J Cancer). Genitourinary (GU) cancers are some of the most commonly diagnosed cancers worldwide. We now compare the efficacy and safety of denosumab (DMAb) or ZA in a subgroup analysis of patients with GU cancers enrolled in the pivotal phase III trials. Methods: Patients were randomized 1:1 to receive DMAb (120 mg, SC) or ZA (4 mg, IV, adjusted for renal function) every 4 weeks. Daily calcium and vitamin D supplements were strongly recommended. Time to 1st on-study SRE, using a Cox proportional hazards model, time to 1st and subsequent on-study SRE, using the Anderson-Gill model, and safety were evaluated for the GU subgroup in an ad hoc analysis. Results: 2,128 patients (1,052 DMAb; 1,076 ZA) had GU cancers (prostate ⫽ 1,901, renal ⫽ 155, bladder ⫽ 63, and transitional cell ⫽ 9). DMAb significantly delayed the time to 1st on-study SRE by 4.0 months compared with ZA (20.7 months vs 16.7 months) in patients with GU cancers (Table). DMAb also significantly delayed the time to 1st and subsequent on-study SRE. Time to disease progression and overall survival were similar between treatment groups. Adverse events (AEs) and serious AEs were reported by similar percentages of patients in both groups (AEs: 96.9% denosumab, 96.8% ZA; serious AEs: 62.8% denosumab, 60.2% ZA). 14.6% of DMAb pts and 15.9% of ZA pts had a renal AE. Hypocalcemia was reported for 12.9% of DMAb patients and 6.2% of ZA patients. There was no significant difference in the incidence of positively adjudicated osteonecrosis of the jaw between the DMAb (2.2%) and ZA (1.6%) groups (p⫽0.34). Conclusions: Among patients with GU cancers and metastatic bone disease, DMAb was superior to ZA in preventing SREs. Clinical trial information: NCT00330759 and NCT00321620. Effect of DMAb vs ZA on SRE, disease progression, and survival in patients with GU cancers. Hazard ratio (95% CI)

Endpoints Time to 1st on-study SRE Time to 1st and subsequent on-study SRE*

0.81 (0.71, 0.93) 0.82 (0.72, 0.93)

P value 0.004 0.002

* Multiple-event analysis; reported as a rate ratio.

5080


Correlation between baseline variables and survival in the radium-223 dichloride (Ra-223) phase III ALSYMPCA trial with attention to total ALP changes. Presenting Author: A. Oliver Sartor, Tulane Cancer Center, New Orleans, LA Background: In patients (pts) with castration-resistant prostate cancer and bone metastases (mCRPC), total ALP (tALP) has been shown to be a prognostic marker for overall survival (OS) (Cook 2006). Here the prognostic value of tALP and other baseline clinical variables in Ra-223 pts is presented, along with the initial results of an exploratory analysis of changes in tALP seen with Ra-223. Methods: Study population included 921 pts (intent-to-treat population) from the ALSYMPCA trial. The Cox proportional hazards model was used to evaluate the prognostic potential of tALP and other baseline variables (albumin, Hb, LDH, ECOG performance status, PSA, and age). Log transformation was done for baseline variables (tALP, PSA, and LDH) with heavily skewed distributions. Baseline variables were assessed for interaction with treatment. To determine changes in tALP from baseline at 12 wk, 708 pts who had tALP measurements at both baseline and 12 wk were included. Results: The baseline variables in the Table were significantly associated with OS. Hb was not a significant factor when adjusting for all other covariates and was therefore removed from the final Cox regression model. No significant treatment-by-covariate interactions were detected. After controlling for other variables, higher baseline tALP was significantly associated with an increased risk of death (p ⬍ 0.0001). At 12 wk, a decline in tALP relative to baseline was seen in 87% (433/497) of Ra-223 pts, compared to 23% (49/211) of placebo pts. The mean percentage change from baseline in tALP at 12 wk was a 32% decline for Ra-223 pts, in contrast to a 37% increase for placebo pts (p⬍ 0.001). Conclusions: In mCRPC pts, higher baseline levels of tALP were associated with an increased risk of death. With the majority of Ra-223 pts experiencing a decline in tALP at 12 wk, and the marked mean percentage tALP decline in these pts, further analysis to determine a correlation between tALP dynamics and survival is warranted. Clinical trial information: NCT00699751. Baseline variable Ra-223 treatment Albumin Log LDH ECOG PS Log PSA Log t-ALP Age

Hazard ratio

P value

0.783 0.973 3.476 1.612 1.401 2.046 1.014

0.0086 0.0047 ⬍ 0.0001 0.0001 ⬍ 0.0001 ⬍ 0.0001 0.0179

5081


Association of bone scan index (BSI) with prognostic biomarkers and survival in men with metastatic castration-resistant prostate cancer (mCRPC) enrolled in a prospective randomized controlled trial of tasquinimod. Presenting Author: Andrew J. Armstrong, Duke Cancer Institute, Duke University Medical Center, Durham, NC Background: Tasquinimod (T) is an oral immunomodulatory and antiangiogenic agent currently in phase 3 testing in mCRPC. In a randomized, double-blind phase 2 multicenter study, 201 men with mCRPC who received T had improved radiographic PFS vs. placebo (P), with a more pronounced effect seen in men with bone metastases. Given the subjectivity/ variability of bone scan measurements, we sought to evaluate the bone scan index (BSI), a quantitative and objective measure of BS activity, over time in this controlled clinical trial. Post-treatment BSI changes were examined given their prior association with survival. Methods: In this retrospective analysis, Exini bone™, an automated software package that generates the BSI (percent tumor involvement) from 99Tc BS, was used to calculate BSI over time from BS collected during central review in this randomized trial of T vs. P. Associations between baseline and on-treatment BSI, survival, prognostic biomarkers, and treatment effect were evaluated. Results: 108 men contributed baseline scans for BSI analysis that met quality control metrics (74 T vs. 34 P), 85 of whom (57 T vs. 28 P) had at least 1 evaluable follow-up week 12 scan. Median baseline BSI was 0.90% and after 3 months median BSI was 1.21%. In univariate analysis (n⫽85) baseline BSI correlated with OS (HR 1.41; p⫽0.01). Both baseline BSI (HR 1.62; p⫽0.006) and week 12 BSI change (HR 1.95; p⫽0.002) remained associated with OS after adjustment for bone alkaline phosphatase, PSA, pain score, hemoglobin, and treatment arm. BSI correlated with baseline PSA, LDH, bone alkaline phosphatase, and the number of bone lesions. The increase in BSI at week 12 vs. baseline was slower with T vs. placebo (0.16% vs. 0.26% increase). Conclusions: BSI and BSI changes were associated with OS in men with mCRPC in this prospective trial. BSI correlates with known biomarkers of OS, but adds independent prognostic information. While underpowered, a delay in objective radiographic bone scan progression with tasquinimod is suggested and the evaluation of BSI and BSI changes in the context of phase 3 trials of men with mCRPC is warranted. Clinical trial information: NCT00560482.


328s 5082


Association of germ-line genetic variation with failure of androgen ablation (AA) in hormone-sensitive advanced prostate cancer. Presenting Author: Manish Kohli, Mayo Clinic, Rochester, MN Background: We evaluated the association of germ-line variation in 10 candidate genes important in prostate cancer biology (NKX3-1, JAK2, SLCO2B1, STAT3, CYP19A1, HSD17B4, TRMT11, PRMT3, HSD17B12, NCOA4) with failure of AA in advanced prostate cancer patients. Methods: Patients (N⫽619) were enrolled for genotyping at the time of AA failure. Candidate genes were selected from the literature and previous pilot studies in smaller cohorts which had identified variation in TRMT11 and HSD17B12 to be associated with AA failure. Genes were tagged using single nucleotide polymorphisms (SNPs) from HapMap with minor allele frequency of ⬎5% and r2ⱖ0.8. DNA was extracted from peripheral blood and genotyped using Illumina Veracode platform. The primary endpoint was time to failure on AA, defined as time from initiating continuous AA to two serial PSA increases over the nadir or clinical or imaging based progression, whichever came first. Principal component analysis was used for gene-levels tests. Association with the primary endpoint was assessed using proportional hazards regression models at the gene-level and at the SNP level. For SNP level results we estimated per allele (ordinal model) hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression, adjusted for Gleason score (GS). Results: We successfully genotyped 60 SNPs (from 10 genes) in 519 subjects. The median age of the cohort was 71 years (range 43, 92). The GS distribution was 51% subjects with GSⱖ8; 33% with GS⫽7 and 17% with GS⬍7. Median time to AA failure for the cohort was 2.3 years (IQ range: 1.0-4.5). In gene level analyses adjusting for GS, TRMT11 (p⫽0.004), HSD17B12 (p⫽0.016), and JAK2 (p⫽0.044) genes were associated with time to AA failure. Four of the 18 genotyped SNPs in JAK2 were associated with AA failure after adjustment for GS (Table). Conclusions: Variation in the JAK2 gene is significantly associated with time to AA failure. Validation is needed to develop these as predictive biomarkers for AA in advanced prostate cancer. JAK2 gene rsIDs rs3808850 rs1887429 rs7849191 rs4372063

5084

5083


Sera cytokine levels to predict survival in men with progressive castrationresistant prostate cancer. Presenting Author: Sumit Kumar Subudhi, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Serum cytokines have been proposed as immunologic biomarkers of clinical responses based on their role in tumor biology. Recently, two whole blood mRNA signatures, which included immunomodulatory gene transcripts, were found to be predictive of survival in CRPC. This study explores serum cytokines, measured with analytically valid assays, as prognostic biomarkers in CRCP. Methods: Serum was collected from 75 progressive CRPC patients treated at MSKCC. A panel of 10 cytokines (M-CSF, IFN-␥, TNF-␣, IL-1 ␤, IL-4, IL-5, IL-6, IL-10, IL-12 and IL-13) was measured in a CLIA-certified laboratory by clinically validated ELISAs. To create a risk group classification based on the 10 cytokines, a regression tree methodology was used with the intent to maximize the survival differences between risk groups. In addition to the cytokine risk groups, PSA, LDH, albumin, hemoglobin and CTC enumeration were also independently prognostic. The Cox model was developed to determine the factors that jointly predicted survival. The concordance probability estimate (CPE) was used to determine the discriminatory power of this model. Results: Among the 10 cytokines, M-CSF (stimulates monocytes and macrophages) and IL-10 (suppresses T-cell-mediated anti-tumor responses), were most predictive of overall survival in a 3 risk-group model. The relative risk for log CTC was 1.78 (95% CI 1.43 – 2.21). The combination of the cytokine risk groups and CTC enumeration provided the best discriminatory power for predicting survival, yielding a discrimination index measured by the CPE equal to 0.77 (se ⫽ 0.03). Conclusions: A risk group classification, based on two serum cytokines, M-CSF and IL-10, and log CTC measured by analytically valid assays, predicted survival in patients with progressive CRPC. These cytokines may reflect the biology within the tumor microenvironment, and may also serve as biomarker for clinical benefit. Independent validation in a similar cohort of patients is ongoing. Risk group (pg/mL)

N

M-CSF > 333.5 and IL-10 > 1.05

33

GS adjusted per-allele HR (95% CI)

P value

M-CSF > 333.5 and IL-10 < 1.05

26

1.20 (1.04-1.38) 0.84 (0.72-0.99) 1.16 (1.01-1.32) 1.17 (1.03-1.33)

0.010 0.032 0.034 0.014

M-CSF < 333.5

16


Aspirin use and mortality in men with localised prostate cancer: A cohort study. Presenting Author: Evelyn M Flahavan, Trinity College Dublin, Dublin, Ireland Background: Cyclooxygenase-2 (COX-2) expression in prostate cancer has been associated with high grade tumours and poorer prognosis. Use of aspirin, a COX-2 inhibitor, has been associated with reduced prostate cancer mortality in some studies. These studies have not, however, provided information on the dose and timing of aspirin use. Methods: National Cancer Registry Ireland data was used to identify men with stage I-III prostate cancer (ICD10 C61) diagnosed 2001-2006. Aspirin use in the year preceding prostate cancer diagnosis was identified from linked prescription refill data (General Medical Services) and stratified by dose (low ⱕ75mg, high ⬎75mg) and dosing intensity (proportion of days in that year with aspirin supply available). Cox proportional hazards models, adjusted for age, smoking status, year of incidence, comorbidity score, Gleason score, tumour size, pre-diagnostic statin use, and receipt of radiation (time varying) were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations between aspirin use and all-cause and prostate cancer-specific mortality. Interactions with tumour characteristics were examined. Results: 2,936 men with stage I-III prostate cancer were identified (aspirin users, N⫽1,131; 38.5%). Median patient follow-up was 5.5 years. In multivariate analyses, aspirin use was not associated with a significant reduction in prostate cancer-specific (HR 0.90, 95% CI 0.68-1.20) or all-cause mortality (HR 0.98, 95% CI 0.84-1.15). In dose response analyses aspirin use was associated with a significantly lower risk of prostate cancer-specific mortality in men receiving ⬎75mg of aspirin (HR 0.59, 95% CI 0.35-1.00, p⫽0.048) but not ⱕ75mg aspirin (HR 1.01, 95% CI 0.75-1.37, p⫽0.938). Stronger associations were also observed in men with higher aspirin dosing intensity or a Gleason score ⬎7. Conclusions: Pre-diagnostic aspirin use, measured using objective prescription refill data, was associated with a significant reduction in prostate cancer-specific mortality in men with stage I-III prostate cancer receiving ⬎75mg of aspirin. These results confirm previous findings, and provide important new information regarding the dose of aspirin associated with survival benefit.

5085

Median survival in months (95% CI) 14.6 (8.6 - 21.1) 23.5 (15.3 - N/A) 50.5 (39.5 - N/A)

RR (95% CI) 1 0.65 (0.35 - 1.20) 0.30 (0.09 - 0.94)


Phase II trial of single-agent ganetespib (STA-9090), a heat shock protein 90 (Hsp90) inhibitor in heavily pretreated patients with metastatic castration-resistant prostate cancer (mCRPC) post docetaxel-based chemotherapy: Results of a Prostate Cancer Clinical Trials Consortium (PCCTC) study. Presenting Author: Elisabeth I. Heath, Karmanos Cancer Institute, Wayne State University, Detroit, MI Background: Hsp90 is a molecular chaperone required for the proper folding and activation of numerous client proteins and is critical to cell survival and proliferation. Ganetespib (G), a synthetic small molecule that binds to the ATP pocket in the N-terminus of Hsp90 causes the degradation of cellular proteins and ultimately death of cancer cells dependent on these proteins. G displays potent anticancer activity in prostate cancer cells. Methods: Eligible patients were ⱖ 18 yrs old with ECOG performance status ⱕ 2. Adequate hepatic, renal, and bone marrow function was required. Patients were treated with G 200 mg/m2 intravenously once weekly for 3 consecutive weeks followed by 1 off-week. The primary objective was to evaluate the 6-month progression-free survival (PFS). Secondary endpoints included overall safety and tolerability of G and overall survival. Exploratory markers including maspin, cytokeratins 8 and 18, and HDAC1 were obtained pre, during, and post G treatment. We sought ⱖ 4 patients with ⱖ 6 months PFS (a success) in Stage 1 of a 2-stage near-optimal Simon design. Results: 18 patients were enrolled at 4 institutions. The patients’ median age was 68 (range 51-82), 13 were Caucasian, 4 were African American, and 1 was Asian. Median PSA was 210.7 ng/mL (range 25.9 – 3,489 ng/mL). One patient never started therapy. Among the 17 treated patients, the median number of cycles was 2 (range 1-5). The most frequent Grade 3 toxicities were diarrhea (3 patients), fatigue (3), and dehydration (3). Prior therapy included abiraterone (8), sipuleucel-T (4), and other targeted therapy (4). With ⬍ 4 successes in Stage 1, the trial was terminated early. Median PFS was 1.9 months (90% CI: 1.7 – 2.7 months); median OS was 10.2 months (90% CI: 2.3 – 18.3 months). Exploratory markers have been evaluated and will be presented. Conclusions: Our study represents the first clinical trial of G in treating mCRPC patients. As a single agent therapy, G did not prolong PFS. Combination therapy is a consideration to improve therapeutic efficacy. Clinical trial information: NCT01270880.




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Vasectomy and risk of lethal prostate cancer: A 24-year prospective study. Presenting Author: Lorelei A. Mucci, Harvard School of Public Health, Boston, MA

Circulating miR-337-3p as a novel biomarker for prostate cancer. Presenting Author: Manuel Valladares Ayerbes, Oncology Service, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain

Background: In the United States, 10 to 15 percent of adult men have undergone a vasectomy. There is conflicting evidence whether vasectomy is associated with increased prostate cancer risk. Methods: We undertook a prospective study among 49,432 men in the US Health Professionals Follow-up Study. The men were age 40 to 75 years at baseline in 1986 and were followed prospectively for cancer incidence and mortality through 2010; 6,398 incident cases of prostate cancer were diagnosed, including 734 with high grade (Gleason 8 – 10) and 813 with cancer causing death or bony metastasis (lethal). We used cox regression models to calculate hazard ratios (HR, 95% confidence intervals) of the association between vasectomy and incidence of high grade and lethal prostate cancer, adjusting for potential confounders. We examined associations in the total cohort, and in a subset of 12,371 men highly screened by PSA in order to disentangle potential diagnostic bias. Results: At baseline, 22 percent of men reported having had a vasectomy. Men who had undergone vasectomy were at increased risk of high-grade (HR 1.23, 95% CI: 1.04-1.47) and lethal (HR 1.20, 95% CI: 1.01-1.43) prostate cancer. In the highly screened cohort, the association was similar for high-grade cancer, and even stronger for lethal disease (HR 1.56, 1.03-2.36). The risk of lethal prostate cancer was higher among men who had a vasectomy before age 38 years compared to at older ages. The increased risks with vasectomy could not be explained by differences in hormone levels, prevalence of sexually transmitted infections, or cancer treatments. Conclusions: Data from this study support the hypothesis that vasectomy is associated with a small increased incidence of aggressive prostate cancer defined as high grade cancer and disease causing death or bony metastasis. Differences in diagnostic intensity or confounding bias do not explain this elevated risk.

Background: Recent studies have demonstrated that the aberrant expression of microRNAs (miRNAs)is related with the development of prostate cancer (PCa). Detection of circulating tumor cells (CTC) may provide diagnostic and prognostic information inPCa. The purpose is identifying circulating miRNAs potentially useful for CTC detection in patients with PCa. Methods: In the first study phase we examined blood levels of 92 miRNAs in 49 patients grouped in pools by risk classification: low-risk 42.8%, intermediate-risk 22.5% and high-risk 34.7% and healthy volunteers (N⫽10) using SYBR-green-based microARN RT-qPCR arrays (Exiqon). Prostate cancer diagnosis was obtained by transrectalultrasound guided biopsy of 10 cores, PSA and digital rectal examination was done previously. In the second study phase using quantitative real-time polymerase chain reaction (qPCR) by TaqMan Human MicroRNAAssays (Life Technologies), we compared the expression levels of miRNAs in blood samples from 34 patients of low-risk, 31 of intermediate-risk, 18 of high-risk localized disease and 22 healthy volunteers paired by age with cases. Receiver-operator characteristic (ROC) curve was used. Results: Blood samples from patients with low, intermediate, high-risk and healthy controls exhibit distinct circulating miRNA signatures. microRNAsdifferential expressed between risk groups (p⬍0.01) (low, intermediate and high) and control group: 0microARNs upregulated (MU), 12 MU and 68 MU respectively. Highlight the significantlyoverexpression in the intermediate risk group and maintained at the high-risk of microRNAs: 337-3p[247 PicTar predictions (PTP)], 330-3p (307 PTP) and 218 (551 PTP). Preliminary results of the second study phase showed that the median level of miRNA,337-3p was significantly higher in patients with high-risk than that in healthy controls (p⫽.001). ROC curve analyses indicated that this blood miRNA may beuseful for discriminating patients with high-risk from healthy controls (AUC⫽.724). Conclusions: miRNAs in the circulation are relatively stable, very accessible, low invasive and easily testable biomarkers. Our preliminary promisingresults suggest miR-337-3p as novel stable blood-based marker for PCa detection.

5088

5089


Effects of abiraterone acetate and enzalutamide on muscle and adipose mass in men with metastatic castration-resistant prostate cancer (mCRPC). Presenting Author: Ecaterina Ileana, Institut Gustave Roussy, Villejuif, France Background: Abiraterone acetate (AA) and enzalutamide (MDV3100), two androgen receptor-directed compounds, have been shown to improve survival for patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after Docetaxel.. Since these drugs might be used at an early-stage in the future, and skeletal muscle (SM) and adipose tissue (AT) are known to be prognosis parameters, the aim of this study was to evaluate the body composition changes in patients with mCRPC treated with AA and MDV3100. Methods: Patients included in AFFIRM (n⫽62 treated with MDV3100 and placebo n⫽28) and COU-AA-301 (n⫽24 treated with AA⫹Prednisone (P)10mg/day and placebo⫹P n⫽ 13) trials at the Institute Gustave Roussy were included in the analysis. Cross-sectional areas (cm2) of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and SM were assessed by computed tomography imaging at 3rd lumbar vertebra and were indexed for height (cm2/m2) with Slice-O-Matic software V4.3 at baseline, 3, 6 and 12 months of treatment. The data from patients treated with AA or MDV3100 were compared to placebo-patients and tissues changes were compared to baseline. We used the validated sarcopenic definitions as SM index less than 52.4 (cm2/m2). Results: For all cohort, median age was 69 years (range: 48-83), median weight was 79 kg (range: 47-150) and median BMI was 25.9 kg/m2(range: 18-46). At inclusion, 74 patients (58%) were overweight or obese (BMI⬎24.9 kg/m2), and only 2 patients were underweight (BMI⬍18.5kg/m2). 97 patients (81%) were sarcopenic, and 56 (75%) of overweight or obese patients were sarcopenic. Over 3 months, the patients from the entire cohort lost muscle mass (mean change: 4.5⫾7.5% (» 0.7 kg of muscle)) (P⫽0.01) . A non significant loss of SAT -4.6⫾19.2% and a non significant increase of VAT (⫹10.7⫾50.3% ) were observed. A similar pattern was observed at 6 months. There was no significant difference between body composition changes in treated groups and placebo. Conclusions: Sarcopenia is highly prevalent in patients with advanced CRPC. Unexpectedly, no difference in body composition changes was observed between patients treated with MDV3100 or AA and placebo.


The role of advanced genetic testing in the management of prostate cancer post radical prostatectomy. Presenting Author: Edward M. Schaeffer, Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD Background: The genomic classifier (Decipher, GC) is a prospectively validated assay that predicts clinical metastasis post radical prostatectomy (RP) more accurately than standard clinicopathologic factors. While over 70% of high risk patients tested in a previous validation had low GC scores and good prognosis, patients with high GC scores had a cumulative incidence of metastasis over 25% over the study duration. Among men diagnosed with localized prostate cancer, these most at risk patients may derive the greatest benefit from novel therapies. We thus examined differential expression (DE) of druggable genes that may be targeted in this group. Methods: High-density microarray expression profiles of primary FFPE tumor specimens from 764 men treated with RP at the Mayo Clinic (1987-2006) were evaluated. A subset of 323 patients was flagged as high risk of clinical metastasis (mets) by virtue of having GC score ⱖ 0.4. Enrichment and identification of DE genes as druggable targets were pursued using DAVID and DrugBank. Results: Median follow-up of patients was 15.1 years. Among the 323 patients with high GC scores, 62% had mets during follow-up.We identified 2,262 genes DE between mets and non-mets, 230 of which are associated with 331 approved pharmaceuticals and 547 experimental agents. These agents included multiple established anti-neoplastic therapies not currently used to treat prostate cancer such as bortezomib, capecitabine, dasatinib, etoposide, gemcitabine, imatinib, irinotecan, pemetrexed and vinblastine. The two most enriched pathways, spliceosome and ubiquitin-mediated proteolysis, have been proposed previously as therapeutic targets in cancer. Conclusions: Advanced genomic testing that includes validated molecular risk scores as well as transcriptome profiling from a single assay may better enable application of directed, multimodal therapy for individual patients with high risk prostate cancer.


330s 5090


Evaluating 18F-16B-fluoro-5␣-dihydrotestosterone (FDHT) and FDG-PET as a measure of disease progression in metastatic castration resistant prostate cancer (mCRPC). Presenting Author: Karen A. Autio, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Prostate Cancer Working Group 2 defines radiographic progression as new lesions on bone scan. Molecular imaging has potential as a biomarker that reflects both alterations in disease burden and tumor biology. FDG and FDHT PET capture glycolytic activity and androgen receptor (AR) expression and tracer binding, respectively. We examined these tracers in mCRPC patients (pts) at progression (POD) to determine patterns of relapse. Methods: mCRPC pts simultaneously enrolled in imaging and therapeutic clinical trials had FDG and/or FDHT PET scans performed at baseline (BL) and within 4 weeks of treatment (rx) discontinuation for protocol-defined POD. BL characteristics, rx, SUVmax, SUVmaxavg (average of 5 index lesions), and presence of new lesion(s) at POD were collected. ⌬SUV was calculated relative to BL. Results: 44 mCRPC pts (86 BL PET scans, 84 scans at POD) receiving novel anti-androgens (eg, enzalutamide) (n⫽18), abiraterone (abi) (n⫽10), chemotherapy-based rx (n⫽5), prednisone (n⫽4), or other targeted rx (n⫽7) were included. Of those with PET POD, 75% (24/32) had ⬎ 1 new lesion on FDG-PET and 96% (25/26) had ⬎ 1 new lesion on FDHT. New lesions on FDHT were seen in 33% (6/18) of pts on novel anti-androgens as compared with 100% (10/10) on abi. Presence of a new FDG avid lesion was similar for both anti-androgens and abi (56% vs 60%). Conclusions: POD on FDG/FDHT is more frequently detected by a new lesion rather than ⌬SUV in existing index lesions. This is possibly an underestimate of change as the BL scan and not the post-rx nadir scan were used as a comparator. AR and glycolytic activity at POD may be dependent on individual and treatment factors. Notably, a third of pts on anti-androgens had a new FDHT avid lesion at POD. Full lesional analysis of metastases may enhance our understanding of tumor biology at POD. Clinical trial information: NCT00588185. New lesions at POD % ⌬SUVmaxa % ⌬SUVmaxavga % pts with worsening SUVmax % pts with worsening SUVmaxavg % with PET POD (new lesion or worsening SUVmax or SUVmaxavg) a

FDG (nⴝ43 pts)

FDHT (nⴝ41 pts)

24 (55.8%) -1.02 (-58.2 to 81.1) 0.84 (-54.9 to 157.2) 46.5% 53.5% 74.4%

25 (61%) -35.2 (-91.2 to 383.0) -35.9 (-95.0 to164.6) 31.7% 34.1% 63.4%

5091


Overall survival in hormone-resistant prostate cancer patients with different transition of care within the Veterans Affairs (VA) system. Presenting Author: S Scott Sutton, University of South Carolina, Columbia, SC Background: Prostate cancer patients with locally advanced /metastatic disease have a poor prognosis and although hormonal therapy can induce long-term remission, development of hormone-resistant prostate cancer (HRPC) is inevitable. The goal of this study is to evaluate overall survival in HRPC patients with different transition of care in the Veterans Affairs (VA) system. We hypothesized that prostate cancer patients with late referral to medical oncologists were more likely to have decreased overall survival. Methods: This is a retrospective, observational analysis of patients enrolled in the Veterans Health Administration system from October 2003 to March 2011. Patients were followed from initial evaluation and treatment by urology until an endpoint of death or the end of the study period. VA patients with a diagnosis of HRPC were identified; prostate specific antigen (PSA), medical and pharmacy records were collected. HRPC was defined as PSA doubling after treatment with hormonal therapy. Transition of care was defined as two encounters with the medical oncology service and at least one encounter was a medical oncologist. Three cohorts were created: patients transitioned to oncology before HRPC, those transitioned to oncology after HRPC, and patients who were never transitioned to oncology. Primary outcome was overall survival (OS). The Charlson score was utilized for comorbidity assessment. Statistical analysis was conducted using chi square test for categorical variables. Results: Total number of patients evaluated was 8,281; 2,168 in transition before HRPC (tbHRPC) cohort, 2,052 in transition after HRPC (taHRPC), and 4,061 patients that never transitioned (tnHPRC). The mean ages for the respective cohorts were: 69.35, 69.69, and 71.64. The Charlson comorbidity scores were 3.79 (tbHRPC), 3.06 (taHRPC), and 3.14 (tnHRPC); p-values ⬍ 0.05. Mortality rates among the cohorts were 57% tbHRPC, 69% taHRPC, and 62% tnHRPC; p-values ⬍0.001. PSA doubling within 10 months were: 57% tbHRPC, 60% taHRPC, and 54% tnHRPC; p-values ⬍ 0.05. Conclusions: Overall survival was improved among prostate cancer patients that transitioned to oncology before becoming HRPC.

Median.

5092


The impact of reducing the frequency of prostate specific antigen (PSA) testing among men on active surveillance for prostate cancer. Presenting Author: Matthew R. Cooperberg, University of California, San Francisco, San Francisco, CA Background: Active surveillance is a management strategy for men with low risk prostate cancer. Most surveillance regimens include routine PSA assessments, typically performed q 3 mos, although recent studies have questioned the utility of short-term PSA kinetics. Moreover, frequent PSA assessments may be associated with repeated intervals of anxiety around the time of testing, decreasing overall quality of life and potentially leading to avoidable interventions. We hypothesized that PSA assessment q 6 mos rather than q 3 mos would yield similar PSA kinetics calculations. Methods: We analyzed data from the Prostate Active Surveillance Study (PASS), a prospective, multicenter cohort accruing data and biospecimens from men on surveillance at 9 sites across North America. In PASS, PSAs are measured q 3 mos, with high completeness of data. We included data from men who had at least 5 PSA assessments after diagnosis, separated by ⱖ6 months (most had 10 PSAs separated by 3 months). PSA doubling time (PSADT) was calculated as ln(2) divided by the slope of a regression line drawn through the 5 PSAs. PSADT3 and PSADT6 were defined as the PSADT calculated from q 3 mos and q 6 mos data, respectively; for PSADT6, PSAs between each 6-month measurement were ignored. In each case, PSADT of 0-3 years defined progression, and PSADT ⬎ 3 years or declining PSA defined non-progression. Results: 161 men had sufficient PSA followup for analysis. 133 had no progression by either PSADT3 or PSADT6, and 16 progressed by both PSADT calculations. 4 and 8 men, respectively, progressed only by the PSADT3 or PSADT6 calculation but not by the other calculation. The ␬ score for agreement of progression ascertainment between PSADT3 and PSADT6 was 0.68, and McNemar’s test indicated no statistically significant difference between the two assessments (p⫽0.39). Conclusions: Calculating PSADT using 6-month rather than 3-month PSA assessments does not significantly change ascertainment of PSA progression in men on surveillance. Our finding suggests that surveillance protocols may reduce the frequency of PSA testing, potentially reducing unnecessary biopsy procedures and patient anxiety due to more frequent PSA measurements.

TPS5093


CA184-095: A randomized, double-blind, phase III trial to compare the efficacy of ipilimumab (Ipi) versus placebo in asymptomatic or minimally symptomatic patients (pts) with metastatic chemotherapy-naive castrationresistant prostate cancer (CRPC). Presenting Author: Tomasz M. Beer, Oregon Health & Science University Knight Cancer Institute, Portland, OR Background: Globally, docetaxel remains the standard of care for metastatic CRPC; however, its use may be delayed until pts develop symptoms. The presence of infiltrating leukocytes in CRPC tumors suggests a natural antitumor immune response is occurring. This is supported by an overall survival (OS) benefit reported in men with asymptomatic or minimally symptomatic metastatic CRPC who received sipuleucel-T. Ipi, a monoclonal antibody that binds CTLA-4, augments antitumoral activity of cytotoxic immune cells. Ipi demonstrated OS benefit in two phase III trials for advanced melanoma, with side effects that were managed using productspecific treatment guidelines. In phase I/II trials in metastatic CRPC, Ipi has shown clinical activity (as measured by prostate-specific antigen [PSA] declines and RECIST response) with a similar toxicity profile to that observed in melanoma. This global (149 sites in 24 countries) phase III study (ClinicalTrials.gov identifier: NCT01057810) evaluates Ipi vs placebo in chemotherapy-naïve pts with asymptomatic or minimally symptomatic CRPC without visceral metastases. Methods: The primary endpoint is OS; secondary endpoints include progression-free survival, time to pain progression, time to non-hormonal systemic therapy and safety characterization. The study is designed to detect a 9.3-month median difference (HR⫽0.7) in OS with 90% power and 0.05 two-sided significance. Pts are randomized at a 2:1 ratio to receive Ipi 10 mg/kg every 3 weeks for up to 4 doses or placebo as induction therapy. Eligible pts will receive maintenance therapy of blinded study drug every 12 weeks. The accrual goal is 600 pts randomized. Clinical trial information: NCT01057810. Inclusion criteria Metastatic CRPC Asymptomatic or minimally symptomatic Progression during prior hormonal therapy Discontinuation of anti-androgens Testosterone ⬍50 ng/dl ECOG performance status 0-1 Exclusion criteria Liver, lung, or brain metastases Prior immunotherapy or chemotherapy for metastatic CRPC Autoimmune disease HIV, Hep B, or Hep C infection Pelvic targeted radiotherapy within 3 months of study


Genitourinary (Prostate) Cancer TPS5094


A phase II trial of cabozantinib (Cabo) in patients (pts) with castrateresistant prostate cancer (CRPC) metastatic to bone (NCT01428219). Presenting Author: Petros Grivas, University of Michigan, Ann Arbor, MI Background: MET overexpression predicts prostate cancer invasion and bone metastasis; inhibition of MET/VEGF pathways has synergistic activity in CRPC (Knudsen et al. Adv Cancer Res 2004; Aftab et al. Clin Transl Oncol 2011). Cabo is a small molecule that inhibits multiple receptor tyrosine kinases, including MET and VEGFR2. A phase II randomized discontinuation trial of Cabo showed clinical activity in CRPC, including reduction of soft tissue lesions, prolongation of progression-free survival (PFS), resolution of bone scans, and reductions in bone turnover markers, pain and narcotic use (Smith et al, JCO 2013). To further define the activity of Cabo in pts with CRPC and bone metastases, we launched a phase II trial to characterize the effects of Cabo on bone metabolism and tumor activity in prostate cancer bone lesions. We hypothesize that the clinical activity of Cabo correlates with measurable pharmacodynamic effects on bone microenvironment. Methods: After informed consent, chemotherapy-naive pts with progressive CRPC and bone metastases accessible to CT-guided biopsy, adequate performance status/organ function, are treated with Cabo 60 mg once daily. Primary endpoint: proportion of pts progression-free (PF) at 12 weeks. Secondary endpoints: safety, PFS, response proportion/ duration, PSA response, PSA time-to-progression. A Simon’s two-stage mini-max design permits early termination after the first 27 evaluable pts in case of unfavorable results. Alternatively, up to 46 evaluable pts will be accrued. Cabo would not be of interest if the 12-week PF proportion is ⬍0.45; it would be of definite clinical interest if the 12-week PF proportion is ⬎0.65 (5% type I error, 85% power). Perfusion/diffusion-weighted MRI (parametric response maps) and bone lesion biopsies are required at baseline and 6 weeks after starting Cabo. Doxycycline is administered prior to bone biopsy for bone labeling. Bone cores are sent for dynamic histomorphometry and immunohistochemistry (phospho-MET/MET, phospho-VEGFR2/VEGFR2, phospho-Akt/Akt). Serum is collected at several time-points to measure markers of bone metabolism. 13 of 27 first-stage pts have been enrolled and started Cabo. Clinical trial information: NCT01428219.

TPS5096


A phase II trial of the aurora kinase A inhibitor MLN8237 in patients with metastatic castrate resistant and neuroendocrine prostate cancer. Presenting Author: Himisha Beltran, Weill Cornell Medical College, New York, NY Background: NEPC can rarely arise de novo but more commonly arises as a mechanism of resistance in the setting of advanced prostate cancer. Transformation to NEPC is likely promoted by potent hormonal therapies and is currently under-recognized. There is no effective therapy for NEPC and most patients (pts) survive less than one year. We have found that Aurora kinase A (AURKA) and N-myc (MYCN) are significantly overexpressed and amplified in NEPC compared to prostate adenocarcinoma, and cooperate to induce neuroendocrine (NE) differentiation in prostate cancer (Beltran et al, Cancer Disc 2011). In preclinical models, aurora kinase inhibition results in dramatic and preferential anti-tumor activity in NEPC. Methods: In this single arm, multi-institutional Phase II trial, pts with metastatic prostate cancer need to meet at least one NEPC entry criterion: 1) histologic diagnosis of small cell or NEPC, 2) ⬎50% immunohistochemical staining for NE markers, 3) development of liver metastases in absence of PSA progression, or 4) serum chromogranin ⬎5x normal or neuron specific enolase ⬎2x normal. Study will be open at 10 institutions including PCCTC sites. After a mandatory on-study research biopsy, pts will be treated with MLN8237, an orally administered Aurora kinase A inhibitor at 50 mg twice daily for 7 days repeated every 21 days. The primary endpoint is objective response rate (ORR). Secondary endpoints include overall survival, progression free survival, PSA response rate, circulating tumor cell response, and serum NE marker response to therapy. A number of correlative studies including AURKA, MYCN, AR, and exome and RNAseq are embedded in this trial in order to molecularly define this aggressive and poorly characterized disease. A Simon 2-stage design will be employed with up to 60 subjects providing 80% power to determine if the true ORR is ⬎30% and 95% power if the true ORR is ⬍15%, assuming a 5% level of significance. A subset of at least 20% meeting histologic entry criteria is embedded.

TPS5095

331s


A phase I study of cabozantinib (Cabo) plus docetaxel (D) and prednisone (P) in metastatic castrate resistant prostate cancer (mCRPC). Presenting Author: Fatima H. Karzai, Medical Oncology Branch, National Cancer Institute, Bethesda, MD Background: In mCRPC, two randomized trials demonstrated an overall survival (OS) benefit with the chemotherapeutic agent D. However, the survival improvement is modest and new strategies are needed to enhance clinical response. D-based combinations have been evaluated as one alternative strategy. Cabo targets multiple tyrosine kinases including c-Met, vascular endothelial growth factor receptor 2 (VEGFR2) and RET. Cabo has shown activity in mCRPC, with resolution of bone lesions on bone scan, regression of soft tissue/visceral disease, and reductions in circulating tumor cells and bone biomarkers (Smith, et al, J Clin Oncol 30, 2012 [suppl; abstr 4513]). We hypothesize the addition of Cabo to D and P, in patients (pts) with mCRPC, will have an acceptable toxicity profile and could lead to improved survival by targeting different cellular pathways simultaneously. This combination therapy may represent a safe and effective strategy to improve the outcome of mCRPC pts treated with D-based chemotherapy. Methods: This is a phase I trial to determine the safety profile and the recommended phase II dose of Cabo in combination with D and P. Pts receive a fixed dose of D (75 mg/m2 IV day 1 of each 21 day cycle) and P (5 mg po q12 hours) in combination with Cabo at three escalating doses: dose level 1 is 20 mg, level 2 is 40 mg, and level 3 is 60 mg (all po qdaily). Using a standard 3 ⫹ 3 design, three patients will initially be treated at each dose level until the maximum tolerated dose (MTD) has been defined. An expansion cohort will then be enrolled at the MTD. The accrual ceiling for the study, including both the dose escalation and the expansion phases, is set at 24 pts. Secondary objectives include assessments of pharmacokinetics of each agent, evaluation of antitumor activity of the combination therapy, and assessment of changes in molecular biomarkers for receptor tyrosine kinase and angiogenesis pathways, as well as biomarkers for bone metabolism. Restaging with bone and CT scan will be undertaken every 3 cycles. Enrollment at dose level 1 has been completed without dose-limiting toxicity. Accrual is ongoing at the second dose level. Clinical trial information: NCT01683994.

TPS5097


Randomized double-blind, comparative study of abiraterone acetate (AA) plus low-dose prednisone (P) plus androgen deprivation therapy (ADT) versus ADT alone in newly diagnosed, high-risk, metastatic hormone-naive prostate cancer (mHNPC). Presenting Author: Karim Fizazi, Institut Gustave Roussy, University of Paris Sud, Villejuif, France Background: Patients (pts) who initially present with metastatic prostate cancer (MPC) (up to 30% of men in Europe; 4% in US) typically progress to metastatic castration-resistant prostate cancer (mCRPC) with a poor prognosis. Prognostic factors impacting survival include high PSA concentration, high Gleason score, high volume of metastatic disease, and bone symptoms. AA decreases testosterone via CYP17 inhibition and is approved for treatment of mCRPC before and after docetaxel-based chemotherapy. Two recent reports (J Clin Oncol. 2012: 30 [suppl. abstr 4521 and 4556]) showed that AA ⫹ P in addition to ADT (LHRH agonist) in the neoadjuvant setting led to higher rates of undetectable PSA and complete pathologic response (cPR) or near-cPR in pts undergoing prostatectomy for high risk-localized prostate cancer than with ADT alone, suggesting a potential role for inhibiting extragonadal androgen synthesis prior to emergence of castration-resistance. Because of its benefit in mCRPC, as well as early activity in high risk-localized prostate cancer, AA is being evaluated in high risk mHNPC. Methods: Approximately 1,270 men with newly diagnosed (within 3 months of randomization) high risk mHNPC with at least 2 of 3 high risk factors (ⱖ 3 bone lesions, presence of visceral metastases or Gleason score ⱖ 8) are being randomized to AA 1000 mg ⫹ P 5 mg daily ⫹ ADT or ADT alone. Pts are stratified by presence of visceral disease and ECOG PS (0-1 vs 2). Distant metastatic disease must be documented by positive bone scan or CT/MRI. ADT or orchiectomy within 3 mos of randomization is allowed. Continued use of anti-androgens after randomization is not allowed on study. The primary endpoint is overall survival. Secondary endpoints include radiographic PFS, time to next skeletalrelated event, PSA progression, and subsequent therapy. Two interim analyses and a final analysis are planned. 300 sites from 36 countries will participate. As of February 4, 2013, one patient has entered screening. Clinical trial information: NCT01715285.


332s TPS5098^


Randomized, double-blind, placebo-controlled proof of concept study of tasquinimod maintenance therapy in patients with metastatic castrateresistant prostate cancer (mCRPC) who experience response or stabilization during first-line docetaxel chemotherapy. Presenting Author: Karim Fizazi, Institut Gustave Roussy, Villejuif, France Background: Docetaxel is the standard first-line chemotherapy for mCRPC. Most patients experience disease response or stabilization on docetaxel, although no treatment is currently used to maintain efficacy when docetaxel is stopped. Tasquinimod is an oral, quinoline-3-carboxamide derivative that binds to S100A9, with immunomodulatory, anti-angiogenic and anti-metastatic activity and a manageable safety profile. Tasquinimod demonstrated significantly improved PFS (7.6 v 3.3 mo) in asymptomatic to mildly symptomatic mCRPC (Pili, R. et al. J Clin Oncol 2011; 29: 4022-8) and is in phase III development. The purpose of this study is to assess whether tasquinimod used as a switch maintenance therapy can postpone cancer progression in patients with mCRPC with response or stabilization on first-line docetaxel therapy. Methods: Design: Phase II, multinational, randomized, double-blind, placebo-controlled proof of concept study. Patients with mCRPC will be randomly assigned (ratio 1:1) to receive tasquinimod or placebo. Randomization will be stratified by presence of visceral metastases and opioid analgesic use for cancer-related pain. Patient population: 140 male patients aged ⱖ18 years with histologically documented mCRPC and ECOG performance status 0 or 1 will be randomized. Before study entry, patients should have received ⱖ6 cycles of docetaxel and not experienced cancer progression according to PSA and RECIST criteria. Recruitment is ongoing. Dosage: Patients will receive a starting dose of 0.25 mg/day tasquinimod or placebo, with escalation to 0.5 mg/day and 1 mg/day based on individual safety and tolerability. Primary endpoint: Radiological PFS including skeletal-related events, from randomization to the date of radiological progression or death due to any cause. Secondary endpoints: Overall survival, symptomatic PFS, quality of life, pharmacokinetics, safety, PFS on next-line therapy, time to PSA progression, and changes in biomarkers over time. Clinical trial information: NCT01732549.

TPS5100


TAXYNERGY (NCT01718353): A randomized phase II trial examining an early switch from first-line docetaxel to cabazitaxel, or cabazitaxel to docetaxel, in men with metastatic castration-resistant prostate cancer (mCRPC). Presenting Author: Emmanuel S. Antonarakis, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD Background: Docetaxel is the standard 1st-line chemotherapy for mCRPC, while cabazitaxel prolongs survival after docetaxel progression. The activity of cabazitaxel in the 1st-line setting is unknown, while the molecular mechanisms of taxane sensitivity/resistance have been understudied. Clinically, a ⱖ30% PSA decline within 3 months predicts survival in docetaxel- and cabazitaxel-treated men. Molecularly, emerging evidence suggests that sensitivity/resistance to taxanes relates to the ability of microtubules to traffic AR into the nucleus. Circulating tumor cells (CTCs) represent a real-time biomarker to assess drug-target engagement (DTE) which may be predictive of clinical outcome, and novel enrichment techniques present opportunities for molecular testing. Methods: This is a multicenter phase 2 trial for chemo-naïve mCRPC. 100 men will be randomized (2:1) to 1st-line docetaxel or cabazitaxel. Following 4 cycles, if a ⱖ30% PSA decline is not achieved, men will switch to the alternative taxane; others will remain on the initial taxane until progression (PCWG2) or unacceptable toxicity. CTCs will be obtained at screening, baseline, after 1 and 4 cycles of chemotherapy, at crossover and at progression to interrogate mechanisms of taxane sensitivity/resistance. CTCs will be enriched via a prostate-specific microfluidic device, enumerated, and analyzed via multiplex confocal microscopy for microtubule bundling and AR localization. TaqMan PCR (and RNA sequencing) will be used to detect AR variants, as preliminary data show that variant ARv567 predicts taxane sensitivity while ARv7 predicts resistance. The primary clinical endpoint of the trial is achievement of a ⱖ50% PSA reduction during the treatment continuum. The primary molecular endpoint is analysis of DTE in CTCs, and correlation with PSA responses. The study will have 80% power to detect a 25% increase in PSA response rate with tight interclass kappa coefficients for primary biomarkers. Secondary endpoints include radiographic and PSA progression-free survival, objective response rates, overall survival, and safety. Clinical trial information: NCT01718353.

TPS5099^


PROSELICA study update: Comparison of two doses of cabazitaxel (Cbz) plus prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel (D)-containing regimen. Presenting Author: Mario A. Eisenberger, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University; James Buchanan Brady Urological Institute, Baltimore, MD Background: Cbz 25 mg/m2 IV Q3W ⫹ P 10 mg PO QD has an established safety profile and significantly improves overall survival (OS) vs mitoxantrone ⫹ P in pts with mCRPC previously treated with a D-containing regimen (phase III TROPIC study; NCT00417079; median OS: 15.1 vs 12.7 mos; HR: 0.70; P ⬍ 0.0001). Pooled data on file suggest that lower Grade 3– 4 neutropenia rates are observed with Cbz ⬍ 25 vs ⱖ 25 mg/m2 (61% vs 74%). In an attempt to further improve the therapeutic index of Cbz in the second-line treatment of mCRPC, PROSELICA (NCT01308580) was designed to assess whether Cbz 20 mg/m2 is associated with lower hematologic toxicity and has non-inferior efficacy compared with the standard 25 mg/m2dose. Methods: PROSELICA is a randomized, open-label, multinational, phase III study comparing the efficacy and tolerability of IV Cbz 20 with 25 mg/m2, Q3W. Pts with a life expectancy ⬎ 6 mos, ECOG PS ⱕ 2, confirmed mCRPC and prior therapy with a D-containing regimen are eligible. Pts are randomized 1:1 to Cbz dosing arms; all pts receive P 10 mg PO QD and are treated until disease progression, unacceptable toxicity or consent withdrawal (max. 10 cycles). Pts are stratified by ECOG PS, measurable disease and region of the world. The primary endpoint is OS (non-inferiority). Secondary endpoints include safety, progression-free survival (PCWG2 criteria), PSA and pain progression and response, tumor response and health-related quality of life. Cbz PK and pharmacogenomics will be assessed in subgroups. Planned enrollment is 1200 pts. The study started in May 2011; by 31 Dec 2012, 851 pts had been enrolled. 158 sites are enrolling pts. Based on a review of safety and efficacy endpoints, the last Data Monitoring Committee meeting (Dec 2012) recommended continuing the study without change. Clinical trial information: NCT01308580. Country Argentina Australia Belgium Brazil Canada Chile France Germany Hungary Netherlands Peru Poland Romania Russia South Africa South Korea Spain Taiwan Tunisia Turkey USA UK Total

TPS5101

Active sites

Pts randomized, n

4 14 14 12 4 4 11 9 5 5 7 3 10 9 5 5 8 2 3 2 15 7 158

15 107 64 47 33 17 116 19 24 35 15 8 42 75 19 24 55 2 9 9 27 89 851


The Pacific trial: A randomized phase II study of OGX-427 in men with metastatic castration-resistant prostate cancer (mCRPC) and PSA progression while receiving abiraterone acetate (AA). Presenting Author: Kim N. Chi, British Columbia Cancer Agency, Vancouver, BC, Canada Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone protein that regulates cell signaling and survival pathways implicated in cancer progression and over-expressed in many cancers including prostate, bladder, lung, and breast. In prostate cancer models, Hsp27 complexes with androgen receptor (AR) and enhances transactivation of AR-regulated genes. OGX-427 is a second-generation antisense oligonucleotide designed to inhibit Hsp27 expression with in vitro and in vivo efficacy that increases apoptosis, inhibits tumor growth, sensitizes cells to chemotherapy and inhibits AR activity (Cancer Res 2007;67(21):10455). A phase 2 study of OGX-427 in patients with mCRPC reported preliminary activity with 50% of patients having a ⱖ50% PSA decline during treatment (J Clin Oncol 30, 2012 (suppl; abstr 4514)). The purpose of this study was to evaluate the clinical activity of OGX-427 in patients with mCRPC progressing on AA. Methods: In this randomized, phase 2 study, 74 evaluable patients with mCRPC who are currently receiving AA and have PSA progression despite a prior response are randomized 1:1 to receive either OGX-427 (600 mg IV x 3 loading doses in week 1 followed by 1000 mg IV weekly) with AA or continuing AA alone. Additional eligibility criteria include: ECOG performance status ⱕ1, no evidence of radiographic progression, adequate liver/kidney/bone marrow function, and ⱕ1 prior chemotherapy for CRPC. Protocol therapy is continued until disease progression, unacceptable toxicity, or patient withdrawal. Eligible control arm patients may cross over to receive OGX-427 following disease progression. The primary objective of the study is to evaluate the proportion of patients progression-free at Day 60 post randomization. Secondary objectives include comparisons between arms of PSA and disease response, progression free survival, time to disease progression, serial serum levels of Hsp27, and circulating tumor cell enumeration. The study is designed to detect a 25% improvement in the primary endpoint (␣ ⫽ 0.2, ␤ ⫽ 0.1). The study was initiated December, 2012. Clinical trial information: NCT01681433.


Genitourinary (Prostate) Cancer TPS5102


A phase II study of trebananib (AMG 386) and abiraterone in metastatic castration resistant prostate cancer. Presenting Author: Avani Atul Shah, National Cancer Institute, Bethesda, MD Background: Preclinical studies support the use of an antiangiogenic approach in the treatment of prostate cancer. Trebananib is a novel peptide-Fc fusion protein that sequesters angiopoeitin 1 and angiopoeitin 2, thereby preventing their interaction with their common receptor Tie2, and inhibiting tumor endothelial cell proliferation and tumor growth. Trebananib is currently in Phase 3 trials for the treatment of ovarian carcinoma and has been shown to have clinical activity in multiple tumor types. Previous studies have demonstrated that in vivo alterations of testosterone levels regulate the expression of vascular endothelial growth factor, fibroblast growth factor, and angiopoietin associated factors. Dual inhibition of the androgen and angiogenic axis represents a novel strategy of combined targeted therapy for patients with metastatic castrationresistant prostate cancer (mCRPC). We hypothesize that the addition of trebananib to CYP17 inhibitor abiraterone and prednisone will increase the median progression free survival (PFS) in chemotherapy-naïve mCRPC. Methods: This phase 2 study will evaluate the treatment effect as measured by progression free survival in patients treated with trebananib plus abiraterone/prednisone relative to abiraterone/prednisone alone. 72 patients with progressive, mCRPC will be randomized 1:1 to either study arm. Trebananib is administered intravenously every week, on days 1, 8, 15 and 22 of each 28-day cycle. Abiraterone acetate is taken once daily with prednisone 5 mg twice daily. We have completed the initial run-in phase of trebananib at 15mg/kg and 30mg/kg. The randomized phase of the study will use the 30 mg/kg dose of trebananib with the standard dose (1000 mg) of abiraterone. The primary end point is radiographic PFS. Secondary end points include overall survival, changes in genetic biomarkers related to the androgen and angiogenesis signaling axis, molecular markers of angiogenesis, circulating tumor cells and androgen receptor signaling status in circulating tumor cells before and after treatment. This combination of angiogenesis inhibition and abiraterone has the potential to improve clinical outcomes in front-line therapy for mCRPC. Clinical trial information: NCT01553188.

TPS5104

TPS5103

333s


Design of the AFFINITY study: A randomized phase III study of a novel clusterin inhibitor, custirsen, plus cabazitaxel/prednisone (CbzP) versus CbzP alone as second-line chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). Presenting Author: Tomasz M. Beer, Oregon Health & Science University Knight Cancer Institute, Portland, OR Background: Custirsen enhances chemotherapeutic activity via inhibition of clusterin expression. Clusterin is a cytoprotective, antiapoptotic chaperone upregulated by anticancer therapies that confers treatment resistance. In a phase 2 study, mCRPC patients who had progressed within 6 mos of completing first-line docetaxel (DOC)/prednisone (P) and who were retreated with DOC/P and custirsen had a median overall survival of 15.8 mos. Lowering of serum clusterin level during second-line treatment was associated with significantly longer survival. CbzP has recently shown a survival advantage in patients with prostate cancer that has progressed after DOC therapy. The AFFINITY study was designed to evaluate in a larger study whether adding custirsen to CbzP will further improve survival in this patient population. Methods: AFFINITY was initiated in August 2012. Eligible patients in this phase 3, international, multicenter, open-label trial must have received ⱖ225 mg/m2 of DOC; have progressive disease as defined by RECIST 1.1, bone scan progression, and/or serum prostatespecific antigen level; have metastatic disease of the chest/abdomen/pelvis/ bone; have adequate renal and liver function; and have a Karnofsky score ⱖ70%. Patients may have received up to 1 DOC regimen as well as abiraterone and/or enzalutamide. Approximately 630 patients will receive 21d cycles of Cbz (25 mg/m2IV q21d) ⫹ P (10 mg PO/d), either alone or with custirsen 640 mg IV given for 3 loading doses and then weekly until disease progression, unacceptable toxicity, or 10 cycles. The primary efficacy measure is overall survival. The secondary measure is proportion of patients alive without disease progression at Day 140 post-randomization. All efficacy analyses are intent to treat. Adverse events of all patients who receive ⱖ1 dose of custirsen or Cbz will be included in the safety analysis. This study is sponsored by Teva BPP R&D, Inc., in collaboration with OncoGenex Pharmaceuticals, Inc. Clinical trial information: NCT01578655.


A randomized phase II clinical trial of enzalutamide in combination with the therapeutic cancer vaccine, PSA tricom, in metastatic, castration resistant prostate cancer. Presenting Author: Nishith K. Singh, Laboratory of Tumor Immunology and Biology, Medical Oncology Branch, National Cancer Institute, Bethesda, MD Background: There is a strong rationale to combine therapeutic cancer vaccines with hormonal abrogation in prostate cancer. Androgen abrogation augments T-cell trafficking to prostate, decreases immune tolerance, increases production of naïve thymic T-cells, enhances cytotoxic T-cell repertoire. PSA TRICOM (PROSTVAC) is a therapeutic, viral-vector based, off-the-shelf, cancer vaccine of PSA & 3 co-stimulatory molecules in phase III testing. This was developed at the NCI in collaboration with Bavarian Nordic Immunotherapeutics. It has demonstrated safety and survival benefit in a randomized phase 2 trial of metastatic castrate resistant prostate cancer (mCRPC). Enzalutamide is a modern androgen receptor inhibitor (ARI) approved for the treatment of mCRPC. Data from the clinical trials with these therapies suggest good individual tolerability without any overlapping toxicities. Analysis of previous trials suggests that vaccines may enhance clinical outcomes with ARI. These data form the scientific basis for a combination approach of a cancer vaccine with ARI to control tumor progression in mCRPC. Methods: A randomized, phase 2, open-label clinical trial at the NCI will enroll 72 chemo-naïve, minimally symptomatic patients with mCRPC. They will be randomized (1:1) to enzalutamide (160 mg daily) alone, or enzalutamide with PSA TRICOM for treatment until radiographic progression. PSA-TRICOM will be administered in a core phase (with day 1, 15 and 29 then 4 additional monthly boosts) followed by continued boosts every 3 months. The primary end point will evaluate time to progression in each arm with secondary endpoints including overall survival and systemic immune responses (lymphocyte subsets, regulatory T-cells, regulatory T-cell function, cytokines, naïve thymic emigrants). If a therapeutic cancer vaccine can enhance the clinical efficacy of a hormonal agent such as enzalutamide, it may help define a new role for vaccines as an adjuvant to standard therapies. We will also evaluate this combination in a second trial in non-metastatic, castration-sensitive patients where this combination may yield its greatest clinical impact.


334s 5500

Gynecologic Cancer Oral Abstract Session, Sat, 3:00 PM-6:00 PM

Chemotherapy or upfront surgery for newly diagnosed advanced ovarian cancer: Results from the MRC CHORUS trial. Presenting Author: Sean Kehoe, School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom Background: First line treatment of advanced ovarian cancer (OC) is accepted to be primary surgery (PS) followed by adjuvant platinum-based chemotherapy (P-CT). However, the EORTC55971 trial suggested neoadjuvant chemotherapy (NACT) is an alternative, showing increased optimal debulking rates and reduced surgical complications without detriment to survival. CHORUS (CRUK 07/009) is the 2nd phase III randomized controlled trial to investigate timing of initial surgery in OC. Methods: Patients (pts) with clinical FIGO stage III-IV OC (pelvic mass, extrapelvic metastases and CA125/CEA ratio ⬎25) were randomized to standard treatment (PS followed by 6 cycles P-CT) or NACT (3 cycles P-CT either side of surgery). CHORUS was designed to demonstrate non-inferiority of NACT, excluding a 6% absolute detriment in 3yr survival from 50% expected with PS (1-sided alpha 10%). Primary outcome was overall survival (OS) and secondary outcomes were progression free survival (PFS), toxicity and quality of life. Results: 550 women (276 PS, 274 NACT) were randomized from 74 centres (72 UK, 2 NZ) between Mar 2004 and Aug 2010. Baseline characteristics were well balanced: median age 65yrs, median tumor size 80mm, 25% FIGO stage IV, 19% WHO PS 2. Median follow-up was 3yrs, 410 pts have died. Treatment data are summarized in the Table. 3yr survival in the control arm was 32%. Intention to treat analysis showed a median OS of 22.8 months for PS vs 24.5 months for NACT (hazard ratio (HR) 0.87 in favor of NACT, 80% CI 0.76 – 0.98) and median PFS of 10.2 vs 11.7 months (HR 0.91, 0.81 – 1.02). OS results represent a 5% absolute benefit in 3yr survival for NACT to 37% and the upper 80% CI allows us to exclude a survival benefit for PS. Conclusions: NACT was associated with increased optimal debulking, less early mortality and similar survival in this poor prognosis group. CHORUS results are consistent with EORTC55971 and strengthen evidence that NACT is a viable alternative to PS. Clinical trial information: ISRCTN74802813. PS NACT (nⴝ276) (nⴝ274) Treatment received Surgery ⴙ 6 cycles P-CT Postop AEs (grade 3ⴙ) Infection Hemorrhage VTE Discharge within 14 days Debulked to 0cm residual disease 12-month survival rate

5502

Surgery 90% P-CT 76% 64%

P-CT 92% Surgery 78% 68%

6% 3% 2% 74% 15% 70%

3% 7% 0% 92% 35% 76%


Final results of OV16, a phase III randomized study of sequential cisplatin-topotecan and carboplatin-paclitaxel (CP) versus CP in first-line chemotherapy for advanced epithelial ovarian cancer (EOC): A GCIG study of NCIC CTG, EORTC-GCG, and GEICO. Presenting Author: Andres Cervantes-Ruiperez, Department of Hematology and Medical Oncology, INCLIVA, University of Valencia, Valencia, Spain Background: Topotecan was evaluated in a novel combination regimen in comparison to standard therapy in front-line EOC. Methods: Women with newly diagnosed advanced EOC stages IIB-IV, ECOG performance status (PS) 0-1, age ⬍ 75, were randomized to either Arm 1: cycles 1 - 4: cisplatin 50 mg/m2 d1 plus topotecan 0.75 mg/m2 d1-5 IV; cycles 5 - 8: paclitaxel 175 mg/m2over 3 hrs d1 followed by carboplatin AUC5 day 1 or Arm 2: paclitaxel plus carboplatin as in Arm 1 for 8 cycles. The primary endpoint was progression free survival (PFS) and secondary endpoints included objective response, overall survival (OS), adverse event (AE) and Quality of Life (QoL). The sample size required 800 pts and 631 events to detect an improvement in PFS from 16 to 20 months (power 80%, 2-sided alpha 0.05). Results with 3.6 years median follow-up (MFU) were reported previously: there was no significant difference in PFS (Hoskins P, JNCI 2010). Final results including OS after MFU of 8.2 years are reported. Results: From 2001 to 2005, 819 pts (409 Arm 1, 410 Arm 2) were randomized. 704 PFS events and 605 deaths have occurred. PFS results are similar to first report: Median (months [mo]): 14.6 (Arm 1) and 16.2 (Arm 2), hazard ratio (HR) 1.03 (95% CI:0.81-1.30; p ⫽ 0.83). Median OS is 44.2 mo (Arm 1) and 44.8 mo (Arm 2), HR: 0.92 (95% CI:0.711.19; p⫽0.54). Baseline factors found to be independent predictors of OS in multivariate analysis are: a) pre-randomization surgery (debulking with no macro residual disease (MRD) to no debulking HR: 0.47; 95%CI:0.370.58; p ⬍ 0.0001; debulking with MRD (⬍1 cm) to no debulking HR: 0.76; 95%CI:0.61-0.94; p ⫽ 0.01), b) Stage (stage II to III or IV HR:0.52; 95%CI:0.36-0.76; p ⫽ 0.0007) and c) PS (0 vs 1 HR:0.76; 95%CI:0.630.91; p ⫽ 0.004). Post-treatment AEs were not significantly different in the two arms. Conclusions: OV16 final results confirm that sequential doublets of topotecan and cisplatin followed by carboplatin and paclitaxel offer no improvement in outcomes compared to carboplatin and paclitaxel. Pretreatment debulking, stage II and PS 0 are predictive of longer OS. Clinical trial information: NCT00028743.

LBA5501


A randomized multicenter phase III study comparing weekly versus every 3 week carboplatin (C) plus paclitaxel (P) in patients with advanced ovarian cancer (AOC): Multicentre Italian Trials in Ovarian Cancer (MITO-7)– European Network of Gynaecological Oncological Trial Groups (ENGOT-ov10)–Gynecologic Cancer Intergroup (GCIG ) trial. Presenting Author: Sandro Pignata, National Cancer Institute, Napoli, Italy


LBA5503


Randomized, double-blind, phase III trial of pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced epithelial ovarian, Fallopian tube, or primary peritoneal cancer (AOC): Results of an international intergroup trial (AGO-OVAR16). Presenting Author: Andreas Du Bois, Kliniken Essen Mitte, Essen, Germany



Gynecologic Cancer 5504


5505

335s Oral Abstract Session, Sat, 3:00 PM-6:00 PM

Phase II trial of volasertib (BI 6727) versus chemotherapy (CT) in platinum-resistant/refractory ovarian cancer (OC). Presenting Author: Eric Pujade-Lauraine, Unité D’Oncologie Médicale, Hôpital Hôtel Dieu, AP-HP, Paris, France

Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer (SOC) and a BRCA mutation (BRCAm). Presenting Author: Jonathan A. Ledermann, University College London Cancer Institute, University College London Cancer Hospital, London, United Kingdom

Background: Volasertib (V) is a potent and selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinases. This study investigated V vs CT as 3rd- or 4th-line therapy in patients (pts) with platinum-refractory or resistant OC. Methods: Pts were randomized to V 300 mg IV Q3W or investigator’s choice single-agent CT (pegylated liposomal doxorubicin, topotecan, paclitaxel, gemcitabine) until progression or intolerance. Primary endpoint was 24-wk disease control rate (DCR; % of pts with complete/partial response [PR] or stable disease [SD]). Secondary endpoints included safety, progression-free survival (PFS), best overall response (RECIST 1.1) and explorative biomarkers. Results: 109 pts received V (n⫽54) or CT (n ⫽ 55) for a median (range) of 95 (22–716) and 114 (7–351) days, respectively. Demographic data were balanced between the treatment arms. Overall, median age was 62.0 yr; ECOG PS 0 –1: 103 pts; 2 prior CTs: 51 pts; ⱖ3 prior CTs: 57 pts; platinum-resistant: 78 pts; platinum-refractory: 31 pts; measurable disease: 89 pts. 24-wk DCR (95% CI) for V vs CT was 31% (18 – 43) vs 43% (30 –57), and median PFS was 13.1 vs 20.6 wks (HR ⫽ 1.01; 95% CI: 0.66 –1.53). Six V pts vs 0 CT pts are ongoing for PFS 1 yr after randomization. Best overall response in pts with measurable disease (V/CT) was: PR, 7/8 pts; SD, 24/24 pts. Adverse events (AEs) led to discontinuation in 20 pts (V, n ⫽ 5; CT, n ⫽ 15); no V pts and 8 CT pts discontinued due to treatment-related AEs (including neuropathy in 3 CT pts). Most frequent all grade AEs (% of pts) regardless of relatedness were neutropenia (61%), anemia (54%), thrombocytopenia (46%), nausea (37%) and asthenia (33%) with V, and asthenia/nausea (47% each), abdominal pain (38%), anemia (36%) and neutropenia/vomiting (31% each) with CT. There were 3 fatal AEs per arm. Conclusions: Single-agent V showed antitumor activity in OC in a range similar to CT. AEs with V were mainly hematologic and manageable, with fewer non-hematologic AEs than CT. Exploration of potential predictive biomarkers for V activity is ongoing. Clinical trial information: NCT01121406.

Background: Previously, we reported that maintenance treatment with the oral PARP inhibitor olaparib (400 mg bid) led to a significant PFS improvement vs placebo in patients (pts) with platinum-sensitive relapsed SOC (Ledermann et al NEJM2012). A preplanned subgroup analysis from this randomized, double-blind Phase II trial (NCT00753545) suggested that olaparib may lead to a greater PFS, and an OS, benefit in pts with a known germline BRCAm (gBRCAm). Since gBRCA wild-type (gBRCAwt) pts may develop somatic tumor (t)BRCAm, efficacy analyses were performed for all pts with BRCAm. Methods: gBRCAm status was determined retrospectively for all consenting pts (n ⫽ 166) using blood samples taken before randomization. tBRCAm status was determined from archival tumor samples of 196 pts. We analyzed PFS/OS by gBRCAm and total BRCAm status. Preliminary data are reported. Results: gBRCA status was known for 218/265 pts (gBRCAm, 96; gBRCAwt, 122). Including tBRCAm, 136 pts had a BRCAm (BRCAwt, 116). gBRCAm pts had the greatest PFS benefit with olaparib maintenance vs placebo (median: 11.2 vs 4.1 months [m]; HR, 0.17; 95% CI 0.09-0.32; P⬍0.001) and a significant QoL improvement, as measured with Trial Outcome Index (OR, 4.08; 95% CI 1.1119.85; p ⫽ 0.03). The PFS benefit was consistent when tBRCAm pts were included (median: 11.2 vs 4.3 m; HR, 0.19; 95% CI 0.11-0.32; p ⬍0.0001). In an interim analysis of OS (58% maturity), a comparison of olaparib vs placebo in the overall population led to a HR of 0.88 (95% CI 0.64-1.21) with medians of 29.8 vs 27.8 m, respectively. Although HRs from the gBRCAm and gBRCAwt subgroups were similar (0.85 and 0.84, respectively), 13/37 gBRCAm placebo pts received a subsequent PARP inhibitor, confounding the OS data in this subgroup. The analysis of all BRCAm pts was less confounded and resulted in an OS HR of 0.74 (95% CI 0.46-1.19; median: 34.9 vs 31.9 m). 19 pts have received olaparib for ⬎3 years. Olaparib tolerability was similar in BRCAm pts and the overall population. Conclusions: Olaparib maintenance treatment led to the greatest clinical benefit in pts with a BRCAm. These compelling data warrant confirmation in phase III trials. Clinical trial information: NCT00753545.

5506

5507^


Phase III placebo controlled double blind randomized trial of radiation therapy for stage 2B-4A cervical cancer with immunomodulator Z-100: JGOG-DT101 study. Presenting Author: Keiichi Fujiwara, Saitama Medical University International Medical Center, Saitama, Japan Background: We previously reported that the lower dose (0.2 ␮g) of immunomodulator Z-100 showed better overall survival (OS) compared to higher dose (40 ␮g) in patients with locally advanced cervical cancer who received radiation therapy (RT). Therefore, we conducted a placebo controlled double-blind randomized trial to elucidate the role of additive immunotherapy in standard RT. Methods: Patients of stages 2B to 4A squamous cell carcinoma of the uterine cervix, who were scheduled to receive standard RT with or without platinum-based chemotherapy, were eligible. Z-100 at 0.2 ␮g (Z) or placebo (P) was given subcutaneously twice a week during the RT, followed by maintenance therapy by administering either Z or P once every two weeks. Therapy was continued until disease progression or termination of the trial in2011. Primary endpoint was OS, secondary endpoints were recurrent-free survival (RFS), response rate (RR), and safety. Sample size was calculated by assuming 5-year survival rates (5YSR) as 60% in Arm Z and 38-44% for Arm P, (hazard ratio HR: 0.526-0.625), and was determined to be 120 patients in each arm. Results: Between 2004 and 2006, 249 patients were randomized. Total of 244 patients were eligible for safety analysis, and 243 patients were eligible for survival analysis. In Arm Z, 29 deaths were reported, and in Arm P, 42. 5YSR was 75.7% (95%CI: 66.4-82.8%) for Arm Z and 65.8 % (95%CI: 56.2-73.8%) for Arm P; HR was 0.646 (95%CI: 0.400-1.043). Survival benefit in Arm Z was observed regardless of chemoradiation or radiation alone. There were no differences between arms in terms of RR and RFS, and side effects. Neoplasms, including benign cases, observed were 4 in Arm Z, and 13 in Arm P. Conclusions: Immunomodulator Z-100, used as an adjuvant therapy after radiation, showed clinically significant improvement of OS in locally advanced cervical cancer, although the statistical power was less than anticipated because survival rates were unexpectedly higher than expected for both arms. Further exploration of Z-100 is warranted. Clinical trial information: C000000221.


Final results of 4-monthly screening in the UK Familial Ovarian Cancer Screening Study (UKFOCSS Phase 2). Presenting Author: Adam N Rosenthal, Barts Cancer Institute, London, United Kingdom Background: Annual transvaginal ultrasound (TVS) and serum CA125 screening for women at high-risk of Ovarian/Fallopian tube cancer (OC/FTC) in Phase 1 of UKFOCSS lacked sensitivity for early stage disease but downstaged disease volume and may have improved optimal debulking rates. More frequent screening might provide greater benefits. Here we report the final results of 4-monthly screening in one of the largest such trials worldwide. Methods: Between 14/06/2007 and 29/03/2012, 4,531 women at an estimated ⱖ10% lifetime risk of OC/FTC were recruited and screened by 42 UK centres for 14,263 women screen years. Screening comprised 4-monthly CA125 tests analysed by a risk of ovarian cancer algorithm, adjusted for menopausal status. TVS was annual in those with normal algorithm results, but was triggered sooner if results were nonnormal. Women with suspicious scan and/or algorithm results were referred for consideration of surgical intervention. Participants were followed prospectively by centres, questionnaire and national cancer registries. Data was censored 365 days after final screen, withdrawal or death. Clinical trial information: 32794457.


336s 5508

Gynecologic Cancer Oral Abstract Session, Sat, 3:00 PM-6:00 PM

Screening for Lynch syndrome in unselected women with endometrial cancer. Presenting Author: Sarah E. Ferguson, Princess Margaret Hospital, University Health Network, Toronto, ON, Canada Background: Endometrial cancer (EC) is often the sentinel cancer in women with Lynch Syndrome (LS) however it is often not recognized in this population. A prospective cohort study comparing family history, immunohistochemistry (IHC) for mismatch repair (MMR) proteins, and tumour morphology to germline mutation status in MMR genes was performed in unselected women with EC to determine which screening strategy was superior in identifying women with LS. Methods: All women with newly diagnosed EC between July 2010 and June 2011 were asked to participate in the prospective screening protocol for LS which included completing an extended family history questionnaire (eFHQ), tumor assessment for LS-associated morphologic features and IHC as well as germline mutation testing. Results: 119 (n ⫽ 182, 65%) consented to the study. The median age was 61 (26-91), 96 (81%) stage I, and 42 (35%) had high risk histology. There were 6 (7.4%, n ⫽ 81) women that were germline mutation positive (MLH1 N⫽3; MSH6 n ⫽ 2; MSH2 n ⫽1), representing a mutation positive rate of at least 5% in this cohort (6/119). All 3 MLH1 mutation positive women had low grade histology while mutations in MSH2/6 were exclusively found in women with high risk histology. Two of the six mutation positive women were not identified by family history. Mutation positivity was higher in women under age 50 (23%; 5/22) compared to women ⬎ age 50 (1%; 1/97)( (p ⫽ 0.0008). LS-morphologic features were found in 58 (59%, n ⫽ 98) women. The sensitivity, specificity, PPV and NPV of the LS-associated features in predicting LS mutation status was 100%, 42.6%, 7.9% and 100% compared to IHC which was 100%, 76%, 18% and 100% and eFHQ which was 67%, 84%, 27%, 97%. Conclusions: In this unselected population of women with newly diagnosed EC the germline mutation rate for LS was 2-3 times that has previously been reported. Previously described LS-associated morphologic features were not specific to germline mutation status and family history missed one third of women with LS. IHC was the best strategy to identify women with EC who should undergo germline mutation testing.

5510

Clinical Science Symposium

5509


Prognostic significance of differential expression of angiogenic genes in women with invasive high-grade serous ovarian carcinoma. Presenting Author: Sharareh Siamakpour-Reihani, Duke University Medical Center, Durham, NC Background: High-grade serous ovarian carcinoma (HGSC) is an aggressive type of epithelial ovarian cancer associated with numerous genetic alterations and poor survival. Our objective was to identify novel angiogenic biomarkers that are associated with tumor angiogenesis and clinical outcome in women with HGSC. Methods: Between 1988 and 2001, 51 snap frozen samples from women with advanced HGSC were obtained. RNA was extracted and analyzed by the Affymetrix GeneChip U133A array. A panel of 285 probe sets (features) linked to 145 genes involved in angiogenesis were screened. Microvessel density (MVD) counts, surrogates of angiogenesis, were determined using CD31 and CD105, markers of proliferating endothelial cells. The association between mRNA expression levels and overall survival (OS) were assessed using a rank score statistic. The effect size was estimated parametrically as a hazard ratio (HR) under a proportional hazards model. We accounted for multiple testing within the false-discovery rate (FDR) framework using the Storey q-value method. The associations between expression level and OS for the implicated genes were further assessed in a published HGSC cohort from the “The Cancer Genome Atlas” (TCGA) database. Results: A panel of 43 features linked to 31 angiogenic genes were significantly associated with long term OS (FDR q-value (q) ⬍ 0.05). In the TCGA cohort, four genes exhibited some level of significance and concordant direction of effect as assessed by HRs: AKT1 (q ⫽ 0.018, HR ⫽ 0.44; TCGA unadjusted p-value (p) ⬍0.011, HR ⫽ 0.81), and CD44 (q ⬍ 0.003, HR ⫽ 0.48; TCGA p ⬍ 0.054, HR ⫽ 0.89) were associated with better survival; while EPHB2 (q ⬍ 0.009, HR ⫽ 8.12; TCGA p ⬍ 0.051, HR ⫽ 1.23) and ERBB2(q ⬍ 0.019, HR ⫽ 2.86, TCGA p ⬍ 0.055, HR ⫽ 1.19) were associated with worse survival. After adjusting for multiple comparisons, CD105-MVD and CD31-MVD were not significantly associated with angiogenic gene expression. Conclusions: Our data demonstrated that mRNA levels of 31 angiogenic genes were associated with OS in advanced HGSC. Among these 4 were externally confirmed using TCGA data. Further evaluation is warranted to verify our preliminary findings.

5511


Prognostic relevance of gene signatures in high-grade serous ovarian carcinoma. Presenting Author: Gottfried E. Konecny, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA

Distinct copy number alteration patterns as prognostic of endometrial cancer outcomes. Presenting Author: Itai Max Pashtan, Harvard Radiation Oncology Program, Boston, MA

Background: Transcriptional profiling of ovarian cancers has proven to be complex. As such it has been difficult to validate existing signatures across studies. Cancer Genome Atlas (TCGA) researchers have identified four molecular subtypes of high-grade serous ovarian cancer (HGSOC). However, survival duration did not differ significantly for the TCGA subtypes. Potential limitations of the TCGA data include short clinical follow-up (45% were alive at the time of last follow-up) and the need to unify gene expression measures from multiple platforms. Methods: Clinically annotated stage-II–IV HGSOC samples (n ⫽ 175) with ⬎70% tumor cell content were profiled using the Agilent Whole Human Genome 4 x 44K chip. To identify subtypes non-negative matrix factorization (NMF) of mRNA expression was performed using ~2000 genes with the highest variability across patients. In parallel differentially expressed genes were identified using the Rosetta Similarity Search Tool as well as analysis of variance based on genes known to be involved in epithelial to mesenchymal transition. Results: Median follow-up time was 35 months (range, 0 –202 months, 12% were alive at the time of last follow-up). NMF clustering confirmed four HGSOC subtypes (immunoreactive, differentiated, proliferative, and mesenchymal) on the basis of gene content in the clusters. Pathway signatures with therapeutic potential were identified for individual or multiple subtypes. Survival differed significantly between the four molecular subgroups in univariate (Hazard Ratio [HR] 2.4, 95% CI 1.5-4.1, p ⫽ 0.007) and multivariate (HR 2.3, 95% CI 1.3-4.0, p ⫽ 0.003) analyses when accounting for age, stage, grade, and postoperative residual tumor. Using the supervised clustering approach two distinct molecular subtypes of HGSOC based on epithelial and mesenchymal gene expression signatures were identified with significantly different survival outcomes. Conclusions: Here we independently validate and expand upon the molecular TCGA classification of HGSOC. The potential of these two prognostic classifiers may lie in their ability to recognize categories of patients that are more likely to respond to particular therapies.

Background: Endometrial cancer is classified by tumor stage, histologic subtype and grade. However, a substantial proportion of presumed nonhigh risk cases recur, supporting the need for improved tools of prognostication. Methods: Using clinical and Affymetrix SNP 6.0 data from The Cancer Genome Atlas (TCGA) endometrial carcinoma project, we identified 4 somatic copy number alteration (SCNA) subtypes, established their prognostic value and validated them in an independent, population-based cohort from Norway. Patients had endometrioid, uterine papillary serous carcinoma (UPSC) or mixed histology tumors. Progression-free survival (PFS) was defined as time from diagnosis to recurrence or progression, and estimated by the Kaplan-Meier method. Results: Four groups of SCNA patterns were identified using hierarchical clustering: low SCNA, moderate SCNA, SCNA dominated by 1q amplification (1q amplified) and high SCNA level (serous-like). Their prognostic value was assessed in all TCGA patients (N ⫽ 292) and in a low risk subset with endometrioid histology, stage 1 disease (N ⫽ 210). In the full TCGA cohort, patients with low SCNA (reference group) had excellent 2-year PFS of 94%, while for moderate SCNA it was 84% (hazard ratio[HR] 2.7, p ⫽ .08). The 1q amplified and serous-like groups had significantly worse outcomes with 2-year PFS of 74% (HR 5.9, p⫽ .002) and 74% (HR 6.0, p ⬍.001), respectively. On multivariable analysis, adjusting for variables including stage and grade, 1q amplified and serous-like SCNA patterns remained independently prognostic (respectively, adjusted HR 6.2, p ⫽ .002 and 4.7, p ⫽ .02). Similar results were found in the low risk subset. The prognostic value of the SCNA patterns was validated in an independent group of patients with low risk disease (N ⫽ 57). 5-year PFS was 91% for low SCNA, 83% for moderate SCNA (HR 2.0, p ⫽ .58), 72% for 1q amplified (HR 3.7, p ⫽ .11) and 50% for the serous-like SCNA group (HR 6.7, p ⫽ .04). Conclusions: Four subtypes of DNA SCNA patterns in endometrial cancer were identified and validated to be prognostic of outcome. These novel biomarkers may be useful in guiding therapeutic decisions, and shed insight on the biology of more, or less, aggressive endometrial cancer.




5513

337s Poster Discussion Session (Board #2), Sun, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

Pazopanib (Paz) monotherapy in Asian women who have not progressed after first-line chemotherapy for advanced ovarian, Fallopian tube, or primary peritoneal carcinoma. Presenting Author: Rongyu Zang, Shanghai Fudan University, Shanghai, China

Paclitaxel/carboplatin with or without sorafenib in the first-line treatment of patients with stage III/IV epithelial ovarian cancer: A randomized phase II study of the Sarah Cannon Research Institute. Presenting Author: Dana Shelton Thompson, Tennessee Oncology, PLLC/SCRI, Nashville, TN

Background: Paz, an oral multikinase inhibitor of VEGF, PDGF and c-Kit has showed activity in advanced ovarian cancer. This study evaluated paz as maintenance therapy in Asian women with advanced ovarian cancer. Methods: Subjects with FIGO stage II, III, or IV ovarian, fallopian tube, or primary peritoneal cancer whose disease had not progressed after debulking surgery and followed by chemotherapy were randomized 1:1 to paz 800 mg once daily or placebo for up to 24 months. Primary endpoint was PFS by RECIST v1.0 based on visit date. If a progression occurred between the 2 scheduled visits (6 mos apart), progression was considered to have occurred at the next scheduled scan date. This minimized potential bias due to any imbalance of visit frequency between the arms. Results: 145 Asian subjects were randomized; 144 were treated. Mean age was 52.9 years. At diagnosis 17% were FIGO stage II, 73% stage III and 10% stage IV. After debulking surgery, 30% (n ⫽ 44) had no residual disease and 41% (n ⫽ 59) had. 47% (28/59) had residual disease ⱕ1cm. Prior to randomization, all subjects received median 8 cycles of chemotherapy; all subjects received platinum and taxane. At randomization 81% had ECOG status 0, 97% were disease free and all had normal CA-125. At clinical data cut-off median PFS was 18.1 months in both arms. Because of the small sample size a HR was not calculated but the KM curves indicated a trend in favor of paz from 6 to 18 mos; the curves crossed after 18 mos. The adverse event (AE) profile for paz was similar to previous reports except rates of hypertension and neutropenia were higher. The most frequent AEs (ⱖ 20%) on the paz arm were hypertension (76%), neutropenia (64%), leucopenia (53%), diarrhea (47%), hair color changes (40%), palmplantar erythrodysaethesia syndrome (29%), ALT increase (28%), thrombocytopenia (24%), AST increase (22%) and TSH increase (21%). Most of these AEs were Grade 1-2. Conclusions: The results of this study alone cannot confirm the efficacy of paz maintenance treatment in Asian women with ovarian cancer, but should be interpreted in conjunction of AGOOVAR16 study. Clinical trial information: NCT01227928.

Background: The combination of paclitaxel and carboplatin is the most widely used chemotherapy regimen for patients (pts) with advanced ovarian cancer, producing a median survival of approximately 36 months. Recently, the addition of bevacizumab, an angiogenesis inhibitor, has improved progression-free survival (PFS) when compared to paclitaxel/ carboplatin alone. Sorafenib is an oral multi-kinase inhibitor with effects on tumor angiogenesis through inhibition of the VEGF receptor. The purpose of this randomized phase II study was to compare efficacy of paclitaxel/ carboplatin with and without sorafenib. Methods: Women with histologically confirmed, maximally debulked, previously untreated stage III/IV epithelial ovarian carcinoma were randomized to receive paclitaxel 175 mg/m2and carboplatin AUC 6 (PC) or PC ⫹ sorafenib 400 mg PO BID (S). All patients received 6 cycles, given every 3 weeks; pts receiving PC⫹S continued single agent sorafenib for 52 weeks total. The primary endpoint was 2-year PFS rate. Results: 85 pts were randomized between 1/07 and 10/11 (PC⫹S 43; PC 42). Pt characteristics were similar between groups, except that more patients with only CA125 elevation received PC⫹S (65% vs 43%). Overall, 67 pts (79%) completed 6 cycles of chemotherapy (PC⫹S 74%; PC 83%). More patients stopped PC⫹S due to toxicity (14% vs 7%). 22 pts (51%) receiving PC⫹S began single agent S after 6 cycles PC, and 12 pts (28%) completed 52 weeks of S. There was no difference in the 2-year PFS rates: PC⫹S 40%, PC 39%. Overall survival comparisons were also similar (p ⫽ 0.36). Pts receiving PC⫹S had more grade 3 rash (33% vs 0%) and hand-foot syndrome (9% vs 0%). Conclusions: The addition of sorafenib did not improve the efficacy of standard first-line PC in pts with stage III/IV ovarian carcinoma, and resulted in additional toxicity. Clinical trial information: NCT00390611.

5514

5515


A randomized placebo-controlled trial of saracatinib (AZD0530) plus weekly paclitaxel in platinum-resistant ovarian, fallopian-tube, or primary peritoneal cancer (SaPPrOC). Presenting Author: Iain A. McNeish, University of Glasgow, Glasgow, United Kingdom Background: Weekly paclitaxel (wPxl) has activity in platinum-resistant ovarian cancer (PROC). Upregulated Src kinase activity is seen in Pxlresistant ovarian cancer models. This trial investigated the combination of wPxl and the oral Src inhibitor saracatinib (AZD0530) in PROC. Methods: Patients with PROC (defined as relapse within 6 months of prior platinum chemotherapy, confirmed either by CT scan or symptomatic CA125 rise) were randomised 2:1 to receive four 8 week cycles of wPxl (80mg/m2/week x6 with 2 week break) plus saracatinib (S; 175mg od) or placebo (P) continuously, starting 1 week prior to wPxl, until disease progression. Patients were stratified as ⬍6 months or ⱖ6 months taxane interval/no prior taxane. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints included overall survival (OS), response rate (RR), duration of response (DoR), time to progression (TTP) and toxicity. Results: 107 patients were randomised during 2011-12, 71 (66.4%) to wPxL⫹S and 36 (33.6%) to wPxL⫹P. Taxane interval was ⬍6 months in 23 (22.1%), ⱖ6 months in 76 (72.4%). 43 (41.0%) had received ⬎2 lines of prior chemotherapy; 78% (wPxL⫹S) vs 72% (wPxL⫹P) of patients received ⱖ1 cycle of wPxl; relative dose intensity was 96% vs 98% for wPxL⫹S and wPxL⫹P respectively. The 6-month PFS rate was 29% (wPxL⫹S) vs 35% (wPxL⫹P). Median PFS was 3.9 vs 5.3 months (HR 1.04; 95% CI 0.68, 1.59; p⫽0.86); median OS was 12.7 vs 12.8 months (HR 1.50, 95% CI 0.63, 3.56; p⫽0.36); RR were 0.0% vs 2.9% (CR) and 29% vs 38.9% (PR) for wPxL⫹S vs wPxL⫹P respectively. Median DoR was 5.6 vs 3.6 months; TTP was 3.9 vs 5.5 months (HR 1.10; 95% CI 0.71, 1.72;p⫽0.67). Grade 3⫹ Serious Adverse Events were 36.2% vs 30.6%; the most frequent toxicities (any grade) were abdominal pain (4.3%) and febrile neutropenia (4.3%) for wPxL⫹S, and vomiting (5.6%) for wPxL⫹P. Conclusions: In this randomised phase II trial, the addition of saracatinib to wPxl did not improve 6-month PFS in patients with PROC. Clinical trial information: NCT01196741.


A multicenter open-label phase II study of the efficacy and safety of ganitumab (AMG 479), a fully human monoclonal antibody against insulin-like growth factor type 1 receptor (IGF-1R) as second-line therapy in patients with recurrent platinum-sensitive ovarian cancer. Presenting Author: Isabelle Ray-Coquard, Centre Léon Bérard, Lyon, France Background: IGF signaling has been implicated in the pathogenesis and progression of ovarian cancer (OC). Single agent activity and safety of ganitumab (AMG 479), a fully human monoclonal antibody against IGF-1R that blocks binding of IGF1 and IGF2, were evaluated in asymptomatic patients with platinum-sensitive recurrent OC. Differential expression of IGF-1R pathway genes in OC underscores the potential of developing predictive biomarkers for patient selection. Methods: Pts with CA125 progression (GCIG criteria) and/or measurable disease per RECIST failing primary platinum-based therapy received 18 mg/kg of ganitumab q3w. Objective response rate per RECIST or CA125 criteria was the primary end point (complete response, CR; partial response, PR). Secondary end points included, progression-free survival (PFS) and safety. Tumor tissue was collected for gene expression profiling (Nanostring) and sequencing. Results: From 02/2009 to 05/2010, 61 pts were accrued from 20 centers. Pt characteristics were: Serous (77%), median platinum-free interval (11 months), measurable disease (74%), and ECOG performance status 0 (67%). According to CA125 criteria median PFS was 6.8 months (95%CI, 2.8-10.8); 2 CR (3.4%) 2 PR (3.4%), and 38 stable disease (SD, 64%) were observed. When using RECIST criteria, median PFS was 2.1 months (95%CI, 2.0-2.8), 2 PR (3.4%) and 22 SD (38%) were observed. Toxicity has been mild; grade 2 hyperglycemia was seen in 5 pts (8.2%). Grade 3 related events included hearing loss (1), nausea (1), asthenia (2), fatigue (1), and hypersensitivity (5). There were no grade 4 or 5 treatment-related events. Efficacy is being correlated with gene expression profiles and mutational data. Conclusions: IGF-1R inhibition with ganitumab was well tolerated and demonstrated modest single-agent activity in unselected patients with platinum-sensitive recurrent OC. However, encouraging activity was seen in a subset of patients. Ongoing predictive biomarker analyses may facilitate patient selection. Clinical trial information: NCT00719212.


338s 5516

Gynecologic Cancer Poster Discussion Session (Board #5), Sun, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

Opsalin: A phase II placebo (Pbo)-controlled randomized study of ombrabulin in patients with platinum-sensitive recurrent ovarian cancer (OC) treated with carboplatin (Cb) and paclitaxel (P). Presenting Author: Michael J. Birrer, Massachusetts General Hospital/Dana-Farber Harvard Cancer Center, Boston, MA Background: Patients with platinum-sensitive recurrent OC are often retreated with CbP due to limited treatment options. Ombrabulin (AVE8062), a combretastatin A4 analog, is a vascular disrupting agent that damages established tumor vasculature causing tumor necrosis and has synergistic antitumor activity with platinum agents in vivo (Cancer Sci. 2003;94:200). OPSALIN evaluated whether adding ombrabulin to CbP improves outcomes in patients with platinum-sensitive recurrent OC (NCT01332656; EFC10260). Methods: Patients (aged ⱖ18 yrs, ECOG PS ⱕ2) with platinum-sensitive measurable ovarian, fallopian tube, or primary peritoneum carcinoma after completion of one line of platinum-based chemotherapy received ombrabulin 35 mg/m² or Pbo plus CbP (AUC 5– 6, 175 mg/m²) every 3 weeks. Randomization (1:1) was stratified by time of first disease recurrence (6 –12 or ⬎12 months). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, response rate (RR), and safety. An interim analysis after ~54 PFS events (60% of the target 90 PFS events) was planned. Results: From May 2011 to August 2012, 154 patients were randomized (n⫽77 in each group). Groups were balanced in terms of baseline characteristics. Overall, the median age was 56 yrs (range 34 –79), 93% had ovarian primary tumors, and 54% had first disease recurrence ⬎12 months. Planned interim analysis was performed after 53 PFS events (27 ombrabulin; 26 Pbo); median follow-up was 6.8 months. Ombrabulin did not improve PFS vs Pbo in any subgroup (global median 8.4 vs 10.4 months, respectively; HR 1.33; 60%CI 1.06 –1.69). Overall, RR was 65% for ombrabulin and 71% for Pbo. Safety profiles were comparable; rates of grade 3– 4 adverse events were 51% for ombrabulin and 41% for Pbo, with no particular safety signals. Conclusions: This interim analysis has suggested no safety concerns or efficacy advantage of adding ombrabulin to CbP in patients with platinum-sensitive recurrent OC. The study was discontinued due to limited probability of the ombrabulin arm showing PFS superiority at the final analysis. Study sponsored by Sanofi. Clinical trial information: NCT01332656.

5518


Targeting p53 mutant ovarian cancer: Phase I results of the WEE1 inhibitor MK-1775 with carboplatin plus paclitaxel in patients (pts) with platinumsensitive, p53-mutant ovarian cancer (OC). Presenting Author: Irene Brana, Princess Margaret Cancer Center, University Health Network, Division of Medical Oncology & Hematology, Department of Medicine, University of Toronto, Toronto, ON, Canada Background: MK-1775 is a highly selective, investigational oral tyrosine kinase inhibitor of WEE1, which regulates G2 cell cycle checkpoint. Functional p53 mutation impairs G1 checkpoint; hence, targeting G2 checkpoint with MK-1775 in p53 mutants should induce synthetic lethality. Methods: Pts with platinum-sensitive disease-recurrent OC who had measurable disease (RECIST 1.1) with loss of function (LOF) p53 mutations by Roche AmpliChip were eligible. All pts received MK-1775 225mg twice daily (BID) D1-D3 (5 doses) plus carboplatin AUC5 ⫹ paclitaxel 175mg/m2 every 21 days (CP) for 6 cycles. The objective for the phase I run-in portion of the study was to determine the recommended phase II dose based on safety data. A Toxicity Probability Interval method [Ji et al, Clin Trials 2010; 7(6):653-63] would determine if additional lower doses should be explored. A randomized phase II portion, assessing the efficacy of the combination vs placebo, would start if ⱖ5 radiological responses and ⬍5 dose-limiting toxicities (DLTs) were observed among the first 13 pts. Results: Of 76 pts screened (26 wt, 43 mutant [24 nonfunctional], 7 undetermined), 19 women had LOF p53 mutations and were eligible. Fifteen consented and were enrolled in the Phase I: median age was 57 (range 38-77); ECOG 0:1 ratio 9:6 pts. Three DLTs were observed: G3 febrile neutropenia, G4 neutropenia, and G4 thrombocytopenia. Diarrhea (84.6%), nausea (76.9%), and fatigue (76.9%) were the most common adverse events (AEs). Seven of 13 pts completed treatment (2 ongoing). Three pts discontinued due to AEs and 3 patients withdrew consent prior to completing treatment. Of 14 evaluable pts by RECIST 1.1 there were 11 partial responses (PRs; 6 confirmed, 5 unconfirmed) and 3 had stable disease; 7 pts were evaluable by CA125 with 3 complete responses and 4 PRs. MK-1775 PK results were similar to those reported for monotherapy studies. Conclusions: The combination of MK-1775 225mg BID x 5 doses with CP is well tolerated, with a preliminary radiological response rate of 78.6%, and has met the safety and efficacy bar for randomized phase II assessment in part 2 of the study. Clinical trial information: NCT01357161.

5517


A multicenter phase II study of bevacizumab (B) and temsirolimus (T) in women with recurrent epithelial ovarian cancer (OC): A study of the Mayo, Chicago, California, New York, Southeast, and Princess Margaret Phase II Consortia. Presenting Author: Robert Morgan, City of Hope, Duarte, CA Background: Anti-angiogenic therapy is active in OC; the combination of VEGF and mTOR inhibitors is hypothesized to further improve activity. This report is the OC cohort of a multi-histology phase II study assessing the activity and toxicity of B/T. Methods: Patients (Pts) with recurrent epithelial OC who had received ⱕ 2 chemotherapy regimens and no prior treatment with a VEGF or mTOR inhibitor were eligible. A two-stage design was used with second stage accrual if ⬎6 pts had objective responses (OR) or ⬎10 pts of the first 25 remained progression-free (PF) at six months (mo). Pre-defined end-points for a recommendation for further clinical trial evaluation included at least 15/50 with OR or 26/50 PF at six mo. Treatment included T 25 mg IV wkly and B 10 mg/kg IV q14 days on 28 day cycles. Results: 58 pts were enrolled (the first 50 pts are used to determine a final recommendation). Median age⫽62 (range 35-82). A median of 4 (range 1-23) cycles were administered. 24 were platinum-sensitive, 34 resistant. Off-study reasons included 13 adverse events and disease progression in 38. 3 refused further therapy due to toxicity. 14 of the first 50 pts had partial response (PR) (9 platinum-resistant); 25/50 remained PF (8 PR, 15 SD, 2 non-progressing) at 6 mo. Grade (gr) 3/4 toxicities occurring ⬎2 events include: fatigue (4), stomatitis (7), hypertension (5), neutropenia (4), thrombocytopenia (4), hypokalemia (3). One rectal and one vaginal fistula, and two colonic perforations (one gr 2 and one gr 3 during cycles 3 and 1 respectively) were observed. Episodes of gr 1/2 oral, nasal, pulmonary, vaginal and gastrointestinal hemorrhage were also observed. Conclusions: Although the OR and PFS did not reach pre-defined standards, the numbers of OR and 6 mo PFS suggest potential enhanced activity with a combination of mTOR inhibitor with anti-angiogenic therapy. Other combinations of these targeted agents may result in more satisfactory activity with less toxicity. N01-CM-62203 (PMH) N01-CM-62208 (Southeast Phase 2) N01 CM-62209 (CCCP) N01-CM-62204 (NYCC) N01-CM2011-0071C (Chicago) N01-CM62205 (Mayo) Clinical trial information: NCT01010126.

5519


A preoperative window study of metformin for the treatment of endometrial cancer. Presenting Author: Kevin M. Schuler, UNC Hospitals, Chapel Hill, NC Background: Obesity and diabetes have been linked to poorer survival and increased recurrence rates in endometrial cancer. The anti-diabetic medication, metformin, has been shown to have anti-tumorigenic effects in vitro and in vivo, via AMPK activation and inhibition of the mTOR pathway. We conducted a pre-operative window clinical trial of metformin in obese endometrial cancer patients to evaluate short-term in vivo molecular changes. Methods: Women with endometrioid endometrial cancer who were obese (BMI⬎30) were recruited from a gynecologic oncology clinic. Once enrolled, patients had a repeat pre-treatment endometrial biopsy and then began metformin at a dose of 850 mg PO once daily for 1-4 weeks prior to hysterectomy/surgical staging. A tissue microarray, using triplicate cores from each specimen, was constructed from paired formalin-fixed, paraffinembedded endometrial biopsy (pre-treatment) and hysterectomy (posttreatment) specimens. The expression of Ki-67, a marker of cell proliferation, was measured by immunohistochemistry. Individual slides were digitized using the Aperio ScanScope (Aperio Technologies, Vista, CA), and digital images were analyzed using Aperio ImageScope software. The Signed Rank Test was used for statistical analysis. Results: Sixteen patients have completed the protocol. The mean duration of treatment was 14.5 days. Percent Ki-67 staining decreased significantly with metformin treatment (mean of 19.5% decrease, p ⫽ 0.026). Two patients experienced grade 1 toxicities, including mild abdominal pain and loose stools. Ten of the 16 patients responded to metformin based on decreased proliferation from their pre- to post-treatment specimens. There were no differences in median age, BMI, HgbA1c, or number of doses taken between responders and non-responders to treatment. Pre-treatment Ki-67 levels were statistically higher in the women that responded to metformin treatment (52% versus 27.5%, p ⫽ 0.0067). Conclusions: Metformin significantly reduced proliferation in a pre-operative window study in obese endometrial cancer patients, providing further support for therapeutic clinical trials of metformin in this obesity-driven disease.




5521


A phase II trial of lenvatinib in patients with advanced or recurrent endometrial cancer: Angiopoietin-2 as a predictive marker for clinical outcomes. Presenting Author: Ignace Vergote, UZ Leuven, Leuven, Belgium

PTEN loss as a context-dependent determinant of patient outcomes in obese and non-obese endometrioid endometrial cancer patients. Presenting Author: Zhenlin Ju, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: Lenvatinib is an oral receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFR␤. The importance of angiogenesis in endometrial cancer (EC) highlights the need to understand clinical mechanisms of escape (eg, angiopoietin-2 [Ang-2]) from antiangiogenic therapy. Methods: Patients (pts) had metastatic/unresectable EC after 1 or 2 prior platinum-based treatments (Tx), ⱕ2 prior chemotherapies, and ECOG PS ⱕ2. Pts received lenvatinib 24 mg once daily until disease progression or development of unmanageable toxicities. Primary endpoint was objective response rate (ORR: complete ⫹ partial response [CR⫹PR]) by RECIST 1.1. Archival tumor tissue and baseline (BL) and post-Tx plasma samples were collected for molecular analyses (reported elsewhere). Results: 133 pts were treated (median age: 62 y) and evaluated for safety, efficacy, and molecular correlative analysis. Dose reduction (31%) or Tx discontinuation (31%) occurred for toxicity. Median Tx duration was 112 days. The most common adverse events were hypertension 55% (Gr 3/4: 33%), fatigue 42% (Gr 3: 12.8%), diarrhea 35% (Gr 3: 5.3%), decreased appetite 35% (Gr 3: 2.3%), and nausea 32% (Gr 3: 3%); 1 pt had Gr 5 asthenia. Bowel obstruction, fistula formation, and perforation occurred in 3.8%, 2.3%, and 1.5%, respectively. Confirmed CR⫹PRs were observed in 19 pts (14.3%) by independent review (IRR) and 29 pts (21.8%) by investigator assessment (Inv). mPFS was 5.4 mos and mOS was 10.6 mos. Among 50 serum factors tested, only BL plasma Ang-2 correlated with maximal tumor shrinkage, R ⫽ 0.36 (Spearman), p ⬍ 0.001; ORR; PFS; and OS. The 24 pts with low BL Ang-2 plasma levels (cut-off value ⬍2082 pg/mL) were compared with the 98 pts with high BL Ang-2 (⬎2082 pg/mL) and improved ORR (61% vs 18%), mPFS (9.5 vs 3.7 mos), and mOS (23 vs 8.9 mos) were observed. Conclusions: Lenvatinib in this population was tolerable and resulted in a 14.3% (IRR) and 21.8% (Inv) ORR and mOS of 10.6 mos.Low BL Ang-2 level appears to predict clinical benefit in a subset of pts with advanced EC who may achieve high response rates and prolonged overall survival. Further assessment is warranted. Clinical trial information: NCT01111461.

Background: Aberrations in the PI3K pathway, the central relay pathway of insulin signals, occur in the majority of endometrioid endometrial cancers. We explored the prognostic utility of PIK3CA, PIK3R1, and PTEN mutations, as well as PTEN protein loss, in the context of patient weight. Methods: Patients (pts) treated for endometrial cancer at a single institution between 2000 and 2009 were identified. Tumor DNA was extracted and exome sequencing performed using a 454 platform with confirmation of hot spot mutations by Sequenom. PTEN protein expression was determined by immunohistochemistry and reverse phase protein array (RPPA). RPPA for 135 relevant proteins was performed using a GeneTAC arrayer to create spot arrays. Slides were scanned, analyzed, and quantitated using Microvigene software. Results: One hundred eighty seven endometrioid endometrial cancer specimens were included. Median age was 61 yrs and median body mass index (BMI) was 33.5 kg/m2. The majority of pts had early stage (I/II) disease (74%) and grade 2 tumors (66%). There were no statistically significant associations between progression free survival (PFS) and PIK3CA, PIK3R1, PTEN mutation or loss. However, when stratified by BMI, PTEN loss was associated with a significantly improved PFS (p⬍ 0.006) in obese (BMI ⬎ 30 kg/m2) pts. In contrast, PTEN loss was associated with a worse PFS (p⬍0.06) in non-obese (BMI ⬍ 30 kg/m2) pts. Further, PTEN loss in obese and non-obese pts resulted in distinct protein changes by RPPA, with canonical PI3K pathway activation observed only in the non-obese PTEN loss cohort. PTEN loss in obese pts was associated with decreased expression of CATENIN and phosphorylated FOXO3A. Conclusions: These data suggest the impact of PTEN loss on tumor biology and clinical outcomes must be interpreted in the context of BMI and provide potential explanation for prior discrepant findings on effect of PTEN status on prognosis in endometrial cancer. These data describe a clinically important interaction between metabolic state and tumor genetics that could potentially unveil the biologic underpinning of obesity-related cancers and may be relevant to ongoing clinical trials with PI3K pathway inhibitors.

5522^ Poster Discussion Session (Board #11), Sun, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

5523

Effect of metformin on recurrence-free survival and overall survival in diabetic patients affected by advanced ovarian cancer. Presenting Author: Cecilia Simonelli, Menarini Ricerche, Firenze, Italy

The impact of diabetes and obesity on endometrial cancer outcomes. Presenting Author: Emily Meichun Ko, The University of North Carolina at Chapel Hill, Chapel Hill, NC

Background: Metformin, has recently shown some anti-cancer activities in ovarian cancer, both in vitro and in vivo. Methods: Analysis of Recurrence Free Survival (RFS) and Overall Survival (OS) was performed in patients (pts) with diabetes (D) treated with metformin (DMet⫹) or not (DMet-) enrolled in the MIMOSA trial, a randomized double-blind placebocontrolled international trial of Abagovomab maintenance therapy in 888 pts with advanced ovarian cancer. In the MIMOSA trial, no differences in the RFS and OS were observed between Abagovomab (n ⫽ 593) and Placebo arm (n ⫽ 295); hence, the present RFS and OS analysis (DMet⫹ vs DMet-) was run regardless of treatment allocation. A Cox proportional hazards model was used for adjusting the analysis for the predefined prognostic factors: Figo stage (III, IV), tumor size after debulking (residual tumor ⬍1 cm, ⬎1cm); CA125 serum level after 3th cycle (⬍35U/ml, ⬎35U/ml). In addition, comparison of RFS and OS was done between DMet⫹and the overall MIMOSA population not exposed to metformin (ALLMet-), and between the overall diabetic pts (ALLD⫹) and non-diabetic pts (ALLD-). Results: In the ALL population (n ⫽ 888), 42 pts were affected by diabetes (ALLD⫹) divided to DMet⫹ (n ⫽ 27) and DMet- (n ⫽ 15), without difference in the prognostic factors distribution. When analysis was done in ALLD⫹, RFS median time was not reached in the DMet⫹ group whereas it was 328 days [CI: 30-660] in DMet- group with HR favoring DMet⫹⫽0.419 [CI:0.175-1.002]; p ⫽ 0.05. Median OS time was also not reached in the DMet⫹ group whereas it was 786 days [CI:262-NE] in DMetgroup with HR⫽0.295 [CI:0.109-0.803]; p ⫽ 0.02. Interestingly HR for RFS time was still in favour of DMet⫹ group when compared to the ALLMet(n⫽861) with HR⫽0.575 (CI⫽0.324-1.022); p ⫽ 0.06. When ALLD⫹ were compared with ALLD-(n ⫽ 846), no significant differences was detected in RFS and OS time. Conclusions: The present results are the first prospectively analyzed data demonstrating a favourable impact of metformin treatment on RFS and OS in pts affected by advanced ovarian cancer. Clinical trial information: NCT00418574.

Background: Diabetes (DM) is a known risk factor for endometrial cancer (EC), yet its effect on cancer outcomes remains unclear. We sought to investigate of the relationship between DM, obesity, and anti-diabetic medication on EC recurrence and survival. Methods: An IRB approved multi-institution retrospective study included all EC patients diagnosed with carcinosarcoma as well as endometrioid, serous, and clear cell cancers between January 2005 to December 2010. Demographics, comorbidities, and medications were captured at the time of cancer diagnosis. Cohorts for comparison included women with and without DM; and diabetics treated with metformin-only (METFO) were compared to those not treated with METFO. Cox regression models were used to evaluate the effect of selected covariates on PFS and OS. Results: Of 1495 EC patients, 364 (24%) had DM. Diabetics were more likely to be African American (30 v 16%, p⬍0.0001) and have higher BMIs (median 37.0 v 31.2, p ⬍ 0.001). After adjusting for age, race, stage, and BMI, women with DM had a worse OS (HR 1.40, 95CI 1.03-1.79), but similar recurrence risk (HR 1.16, 95CI 0.91-1.48) to non-diabetics. In a subset analysis of women with endometrioid EC (n ⫽ 1144), those with DM were 1.6 times more likely to recur (95CI 1.01-1.89, p ⫽ 0.04) and 2.4 times more likely to die (95CI 1.6-3.46, p ⬍ 0.0001). METFO use was associated with a decreased risk of recurrence (PFS HR 0.54, 95CI 0.3-0.96, p ⫽ 0.04), and death (OS HR 0.43, 95CI 0.22-0.83, p ⫽ 0.01) compared to no METFO use. METFO users had a similar clinical outcome compared to non-diabetics (PFS HR 1.05, p ⫽ 0.82; OS HR 1.3, p ⫽ 0.46). Obese women with DM who were treated with non-METFO regimens had a 1.8-fold increased risk of recurrence (95CI 0.94-3.7, p ⫽ 0.07) and 2.7-fold increased risk of death (95CI 1.2-5.9, p ⫽ 0.01). No survival differences were seen in women with serous, clear cell, or carcinosarcoma. Conclusions: Our data demonstrates worse clinical outcomes for EC patients with DM and improved outcomes for METFO users, suggesting a link between tumor pathogenesis and insulin growth factor and mTOR pathways. Future investigation is required to elucidate the complex relationship between diabetes, anti-hyperglycemic agents, and cancer outcomes.



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Phase II, two-stage, two-arm, PIK3CA mutation stratified trial of MK-2206 in recurrent endometrial cancer (EC). Presenting Author: Andrea P. Myers, Dana-Farber Cancer Institute, Boston, MA Background: EC has high rates of PI3K pathway alteration including PTEN mutation (50%) or IHC loss (⬎50%), PIK3CA mutation (25-40%) and PIK3R1 (20%) mutation. MK-2206 is an allosteric inhibitor of AKT, an effector kinase of PI3K signals. We hypothesized that pts whose tumors harbored PIK3CA mutations would be more likely to benefit from MK-2206 than those without PIK3CA mutation. Methods: Pts had recurrent or advanced EC; all histologies except MMMT were eligible. Up to 2 prior chemo lines were permitted; excluding prior treatment with PI3K/MTOR inhibitors. The first 19 pts were treated with MK-2206 200mg QW; due to initial skin toxicity rates, the starting dose was amended to 135mg QW. Co-primary endpoints were objective response and 6 mo PFS. The first 37 pts were stratified retrospectively. PIK3CA MT included R88Q, K111N, E110K, E418K, C420R, E453K, E542K/V,E545K, Q546R, H701P, M1043V, H1047R/L/Y changes. Independent Simon 2-stage tests were planned within PIK3CA MT and WT stratum: for MT, n1⫽15 and n2⫽10 pts would allow discrimination of RR⬍5% and 6moPFS⬍10% versus RR⬎25% or 6moPFS⬎35%; for WT, n1⫽31 and n2⫽24 pts would discriminate RR⬍5% and 6moPFS⬍10% versus RR⬎20% or 6moPFS⬎25%. Results: 37 pts were enrolled (1 ineligible) before accrual was stopped as timely CLIA-compliant prospective mutation analysis was not feasible. By PIK3CA mutation analysis, 9 pts were MT: 1 pt had both PR and 6moPFS. 27 pts were WT: 1 pt had PR and 3 pts had 6moPFS. 2 pts with 6moPFS were treated at 200mg; 2 pts with 6moPFS were treated at 135mg. Each group had 1 PR. The most common toxicity was grade 3 rash (19%). Grade 3 and 4 toxicities occurred in 50% and 8% of pts. Exploratory analysis of histology found all pts with 6moPFS were classified as serous (4 of 8) as compared to all other histologies (0 of 28, p⫽.001). Targeted exome sequencing and copy number analysis of the PI3K pathway and PTEN IHC are underway. Associative studies will be reported. Conclusions: There is limited single agent activity of MK-2206 in both PIK3CA MT and PIK3CA WT EC populations. Activity was detected in pts with serous histology tumors and warrants further study. Clinical trial information: NCT01307631.

Grade 3 rash Any grade 3ⴙ Any grade 4ⴙ

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Init dose: 200mg (nⴝ18)

Init dose: 135mg (nⴝ18)

Total (nⴝ36)

6 13 5

1 9 3

7 22 8


Chemoresistance in gastric-type mucinous adenocarcinoma of the uterine cervix: Multi-institutional study by Sankai Gynecology Study Group (SGSG). Presenting Author: Atsumi Kojima, Shikoku Cancer Center, Matsuyama, Japan Background: Gastric-type adenocarcinoma (GAS) is a novel variant of mucinous adenocarcinoma of the uterine cervix, characterized by aggressive clinical behavior and absence of high risk HPV detection. However, the cause of its aggressive nature remains unknown. Methods: We have evaluated the chemosensitivity of GASs, which were diagnosed by central pathological review of cases enrolled in the phase II study of neoadjuvant chemotherapy with docetaxel and carboplatin for stage Ib2 to IIb nonsquamous cervical cancer (SGSG-005) as an advance study. Results: In a total of 47 cases enrolled in the study, 20 (42.6%), 13 (27.7%), and 12 (25.5%) tumors were diagnosed as usual-type endocervical adenocarcinoma (UEA), GAS, and adenosquamous carcinoma, and each one (2%) as small cell carcinoma and serous adenocarcinoma, respectively. Response rate of UEA and GAS to the protocol was 85.0% and 46.2%, respectively (p ⫽ 0.018). Among 47 patients, 33 (70.2%) were assigned FIGO stage II, and 31 of these patients underwent surgery, while remaining 2 were inoperable because of progressive disease or intraabdominal dissemination. By microscopic examination of radical hysterectomy specimens, 12 of 14 (80%) UEAs were down-staged, whereas none of 6 (0%) GASs showed any response with residual vaginal and/or parametrial invasion even after chemotherapy (P⬍0.001). Two inoperative tumors were GAS. Median follow-up duration was 41 months with a range of 10-65 months. The 3-years progression-free survival rate in cases of UEA and GAS were 73.7% and 35.9%, respectively (p ⫽ 0.023), and 3-years overall survival rate were 88.9% and 51.9%, respectively (p ⬍0.001). Conclusions: Our data suggests that GAS is distinguished from UEA by chemoresistance, which appears to be an intrinsic nature of this particular tumor. Alternative treatment strategy should be established for GAS. Clinical trial information: 000000560.

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Recombinant adenovirus-p53 combined with chemotherapy in treatment of locally advanced cervical cancer (a phase II study). Presenting Author: Jian Zhou, Affiliated Woman and Children’s Healthcare Hospital of Xuzhou Medical Collage, Xuzhou, China Background: To evaluate the efficacy and safety of recombinant adenovirusp53 (rAd-p53) combined with chemotherapy in treatment of locally advanced cervical cancer. Methods: Forty patients with stage IIb2 IV locally advanced cervical cancer were randomly divided into 2 groups: 20 patients receiving gene plus chemotherapy (PCG) and 20 receiving sole chemotherapy (CG). The patients in PCG were given one course of PVB (cisplatin ⫹ vincristine ⫹ pingyangmycin) and 5 times intratumoral injections of rAd-p53 at a dose of 2 x 1012 viral particles once per 3 days. The CG patients received a sole course of PVB. The study patients were followed up for at least one year. The VEGF, p53, Bax, and p21 protein expression in pre- and post-treatment tumor tissues were examined by immunohistochemistry. Results: The response was evaluated at 3 months after treatments. The response rates (CR ⫹ PR) were 95% and 75% for the PCG and CG patients, respectively. P53 proteins were strongly expressed in the tumor tissues from both groups. There were no significant changes in expression level of the p53 protein in the tumor tissue from pre- and post-treatment. However, the VEGF, Bax, and p21 protein expressions significantly increased in PCG after treatment. The overall one-year survive rates were 90% and 65%, respectively. A mild to medium grade of fever was found in 90% of the PCG patients. No serious of adverse events relative to rAd-p53 were observed. Conclusions: Combined the rAd-p53 gene with chemotherapy is an effective treatment for the patients with advanced cervical cancer. The rAd-p53 gene therapy is a safe treatment.

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GOG0076-GG: A limited access phase II trial of pemetrexed (LY231514) (NSC #698037) in combination with cisplatin (NSC #119875) in the treatment of advanced, persistent, or recurrent carcinoma of the cervix—A Gynecologic Oncology Group study. Presenting Author: David S. Miller, The University of Texas Southwestern Medical Center, Dallas, TX Background: To estimate the antitumor activity of Pemetrexed and cisplatin with objective tumor response (partial and complete) in patients with advanced, persistent, or recurrent carcinoma of the cervix and to determine the nature and degree of toxicity of this regimen. Secondarily, to determine the effects of this regimen on progression-free survival and overall survival. Methods: Eligible, consenting patients received pemetrexed 500mg/m2 and cisplatin 50 mg/m2 IV repeated every 21 days until disease progression or adverse effects prohibited further therapy. Patients had received no prior therapeutic chemotherapy, except when administered concurrent with primary radiation therapy. Subsequent doses were adjusted according to observed toxicity and protocol guidelines. Adverse events were assessed with CTCAE v 3.0. Primary measure of efficacy was tumor response by RECIST. The study was stratified by prior radiation therapy. Results: From September 2008 to November 2011, 55 patients were enrolled by 5 GOG member institutions. Of those, 49 patients were eligible and assessable. The regimen was well tolerated with 14 (29%) receiving ⬎9 cycles. Common grade ⬎2 toxicities were neutropenia 35%, leukopenia 28%, and metabolic 28%. The overall response rate was 31% (one complete and 16 partial responses). The median response duration was 7 months and survival 12 months. Conclusions: Pemetrexed in combination with cisplatin has demonstrated activity in the treatment of advanced, persistent, or recurrent carcinoma of the cervix. Additional study of this regimen in a phase III setting is justified in this patient population. Clinical trial information: NCT00691301.




Pathologic complete response to cisplatin with dose-dense paclitaxel as neoadjuvant chemotherapy for locally advanced cervical cancer: Preliminary results of a multicenter phase II study with additional mutation analysis of adeno/adenosquamous carcinoma. Presenting Author: Maki Tanioka, Medical Oncology Division, Hyogo Cancer Center, Akashi, Japan Background: We report efficacy and safety of neoadjuvant cisplatin plus dose-dense paclitaxel (ddTP) within a phase II trial (UMIN-CTR ID: UMIN000006440), designed to investigate recurrence-free survival of neoadjuvant ddTP plus radical hysterectomy followed by adjuvant ddTP without radiotherapy for patients (pts) with stage IB2, IIA2, and IIB cervical cancer, whose driver mutations have been poorly understood. Methods: All enrolled pts received 3 cycles of cisplatin 75 mg/mq on day1 with paclitaxel 80 mg/mq on days 1, 8, and 15 every 21 days. Pathologic complete response (pCR) was defined as no evidence of malignancy in all surgical specimens observed. Using a selected panel of 535 oncogenes (Otogenetics, Norcross, GA), mutations of pretreatment biopsy tissues were analyzed in 6 non-pCR pts with adeno/adenosquamous carcinoma (AC/ ASC). Results: Among 51 enrolled pts, 50 were evaluable (40 with squamous cell carcinoma [SCC], 9 with AC/ASC, and 1 with small cell carcinoma). Median age was 52 years (range 30-70), the FIGO stage was IB2 in 14 pts, IIA2 in 3, and IIB in 34. Eighteen pts achieved complete response and 29 pts achieved partial response, with response rate of 94% (47/50). A total of 14 pts (28%; 13 with SCC, 1 with AC) achieved pCR. Grade 3/4 adverse events were neutropenia (34%), nausea (12%), appetite loss (10%), fatigue (6%), and anemia (6%). Febrile neutropenia was uncommon (2%). The analysis of oncogenes revealed that all 6 pts had mutations in the mixed-lineage leukemia (MLL3) gene, a histone methyltransferase, whose mutations have recently been reported in breast, pancreas, and colorectal cancers. Specifically, in MLL3 gene, identical frameshift mutation was found in 2 pts and 2 common non-synonymous point mutations were found in 4 pts, despite no relevance to the ddTP response. No mutations were detected in TP53 and PIK3CA genes. Conclusions: The pCR rate with neoadjuvant ddTP for locally advanced cervical cancer was one of the highest reported in a prospective trial setting. Novel mutations of the MLL3 gene were identified in non-pCR pts with AC/ASC. Clinical trial information: UMIN000006440.

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Locally advanced adenocarcinoma and adenosquamous carcinoma of the cervix compared to squamous cell carcinoma of the cervix in Gynecologic Oncology Group trials of chemoradiation. Presenting Author: Peter Graham Rose, Cleveland Clinic Foundation, Cleveland, OH Background: Conflicting results have been reported for adeno- and adenosquamous carcinomas the cervix with respect to their response to therapy and prognosis. Adeno- and adenosquamous carcinoma comprise the majority of non-squamous carcinomas of the cervix enrolled in GOG trials of chemoradiation. Methods: Adeno- and adenosquamous cervical carcinomas were retrospectively studied and compared to squamous cell carcinomas in GOG trials of chemoradiation. Results: Among 1672 patients enrolled in clinical trials of chemoradiation, 182 adeno- and adenosquamous carcinomas were identified (10.8%). A higher percentage of adeno- and adenosquamous carcinomas were stage IB (27% versus 20%) and fewer were stage IIIB (21.4% versus 28.6%). The mean tumor size was larger for squamous than adeno- and adenosquamous carcinomas, but adeno- and adenosquamous carcinomas were more often poorly differentiated (46.2% versus 26.8%). Among patients that received cis-platinum during radiation therapy, 843 with squamous cell carcinoma were compared to 112 with adeno- or adenosquamous carcinoma for overall survival, with no significant difference in risk of death (p⫽0.472). However, among patients that did not receive cis-platinum, 647 with squamous cell carcinoma and 70 with adeno- or adenosquamous carcinoma, there was a slightly higher risk of death for the adeno- or adenosquamous group (p⫽0.049). Adverse effects to treatment were similar across histologies. Conclusions: Patients with adeno- and adenosquamous carcinomas of the cervix have worse overall survival when treated with radiation alone, but have progression-free and overall survival similar to patients with squamous cell carcinomas of the cervix when treated with cis-platinum based chemoradiation.

5529


ADXS11-001 immunotherapy targeting HPV-E7: Preliminary survival data from a P2 study in Indian women with recurrent/refractory cervical cancer. Presenting Author: Robert G. Petit, Advaxis, Inc., Princeton, NJ Background: ADXS11-001 immunotherapy is a live attenuated Listeria monocytogenes (Lm) bioengineered to secrete a HPV16-E7 fusion protein targeting HPV transformed cells. The Lm vector serves as its own adjuvant and infects APC where it naturally cross presents, stimulating both MHC class 1 and 2 pathways resulting in specific T-cell immunity to tumors. Here we describe the preliminary survival data associated with ADXS11001 administration in Lm-LLO-E7-015, a randomized P2 study being conducted in India in 110 patients with recurrent/refractory cervical cancer who have been treated previously with chemotherapy, radiotherapy or both. Methods: Patients were randomized to either 3 doses of ADXS11-001 at 1 x 109 cfu or 4 doses of ADXS11-001 at 1 x 109cfu with cisplatin chemotherapy. Naprosyn and oral promethazine were given as premedications and a course of ampicillin was given 72h after infusion. Patients received CT scans at baseline and 3, 6, 9, 12 and 18 months. The primary endpoint is overall survival. Results: As of February 2013, the trial has completed enrollment and 110 patients have received 264 doses of ADXS11-001. The percentage of patients alive at 6 months is 63% (67/107); at 9 months is 46% (49/106); at 12 months is 34% (30/87) and at 18 months is 15% (8/54). Tumor responses have been observed in both treatment arms with 6 CRs and 6 PRs; 36 additional patients had stable disease ⬎ 3 months, for a disease control rate of 44% (48/110). Activity against different high risk HPV strains has been observed. Three serious adverse events and 69 mild-moderate adverse events possibly related/related to ADXS11-001 treatment have been reported in 41% (45/110) of patients. The nonserious adverse events consisted predominately of transient, noncumulative flu-like symptoms associated with infusion that either resolved on their own or responded to symptomatic treatment. Conclusions: ADXS11001 can be safely administered to patients with advanced cancer alone and in combination with chemotherapy. ADXS11-001 is well tolerated and presents a predictable and manageable safety profile. Final 12-month OS, updated safety and translational analyses will be presented at the meeting.

5531


Outcome parameters in node-negative vulvar cancer: A subset analysis of the AGO Care 1 study. Presenting Author: Linn Lena Woelber, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Background: Prognosis of node-negative vulvar cancer is generally favorable compared to node positive disease. However, a small proportion of node-negative pts experience early recurrence with subsequent need for radical interventions. Aim of this analysis was to identify possible prognostic factors in this subset of pts. Methods: The AGO CaRE 1 study was designed as retrospective survey of treatment patterns and prognostic factors in vulvar cancer. Pts with primary squamous-cell vulvar cancer stage ⱖ1b treated at 29 gynecologic cancer centers in Germany 19982008 were included in a centralized database. Results: A total of 1618 pts were documented, 802 were node negative (pN0) after surgical staging and further analyzed. Median age was 66 yrs (21-94); 399 (49.8%) had pT1b, 365 (45.5%) pT2, 36 (4.5%) pT3 and 1 pT4 tumors; in 1 pt tumor stage was unknown. Median tumor size was 20 mm (1–345) and depth of invasion 4 mm (0.75– 60). 703 (87.7%) pts had an R0 resection with a minimal margin of 5 mm (0.2–33); there were 46 R1 (5.7%) resections and 53 (6.6%) pts with unknown margin status. 692 pts (86.3%) received a full groin dissection (178 after sentinel node dissection) and in 85 pts (10.6%) only a sentinel node procedure was performed; surgery type was unknown in 25 pts (3.1%). 73 pts (9.1%) underwent adjuvant radiotherapy to the vulva. Median follow-up was 40 months. 169 pts (21.1 %) developed disease recurrence (thereof 111 (65.7%) at the vulva only and 53 (31.4%) at other locations, in 5 cases the localization was unknown) after a median of 17.7 months. 101 pts (12.6 %) died. To assess potential prognostic factors, multivariate analyses were performed including age, stage, tumor size, invasion depth, tumor grade, resection margin, adjuvant radiation, and mode of groin dissection [sentinel vs. full]) showing age as the only consistent prognostic factors for recurrence-free and overall survival. Conclusions: Even in the very large patient cohort of the AGO-CaRE database with more than 800 node-negative pts it was not possible to identify reliable clinicopathologic prognostic factors for node-negative disease. Identification of new biological markers will therefore be necessary to select high risk node negative pts for adjuvant treatment.


342s 5532


Tumor-associated CD66bⴙ neutrophil and CD8ⴙ lymphocyte densities as independent prognostic factors for recurrence in localized cervical cancer: Automated digital image analysis and observer-assisted stereological assessments. Presenting Author: Andreas Carus, Department of Oncology and Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark, Aarhus, Denmark

5533


Malignant germ cell ovarian cancer (MGCOC) in the Cancer Registry of Norway (CRN): A long-term follow-up study of presentation, survival, and second cancers. Presenting Author: Olesya Solheim, Department of Gynaecological Oncology, Oslo University Hospital, the Norwegian Radium Hospital, Oslo, Norway

Background: The prognostic impact of tumor-associated immune cells in cervical cancer is unclear. Methods: Automated digital image analysis (DIA) software and observer-assisted stereological (OAS) assessments were used to obtain densities of immunostains for CD66b⫹ neutrophils, CD163⫹ macrophages, and CD8⫹lymphocytes in scanned whole slide images of tumor sections from 101 patients with FIGO stage IB and IIA cervical cancer. Primary end-point was recurrence-free survival (RFS). Results: The highest densities of CD66b⫹ neutrophils and CD163⫹ macrophages were observed by OAS in the peritumoral compartment (median 53.1 cells/mm2 and 1.3% area fraction, respectively). DIA required far less human resources than OAS assessments. We observed high correlations between DIA and OAS variables of corresponding parameters; spearman ␳ was 0.79 for CD8⫹ lymphocytes , 0.85 for CD66b⫹ neutrophils, and 0.92 for CD163⫹ macrophages (all p ⬍0.0001). Hazard rates for DIA assessments in the global tumor area were comparable with the prognostically strongest OAS assessments in the peritumoral compartment. In multivariate analysis, high density of CD66b⫹ neutrophils (HR 2.6; 95% CI 1.2–5.7; p ⫽ 0.02), low density of CD8⫹ lymphocytes (HR 2.3; 95% CI 1.1– 4.9; p ⫽ 0.03), and presence of lymph node metastases (HR 2.6; 95% CI 1.2–5.5; p ⫽ 0.02) were independent predictors of poor RFS, whereas FIGO stage and CD163⫹macrophage density were not. The CD66b/CD8 immunostain index obtained by DIA had excellent discriminatory power for each quartile with 5-year RFS of 92%, 80%, 65%, and 48% for quartile I (⬍0.019), II (0.02-0.05), III (0.06-0.24), and IV (⬎0.25), respectively (p ⫽ 0.001). Conclusions: High tumor-associated CD66b⫹ neutrophil and low CD8⫹ lymphocyte densities are independent prognostic factors for short recurrence-free survival in cervical cancer assessed by DIA and OAS. Combined CD66b⫹ neutrophil/CD8⫹ lymphocyte immunostain index obtained by DIA is a strong and cost-efficient prognostic variable with potential for routine application.

Background: Significant improvements in the management of MGCOC have been achieved during the past two decades. However, data on long term risk conferred by radiation and chemotherapy is scarce. This is a long-term follow-up study of presentation, survival and second cancers. Methods: 360 female patients with histologically confirmed MGCOC, recorded in the CRN between 1953 and 2009 were identified. Patients, diagnosed before 1980 were separated from those with a diagnosis 1980⫹, reflecting the introduction of cis-platin based chemotherapy. Data on survival and second cancer incidence were obtained by linkage to the CRN. Cox Hazards Models and Kaplan Meier estimates were used. Results: The annual incidence doubled during the observation time. Malignant teratoma was the most common histological subtype (n ⫽ 190 [53%]), followed by dysgerminoma (n ⫽ 113 [31%]) and other non - dysgerminoma tumors (n ⫽ 57 [16%]). Over two thirds of the patients (median age 34 years [range 2-92]) had localized disease with distant disease in 23%. Before 1980 70% of 159 patients received subdiaphragmatic radiotherapy, this percentage was reduced to 24% after 1980, while chemotherapy increased from 11% to 38%. The 10 years ovarian cancer specific survival (OvCSS) (median follow-up time of 9.8 years [range: 0 - 54]) increased significantly to 93% in women treated in 1980⫹ compared to 62% to those with an earlier diagnosis (p ⬍0.001) . Significant period-related improvement in OvCSS was observed independently from the extent of the disease and for all histological subtypes. Women aged ⬎50 years had a significantly poorer OvCSS than younger ones, (HR⫽5.98, 95%CI [3.39 to 10.57]) adjusted for histological type and stage. A second cancer was diagnosed in 27 women, 63% of these cancers were located below the diaphragm within or close to the radiation field. Conclusions: The incidence of MGCOC is rising in Norway. We observed significant improvement of ovarian cancer specific survival after the introduction of cisplatin-based chemotherapy. The development of second cancer after treatment for MGCOC seems to be related to abdominal radiotherapy.

5534

5535


An evaluation of survival of ovarian cancer patients with clear cell carcinoma versus serous carcinoma treated with platinum therapy: A Gynecologic Oncology Group experience. Presenting Author: John H. Farley, University of Arizona School of Medicine, Phoenix, AZ Background: We examined disparities in prognosis between patients with ovarian clear cell carcinoma (OCCC) and serous epithelial ovarian cancer (SOC). Methods: Data from stage I-IV epithelial ovarian cancer (EOC) patients who participated in 12 randomized GOG protocols using platinumbased chemotherapy were reviewed. Proportional hazards models adjusted for age and stratified by protocol, treatment arm, stage, performance status (PS), and race were used to compare progression-free survival (PFS) and overall survival (OS) by cell type (clear cell versus serous). Results: There were 10,803 patients enrolled, 1272 were not eligible: leaving 9,531, of whom 544 (6%) had OCCC, 7,054 (74%) had SOC, and 1,933 (20%) had other; only the OCCC and SOC are considered here. OCCC were significantly younger, more often of Asian race, stage I, good PS, and optimally surgically debulked than SOC patients. Prior to adjustment, OCCC had better PFS and OS due to better prognostic factors. There was no significant difference in PFS or OS for early stage OCCC patients compared to high-grade (HG) SOC patients. For late stage patients, OCCC had poorer PFS and OS compared to SOC, OS HR⫽ 1.66 (1.43, 1.91; p ⬍ 0.001). For both optimal, HR ⫽ 1.34 (1.10, 1.63; p ⫽ 0.003) and suboptimal, HR ⫽ 3.18 (2.13, 4.75; p ⬍ 0.001) OCCC had a significantly poorer OS than SOC. After adjusting for age and stratified by protocol and treatment arm, stage, performance status, and race, OCCC had a significantly decreased OS, HR⫽ 1.53 (1.33,1.76; p ⬍ 0.001). In early stage cases, there was a significantly decreased treatment effect on PFS for consolidative therapy with weekly taxol versus observation in SOC compared to OCCC (p ⫽ 0.048). Conclusions: This is one of the largest analyses to date of OCCC treated in a uniform manner . OCCC patients have better PFS and OS compared to SOC; this, is due to their better prognostic factors. There was no observed difference in PFS or OS for early stage OCCC versus HGSOC. In late-stage patients, OCCC was significantly associated with decreased OS which was true for both optimal and suboptimally debulked patients. Finally, treatment effect was influenced by histology.


A multiplex methylation-specific PCR assay for detection of early-stage ovarian cancer using cell-free serum DNA. Presenting Author: Beihua Kong, Qilu Hospital, Shandong University, Jinan City, China Background: Epithelial ovarian cancer (EOC) remains the most lethal disease among gynecological malignancies. Prompt diagnosis is challenging because of the non-specific symptoms exhibited during the early stage of the disease. So there is an urgent need for better detection methods. Here we performed this work to build up a platform of multiplex methylationspecific PCR (MSP) assay to improve the early detection of ovarian cancer, via identifying the methylation status of cell-free serum DNA. Methods: After screening, we chose seven genes (APC, RASSF1A, CDH1, RUNX3, TFPI2, SFRP5 and OPCML) with a high frequency of methylation as candidate genes to construct the multiplex-MSP assay. When methylation of at least one of the seven genes was observed, the multiplex-MSP assay was considered positive. We performed the retrospective and screening study to verify its specificity and sensitivity in the detection of EOC. Results: The methylation status of cell-free serum DNA was examined in the preoperative serum of 202 patients, including 87 EOC cases (stage I, n⫽41, stage II-IV, n⫽46), 53 benign ovarian tumors and 62 healthy controls. As expected, multiplex MSP assay achieved a sensitivity of 85.3% and a specificity of 90.5% in stage I EOC, strikingly higher than that of single CA125, producing a sensitivity of 56.1% at 64.15% specificity [p⫽0.0036](Table). Conclusions: Multiplex MSP assay analyzing the methylation status of cell-free serum DNA is a suitable and reliable approach to improve the early detection of ovarian cancer, potentially benefiting a broad range of applications in clinical oncology. Retrospective study CA125 Specificity Sensitivity

Multiplex-MSP

Screening study CA125

Multiplex-MSP

All All Early stage Advanced stage All

64.15% 90.57% 72.41% 82.76% 73.56% 89.66% 82.05% 92.31% 56.10% 85.37% 50.00% 83.33% 89.13% 93.48% 84.85% 93.94% ROC-AUC 0.8090 0.9126 0.8837 0.8988 (95% CI) (0.7376-0.8805) ( 0.8643-0.9609) (0.8017-0.9658) (0.8192-0.9783) Early stage 0.6986 0.8916 0.8103 0.8218 (0.5904-0.8068) (0.8258-0.9574) (0.5984-1.022) (0.6375-1.006) Advanced stage 0.9075 0.9313 0.8970 0.9127 (0.8461-0.9689) (0.8788-0.9838) 1(0.8146-0.9796) (0.8364-0.9891)




Adult granulosa cell tumors (GCT): 56 years of clinicopathologic outcomes including FOXL2 mutational status. Presenting Author: Michelle Wilson, Department of Oncology, Auckland City Hospital, Auckland, New Zealand

5537

343s General Poster Session (Board #44A), Mon, 8:00 AM-11:45 AM

Phase II trial of oral etoposide plus IV irinotecan for patients with platinum-resistant and taxane-pretreated ovarian cancer (JCOG0503). Presenting Author: Koji Matsumoto, Medical Oncology Division, Hyogo Cancer Center, Akashi, Japan

Background: GCT account for 2-3% of ovarian cancers with a tendency for late relapse. Treatment is primarily surgical. The role of chemotherapy and hormonal therapy is more controversial. The FOXL2 mutation (402C¡G) has been identified as a potential driver mutation and may be useful in diagnosis and treatment. Methods: We performed a retrospective review of GCT patients (pts) referred to the Auckland Gynae-Oncology Multidisciplinary Team from 1955 to 2011. Baseline characteristics, clinical course, histopathology and survival data was recorded. FOXL2 mutation status was determined by DNA sequencing, and correlated with clinical data. Results: 56 GCT pts were identified. Median (med) age 48.6 years (y) (22-86). Stage I were 82.1%. 48% of tumours were ⱖ10cm. Med follow up was 10.0y (0.2-40.4). 25 pts progressed, med time to progression (TTP) was 4.5y (0.1-17.7). Med progression free survival was 14.5y. Med overall survival (OS) was 21.8y but med disease specific survival was not reached. 9/18 pts died of disease. Stage III GCT and size ⱖ10cm had a higher risk of relapse (RR 3.1 and 2.9) and death (RR 8.2 and 8.6) respectively. 17/46 (37%) Stage I pts progressed. Med TTP was 8.3y (1.3 to 17.7), med OS was 29.0y. Stage I relapse rate was higher in tumours ⱖ10cm (RR 3.9 p⬍0.01). 12/17 1st relapses were treated with surgery. 10/17 pts received ⱖ1 line of chemotherapy and 7 ⱖ1 hormonal therapy. Clinical benefit rates (CR, PR and SD⬎6m) for first-line chemotherapy was 25% and 71% for hormones. All 7 Stage III pts progressed with med OS of 6.3yr (0.2-12.3y). Currently the FOXL2 mutation statuses are known for 18 patients. 89% carried the mutation. Homozygous, heterozygous and wild-type mutations had no difference in risk of relapse or death. Further FOXL2 mutation analysis is ongoing. Conclusions: This long term series confirms the protracted natural history of this disease. Early stage GCT, despite progression has a good prognosis with med OS ⬎25y. Stage and tumour size remain the most consistent prognostic factors. Whilst surgery remains the mainstay of therapy, the high response rate to hormonal therapy deserves investigation. Currently the FOXL2 mutation status does not appear prognostic but this needs further research.

Background: Developing effective chemotherapy for patients (pts) with platinum (Pt) resistant ovarian cancer is unmet medical needs. Topoisomerase inhibitors, such as oral etoposide and iv irinotecan, have been reported to show some efficacy for Pt - resistant ovarian cancer as monotherapy. Combining these two agents should be an intriguing idea. Following phase 1 and feasibility study reported in ASCO2002 and 2005, this study aimed to assess safety and efficacy of oral etoposide plus iv irinotecan for pts with Pt -resistant and taxane pre-treated ovarian cancer (UMIN-CTR ID: UMIN000001837). Methods: Eligible pts are given etoposide at 50 mg/m2 p.o. from day 1 to 21, and irinotecan 70 mg/m2iv, at day1 and day15, repeated every 28 days, up to 6 cycles. Primary endpoint is response rate (RR), secondary endpoints are adverse events, progressionfree survival (PFS), and overall survival (OS). As a SWOG two-stage design, at least 55 pts are required with one-sided alpha of 0.05, beta of 0.2 and expected and threshold value for primary endpoint as 35% and 20%. Sixty pts are to be registered. Results: From April 2009 to January 2012, 61 pts were entered to this study. One patient was ineligible, thus 60 pts were analyzed for the study. RR was 21.7% (1 CR ⫹ 12 PR, 89% C.I. 13.5 – 31.9 %, one-sided p⫽0.42). At the data cut-off at November 2012, median PFS and OS were 4.1 (95% C.I. 3.5 – 5.6) and 12.4 (95% C.I. 10.1 – 14.8) months, respectively. Six months-PFS was 35.0 %. For pts with Pt --free interval (PFI) ⬎⫽ three months (n ⫽ 33), RR was 30.3 % (95% C.I. 15.6 -48.7 %), median PFS and OS was 5.8and 16.9 months, respectively. For safety, G3/4 neutropenia, anemia, and thrombocytopenia were 60.0 %, 36.7 % and 11.7%, respectively. G3/4 non-hematological toxicities over 10 % were febrile neutropenia (FN) (18.3%), fatigue (13.3%), nausea (11.7 %) and anorexia (11.7 %). FN was more frequent in elderly pts of 65 years or older (28.6 %). Two treatment-related deaths occurred, both in elderly. Conclusions: As a whole, this regimen did not meet primary endpoint for further phase 3 study. Elderly pts should be treated very cautiously with this regimen. However, promising efficacy could be expected for those with PFI ⬎⫽ 3 months. Clinical trial information: UMIN000001837.

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Phase I study of combination chemotherapy with irinotecan and gemcitabine for taxane/platinum resistant ovarian, fallopian tube, or primary peritoneal cancer. Presenting Author: Kiyoshi Yoshino, Department of Obstetrics and Gynecology, Osaka University Faculty of Medicine, Suita, Japan

The retention index calculated with dual-phase 18F-FDG PET/CT in ovarian carcinoma: Determination of the optimal cutoff level using ROC analysis. Presenting Author: Jin Hwa Hong, Department of Obstetrics and Gynecology, Guro Hospital, College of Medicine, Korea University, Seoul, South Korea

Background: Development of new regimen is required to overcome platinum resistant ovarian cancer. Irinotecan and gemcitabine have a synergistic effect to inhibit the growth of ovarian cancer cell line in vitro. The objective is to evaluate the feasibility of combination chemotherapy with irinotecan and gemcitabine for taxane/platinum resistant recurrent ovarian, fallopian tube or peritoneal cancer and to determine the recommended dose. Methods: Nine patients with measurable disease (age range 51-70 years) were enrolled. Patients were treated with irinotecan and gemcitabine on days 1 and 8 every 3 weeks with starting dose of level 1. Dose levels included irinotecan/gemcitabine: 65/650 (level 0), 80/800 (level 1), 100/1000 (level 2), mg/m2 respectively. Level 2 is defined as the maximum dose as used in other malignancies. Dose-limiting toxicity (DLT) was assessed during the first cycle; toxicities were monitored throughout the treatment according to the CTCAE v4.0. Treatment continued until disease progression or unacceptable toxicity. Results: In level 1 (n ⫽ 6), grade 3/4 neutropenia was observed in 5 patients. Grade 3 nausea and vomiting was observed in 1, grade 3 diarrhea in 1. One patient of level 1 experienced DLTs. In level 2 (n ⫽ 3), grade 3/4 neutropenia are observed in 3, anemia in 1, and thrombocytopenia in one patient. Other toxicities were mild. Three patients who received level 2 did not show DLT. The objective response was CR/PR/SD/PD, 0/2/5/2. Conclusions: The dose level of irinotecan 100 mg/m2 and gemcitabine 1000 mg/m2 on day 1 and 8 every 3 weeks is recommended for a phase II study. Clinical trial information: UMIN000005926.

Background: Although 18F-fluorodeoxyglucose (FDG) positron emission tomography /computed tomography (PET/CT) is useful as a clinical tool in various malignancies, the maximum standardized uptake value (SUVmax) overlap between malignant and benign lesions is significant. The dualphase PET/CT has shown its usefulness to differentiate benign from malignant conditions in some solid tumors, but its usefulness has not yet been evaluated in patients with ovarian cancers. Methods: Twenty consecutive patients (thirteen with ovarian cancers and seven with benign lesions) were evaluated preoperatively by dual-phase 18F-FDG PET/CT (Time of Flight, Philips), performed 1 and 2 hour after injection of 370-555 MBq of 18 F-FDG. The SUVmax at 1 hour (SUVmax1) and at 2 hour (SUVmax2) were determined, and the retention index (RI) was calculated by subtracting the SUVmax1 from the SUVmax2 and dividing by SUVmax1. Results: Area under the receiver operating characteristic (ROC) curve of SUVmax1 and SUVmax2 were 0.753 and 0.835, respectively (95% CI; 0.512, 0.915 versus 0.604, 0.961; p ⫽ 0.062 versus 0.001). Area under the ROC curve of RI was 0.901 (95% CI; 0.684, 0.988; p ⬍0.001). When the SUVmax1 cutoff was set to 3.2, the sensitivity and the specificity of the SUVmax1 were 100% and 57.1%, respectively. When the SUVmax2 cutoff was set to 3.9, the sensitivity and the specificity of the SUVmax2 were 100% and 57.1%, respectively. The sensitivity and the specificity of RI were 92.3% and 71.4% when the cutoff was set to 16.67. By pairwise comparisons, the area under the ROC curve of SUVmax2 was significantly higher than that of SUVmax1 (p ⫽ 0.032). The area under the ROC curve of the RI was higher than those of SUVmax1 and SUVmax2, but not statistically significant (p ⫽ 0.166 and 0.459, respectively). Conclusions: The RI and SUVmax2 are proved to be useful in differentiating ovarian cancers from benign lesions. The use of dual-phase 18F-FDG PET/CT should be taken into account when the preoperative imaging is ambiguous. Acknowledgements: This study was supported by a grant of the Korean Health Technology R&D Project, Ministry for Health, Welfare & Family Affairs, (A070001) Republic of Korea.


344s 5540

Gynecologic Cancer General Poster Session (Board #44D), Mon, 8:00 AM-11:45 AM

Neoadjuvant chemotherapy with six cycles of carboplatin and paclitaxel in advanced ovarian cancer patients not candidates for optimal primary surgery: Safety and effectivenes. Presenting Author: Vanessa Costa Miranda, Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil

5541


Feasibility and safety of front-line bevacizumab (BEV)-containing therapy after neoadjuvant (NA) chemotherapy (CT) for ovarian cancer (OC): The ROSiA experience. Presenting Author: Jacob Korach, The Chaim Sheba Medical Center, Tel Hashomer, Israel

Background: Primary debulking surgery (PDS) has been considered the standard of treatment in advanced ovarian cancer, while neoadjuvant chemotherapy, three cycles followed by interval debulking (ID) surgery, is a valid treatment alternative for patients with non-resectable disease. This study aimed to show the efficacy and safety of six cycles of neoadjuvant chemotherapy (N-CT) followed by cytoreduction, a single institution experience. Methods: Aretrospective analysis was performed of all patients (pts) with advanced ovarian cancer treated with platinum based N-CT, between January/2004 and February/2012. Results: 97 pts underwent N-CT in our institution; 78.1% and 18.8% the patients had extensive stage IIIC or IV disease at diagnosis, respectively. Median age 60 years (36 – 82). Histologic types: serous 84.5%, adenocarcinoma not specified 11.3%, endometrioide 1.0%. A median of six cycles of chemotherapy were performed. Patients did not received chemotherapy after debulking surgery. During the treatment 31.4% had grade 3/4 toxicity, the most commonly observed toxicities were hematologic toxicities and nausea, four (4.1%) patients died during chemotherapy due to disease progression. After N-CT 24.7% achieved clinical complete response, 57.7% partial response and 12.4% disease progression. From this cohort 63.1% underwent a complete resection of all macroscopic and microscopic disease (R0). Median length of hospital stay and postoperative ICU stay was 5 and 0.8 days respectively, surgical complications were not common however five (7.1%) patients needed second surgery due to operatory complications and 19 pts (27.1%) needed blood transfusion after debulking. With a median follow up of 21.8 months (0.5-139.7), median overall survival and chemotherapy-free interval were 57,7 and 9,5 months, respectively. Conclusions: Six cycles of neoadjuvant carboplatin and paclitaxel is safe, effective and does not increase perioperative and postoperative complications for patients with stage IIIC-IV not candidates for optimal/R0 PDS. The overall survival of this cohort is higher than those treated with interval debulking surgery.

Background: BEV significantly improved the efficacy of front-line CT for OC in the GOG-0218 and ICON7 phase III trials. The ongoing single-arm ROSiA study, which has completed recruitment of 1039 patients (pts), is assessing BEV ⫹ CT in routine oncology practice. Unlike GOG-0218 and ICON7, prior NACT is permitted. We assessed the surgical safety of BEV ⫹ CT in the subgroup of pts with prior NACT. Methods: Inclusion criteria include: FIGO stage IIb–IV or grade 3 stage I–IIa epithelial ovarian, fallopian tube, or primary peritoneal carcinoma; no prior post-surgical therapy for OC; and ECOG PS 0 –2. Pts with uncontrolled hypertension or clinical signs/symptoms of GI obstruction or history of abdominal fistula, GI perforation, or intra-abdominal abscess in the preceding 6 mo are excluded. Pts in the NA subgroup were enrolled into the study after up to 4 cycles of NACT without BEV. After interval debulking, pts received BEV 15 mg/kg q3w (or 7.5 mg/kg at the investigator’s discretion) in combination with CT (paclitaxel [175 mg/m2 d1 q3w or 80 mg/m2 qw] ⫹ q3w carboplatin [AUC 5 or 6]), to a maximum total of 8 cycles including the pre-study NA cycles. Single-agent BEV was continued until progression, unacceptable toxicity, or for up to 36 cycles in total. The primary objective is evaluation of safety (CTCAE v4.03). Additional endpoints include efficacy (including PFS, response rate, OS) and exploratory translational research. Results: Of the 1039 pts enrolled in ROSiA, 150 (14%) had received NACT. Of these, most had stage IIIc (60%) or IV (29%) disease; 65% had residual disease ⱕ1 cm; and 19% underwent bowel resection. At the data cut-off 22 mo after enrollment began, median follow-up from post-surgery study entry was 12.6 mo; 69 patients (46%) remained on BEV therapy. At cut-off, pts had received a median of 13 cycles of BEV (range 1–31), including 4 cycles (range 1– 6) of BEV in combination with CT after surgery. To date, no pts have had grade ⱖ3 wound-healing complications during study therapy; 1 pt experienced grade 4 GI perforation 10 weeks after surgery (3 weeks after the first BEV dose), which resolved within 4 weeks. Conclusions: NACT followed by BEV ⫹ CT was feasible and tolerable. Clinical trial information: NCT01239732.

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Health-related quality of life (HRQoL) results from the AURELIA trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinumresistant recurrent ovarian cancer (OC). Presenting Author: Martin R. Stockler, The University of Sydney, Sydney, Australia

Ovarian cancer distribution of histology, stage, and screening performance. Presenting Author: Lua R Eiriksson, University of Toronto, Department of Obstetrics & Gynecology, Division of Gynecologic Oncology, Toronto, ON, Canada

Background: Adding BEV to CT significantly improved PFS in platinumresistant OC in the open-label phase III AURELIA trial. As symptom improvement is a major goal of treatment, determining effects on HRQoL was a key secondary aim of AURELIA. Methods: After investigator selection of single-agent CT (pegylated liposomal doxorubicin, topotecan, or weekly paclitaxel), patients (pts) with measurable/assessable platinum-resistant OC were randomized to CT ⫾ BEV. HRQoL and symptoms were assessed at baseline and every 2 or 3 cycles (8/9 wks) until PD using the EORTC OC Module (OV28) and FOSI. The primary HRQoL endpoint was an absolute improvement of ⱖ15% (ⱖ15 points) on the 100-point OV28 subscale for abdominal (abdo)/GI symptoms (items 1– 6) at wk 8/9. Pts with missing questionnaires (Qs) were included and considered not to have improved. A sensitivity analysis excluded pts with Qs missing for reasons other than PD/death or switch from CT to BEV. Subgroup analyses of symptomatic pts included only those with a baseline score ⱖ15 (sufficient to show ⱖ15-point improvement). Mixed-model repeated measures (MMRM) analysis was used to compare Qs from all time points until PD/death, not just wk 8/9. The FOSI was analyzed similarly. Results: Baseline Qs were available from 89% of 361 randomized pts. At wk 8/9, 81% of BEV–CT vs 68% of CT pts who were alive and PD-free returned OV28 Qs. For the primary HRQoL endpoint, more BEV–CT than CT pts had a ⱖ15% improvement in the OV28 abdo/GI symptom subscale at wk 8/9 (21.9% vs 9.3%, 12.7% difference [95% CI 4.4 –20.9]; p ⫽ 0.002). The sensitivity analysis described above showed a 13.3% difference [95% CI 4.5–22.1]. In the subgroup of 233 pts with a baseline score ⱖ15, there was a 16.9% difference (95% CI 6.1–27.6) favoring BEV–CT (29.6% vs 12.7%). MMRM analysis of OV28 abdo/GI symptom subscale scores also favored BEV–CT (6.4-point difference [95% CI 1.28 –11.6]). More BEV–CT than CT pts had a ⱖ15% improvement in FOSI score at wk 8/9 (12.2% vs 3.1%, 9.0% difference [95% CI 2.9 –15.2]). Conclusions: Adding BEV to CT resulted in more frequent ⱖ15% improvements in patient-reported abdo/GI symptoms in platinum-resistant OC. Clinical trial information: NCT00976911.

Background: Survival in women with ovarian cancer is strongly influenced by stage of disease at diagnosis. As such, strategies have been investigated to identify biomarkers for early detection. This premise assumes a progression of disease from early to late stage. Varying histologic subtypes in ovarian cancer have distinct etiologies. It is likely that early detection strategies will need to be subtype specific. This study sought to evaluate histologic subtypes, stage of disease, and screening performance in a cohort of women diagnosed with ovarian cancer. Methods: This analysis was performed as an REB approved sub-study of a single institution ovarian cancer tumor banking protocol for which all patients presenting with suspected ovarian cancer, since February 2011, were eligible. This analysis included all patients with confirmed ovarian cancer. Patients were identified and tracked prospectively. Results: There were 135 patients with ovarian cancer (mean age 57 ⫾ 12 years). 67% were post-menopausal. The distribution of histologic subtypes was 42% high-grade serous (HGS), 18% endometrioid, 12% clear cell, 6% low-grade serous (LGS), 6% sex-cord stromal, 5% germ cell, 3% mucinous, 3% mixed, 3% carcinosarcoma, and 2% other. 64 (47%) women presented with advanced disease with a median CA 125 of 260 (range 14 – 21 782), of whom 43 (68%) were found to have HGS histology. 46 (34%) patients presented with stage I disease with a median CA 125 of 41 (range 3 – 9305). Of these, the distribution of histologic subtypes included 13 (28%) endometrioid, 9 (20%) clear cell, 5 (11%) sex-cord stromal, 5 (11%) HGS, 3 (7%) mucinous and 23% other. Risk of Malignancy Index (RMI) scoring for women with stage I disease (N ⫽ 35) revealed a false negative rate of 31%, including 4 clear cell, 2 LGS, 2 endometrioid and 1 each of HGS, mucinous, and mixed (clear cell and endometrioid) histologies. Conclusions: Stage I ovarian cancer consists primarily of non-serous histologies, which are not reliably detected using CA 125 and ultrasound markers. Current approaches to screening for early stage disease may require the identification of biomarkers unique to clear cell and endometrioid histologies and novel strategies for the identification of patients at risk for HGS carcinomas.




5545


Efficacy and safety of front-line bevacizumab (BEV), weekly paclitaxel (wPAC), and q3w carboplatin (C) in elderly patients (pts) with ovarian cancer (OC): Subgroup analysis of OCTAVIA. Presenting Author: Antonio Gonzalez-Martin, Medical Oncology Service, Centro Oncologico M. D. Anderson International Spain, Madrid, Spain

Bevacizumab (Bev) for treatment of recurrent serous borderline (SB) or low-grade serous (LGS) ovarian cancer: A retrospective review of the Memorial Sloan-Kettering Cancer Center (MSKCC) experience. Presenting Author: Rachel N. Grisham, Gynecologic Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY

Background: Front-line BEV significantly improved PFS when combined with q3w paclitaxel and C in two randomized phase III OC trials. The single-arm OCTAVIA study combined two successful strategies, antiangiogenic therapy and wPAC administration, demonstrating median PFS of 24 months at the primary analysis [IGCS 2012]. We report exploratory analyses of safety and efficacy in the subgroup of pts aged ⱖ65 y treated in OCTAVIA. Methods: Pts received 6 – 8 cycles of BEV (7.5 mg/kg, d1) ⫹ wPAC (80 mg/m2 d1, 8, 15) ⫹ C (AUC 6, d1) iv q3w, with BEV q3w continued alone for a total of up to 17 cycles (1 y) as front-line therapy for newly diagnosed OC (FIGO stage I–IIa [grade 3/clear cell] or stage IIb–IV [any grade]). The primary endpoint was PFS. Results: Of the189 treated pts, 37 (20%) were aged ⱖ65 y (11% 65–⬍70 y; 6% 70 –⬍75 y; 3% ⱖ75 y). Compared with pts aged ⬍65 y, the subgroup of pts aged ⱖ65 y included fewer pts with no residual disease after surgery (24% vs 34%) and more pts with grade 3 OC (62% vs 55%) or comorbidities at baseline (hypertension: 38% vs 17%; dyslipidemia: 14% vs 5%). Pts aged ⱖ65 y received a median of 6 chemotherapy cycles (range 1– 8) and 17 BEV cycles (range 0 –18). C or wPAC was given for ⱖ6 cycles to 86% and 68% of pts, respectively. AEs led to early discontinuation of C, wPAC, or BEV in 14%, 38%, and 14% of pts, respectively. After median follow-up of 26.5 months and events in 62%, median PFS was 20.5 mo (95% CI 17.8 –29.1 mo) in the elderly subgroup. Seven pts (19%) had died, all from disease progression; the 1-y OS rate was 97.3%. The most common grade ⱖ3 AEs were hematologic (neutropenia 62%, thrombocytopenia 14%), with no major differences according to age. Overall, there was a numerically higher incidence of grade 3/4 AEs in pts aged ⱖ65 vs ⬍65 y (86% vs 76%, respectively), driven by non-hematologic AEs. The incidences of grade ⱖ3 AEs of special interest were similar in older and younger pts, except for hypertension (11% in pts ⱖ65 y vs 3% in pts ⬍65 y) and bleeding (3% vs 0%, respectively). Conclusions: BEV combined with wPAC and C is a feasible, well-tolerated, active front-line regimen, even in the small subgroup of pts aged ⱖ65 y, many of whom had comorbidities. Clinical trial information: NCT00937560.

Background: LGS ovarian cancer is a rare subtype of ovarian cancer, accounting for 10% of ovarian cancer cases. Patients typically present at an early age, exhibit a protracted clinical course, and have response rates to chemotherapy of ⬍ 4%. Limited clinical data suggests that bev may have activity in this disease. The objective of this study was to determine the response rate to treatment with bev in patients with SB or LGS ovarian cancer treated at MSKCC. Methods: Following IRB approval, all patients with a diagnosis of SB or LGS ovarian or primary peritoneal cancer treated with ⱖ 1 dose of bev for persistent or recurrent disease were identified. 17 patients were treated at MSKCC between July 2005 and June 2012. Diagnosis was confirmed by a gynecologic pathologist. All imaging was independently reviewed by the study radiologist and response was determined by RECIST 1.1 criteria. Results: 17 patients, 10 with LGS ovarian cancer, 3 with LGS primary peritoneal cancer, and 4 with SB disease were included in the analysis. The mean number of prior therapies was 3.4 (range: 1-9, median: 2). Two patients were treated with bev alone, the remainder (15) received bev in combination with paclitaxel (Pac, 6), topotecan (1), pemetrexed (1), oral cyclophosphamide (3), gemcitabine (Gem, 2), Gem and carboplatin (Carbo) (1), or Pac and Carbo (1) .Two patients were not evaluable for response due to termination of treatment prior to first radiographic assessment. The median duration of bev treatment was 23 weeks (mean: 32.2; range 6-79.4). Conclusions: This data suggests that the addition of bev to cytotoxic chemotherapy may produce dramatically higher response rates than chemotherapy alone in patients with SB and LGS ovarian cancer. A prospective study of bev for treatment of this chemotherapy resistant disease is warranted.

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The role of CHFR expression in ovarian cancer and response to taxane therapy. Presenting Author: Andrea Elisabeth Wahner Hendrickson, Mayo Clinic, Rochester, MN Background: CHFR, an E3 ubiquitin ligase that regulates Aurora A and Pololike Kinase 1, plays a critical role in the cellular response to mitotic stress. In particular, cells containing CHFR arrest in G2 when microtubule dynamics are disrupted. Conversely, low CHFR expression is associated with hypersensitivity to mitotic spindle poisons in breast cancer cell lines. Despite the extensive use of taxanes in front line treatment of epithelial ovarian cancer (EOC), little is known about CHFR expression in this disease. We examined CHFR expression and its relationship with clinical characteristics and outcome in women with EOC. Methods: Pretreatment EOC samples from women enrolled in the Mayo Clinic Biospecimen Resource for Ovarian Cancer Research who underwent initial surgical debulking between 1999-2009 were stained in triplicate with anti-CHFR antibodies. Samples were scored in a blinded fashion for CHFR expression. Associations between CHFR staining and histology, grade, and stage were assessed using chi-squared tests; associations between CHFR and overall survival (OS) or time to disease recurrence (TTR) were assessed using Cox proportional hazards models. Results: Samples from 354 women were stained; median age at diagnosis was 60.5 (range 21-93). At a median follow-up of 67 months, 221 women (62%) had died. Across all patients, moderate/strong CHFR staining was associated with poor OS (HR ⫽ 1.39, 95% CI: 1.07-1.81, p ⫽ 0.015). Moreover, moderate/strong CHFR expression was strongly associated with serous histology (p ⬍ 0.0001), high grade (p ⬍ 0.0001) and advanced stage (p ⫽ 0.0002). To assess whether the association between CHFR expression and OS was related to taxane sensitivity, a subgroup analysis was performed in the subset of patients (N⫽131) with high-grade serous EOC who received initial platinum/ taxane chemotherapy. Moderate/strong CHFR expression failed to correlate with OS (HR⫽0.91, 95% CI: 0.57-1.45, p ⫽ 0.68) or TTR from the start of chemotherapy (HR ⫽ 0.85, 95% CI: 0.55-1.31, p ⫽ 0.55) in this subset. Conclusions: CHFR expression is associated with poor OS and adverse clinical characteristics in patients with EOC but does not appear to be related to taxane sensitivity in high-grade serous tumors.

Response (RECIST 1.1) Partial response (PR) Stable disease (SD) Clinical benefit rate (PRⴙSD) Progressive disease (PD)

Number of patients

Percentage

6 5 11 4

40% (95%CI: 16.3-67.7%) 33.3% 73.3% (95%CI: 44.9-92.2%) 26.7%


Benefit in progression-free survival (PFS) to expect based on CA125 reduction at week 6 in recurrent ovarian cancer (ROC) patients: CALYPSO phase III trial data (a GINECO-GCIG study). Presenting Author: Melanie Wilbaux, EMR 3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Université Claude Bernard Lyon1, Oullins, France Background: Prediction of the expected survival benefit based on CA125 change in treated recurrent ovarian cancer (ROC) patients would be very useful. It may help for early selection of the best drug candidates during drug development, and for clinical trials. We used mathematical modeling to: 1) quantify the links between CA125 kinetics and progression-free survival (PFS) benefit, and 2) to estimate the CA125 decline required to observe a 50% PFS improvement. Methods: CALYPSO randomized phase III trial database, comparing 2 platinum-based regimens in ROC patients was used. The cohort was randomly split into a “learning dataset” (N⫽356) to estimate model parameters and a “validation dataset” (N⫽178) to validate model performances. A full parametric survival model was developed to quantify the links between tumor size changes; CA125 kinetics; prognostic factors and PFS. The predictive performance of the model was evaluated with simulations on the validation dataset. Results: PFS from 534 ROC patients was properly described by a parametric model with log-logistic distribution. The factors significantly linked to PFS were fractional changes in CA125 (⌬CA125) and in tumor size (⌬TS) from baseline at week 6; baseline CA125 (CA125BL); and patient therapy free interval. By reducing this model, ⌬CA125 was a better predictor of PFS than ⌬TS. Simulations verified the predictive performance of this model. Patients should achieve at least 49% ⌬CA125 decline induced by treatment to observe 50% PFS improvement. This effect was independent on treatment arm. Conclusions: This is the first drug-independent parametric survival model quantifying links between PFS and CA125 kinetics in ROC. The CA125 modeled decline required to observe a 50% improvement in PFS in treated ROC patients was defined. It may be a surrogate marker of PFS gain, and may embody an early predictive tool for go/no go drug development decisions and for clinical trials. Validation in other datasets is warranted.


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Analysis of clinical features of ovarian cancer (OC) and breast cancer (BC) among BRCA-mutated (BRCAⴙ) and sporadic (NH) double tumours. Presenting Author: Maria Ornella Nicoletto, Medical Oncology 1, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy Background: The clinical outcome of double OC and BC is specifically unknown either BRCA⫹ and in double tumours NH patients. Methods: The present databases made of 106 patients, 67 cases of NH (negative, no-tested or ongoing test for BRCA1/2 mutations) and 39 of BRCA⫹, were constituted to identify the clinical and pathological features of BC and OC. The primary endpoint was to evaluate biological characteristics of both cancers and clinical outcome of OC in coexistence with BC. Patients were censored at last follow-up or death (any cause) for determination of overall survival (OS). OS were determined using the Kaplan-Meier method and log-rank test to compared the different levels of a variable. Pearson Chi-Square or Fisher’s exact test were used to compare relationship between variables in to groups and Mann-Whitney U test to compare the medians. Results: 32/39 (82 %) BRCA⫹ and 44/67 (66 %) NH had BC as their first malignancy. As regards the genetic test on NH patients, 28 were BRCA negative, 22 have not been tested and in 10 patients the test is still in progress. All BRCA2 patients had BC as first malignancy, while 20/22 of BRCA1. Bilateral BC was more frequent in BRCA⫹ than in NH (33 % vs 9 %), resulted in a fivefold higher risk (p ⫽ 0.002). III-IV stage OC at diagnosis was 79% in BRCA⫹ vs 55 % in NH (p ⫽ 0.013); indeed BRCA⫹ patients have a threefold higher risk (however moderate) to develop an advanced stage OC. Death for progression of ovarian cancer involved both groups, and third neoplasm was involved in death cause in 1/1 of BRCA and 5/6 of NH. Two BRCA1 with OC as first neoplasm are alive. Conclusions: III-IV stage OC is more frequent in BRCA⫹ than in NH, and the main cause of disease progression and death is due to OC. Eventually the most relevant conclusive assessment is the suggestion of a more conserving management for BC and an intensive follow-up for OC in patients with double tumours, irrespective of their pathological or genetic features. Prospective trials are also indicated.

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Polyvalent vaccine-KLH conjugate and OPT-821 with bevacizumab (BEV) in patients with ovarian cancer in second or greater remission. Presenting Author: Roisin Eilish O’Cearbhaill, Memorial Sloan-Kettering Cancer Center, New York, NY Background: We previously completed a phase I study of a polyvalent vaccine containing GM2, Globo-H, LeY, Tn-MUC1, Tn(c), STn(c) and TF(c) antigens (AGs) individually conjugated to KLH and mixed with adjuvant OPT-821. We showed safe induction of antibody (ab) responses to 5 of the 7 vaccine AGs. Data has shown that tumor vaccine efficacy may be enhanced through disruption of angiogenesis thus providing a rationale for combining BEV with the polyvalent vaccine. We conducted an IRBapproved pilot study to evaluate the safety and immunogenicity of the poly-KLH-vaccine when given with BEV in OC in remission. Methods: Pts with recurrent OC in ⱖ2nd complete or partial remission were enrolled from 12/2010-03/2012. Pts received 6 vaccines and BEV over 17 weeks. BEV was continued beyond the vaccination phase. Treatment was continued until disease progression or toxicity. Serologic IgM and IgG responses were measured by ELISA against each AG. Wilcoxon signed rank test was used to test changes in cytokines (CKs): FGF␤, IL-8, PDGF, VEGF measured by angio multiplex assay. Results: n⫽21 Median age 56yrs (51-70). 2, 8, 8, 3 pts were in 2nd, 3rd, 4th, 5th remission, respectively. 1 DLT (gr 4 fever post vaccine #2). Immune Results: n⫽19 IgG ⫹/or IgM: ⱖ3 AGs in 17pts. IgM: ⱖ1 AG in 19pts, ⱖ3 AGs in 15pts. IgG: ⱖ1 AG in 17pts, ⱖ3 AGs in 3pts. CK Results: In 10 pts who completed 6 vaccines there was a mean (median) decrease in VEGF of 144 (111) pg/ml at the 17-week timepoint compared to baseline (p⫽0.05). For 8 pts who did not complete all 6 vaccines there was a mean (median) increase of 76 (69) pg/ml compared to baseline at the off-study visit (p⫽0.16). There was no statistically significant change in the other CKs compared to baseline values. At last follow-up, 18 pts had recurred and 3 pts had died. The median PFS was 5.6mths. Conclusions: 89% of pts responded to ⱖ3 AGs comparable to the 89% response in our prior phase I trial without BEV. BEV and polyvalentKLH vaccine can be safely administered together with retention of the vaccine’s immunogenicity. Serum VEGF levels decreased in patients on continued BEV therapy. Clinical trial information: NCT01223235. Immune response. AG

GM2 GM2 GloboH GloboH

Ab No. pts ⴙ

IgM 13

IgG 0

IgM 17

IgG 2

Tn

Tn

TF

TF

IgM IgG IgM IgG 8 4 18 5

MUC1 MUC1 IgM 15

IgG 16

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Surgical outcome score (SOS), a new algorithm based on HE4 and CA125, to predict surgical outcome in primary epithelial ovarian cancer (EOC) patients (pts). Presenting Author: Elena Ioana Braicu, Department of Gynecology, Campus Virchow Clinic, Charité, Medical University, Berlin, Germany Background: There are no clinical or biomolecular algorithms to predict surgical outcome in EOC pts. Recently, we showed that the combination of HE4 and CA125 predict surgical outcome in advanced primary EOC (ASCO 2012). We validated the cut-off values in an independent cohort and developed a new algorithm to predict surgical outcome-SOS. Methods: Pts with primary EOC (n ⫽ 193) were selected for a retrospective study between 2003 and 2011. Preoperative serum HE4 and CA125 levels were measured. The predictive values of HE4 and CA125 were analyzed using the receiver operator characteristic (ROC) with the corresponding area under the curve (AUC). Separate logistic regression algorithms for pre- and postmenopausal women were utilized to categorize pts into low and high-risk for residual disease, using CA125 and HE4 within SOS algorithm. Furthermore we performed a multivariate analysis for prediction of progression free- (PFS) and overall survival (OS). Results: Maximal cytoreduction was achieved in 67.4% pts. Serum HE4 expression correlated with residual disease (p⬍0.001, RR: 2.74, 95%CI 1.65-4.54), reaching a 76.2% sensitivity (Se), 56.9% specificity (Sp) and 83.1% negative predictive value (NPV), with 235 pM cut-off value. CA125 correlated with residual disease in premenopausal pts (p⫽0.031, RR: 3.13, 95%CI 1.28-7.65). For a CA125 cut-off of 500 IU/l, the Se, Sp and NPV were 39.7%, 69.8%, and 70.3%, respectively. ROMA predicted surgical outcome (AUC ⫽ 0.70, p ⬍0.001, 95% CI ⫽ 0.624-0.776, RR ⫽ 2.54), reaching a 76.2% Se, 53.5% Sp for 81% cut-off value. SOS algorithm performed better than HE4 or CA125 alone, and ROMA (AUC⫽ 0.741, p ⬍ 0.001, 95% CI 0.670-0.812, RR ⫽ 4.98). The Se, Sp and NPV was 90.5%, 46.5% and 90.9%, respectively, for a SOS cut off value of 21.5%. FIGO stage and residual disease were the only prognostic factors for both PFS and OS. SOS was an independent prognostic for PFS (p ⫽ 0.009, HR ⫽ 1.014, 95% CI ⫽ 1.004-1.025), but not for OS. Conclusions: This independent validation study confirm the predictive value of CA124 and HE4 on surgical outcome. The combination of HE4 and CA125 within the SOS score improve the prediction of surgical outcome, and therefore of PFS.

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Tasisulam-sodium in combination with liposomal doxorubicin in patients with ovarian cancer. Presenting Author: D. Scott McMeekin, University of Oklahoma Health Sciences Center, Oklahoma City, OK Background: Tasisulam-sodium (TASI) is a novel, highly albumin-bound small molecule that induces tumor cell apoptosis and has antiangiogenic activity. This phase 1b study was designed as a dose-finding study for TASI in combination with liposomal doxorubicin (DX) in patients (pts) with advanced solid tumors, followed by a dose-confirmation phase in platinum-resistant DX-naïve ovarian cancer (OvCa) pts. However, the study was stopped early for business reasons. Nonetheless, the dataset allowed partial characterization of the safety and antitumor activity of TASI ⫹ DX among OvCa pts who achieved an albumincorrected exposure (AUCalb) within a hypothesized therapeutic range identified in phase II monotherapy trials. Methods: In the dose-escalation phase (3⫹3 schema), pts received TASI (escalating Cmax targets of 300-380 ␮g/mL, 2-h IV) plus DX (40 mg/m2, 1-h IV) every 28 days. Pharmacokinetic and safety analyses identified an AUCalb target of 3500 h*␮g/mL for the dose-confirmation phase. We analyzed data for OvCa pts from both phases who achieved TASI AUCalbof 1200-6400 h*␮g/mL in cycle 1. Results: Of the 13 OvCa pts who completed the dose-escalation phase and 6 OvCa pts who completed the dose-confirmation phase, 10 had AUCalbof 1200-6400 h*␮g/mL in cycle 1. For these pts, the most common possibly drug-related Grade 3-4 adverse event was neutropenia (see table). Although no pt achieved complete response, 2 pts achieved partial response. Data from the other OvCa pts will also be presented. Conclusions: The early closure of the study did not allow complete assessment of TASI in combination with DX; however, acceptable tolerability and some antitumor activity were observed for OvCa pts with TASI AUCalbwithin the hypothesized therapeutic range. Clinical trial information: NCT01214668. Variable TASI ⴙ DX(nⴝ10)a Most common possibly-related grade 3-4 AEs; n Neutropenia Thrombocytopenia Anemia Mucositis Best overall response; n Complete response (CR) Partial response (PR) Stable disease (SD) Response rate (CRⴙPR) Disease control rate (CRⴙPRⴙSD) Kaplan-Meier estimate; median months Overall survival Progression-free survival No. of cycles; median, range a

5 2 2 2 0 2 6 2 8 9.2 5.8 4.5, 1-16

Pts with TASI AUCalb 1200-6400 h*␮g/mL in cycle 1.




Benefit of adjuvant chemotherapy for stage I epithelial ovarian cancer according to the histologic type. Presenting Author: Hiroyuki Fujiwara, Department of OBGYN, Jichi Medical Univerity, Shimotsuke, Japan

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Does alopecia predict response to chemotherapy and prognosis in patients with advanced ovarian cancer? A meta-analysis of prospective randomized phase III trials with 5,114 patients of the AGO meta data base. Presenting Author: Jalid Sehouli, Department of Gynecology, European Competence Center for Ovarian Cancer, Charité Campus Virchow Klinikum, Berlin, Germany

Background: The benefit of adjuvant chemotherapy in stage I epithelial ovarian cancer (EOC) remains controversial. We retrospectively examined stage I EOC patients to clarify the benefits of adjuvant chemotherapy according to the histological type. Methods: The outcomes of 131 patients with stage I EOC that was diagnosed by exact staging laparotomy at the Jichi Medical University Hospital over a 22-year period from 1988 to 2009 were evaluated. Eighty-seven of the patients had received adjuvant chemotherapy (stage: IA 17, IC(intraoperative rupture;R) 27, IC(other) 43; histological type: clear cell adenocarcinoma(CCC) 38, mucinous adenocarcinoma(MC) 18, endometrioid adenocarcinoma(EC) 18, serous adenocarcinoma(SAC) 13), while 44 had undergone observation alone (stage: IA 31, IC(R) 12, IC(other) 1; histological type: CCC 11, MC 17, EC 11 and SAC 5). Outcomes for patients were compared between the two groups. Results: The overall recurrence rate in the adjuvant chemotherapy group was 18.4% (16/87). The rates of recurrence according to stage were IA 5.9% (1/17), IC(R) 14.8% (4/27), and IC (other) 25.6% (11/43). Recurrence by histological type were CCC 12, SAC 2(G1and G2), and one each for EC and MC. Recurrence was seen in all stages in CCC patients; however, there was no recurrence in stage IA in patients with non-CCC. The overall recurrence rate in the observation group was 11.4% (5/44). All five recurrences occurred in CCC patients, and no recurrence was observed in the 33 non-CCC patients (IA 26, IC(R) 7). In patients with IC(R) CCC, the recurrence rate was significantly higher in the observation group (80%;4/5) than in the adjuvant chemotherapy group (18.8%; 3/16) (p ⫽ 0.025). Conclusions: This retrospective study showed that the CCC is associated with recurrence in stage I EOC and adjuvant chemotherapy for these patients may improve outcomes. The recommended states for adjuvant chemotherapy in stage I EOC are as follow: 1) all subtype of stage I for CCC, and 2) IC(other) for non-CCC. Although further prospective studies are required, these results afford useful information with which to determine the adjuvant chemotherapy in stage I EOC.

Background: Alopecia is a relevant side effect of chemotherapy. Our aim was to validate and unconfirmed broad patient´s opinion that a low rate of alopecia may predict poor response to chemotherapy and poor overall survival (OS). Methods: Individual patient data analysis of 5114 patients from four prospective randomised phase III trials conducted between 1995 and 2004 to investigate platinum-taxane based chemotherapy regimens in advanced ovarian cancer. Uni- and multivariate analyses were performed adjusted for age, number of cycles, individual trial, residual mass, tumor stage and histology. Results: 5,114 patients with ovarian cancer (OC) were analyzed. Most patients presented with advanced stage FIGO III/IV (87.8%). A median of 6 cycles were applied (range 0-11). Worst alopecia grade was 0 in 2.2%, 1 in 2.7% and 2 in 87.1%. In 8% patients no data about alopecia were documented. Patients with complete alopecia were more likely to achieve remission (OR 2.83, 95% CI 1.68-4.78 for grade 2 compared to grade 0/1) and had favourable progression-free survival of 19.0 months, (95%CI 18,2-19.7) compared to patients with grade 0/1 (13.8, 95%CI 12.2-15.3 and 14.3, 95%CI 10.8-17.8). Median OS was also significantly longer after grade 2 alopecia 48.8 months (95%CI 47.0-50.5), compared to 28.1 months (95%CI 22.3-33.9) and 33.9 months (95%CI24.3-43.6) for grade 0 and 1, respectively. This prognostic impact was not reteined in multivariate analysis. However, onset of alopecia was an independent prognostic factor for OS: patients with complete alopecia after cycle 3 had a favourable outcome compared to patient who experienced alopecia later during therapy (HR 1.22, 95%CI 1.02-1.46) or no alopecia (HR 1.29, 95%CI 0.98-1.70). Conclusions: We could show for the very first time that there is no evidence that the rate of alopecia is associated with the effect of chemotherapy is of any prognostic relevance. The observation that early onset of alopecia is associated with OS should be confirmed.

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A phase II study of oral metronomic combination therapy in relapsed epithelial ovarian cancer. Presenting Author: Sudeep Gupta, Tata Memorial Centre, Mumbai, India

Comparison of two multimarker serum tests for the prediction of ovarian cancer in women with a pelvic mass. Presenting Author: David G. Grenache, University of Utah School of Medicine, Salt Lake City, UT

Background: Etoposide (E), cyclophosphamide (C) and tamoxifen (T) have been used as single agents in relapsed epithelial ovarian cancer (EOC) patients. We tested a low dose, continuous, daily, oral metronomic regimen that combined these 3 agents. Methods: This single centre prospective study included patients of relapsed EOC with exposure to at least 2 prior lines of chemotherapy (CT) and at least partial as the best response to most recent regimen. Study regimen comprised daily oral administration of E (50 mg/m2) and C (50 mg/m2) for 21 of a 28 day cycle plus T (20 mg/m2, twice per day) continuously. The primary endpoint was serological (CA-125) progression-free survival (PFS) as per Rustin Criteria and secondary endpoints were radiological (RECIST) PFS, overall survival (OS), duration of response (DOR), response rates and toxicity. The data cut-off date was 15 Jan 2013. Results: 26 patients with a median age of 48 years were accrued, of whom 21 had received 2 prior lines of CT and 5 had received 3 lines. 25 patients who were evaluable for analysis received a median of 6 (1-19) cycles of metronomic regimen. The median delivered relative dose intensities of E, C and T were 0.71, 0.71 and 0.97 respectively. 13 (52%) patients needed dose reduction after a median of 3 (1-9) cycles. Most common grade 3 or 4 toxicities included anemia, neutropenia, febrile neutropenia, nausea, vomiting and diarrhea in 44%, 36%, 12%, 16%, 16% and 12% patients respectively. 19 (76%) patients had serological CR or PR with a median time to response (TTR) and DOR of 1.8 (0.83-2.96) and 7.0 (95% CI, 5.8-8.2) months respectively. 11 (45.8%) of the 24 evaluable patients achieved radiological CR or PR with median TTR and DOR of 3.7 (1.8-7.2) and 5.5 (95% CI, 3.9-7.2) months respectively. 17, 18 and 7 patients have respectively experienced serological progression, radiological progression and death at the time of analysis. The median serological PFS, radiological PFS and OS are 7.9 (95% CI 7.2-8.6), 7.97 (95% CI, 5.95-9.98) and 22.3 (95% CI, 17.4-27.3) months, respectively. Conclusions: The oral metronomic combination of E, C and T has substantial and durable activity in relapsed EOC and is worthy of further evaluation in a larger randomized study.

Background: Distinguishing between benign and malignant disease in women with a pelvic mass is difficult. OVA1 and ROMA are two multimarker serum tests that are FDA-cleared to assess risk of malignancy in individuals with a pelvic mass. This study compared the accuracy of these tests for the prediction of ovarian cancer (OCa) in women with a pelvic mass. Methods: OVA1 and ROMA risk scores were determined in a subset of 146 serum samples obtained prospectively from pelvic mass patients. Patients were categorized by an initial cancer risk assessment (ICRA) performed by a physician and true cancer status determined surgically. 31 patients with malignancy (6 with a benign ICRA) and 115 patients with benign disease (25 with a malignant ICRA) were evaluated. Quest Diagnostics performed the OVA1 tests (CA-125, prealbumin, apolipoprotein A-1, ␤2-microglobulin, transferrin) and calculated and interpreted the risk score. ROMA tests (CA-125 and HE-4) were determined by automated immunoassay using an Abbott Architect analyzer. ROMA risk scores were calculated using published formulas and interpreted against cutpoints previously established for automated CA-125 and HE-4 performed by manual ELISA. Results: There were 70 pre- and 76 post-menopausal subjects. Of the 31 with malignancy, 26 had OCa (54% ⬎stage II), 5 with an ICRA of benign. ROC curve analysis of the entire cohort produced an AUC of 0.88 (95% CI 0.80-0.95) and 0.93 (95% CI 0.87-0.99) for OVA1 and ROMA, respectively. OVA1 had a sensitivity of 0.97 and a specificity of 0.55. ROMA had a sensitivity of 0.84 and a specificity of 0.83. The sensitivity of OVA1 for OCa in the ICRA benign cohort (N ⫽ 5) was 0.80 and for ROMA was 0.40. The respective specificity for benign disease in this cohort (N⫽90) was 0.64 and 0.90. The sensitivity of ROMA for OCa increased to 0.60 with a slight decrease in specificity (0.87) when a cutpoint determined by ROC curve analysis was used. Conclusions: Overall, OVA1 and ROMA have similar performance characteristics. In women with an ICRA of benign, OVA1 was more sensitive among those who had OCa but ROMA was more specific among those who did not. The use of a ROMA cutpoint specific for the combination of automated CA-125 and HE-4 tests improved sensitivity.


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Clinical relevance of VEGF-receptor status in primary ovarian cancer: A pilot study for future biomarker analyses. Presenting Author: Pauline Wimberger, Department of Gynecology and Obstetrics, Technical University of Dresden, Dresden, Germany Background: Antiangiogenic treatment in addition to platinum/taxane based chemotherapy was shown to improve progression-free survival in first- and second-line chemotherapy in ovarian cancer patients. Predictive markers for antiangiogenic treatment are of high interest. Therefore we investigated VEGF-receptor (VEGFR) expression as possible biomarker candidate in primary ovarian cancer tissue and its clinical impact. Methods: A total of 82 patients with primary ovarian cancer were enrolled into this study. Primary tumor tissue was analyzed for the expression of VEGFR1, VEGFR2 and VEGFR3 by immunhistochemistry. Moreover, the presence of circulating tumor cells (CTC) in the blood was detected by immunomagnetic enrichment and multiplex reverse transcriptase-polymerase chain reaction (Adnatest Ovarian Cancer, Adnagen). Disseminated tumor cells (DTC) in the BM were identified by immunocytochemistry using the pancytokeratin antibodyA45B/B3 and subsequent automatic detection based on staining and cytomorphology. Results: Positivity for at least one VEGFR was observed in 43% of cases. The positivity rates for VEGFR1, -2 and -3 were 34%, 17% and 27%, respectively. VEGFR-status of the primary tumor neither correlated with established clinicopathogical parameters (age, FIGO-stage, nodal status, grading, histological subtype) nor with the presence of CTC or DTC. In addition, VEGFR-status does not provide prognostic significance in regard to progression-free and overall survival (OS). Nevertheless, a trend was observed that patients, being positive for VEGFR3 at primary diagnosis, were more likely to experience suboptimal debulking (p ⫽ 0.074). CTC-positivity after adjuvant therapy significantly correlated with OS, but multivariable analysis showed only residual tumor as prognostic factor for OS. Conclusions: The VEGFR-family, albeit frequently expressed in our patient cohort, provided neither prognostic nor predictive relevance, but could probably be a predictor for debulking efficiency. The implementation of VEGFR-status into future biomarker studies should carefully be considered.

5558


Clinical study of intraperitoneal injection bevacizumab (BV) combined with intraperitoneal hyperthermic perfusion chemotherapy (CT) in treatment of malignant ascites of ovarian cancer (OC). Presenting Author: Hui Zhao, Department of Oncology, First Affiliated Hospital, Chinese PLA General Hospital, Beijing, China Background: To study the efficacy and safety of intraperitoneal injection BV combined with intraperitoneal perfusion CT in treatment of malignant ascites of OC and to investigate the clinical significance of the concentration change of vascular endothelial growth factor (VEGF). Methods: Patients with malignant ascites of OC were randomly divided into treatment group (n ⫽ 31) and control group (n ⫽ 27). All enrolled patients received TC (paclitaxel 135mg/m2, iv d1⫹ carboplatin AUC⫽5, iv d1), 1 time/3 weeks for 6 weeks. Patients in the control group were treated with intraperitoneal perfusion CT combined with intraperitoneal cisplatin (40mg/m2)1 time/2 weeks for 6 weeks. Besides the treatment of the control group, patients in the treatment group received intraperitoneal injection with BV 300mg after each intraperitoneal perfusion CT for 6 weeks. The improvement of life quality, efficacy and adverse effects were evaluated. The concentrations of VEGF and CA-125 in ascites of the two groups were assayed by ELISA method. Results: No severe side effect was observed in all the patients. The response rate of the treatment group was higher than that of the control group (90.32% vs. 59.26%, p ⬍ 0.05). The improvement rate of quality of life (QOL) of the patients in the treatment group was also higher than that of the patients in the control group (93.55 % vs. 48.15%, p ⬍ 0.05). The concentration of VEGF in ascites of the treatment group after treatment was lower than that before treatment (p ⬍ 0.05). And after treatment, the concentration of VEGF in ascites of treatment group was lower than that of the control group (p ⬍ 0.05). Conclusions: Intraperitoneal injection BV combined with intraperitoneal perfusion CT in the treatment of malignant ascites of OC is effective and safe. The concentration of VEGF and CA-125 levels, in ascites may be used as monitoring index for treatment effect of malignant ascites of OC with intraperitoneal injection BV.

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Relationship of microRNA expression profiles and recurrence in advanced serous ovarian carcinoma. Presenting Author: Eun Ji Nam, Yonsei University College of Medicine, Seoul, South Korea Background: Most patients with epithelial ovarian cancer eventually succumb to chemo-resistant disease. Although microRNAs have been recognized as important regulators of gene expression, little is known about microRNA expression profiles in recurrent serous ovarian carcinoma. We assessed the microRNA expression profiles which contribute to recurrence in advanced serous ovarian carcinoma. Methods: Eight pairs of primary and recurrent tumor samples from 8 patients with advanced serous ovarian carcinoma and 4 normal ovarian samples from patients treated for benign uterine disease between May 2006 and Dec 2012 were examined using miRNA microarray. microRNA profiling were validated using real-time reverse transcription-polymerase chain reaction (RT-PCR). Results: Alterations of microRNA expression profiles in primary and recurrent tumor samples have similar patterns when compared with normal ovarian tissues. Among 31 up-regulated microRNAs more than 4-fold in primary tumors, 27 microRNAs were also significantly up-regulated in recurrent tumor samples. Likewise, Among 35 down-regulated microRNAs more than 4-fold in primary tumors, 34 microRNAs were also significantly down-regulated in recurrent tumor samples. Comparing to primary tumor, we found 60 microRNAs which were significantly up-regulated, including miR-630, 370, and 575, and 52 microRNAs which were significantly downregulated, including miR-509-3p, 514a-3p, and 506-3p in recurrent serous ovarian carcinoma. Conclusions: Our results indicate that dysregulation of microRNAs may play a role in recurrence of serous ovarian carcinoma.

5559


Phase II study of trabectedin in pretreated patients with recurrent epithelial ovarian cancer (REOC). Presenting Author: Marco Marinaccio, Department of Gynecology and Obstetrics, University Medical School, Bari, Italy Background: The prognosis of patients with REOC is extremely poor after several lines of chemotherapy. The choice and timing of therapies must be individualized to optimize survival and quality of life. This open-label, nonrandomized, phase II study was aimed at evaluating efficacy and toxicity of Trabectedin as a single-agent therapy in patients with preteated Recurrent Epithelial Ovarian Cancer (REOC). Methods: Sixteen patients (median age 51 yrs, range 44 – 71) with REOC who progressed after 2 (18.7%), 3 (56.3%) or 4 (25.0%) previous lines of chemotherapy were treated with Trabectedin at the dose of 1.1 mg/m2 via a 3-hour i.v. infusion with dexamethasone pretreatment every 3 weeks until disease progression, unacceptable toxicity or when a stability of disease was reached. Clinical objective response was the primary efficacy endpoint; the secondary one was safety. Response to treatment was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST, version 1.1), and toxicities were graded according to NCI Common Toxicity Criteria, version 2.0. Results: The median number of treatment cycles per patients was 5 (range, 2-9 cycles). A total of 81 cycles were administered. A dose reduction was never required. Main toxicities included anemia (20.9%), leucopenia (15.0%), thrombocytopenia (4.5%) and asthenia (22.2%). No deaths were attributable to therapy. No one showed complete response, while 9/16 partial response (56.2%) and 4/16 stable disease (25.0%) were observed. 3/19 pts (18.8%) progressed on therapy. The median progression-free interval was 18 weeks in patients with partial response; stable disease was maintained for a median time of 12 weeks. Conclusions: Trabectedin 1.1mg/m2 given as a 3-hour i.v. infusion every 3 weeks was well tolerated and has confirmed a very interesting antitumor activity in this heavily pretreated population and it seems also to be a very tolerable regimen. The co-treatment with dexamethasone improves the safety of Trabectedin by reducing drug-induced myelosuppression and hepatotoxicity. Trabectedin has a manageable toxicity profile, and can be safely administered thanks to its secure action profile also in patients with no other viable therapeutic options.




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Protein network mapping of platinum-resistant and poor-survival ovarian cancer. Presenting Author: Maria Isabella Sereni, George Mason University, Manassas, VA

Does aggressive primary debulking surgery influence survival in ovarian cancer? Presenting Author: Yakir Segev, Division of Gynecologic Oncology, Princess Margaret Hospital and University of Toronto, Toronto, ON, Canada

Background: Epithelial ovarian carcinoma (EOC) is the fifth leading cause of tumor related death in the female population, with only 30% of patients alive at 5 years after diagnosis. Platinum resistance is a major cause of treatment failure. The aim of the study was to perform broad-scale drug target activation mapping of EOC to identify new druggable targets for personalized therapy. Methods: 72 ovarian primary lesions collected from chemo-naïve EOC patients were analyzed. Highly enriched tumor epithelial cells were isolated by laser capture microdissection, lysed and subjected to reverse phase protein microarray analysis for multiplexed protein pathway activation mapping. The activation/phosphorylation level of 156 key signaling proteins was analysed. Based on the disease-free interval to platinum therapy, 61 stage II-IV patients were segregated into platinumresistant (⬍6 months), platinum-sensitive (6-12 months), and platinumsupersensitive disease (⬎12 months). One-way analysis of variance was used to detect significant differences among the three groups in the drug target activation profile. Results: Expression of the drug target PDGF Receptor ␤ and activation of ErbB2/HER2 (Y1248) were significantly higher in patients with resistant disease compared to sensitive groups (respectively, p 0.0033 and p 0.0134), while the expression of Estrogen receptor ␣ was greater in the supersensitive group (p 0.0295). Moreover, overall survival analysis including all stages revealed that the expression level of Cox2 is significantly higher in patients with shorter survival (HR: 2.48, p 0.0179). Conclusions: Functional drug target activation mapping revealed the unique signaling architecture of platinum-resistant EOC. If confirmed in independent study sets, these results suggest that the utilization of drugs targeting PDGF Receptor ␤ and ErbB2/HER2 could be evaluated in platinum resistant EOC and/or in combination with platinum therapy in order to overcome acquired resistance. Finally, this study indicates that Cox2 may play an important role in aggressive EOC, and that the addition of Cox-inhibitors to standard of care could be rationally evaluated as a novel therapeutic regimen for ovarian cancer.

Background: Evidence comparing outcomes in patients receiving primary debulking surgery (PDS) to those receiving neoadjuvant chemotherapy (NACT) for advanced stage ovarian carcinoma is conflicting. We conducted a retrospective survival analysis of all patients with stage IIIC and IV serous ovarian cancer treated at our institute by either PDS or NACT. Methods: Data was extracted from patient synoptic OR reports and medical records between January 2003 and December 2011. Survival comparisons between patients receiving NACT and PDS were made according to aggressiveness of surgery and residual disease following surgery. Aggressive surgery was defined by one of the following procedures; pelvic peritonectomy, any bowel resection, diaphragm resection, diaphragm peritonectomy and splenectomy. Results: Out of 342 patients, 143 (41%) had NACT and 199 (59%) had PDS. Patients undergoing PDS had a median survival (MS) of 58 months compared to 34 months for NACT. Patients undergoing PDS with ⬎ 10mm and ⬍10mm residual disease, had a MS of 33 and 55 months, respectively; whereas those with microscopic disease have not yet reached their MS. In the NACT group, MS for ⬍ and ⬎ 10 mm residual disease was 30 months for both, compared with 39 months for those with microscopic disease. Within the PDS group, those undergoing limited surgery had a MS of 48 months whereas MS has not been reached for those undergoing aggressive surgery. Over 60% of patients undergoing PDS with microscopic residual were alive at 7 years. In the NACT group, there was no difference in survival according to extent of surgery. Conclusions: Patients withPDS, whether debulked to ⬍ 10mm or to microscopic disease have a significant and lengthy survival advantage over patients receiving NACT.

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Continuous low-flow ascites drainage and sequential non-invasive tumorcell sampling through the urinary bladder via the alfa-pump closed system in platinum-resistant ovarian cancer (PROC): First clinical experience in a cancer patient. Presenting Author: Christina Fotopoulou, Imperial College NHS Trust, London, United Kingdom Background: Malignant ascites in PROC causes significant impairment in quality of life. The Sequana Medical alfapump System (AP), a remotely controlled device connecting the patients’ peritoneal cavity to their urinary bladder, has been evaluated for the continuous drainage of ascites in liver cirrhosis, but not as yet for malignant ascites. Methods: We implanted the AP in the peritoneal cavity of a 67y old heavily pretreated PROC patient with recurrent malignant ascites requiring 3-5 liters drained 3 times/ month. The AP was evaluated for its ability to drain ascites into the urinary bladder using an electronic download of recorded volume pumped, cross correlated with weekly ultrasound, symptomatic scores and QoL evaluation. Early morning urine for evaluation of urinary cytology and tumor-cell molecular analysis was collected weekly. Results: The implantation was performed under general anaesthesia in a 60 minute procedure. Before insertion the patient had 3 liters of malignant ascites; 2 liters were drained during surgery. The pump, draining 350ml ascites per day successfully drained the ascites to dryness after 3 days. The patient underwent weekly sonography and monthly cystoscopies. She did not report pollaki- or dysuria, only an increased micturition volume. Histopathological analysis of the urine revealed rich malignant cell content, used to create FFPE cell blocks weekly for molecular- pathological profiling with sequential Caris Target Now analysis and full exome sequencing. Conclusions: On initial evaluation, the AP represents a tolerable and effective means of diverting peritoneal ascites into the urinary bladder and thus preventing its recumulation in PROC. This innovative approach not only addresses an area of unmet need for the control of malignant ascites but also provides a method of collecting tumor tissue and evaluating longitudinal change in molecular tumor characterization. A EUTROC multicenter European randomized trial (AMAZE) is planned for evaluation of clinical and translational implications of the AP in PROC.


Validation of urinary HE4 as a biomarker for ovarian cancer. Presenting Author: Zhong-Qian Li, Fujirebio Diagnostics, Inc., Malvern, PA Background: Urinary HE4 has been reported as a promising biomarker for ovarian cancer (OC). In the current study, a large validation was performed to evaluate urinary HE4 as a biomarker for the stratification of OC from benign pelvic masses. Methods: Normalized HE4 was obtained from the ratio of HE4 (pmol/L measured with HE4 EIA) and creatinine (mg/dL measured with a Jaffe Reaction) in single-point urine samples from female subjects with a pelvic mass (N ⫽ 809). The samples were from one case-control prospective study (Moore RG, 2008) and two prospective clinical trials (NCT00315692 and NCT00987649). R Package was used to randomly distribute the subjects into the Training and Testing Sets. Analyze-it was used to analyze the clinical performance. Results: Medians of Normalized HE4, sensitivities (SN) and likelihood ratios (LR) (⫹) of Normalized HE4 at two levels of specificity (SP) are presented in the Table. Conclusions: Urinary HE4 normalized with urinary creatinine appears to be a valid biomarker for the stratification of OC from a benign pelvic mass. Training set (N ⴝ 405) N Benign OC ⴙ LMP LMP OC Stage I-II OC Stage III-IV OC

OC ⴙ LMP LMP OC Stage I-II OC Stage III-IV OC

OC ⴙ LMP LMP OC Stage I-II OC Stage III-IV OC

282 123 16 107 27 78

Median (95% CI)

70 (65 - 76) 357 (272 - 484) 97 (72 - 111) 458 (314 - 614) 178 (74 - 341) 671 (480 - 869) Cut point ⱖ 134 to reach 90% SP with benign LR (ⴙ) SN (95% CI) 7.0 69.9% (61% - 78%) 1.9 18.8% (4% - 46%) 7.8 77.6% (68% - 85%) 5.2 51.9% (32% - 71%) 8.9 88.5% (79% - 95%) Cut point ⱖ 95 to reach 75% SP with benign LR (ⴙ) SN (95% CI) 3.3 81.3% (73% - 88%) 2.3 56.3% (30% - 80%) 3.4 85.0% (77% - 91%) 2.7 66.7% (46% - 83%) 3.8 93.6% (86% - 98%)

Testing set (N ⴝ 404) N

Median (95% CI)

282 72 (67 - 77) 122 276 (172 - 439) 21 113 (70 - 138) 101 438 (277 - 668) 31 145 (96 - 246) 66 763 (439 - 1009) 92% SP obtained with benign at the cut point ⱖ 134 LR (ⴙ) 8.8 3.7 9.9 7.0 11.7

SN (95% CI) 68.9% (60% - 77%) 28.6% (11% - 52%) 77.2% (68% - 85%) 54.8% (36% - 73%) 90.9% (81% - 97%) 74% SP obtained with benign at the cut point ⱖ 95 LR (ⴙ) SN (95% CI) 3.2 83.6% (76% - 90%) 2.6 66.7% (43% - 85%) 3.4 87.1% (79% - 93%) 2.9 74.2% (55% - 88%) 3.7 95.5% (87% - 99%)


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Evaluating the accuracy of frozen section in borderline ovarian tumors. Presenting Author: Natasha Gupta, Mount Sinai Hospital, Chicago, IL Background: The objective of this study was to evaluate accuracy of frozen section in borderline ovarian tumors and to determine the tumor characteristics that lead to higher likelihood of inaccurate intraoperative diagnosis (IAIOD). IAIOD is a clinical problem that restricts the diagnostic accuracy of frozen section in borderline ovarian tumors. Methods: This was a retrospective chart review of 622 consecutive cases that were diagnosed with pelvic mass and underwent surgery at busy gynecology services of two institutions, between 2006-2011. Of these cases, 52 were diagnosed as borderline ovarian tumors by frozen section. Experienced pathologists performed frozen section with second opinion from specialized gynecologic pathologists as needed. Terms such as “at least borderline” were also evaluated to help stratify patients. Frozen section and final permanent histology reports were compared. Patient and tumor characteristics that may cause IAIOD such as age of patient, histological subtype, size of tumor, bilaterality, CA-125 levels were studied. Staging was performed when borderline or malignant ovarian tumors were identified by frozen section. Results: Agreement of the frozen section results with final pathology was observed in 37 out of 52 patients with a diagnostic accuracy of 71.15 %. Under diagnosis occurred in 12 out of 52 patients and over diagnosis occurred in 3 out of 52 patients. Age ⬎40 years, size of tumor ⬎5 cm, bilaterality of tumors and CA-125 were not found significant in causing IAIOD when chi-square analysis was performed. Characterization by “atleast” borderline terminology at the time of frozen section did not help identify patients with higher likelihood of IAIOD. Conclusions: In our study, the rate of IAIOD was high, at 23% despite experienced pathologists and using “at-least borderline” terminology. Traditionally described features leading to inaccuracy with frozen sections, such as large tumors with mucinous histology did not increase the risk of IAIOD in this study. Patients with unilateral, small tumors and non-mucinous histology had greatest risk for IAIOD. Given this information, full staging of all borderline ovarian tumors identified at time of frozen section should remain the standard of practice.

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Prognostic effect of EIF4EBP1 on ovarian cancer: A single gene biomarker for overall survival and platinum response. Presenting Author: Victor Manuel Villalobos, Stanford University, School of Medicine, Stanford, CA Background: Using a novel computational approach, Gene Set Outcome Analysis (GSOA), we were able to identify an area of amplification on chromosome 8p12 that leads to worse prognosis in high grade/high stage ovarian cancer. Located within this amplicon is EIF4EBP1, an effector of DNA translation that is activated by mTOR. Methods: We utilized the MSKCC CBIO cancer genetics portal and the ovarian TCGA clinical dataset, to detect variation in mRNA expression (EXP), (z-scores thresholds ⫾ 2) and copy number variation (CNV), determined using GISTIC 2.0, that are associated with significant differences in PFS and overall survival in grade 3 and stage III/IV ovarian cancer. Results: 6.7% of tumors exhibited upregulation of EIF4EBP1 (CNV amplified and mRNA z ⬎ 2) and poorer prognosis with OS of 30.2 vs. 43.8 months (p ⫽ 0.0007, n ⫽ 445) in tumors not upregulated. Patients with upregulated vs. normal expression showed inferior PFS with first line, platinum based therapy, 10.0 vs. 15.2 months (p ⫽ 0.0406, n ⫽ 400), respectively. An additional 4.9% of cases had downregulation of EIF4EBP1, with homozygous deletion or mRNA expression z-scores ⬍ -2. Downregulation vs. normal expression also showed worse OS of 27.0 vs. 42.1 months (p ⫽ 0.0178) and PFS of 11.0 vs. 15.0 months (p ⫽ 0.028), respectively. As these groups are mutually exclusive and show a similar trend towards poor prognosis, when combined to compare aberrant vs. normal mRNA expression and copy number, we found an OS of 28.2 vs. 44.6 months (p ⫽ ⬍0.0001) and PFS for first line platinum therapy of 10.2 vs. 15.3 months (p ⫽ 0.0024), respectively. Conclusions: In this dataset of 445 high-risk ovarian cancer patients, 11.8% exhibited aberrant expression of EIF4EBP1. While amplification of this region showed highly significant changes in OS and PFS, inclusion of both increased and decreased EIF4EBP1 mRNA expression achieved high statistical significance, demonstrating a “Goldilocks effect”, wherein normal expression leads to better outcomes. The potential relationship of gene expression levels of EIF4EBP1 to responsiveness to mTOR inhibitors should be explored in ovarian carcinomas.

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Exploratory analysis of nibrin in advanced ovarian cancer (AOC) patients treated in the phase III OVA-301 trial. Presenting Author: Miguel Aracil Avila, Pharmamar, Madrid, Spain

Results of the MARS study on the management of antiangiogenics’ renovascular safety in ovarian cancer. Presenting Author: Vincent LaunayVacher, Service ICAR - Pitie-Salpetriere Hospital, Paris, France

Background: Nibrin (p95/NBS1) is a protein with an essential function in DNA double-strand break repair by homologous recombination. Therefore, we have investigated its value as a possible biomarker in patients with AOC by immunohistochemistry (IHC). Methods: IHC staining was performed in 138 samples from a subset of patients that have participated in the phase III OVA-301 trial, in which the combination of trabectedin plus pegylated liposomal doxorubicin (PLD) or PLD alone were randomly administered for advanced disease after failure of platinum-based chemotherapy (Monk 2010; Monk 2012). A computerized image analysis system was used to calculate the total percentage of nibrin-positive cells. Nibrin expression was considered as a continuous variable. The analysis of overall response rate (ORR) and progression-free survival (PFS) was based on independent oncologist assessment. Overall survival (OS) was defined from randomization to death/last contact. All the comparisons had an exploratory nature; an alpha cut-off value of 0.05 (two-sided) was established as statistically significant. Results: For PFS, there was a statistically significant correlation between high levels of nibrin and short PFS (HR ⫽ 1.014, 95% CI: 1.004-1.024, p⫽0.0047). Similarly, for OS, there was a statistically significant correlation between high levels of nibrin and worse OS (HR ⫽ 1.009, 95% CI: 1.001-1.017, p ⫽ 0.0295). A multivariate analysis showed that high levels of nibrin were independently correlated to a worse PFS (HR ⫽ 1.012, 95% CI: 1.002-1.022, p ⫽ 0.0147) and to a worse OS (HR ⫽ 1.010, 95% CI: 1.002-1.018, p⫽0.0192). After stratification according to platinum-sensitivity, high nibrin showed a significant correlation with lower ORR (ORR ⫽ 1.02, 95% CI: 1.01-1.03, p⫽0.0009), short PFS and OS values only in the platinum-sensitive patients. Conclusions: The results point out the potential importance of nibrin expression in the clinical outcome of patients with AOC. In particular, high protein expression of nibrin seems to be associated with a worse clinical outcome. Prospective clinical trials evaluating the clinical usefulness of this marker with other standard of care treatments are warranted. Clinical trial information: NCT00113607.

Background: Anti-VEGF drugs (AVD) are widely used in cancer patients (pts). Hypertension (HTN) and proteinuria (Pu) are class-side-effects of AVD, related to the inhibition of the VEGF pathway. The MARS study has been conducted to assess the renovascular tolerance of these drugs in the clinical setting. Methods: This multicentric, prospective, observational study evaluated the renovascular safety of AVD in pts naive from any AVD, conducted in 7 centres in France, from 2009 to 2012, with a follow-up (f/u) of 1 year. Data collected included: gender, age, serum creatinine (SCr), HTN, hematuria (Hu) and dipstick Pu, at baseline and at each visit. Results: 1,124 pts were included. 79 pts had ovarian cancer (OC) and all received bevacizumab. Median age at inclusion was 61 years. Visceral, bone and cerebral metastasis frequencies were 74.1, 52.7 and 6.0%, respectively. HTN prevalence was 16.5%. Baseline renal assessment retrieved: Pu 36.0%, Hu 21.3%, mean aMDRD 83.0 ml/min/1.73m2 and 5 pts with aMDRD⬍60. The incidence of de novo Pu and HTA during f/u was 56.8 and 21.2% (Table). 88.9 % of pts with Pu at inclusion improved or remained stable. Among pts with de novo Pu, 64.0% afterwards improved/normalized. No Grade 4 Pu has been reported (at inclusion or during f/u). Renal function remained stable with a mean aMDRD of 83.2 at the end of f/u. 6.0% had grade 2 SCr increase (no grade 3-4). No thrombotic micro-angiopathy (TMA) was reported. Conclusions: These results on the renovascular safety of bevacizumab in OC patients showed that 1) TMA is rare, 2) Pu develops in 56.8% of the pts, however with only 1 Grade 3/4, 3) 21.2% developed HTN, and 4) aMDRD was stable. Furthermore, in case of a renovascular effect, investigators followed the recommendations from the French Society of Nephrology (Halimi JM. Nephrol Ther 2008) and no treatment withdrawal for unmanageable renovascular toxicity occurred. Renovascular effects Pu* All G G1 G2 G3 HTN Hu All Hu Traces/ⴙ ⴙⴙ ⴙⴙⴙ SCr increase* All G G1 G2 G3-4

Prevalence at inclusion

Incidence during f/u

n⫽75 36.0% 30.7% 5.3% 0.0% n⫽79 16.5% n⫽75 21.3% 12.0% 5.3% 4.0%

n⫽44 56.8% 38.6% 15.9% 2.3% n⫽66 21.2% n⫽49 28.6% 20.4% 6.1% 2.1% n⫽67 74.6% 68.6% 6.0% 0.0%

* NCI-CTC v4; G: Grade; Number of pts may vary due to missing data.




An open label, randomized, parallel, phase II trial to evaluate the efficacy and safety of cremophor-free, polymeric micelle formulation of paclitaxel compared to paclitaxel in subjects with ovarian cancer. Presenting Author: Yong-Man Kim, Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea Background: Cremorphor EL, used to enhance drug solubility, may add to paclitaxel’s toxicities such as hypersensitivity reactions or peripheral neuropathy. This multi-institutional phase II trial is to evaluate the efficacy and safety of Cremophor-Free, Polymeric Micelle Formulation of Paclitaxel (Genexol-PM) compared to Paclitaxel (Genexol) as a combined chemotherapy with carboplatin in patients with advanced epithelial ovarian cancer. Methods: In this phase II, randomized, parallel study, patients with FIGO stage IC-IV epithelial ovarian cancer after debulking surgery received intravenously Genexol-PM 260 mg/m2 or Genexol 175 mg/m2 combined with carboplatin iv (AUC 5) on day 1 of every 3-week cycle for a maximum of six cycles. The primary endpoint was composite response by GCIG CA-125 Response and Response Evaluation Criteria In Solid Tumors (RECIST). Secondary and exploratory endpoints included overall survival, progressionfree survival, time to tumor progression, and safety and tolerability. Results: A total of 102 patients were randomized to Genexol-PM plus carboplatin (n ⫽ 51) or Genexol plus carboplatin (n ⫽ 51). Composite response rate in patients with or without measurable disease was 88.0% in the Genexol-PM plus carboplatin group and 77.1% in the Genexol plus carboplatin group. Noninferiority of Genexol-PM plus carboplatin compared with Genexol plus carboplatin was confirmed for composite response rate by CA-125/RECIST criteria. There were no differences in progression-free survival and overall tumor progression between the groups. Although there was a higher rate of grade 3 neutropenia in the Genexol-PM plus carboplatin group, the overall rate of hemodynamic adverse events was comparable between the 2 groups. There was no difference in peripheral neuropathy and hypersensitivity. No unexpected safety concerns were identified in this study. Conclusions: High-dose of Genexol-PM in combination with carboplatin was well tolerated, and its response rate was noninferior to that of Genexol plus carboplatin in patients with advanced epithelial ovarian cancer. Clinical trial information: NCT01276548.

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Expression III: What do primary and recurrent ovarian cancer (OC) patients expect from their doctors and therapy management? Results of a survey in eight European countries with 1,743 patients (NOGGO/ENGOT-OV9 study). Presenting Author: Gülten Oskay-Özcelik, NOOGO, Berlin, Germany Background: The primary aim of this study was to investigate information needs and preferences among patients with ovarian cancer, focusing especially on doctor-patient relationships and therapy management in different European countries. Methods: A questionnaire was developed based on the experiences of expression II, a German survey, and then provided to primary and recurrent ovarian cancer patients via internet (online) or as a print-version in 8 countries in Europe (Austria, Belgium, France, Germany, Italy, Poland, Rumania, Spain). In the first part basic data (age, tumour status, therapy) were requested from the patient. In the second part, most of the questions tried to evaluate the expectations and needs concerning their therapy management and doctor-patient communication. Results: From December 2009 to October 2012, a total of 1743 patients with ovarian cancer from 8 European countries participated in the survey.The median age was 58 years (range 16-89). Nearly all patients (96,3%) had a primary surgery and a first-line chemotherapy (91,5%). About 423 (25,7%) patients were included in another clinical trial.Most of the patients in each country were pleased with the completeness and understandability of the explanations about the therapies from their doctors. About 68% of patients would be interested in having the opportunity to have a second opinion. The three most important aspects, which were proposed by patients to improve therapy against ovarian cancer were: “the therapy should not induce alopecia” (42%), “there must be more done to counter fatigue” (34%), and “the therapy should be more effective” (29%). Conclusions: This study underlines the high need of ovarian cancer patients to discuss all details concerning treatment options and clinical management with only minor difference between the countries. Patients also need more information about side effects of cancer therapies and second opinion opportunities. Besides effectiveness of therapy, alopecia and fatigue are the most important side effects bothering the patients.

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Venous thromboembolism in advanced ovarian cancer patients undergoing front-line adjuvant chemotherapy. Presenting Author: Alok Pant, Northwestern University, Chicago, IL

Chemotherapy-induced myelosuppression in ovarian cancer patients with germline BRCA1/2 mutations: A case control study. Presenting Author: Alan Christie, Western General Hospital, Edinburgh, United Kingdom

Background: To define the incidence and prognostic significance of venous thromboembolism (VTE) in patients with advanced, epithelial ovarian cancer undergoing front-line adjuvant chemotherapy after extended period (28 day) post-operative prophylaxis. Methods: A retrospective analysis of patients with advanced, epithelial ovarian cancer who underwent surgery and chemotherapy at a single institution from January 2008 through December 2011 was performed. Exclusion criteria were prior history of VTE, VTE during the post-operative period, clear cell histology, use of anti-coagulation for a different indication, and lack of compliance with 28 days of post-operative prophylaxis with a low molecular weight heparin. Results: 128 patients met criteria for inclusion. Sixteen patients had a reported VTE during the time they were on front line chemotherapy (12.5%). Nine patients (7%) had a pulmonary embolus (PE) and 8 (6.3%) had a deep vein thrombus (DVT). The average BMI in the group that developed VTE was 28 and in the group without VTE was 26.5 (p ⫽ 0.23). Three out of 16 (23%) patients who developed VTE had undergone a suboptimal cytoreduction compared to 12/112 (11%) in the group with no VTE (p ⫽ 0.4). Six of the 16 (37%) patients who developed VTE during chemotherapy underwent a bowel resection and/or splenectomy during their cytoreductive surgery compared to 18 of 112 (16%) patients who did not develop VTE (p⫽0.079). Eight of the patients in the VTE group had indwelling venous catheters during chemotherapy (50%) compared to 39 (35%) in the group with no VTE (p ⫽ 0.27). In the group that developed VTE, there was a trend towards increased pre-operative CA-125, higher rates of bowel resection and/or splenectomy during surgery, decreased use of aspirin, and inferior survival. On multivariate analysis, patients who developed VTE had significantly longer post-operative hospital stays (7 vs 5 days [p ⫽ 0.009]) and lower rates of complete response (p ⫽ 0.01). Conclusions: A 12.5% risk of VTE merits consideration of prophylaxis during chemotherapy in this cohort. A randomized, controlled trial is needed to clarify whether the benefits of long term prophylaxis outweigh the risks and costs of such therapy.

Background: Ovarian cancer patients with germline BRCA1 or BRCA2 (gBRCA1/2) mutations frequently respond to multiple lines of chemotherapy. Having noticed significant myelosuppression during chemotherapy in gBRCA1/2 patients we wished to determine whether this was a chance finding or related to a heterozygous gene dosage effect in the bone marrow. Methods: gBRCA1/2 ovarian cancer patients from Edinburgh, Glasgow and Dundee were identified and matched for chemotherapy regimen, dose and age to controls from the Edinburgh Ovarian Cancer Database. Case notes and transfusion service records were analysed for chemotherapy details, haematology results, G-CSF use, red cell and platelet transfusions during first line chemotherapy. Results: Of 91 gBRCA1/2 patients, 35 patients were excluded who had previously received cytotoxic chemotherapy (mostly for breast cancer) or unusual chemotherapy regimens unable to be matched to controls. 56 were matched to controls. Baseline haematological indices were similar. There was a significant difference in the fall in haemoglobin levels from baseline to cycle 4 in gBRCA1/2 patients compared to controls (12.23% v 5.14%, p ⫽ 0.0005) and gBRCA1/2 patients had longer delays during their chemotherapy (mean 7.73 v 4.51 days, p ⫽ 0.0375) and more dose reductions for haemotoxicity (14 v 4 p ⫽ 0.0011). gBRCA1/2 were more likely to have a red cell transfusion (19 v 11, p ⫽ 0.099), and received more red cells (69 v 31 units, p ⫽ 0.0318). G-CSF was required in 3 BRCA patients versus 0 controls. Differences in platelet and white cell counts at cycle 4 were not significant. Conclusions: Patients with ovarian cancer and germline BRCA1/2 mutations were more likely to have significant falls in haemoglobin levels and require red cell transfusions and to experience delays during chemotherapy. This susceptibility to anaemia may be a hemizygous BRCA1/2 gene dosage effect manifest in the bone marrow and may have implications for the optimisation of cytotoxic and PARP inhibitor therapy in this patient group.


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Adverse event profile by therapy cycle for vintafolide plus pegylated liposomal doxorubicin (PLD) versus PLD alone in platinum-resistant ovarian cancer. Presenting Author: James Thomas Symanowski, Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC Background: Vintafolide (EC145), a folic acid/desacetylvinblastine conjugate, binds with high affinity to folate receptors expressed in epithelial ovarian cancers. This analysis evaluated the incidence of adverse events (AEs) by treatment cycle and as a percent of total treatment cycles administered in the PRECEDENT trial, a randomized open-label study of subjects with platinum-resistant ovarian cancer receiving either vintafolide⫹PLD or PLD alone. Methods: Women ⱖ18 years old with ECOG status 0-2 and exposure to ⱕ2 prior systemic cytotoxic regimens were randomized 2:1 to vintafolide (2.5 mg IV tiw, weeks 1 and 3, q28 days)⫹PLD (50 mg/m2 IV day 1, q28 days) or PLD alone (same dose ⫹ schedule). AEs in the safety population (received at least 1 dose of study drug) were evaluated by cycle. Results: 157 patients received a total of 720 treatment cycles (518 vintafolide⫹PLD, 202 PLD alone). AEs (all grades, vintafolide⫹PLD vs PLD alone): 85.9% and 80.2% of cycles. Anemia, neutropenia, and thrombocytopenia were observed in 16.6% (vs 10.4% administered PLD alone), 19.1% (vs 10.4%), and 2.7% (vs 3.0%) of all cycles, respectively. Febrile neutropenia was observed in 0.2% (vs 0.5%) of cycles, respectively. Stomatitis and hand-foot syndrome (HFS) occurred in 16.6% (vs 22.8%) and 19.1% (vs 15.8%) of cycles, respectively. Peripheral sensory, motor, or sensorimotor neuropathy or polyneuropathy occurred in 10.1% (vs 2.5%) of cycles, and constipation and small intestinal obstruction/ileus were observed in 12.7% (vs 10.4%) and 2.9% (vs 4.0%) of cycles, respectively. Fatigue was similar between arms— 15.8% of vintafolide⫹PLD vs 14.9% of PLD cycles. All AEs were noncumulative except for HFS, which for both arms increased in frequency through Cycle 6 compared with Cycles 1 and 2. Grade 3/4 AEs (vintafolide⫹PLD vs PLD alone): 29.3% vs 18.3% of cycles. Conclusions: After the number of treatment cycles was accounted for, anemia, neutropenia, and neuropathy were numerically greater in patients on vintafolide⫹PLD. Thrombocytopenia, constipation, small intestinal obstruction/ileus, fatigue, and HFS were similar. Stomatitis was numerically greater in patients administered PLD alone. Clinical trial information: NCT00722592.

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␥-synuclein expression in ovarian cancer. Presenting Author: Kristina Mori, Department of Obstetrics and Gynecology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL Background: ␥-synuclein (SNCG) expression is associated with advanced disease and chemo-resistance in multiple solid tumors. Our goal was to determine if SNCG expression in ovarian cancer was correlated with clinicopathologic variables and patient outcomes. Methods: Tissue microarrays from primary tumors of 358 ovarian, fallopian tube, and primary peritoneal cancer patients, who underwent primary surgery at Roswell Park Cancer Institute between 1995 and 2007 were constructed and stained for SNCG. A blinded pathologist scored tumors as positive if ⱖ10% of the sample stained. Medical records were reviewed for clinicopathologic and demographic variables. Between the positive and negative groups, Wilcoxon rank-sum test was used to compare the median ages and Fisher’s exact test was used to compare groups in categorical variables. Cox proportional hazard models were used to determine associations between SNCG and overall (OS) and progression-free survival (PFS). Results: The median follow-up was 36 months, median OS was 39 months, and median PFS was 18 months. SNCG presence was significant in patients with serous histology, grade 3 disease, suboptimal debulking, ascites at surgery, FIGO stage III-IV cancer, or initial CA-125 level ⬎485. There was no significant difference in OS (HR 1.06 95% CI 0.81-1.39 P 0.69) or PFS (HR 1.16 95% CI 0.89-1.50 P 0.28) for patients with SNCG expression. Conclusions: SNCG expression in ovarian cancer is more frequent in patients with high-risk features, but it does not correlate with chemotherapy response, OS, or PFS. SNCG expression FT (Nⴝ2) 2 (100.0%) Non-serous(Nⴝ88) 38 (43.2%) Optimal (Nⴝ245) 169 (69.0%) Grade 1/2 (Nⴝ 23) 11 (47.8%) FIGO stage I/II (Nⴝ64) 30 (46.9%) No Ascites (Nⴝ73) 44 (60.3%) CA 125 < 485 (Nⴝ141) 93 (66.0%) No recurrence (Nⴝ64) 40 (62.5%) Alive (Nⴝ89) 60 (67.4%) Optimal Disease/progression (Nⴝ63) 50 (79.4%) Suboptimal Disease/progression (Nⴝ21) 19 (90.5%)

Ovarian (N⫽ 300) PP (N ⫽ 53) 219 (73.0%) 34 (64.2%) Serous (N⫽212) 181 (85.4%) Suboptimal (N⫽ 52) 46 (88.5%) Grade 3 (N⫽240) 177 (73.8%) FIGO stage III/IV (N⫽274) 215 (78.5%) Ascites (N⫽178) 136 (76.4%) CA 125 ⬎ 485 (N⫽124) 98 (79.0%) Recurrence (N⫽131) 217 (74.1%) Dead (N⫽268) 197 (73.5%)

P value 0.28 ⬍ 0.0001 0.004 0.01 ⬍0.0001

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A panel of biomarkers to improve specificity in presurgical assessment of adnexal masses for risk of ovarian malignancy. Presenting Author: Zhen Zhang, The Johns Hopkins University, School of Medicine, Baltimore, MD Background: OVA1 is a panel of biomarkers cleared by FDA currently in clinical use for pre-surgical assessment of adnexal masses for risk of ovarian malignancy. To further improve the specificity of OVA1, we evaluated biomarkers using a designed set of clinical samples enriched with OVA1 false positive benign patients and selected insulin-like growth factor binding protein 2 (IGFBP2), interleukin 6 (IL6), and folliclestimulating hormone (FSH) to be further evaluated along with the original five biomarkers of OVA1 on a prospectively collected clinical sample set. The inclusion of FSH was to eliminate the need for menopause-specific cutoffs. Methods: Consecutive patients with a documented pelvic mass planned for surgical intervention were prospectively enrolled at 27 sites. Exclusion criteria included a diagnosis of malignancy in the previous 5 years or initial enrollment by a gynecologic oncologist. At the time of analysis, 384 subjects had all biomarker values. Among them 69 were ovarian cancer cases (13 LMPs, 27 stages 1/2, 19 serous, 11 endometrioid , 5 mucinous, and 4 clear cell). Biomarkers were tested by ELISA and reported as continuous values. Using a subset of the samples, the biomarkers were first selected for inclusion in a final panel based on contributions in multivariate models estimated by bootstrap. The selected biomarkers were further assessed for ability to improve specificity of risk stratification at a fixed sensitivity over that of OVA1 using the full data set. This was done by cross-validation of multivariate models with 50/50 split between training and testing. Results: The final panel of biomarkers consisted of CA125II, prealbumin, IGFBP2, IL6, and FSH. At a fixed sensitivity of 90%, the mean and median specificity of models using the new panel in testing were 78.2% (95% CI: 76.7 – 79.8%), and 80.6%, respectively. The mean and median absolute improvements over that of OVA1 were 18.6% (95% CI: 16.4% – 20.9%) and 20.3%, respectively. Conclusions: The new panel demonstrated the potential to significantly improve specificity over that of the first-generation OVA1 algorithm, while maintaining a high sensitivity in pre-surgical assessment of adnexal masses for risk of malignancy.

5575


Serum mass spectrometry analysis in primary ovarian cancer (OC) treated with surgery and adjuvant chemotherapy (CT). Presenting Author: Heinrich Roder, Biodesix Inc., Boulder, CO Background: To address the unmet need for non-invasive tests to predict outcomes in OC we investigated the effect of the serum test, VeriStrat (VS), in independent cohorts of OC patients (pts) who were treated with platinum based chemotherapy following surgery. VS assigns “Good” (VSG) and “Poor” (VSP) classifications and has been shown to be prognostic in various tumor types and predictive for certain treatments. Methods: Samples from primary OC pts from the University Hospital, Essen (ESSEN), N⫽ 108, and from OVCAD consortium (Berlin, Leuven, Hamburg, Vienna), N ⫽ 138, were obtained within 1 week before surgery that was followed by platinumbased CT. VS testing was done blinded to clinical data. Overall survival (OS) was analyzed by Kaplan-Meier method and compared using log-rank p-values. Cox models were used in multivariate analysis. Associations with categorical variables were analyzed by Fisher’s exact test. Results: The cohorts had similar distribution of VSG/VSP classification: 73% VSG (ESSEN), 71% VSG (OVCAD). The distribution by histology (non-serous/ serous), and nodal status were different (p ⫽ 0.003 and p ⫽ 0.049). The results for OS in all pts (ALL), in pts with tumor (and/or metastases) present post-surgery (TPPS-pos), and in pts with complete resection and no metastases (TPPS-neg) are presented in the Table. VS was not associated with circulating tumor cells (ESSEN, p⫽0.736). In a Cox model analysis for TPPS-pos groups VS was independently significant (p⫽ 0.016, ESSEN) or trended to significance (p⫽0.063, OVCAD). Conclusions: VS demonstrated similar results in two independent cohorts; in ALL and TPPS-pos populations it significantly correlated with OS in ESSEN, showed same trends in OVCAD, and was not correlated with OS in TTPS-neg pts. While requiring further investigation, VS may provide useful prognostic information.

0.01

Cohort

0.02

Pts

0.07

ALL

0.28

NED (N⫽130) 89 (68.5%)

0.13

NED (N⫽21) 18 (85.7%)

0.99

Test

VSG VSP TPPS-pos VSG VSP TPPS-neg VSG VSP

ESSEN

N

OS median, months

80 28 23 10 42 8

50 21 23 10 NR* NR


OVCAD p

N

0.36 (0.20-0.66) ⬍0.001 138 50 0.37 (0.18-0.76) 0.004 52 21 0.90 (0.19-4.20) 0.894 60 15

OS median, month NR 43 36 27 NR NR


p

0.66 (0.42-1.04) 0.074 0.60 (0.34-1.08) 0.085 0.83 (0.30-2.29) 0.719

* NR⫽ not reached.




5577


Statin and aspirin use and risk of VTEs in ovarian cancer patients. Presenting Author: Hedy S Rennert, CHS National Israeli Cancer Control Center, Haifa, Israel

Utilizing propensity scores to determine the risk of recurrence and death in epithelial ovarian cancer. Presenting Author: Lindsay Louise Morgenstern Warner, Mayo Medical School, Rochester, MN

Background: Deep vein thrombosis and pulmonary embolism - venous thromboembolic events (VTEs) - are associated with significant morbidity and increased risk of mortality in cancer patients. Ovarian cancer patients are at a particularly increased risk for VTEs. Statins and aspirin have been shown to reduce the risk of VTEs in the general population in randomized trials. However, the effect of these medications on the incidence of VTEs in ovarian cancer patients has not been studied. Methods: Patients diagnosed with ovarian cancer between years 2000 and 2011 were identified through the Israeli Cancer Registry (ICR). Patients insured by Clalit Health Services, the largest HMO in Israel, were included. Data regarding medication use, chronic diseases and VTE diagnosis were extracted from the computerized database. Patients taking Warfarin or Low Molecular Weight Heparin for 3 months or longer were excluded. Statistical analysis was performed using SPSS (v 18). Use of medications was analyzed as a time dependent covariate in a Cox regression model. Results: Of 1,886 patients 179 (9.5%) had a VTE during a median follow up of 3.13 years. 95 patients (5%) had a VTE 2 years after diagnosis of ovarian cancer. In a multivariate analysis use of chemotherapy and stage 3 or 4 at presentation were associated with an increased risk for VTE’s 2 years after diagnosis. Age was associated with a trend for increased risk. Statins were used by 43.2% of the patients, and 31.9% used aspirin. Aspirin use was associated with a reduced incidence of a VTE, which was borderline statistically significant (p⫽0.054). Statin use did not affect the incidence of VTE’s in the group of ovarian carcinoma patients. Conclusions: Our results suggest that in patients with ovarian cancer aspirin use is a possible protector from deep vein thrombosis and pulmonary embolism. Prospective trials are warranted to assess the benefit of aspirin and statins for prevention of VTE’s in the high risk population of ovarian cancer patients.

Background: Perioperative red blood cell transfusion (PRBCT) may be a negative prognostic marker in surgical oncology. We assessed PRBCT as an independent risk factor for recurrence and death from epithelial ovarian cancer (EOC) in the largest cohort to date. Methods: Patient characteristics and process-of-care variables (NSQIP-defined, ⬎130 variables) were retrospectively abstracted from 587 women who underwent primary staging and cytoreduction for EOC (1/1/03-12/29/08). Evaluated using propensity scoring with univariate logistic regression and odds ratios (OR) and Cox proportional hazards regression and hazard ratios (HR). Factors with p⬍0.1 used in multivariate models. Results: Rate of PRBCT was 77.0% (452/ 587). In univariable analysis, PRBCT was associated with older age (OR 1.25[95% CI 1.06, 1.48]/10yr increase), stageⱖIIIa (4.66[3.04, 7.13]), splenectomy (26.63[3.67, 193.17]), higher surgical complexity (1.86[1.17, 2.95] score 2; 21.48 [7.37, 62.59] 3; referent 1), serous histology (2.36[1.57, 3.55]vs non-serous), longer operating time (1.58[1.36, 1.83]/hr increase), and residual disease (3.26[1.97, 5.41]ⱕ1cm; 1.97[1.09, 3.56]⬎1cm), and lower preop hemoglobin (Hb) (1.89[1.59, 2.27]per 1g/dL decrease). In univariable analysis, PRBCT was associated with a higher risk of recurrence (HR 1.96[95% CI 1.43, 2.68]) and death (1.71[1.28, 2.28]). However, in multivariable analysis, stageⱖIIIa (4.03[2.05, 6.49]), splenectomy (1.41[1.02, 1.95]), residual disease (1.86[1.41, 2.46]ⱕ1cm; 2.91[2.02, 4.18]⬎1cm), and lower preop Hb (1.09[1.01, 1.19]) were associated with higher risk of recurrence. Older age (1.24[1.12, 1.37]), stageⱖIIIa (3.07[1.93, 4.90]), albumin ⱕ3 g/dL (2.06[1.28, 3.31]), residual disease (1.63[1.22, 2.19]ⱕ1cm; 3.03[2.19, 4.18]⬎1cm), and low Hb (1.08[1.00, 1.19]) were associated with higher risk of death. Serous histology (0.70[0.52, 0.95]) associated with lower risk of death. Conclusions: PRBCT does not appear to be directly associated with disease-free and overall survival in EOC. Lower preoperative Hb was associated with a higher risk of both recurrence and death. The need for PRBCT appears to be a stronger prognostic indicator than the receipt of PRBCT.

Variable Aspirin Statins Chemotherapy Stage 3 or 4 Age Comorbidity index

5578

HR

P value

95% CI

0.49 1.42 3.33 2.8 1.017 1.096

0.054 0.159 ⬍0.001 0.047 0.154 0.641

0.182- 1.0130 0.871 – 2.3310 2.052 – 5.402 1.012 – 7.744 0.994 – 1.0410 0.744 – 1.615


Inhibition of gamma-secretase activity in combination with paclitaxel to reduce platinum-resistant ovarian tumor growth. Presenting Author: Jolijn W Groeneweg, Massachusetts General Hospital, Boston, MA Background: Ovarian cancer (OvCa) is the most lethal gynecologic malignancy in the United States. Chemotherapy is effective but seldom curative, mainly due to the development of chemoresistant recurrent disease. Our current research investigates the efficacy of inhibiting the Notch pathway with a gamma-secretase inhibitor (GSI), MRK-003, in an OvCa xenograft model as a single agent therapy and in combination with standard chemotherapy. Methods: Mice bearing xenografts derived from clinically platinum sensitive human ovarian serous carcinomas were treated with GSI or vehicle, or with either vehicle, GSI alone, paclitaxel and carboplatinum (T/C) alone, or the combination of GSI and T/C. In addition, mice bearing xenografts derived from patients with clinically platinum resistant disease were given GSI with or without paclitaxel. Gene transcript levels of several factors in the Notch pathway were analyzed using RT-PCR. Notch1 and Notch3 protein levels were evaluated by western blotting. The Wilcoxon rank-sum test was used to assess significance between the different treatment groups. Results: Expression of Notch1 and Notch3 was highly variable across all analyzed OvCa samples. Treatment with GSI alone significantly decreased tumor growth in 3 of 4 platinum sensitive ovarian tumors (all p ⬍ 0.05), as well as in 1 of 3 platinum resistant tumors (p ⫽ 0.04). Furthermore, the combination of GSI and paclitaxel was significantly more effective than GSI alone and paclitaxel alone in all platinum resistant ovarian tumors (all p ⬍ 0.05). The addition of GSI did not alter the effect of T/C in platinum sensitive tumors. Although the response of each tumor to GSI did not correlate with its endogenous level of Notch expression, 2 of the 3 tumors resistant to paclitaxel but sensitive to the combination of GSI and paclitaxel showed elevated Notch activity by RT-PCR. Conclusions: Inhibition of the Notch signaling cascade with a gamma-secretase inhibitor reduces tumor growth in vivo, most notably in combination with paclitaxel in a platinum resistant setting. These promising findings underscore the need for further investigation of the preclinical and clinical effectiveness of Notch inhibitors in OvCa.

5579


Expression of glucose-regulated protein 78 (GRP78) and its regulator microrna-181 during the development and progression of ovarian cancer. Presenting Author: Animesh Barua, Rush University Medical Center, Chicago, IL Background: Ovarian cancer (OVCA) is a lethal malignancy of women with a distinct pattern of metastasis through peritoneal dissemination. Sustained exposure of the ovaries to oxidative stress due to inflammatory processes including ovulatory genotoxicity, makes the ovarian microenvironment conducive to malignant cell proliferation. GRP78 is a stress-inducible protein which resides in the endoplasmic reticulum of the cell. Thus GRP78 may be a marker of ovarian tumor associated stress and could represent a therapeutic target for OVCA. The goal of this study was to examine if GRP78 expression increases in association with OVCA development and determine the molecular mechanism of its increase in ovarian tumors. Methods: All tissues were collected from patients who underwent surgery and processed for immunohistochemistry (IHC), proteomic study (2D-WB) and miRNA expression. Expression of GRP78 was examined in paraffin sections of normal ovaries (n ⫽ 20), benign (serous cystadenoma, n ⫽ 15 and cystadenofibroma, n ⫽ 5) and ovaries with papillary serous carcinoma at early stage (n⫽ 20 at stages I and II) and late stage (n ⫽ 20, stages III and IV) by IHC and confirmed by 2D-WB (representative samples). Changes in miRNA-181 (post-translation regulator of GRP78) expression were examined by qRT-PCR. Results: GRP78 expression by normal ovarian surface epithelium and epithelium of benign tumors was very weak. In contrast, the intensity of GRP78 expression was significantly (p⬍0.05) high in early stage OVCA and increased further in late stage OVCA. An immunoreactive band of 78kDa detected by 2D-WB confirmed IHC observations. In contrast, expression of miRNA-181 by malignant tumors significantly (p⬍0.05) decreased as the tumor progressed to late stages. Conclusions: The results of the present study suggest that GRP78 expression is associated with the development and progression of malignant ovarian tumors. Increase in GRP78 expression was associated with the down-regulation of miRNA-181. Expression of GRP78 by malignant ovarian epithelium represents a potential marker with usefulness for targeted drug delivery. Support: Elmer and Sylvia Sramek Foundation.


354s 5580


Benefits of neoadjuvant chemotherapy in ovarian, primary peritoneal, or fallopian tube carcinoma. Presenting Author: Alaina J. Brown, The University of Texas MD Anderson Cancer Center, Houston, TX

5581


Changes in renal function following treatment for ovarian cancer. Presenting Author: Matthew James Butler, Geisinger Medical Center, Danville, PA

Background: NCCN guidelines recommend consideration of neoadjuvant chemotherapy (NACT) for poor surgical candidates with bulky stage III or IV ovarian, fallopian tube, or primary peritoneal cancer. However, new convincing evidence favoring NACT instead of primary tumor reductive surgery (PTRS) has resulted in shifting practices among gynecologic oncologists. This study compares operative and post-operative outcomes between patients receiving NACT and those undergoing PTRS. Methods: After IRB approval, patients who received NACT or PTRS were identified through the tumor registry and surgical database at a single institution from 2008-2012. Statistical analyses included Wilcoxon Mann-Whitney, Chi square and Fisher’s exact test. Results: Of 163 patients, 109 (67%) received NACT and 54 (33%) underwent PTRS. The majority in both groups was Caucasian (82%) and had ovarian cancer (85%). The median age of all patients was 62 years. There was no difference in median age between groups. High-grade serous histology was most common. In the PTRS group, 72% were stage IIIC. During cytoreductive surgery, NACT cases had significantly shorter total operative and anesthesia time compared to PTRS cases (p ⫽ 0.005). NACT patients had significantly less blood loss (p⫽0.002) than PTRS patients. Based on available data, there was no difference in intraoperative transfusion rate (p ⫽ 0.098). However, PTRS cases had a higher rate of postoperative transfusion compared to NACT cases (p ⫽ 0.043). There was no difference in the proportion of optimal surgical cytoreduction between groups (p ⫽ 0.422). Available data demonstrated that PTRS patients had significantly more complications and intensive care unit (ICU) admissions compared to those receiving NACT (p ⫽ 0.024, p ⫽ 0.002 respectively). Conclusions: NACT offers advantages regarding operative and anesthesia time, blood loss, postoperative complications, and ICU admissions. NACT may offer a valuable alternative to PTRS. Further studies are warranted to better define the role of NACT in the upfront treatment of advanced ovarian cancer.

Background: Among women treated for Epithelial Ovarian Cancer (EOC), new or worsening renal dysfunction has been observed but not systematically studied. We conducted a retrospective cohort study to estimate the rate of decline in renal function following a diagnosis of EOC, compared with the rate of decline among the same patients prior to diagnosis. Methods: We study a historical cohort of women diagnosed with EOC between 1/1/2000 and 12/31/2011, who received health care services within a large community medical center. Data were retrieved from institutional electronic records. We develop a Generalized Estimating Equations (GEE) model to quantify changes in estimated glomerular filtration rate (eGFR) over time, with the date of EOC diagnosis as the reference point (time zero). All analyses were conducted using SAS version 9.2 (SAS Institute Inc., Carey, NC). Results: The cohort is comprised of of 323 women. At diagnosis, the mean age was 63.4 (⫾ 13.5) years and the mean eGFR was 81.0 (⫾ 22.7). There were 74 (22.9%) patients carrying a diagnosis of hypertension, 25 (7.7%) with diabetes, and 73 (22.6%) who were clinical obese. Prior to EOC diagnosis the decline in mean monthly eGFR was not significant (- 0.052, 95% CI -0.11-0.009, p ⫽ 0.092), after controlling for age, obesity, hypertension, and diabetes. This monthly decline increased by almost 4-fold (p ⫽ 0.0007) subsequent to EOC diagnosis. To discern the potential effect of chemotherapy on renal function, we conducted a secondary analysis on the 120 women for whom detailed chemotherapeutic data is available. For women who received standard first-line chemotherapy (paclitaxel and carboplatin) the rate of eGFR decline increased 10-fold (-0.025 vs. -0.25, p ⫽ .0066) relative to their baseline rate of decline. For those who received other regimens, the increase was 11.4 times (-0.025 vs. -0.286, p ⫽.0011); this was not significantly higher than those receiving the standard regimen (p ⫽ 0.72). Conclusions: This ongoing study suggests that women treated for EOC suffer an accelerated rate of renal function decline, independent of major comorbid conditions, that is therefore attributable to the disease and/or its treatment.

5582

5583


Results of a phase II clinical trial to evaluate a re-challenge of intraperitoneal catumaxomab for treatment of malignant ascites (MA) due to epithelial cancer (SECIMAS). Presenting Author: Klaus Pietzner, CharitéUniversitätsmedizin Berlin, Berlin, Germany Background: Catumaxomab is approved in Europe for the i.p. treatment of MA. With a growing number of patients (pts) treated, the question arises, if a re-challenge is feasible and effective despite the immunogenicity of this non-humanised antibody. Methods: Pts were eligible if they received 4 i.p. applications of catumaxomab in the CASIMAS study and benefitted with a puncture free interval of ⬎ 60 days. Primary endpoint was to determine the proportion of pts who were able to receive at least 3 catumaxomab applications. Secondary endpoints were the development of human antidrug antibodies (ADA) as well as the safety profile of a second catumaxomab cycle including a composite safety score (CSS) summarizing the worst CTCAE grades for the main adverse reactions (pyrexia, nausea, vomiting, abdominal pain). Efficacy endpoints were time to puncture (TTPu), overall survival (OS) and puncture-free survival (PuFS). Results: Median age was 59.0 years. 8 out of 9 screened pts were treated with a second cycle of catumaxomab. The primary tumor was ovarian cancer in 5 (62.5%), breast cancer in 2 (25%) and urachal cancer in 1 (12.5%) pts. All 8 (100%) pts received all 4 infusions within 20 days. Median CSS was 3.0 after the second cycle while it was 3.4 after the first cycle in the CASIMAS study for these 8 pts. Only less pts had AEs with CTC ⬎3 (SECIMAS 25%; CASIMAS 70.1%). All 8 (100%) pts were ADA-positive at study entry. ADA levels were consistently higher in the plasma than in the ascites fluid. During treatment, highest ADA values were found on day 10 for ascites and day 11 for plasma up to values of ⬎ 1 mg/ml. PuFS was 47.5 days and TTPu 60 days after the second cycle, and 37 days and 102 days, respectively after the first cycle. Median OS was 406.5. Conclusions: This first experience with a re-challenge of catumaxomab in MA, demonstrates a tolerable safety profile without acute allergic reactions, in spite of the high immunogenicity of catumaxomab and the repeated application. Efficacy was not impaired despite ADA response and the advanced disease of the pts. A re-challenge seems feasible for selected pts suffering from recurrent MA after a first cycle of catumaxomab. Clinical trial information: NCT01065246.


Frequently deleted genes in ovarian cancer as indicators of platinum response. Presenting Author: Scooter Willis, The Edith Sanford Breast Cancer Research Institute, Sioux Falls, SD Background: Integrating chromosomal deletions/amplifications with sequencing alterations is increasingly important in the determination of key drivers of outcome in cancer (Leary 2008, Curtis 2012). We introduce a novel computational approach, Gene Set Outcome Analysis, to determine gene signatures constrained to regions with frequent deletion or amplification events in ovarian cancer identified by TCGA. Differential expressions of mRNA from these genes are used as a proxy for loss of function from deletions or amplifications. Methods: Gene signatures from each region were evaluated using log-rank test comparing high and low gene expression groups split by cohort mean. In total, 30,119,708 signatures constrained to 47 deleted and 36 amplified regions were tested for PFS for first line platinum treatment in a random 2/3 split of TCGA ovarian cohort (n⫽262) resulting in 26,271 gene signatures with p ⬍ .001. The remaining 1/3 cohort (n⫽135) and full cohort (n⫽397) were used as a replication study where 111 signatures have a p ⬍ .01 located in 2 deletion and 1 amplification region. The signature with the lowest p-value from each region that validated in the replication study, were evaluated in GSE9891 (n⫽179) (Tothill 2008) for PFS when treated with platinum and taxol resulting in gene signatures from 2 deletion regions with p⬍.05. Results: Greater than mean expression in this gene signature [OXTR, SATB1, WNT7A, SH3BP5, CRBN, ATG7, CRELD1, TMEM43] located at 3p23p26.2 predicts poor response to platinum chemotherapy in TCGA full ovarian cohort (17.9 vs 14 months p ⫽ 1.4E-7) and validates in GSE9891 (19.6 vs 13.3 months p ⫽ .014). Using a separate, compact gene signature [CAAP1, LRRC19, IFNA8] located at 9p21.2, samples with lower than mean expression demonstrate increased platinum sensitivity in TCGA full ovarian cohort (12.2 vs 18.2 months p ⫽ 1.0E-6) and in GSE9891 (15.5 vs 18.6 p ⫽ .055). Conclusions: Response to platinum therapy is an important predictor of survival in high-risk ovarian cancer patients. These signatures arising from common deletion and amplification events in ovarian cancer can anticipate platinum sensitivity and merits further study for use in choosing optimal therapies studying platinum resistance mechanisms.




5585


Pathologic distribution of disease at the time of interval debulking versus primary tumor reduction in women with primary peritoneal, ovarian, or Fallopian tube carcinoma. Presenting Author: Tarrik M. Zaid, The University of Texas MD Anderson Cancer Center, Houston, TX

Multimodal therapy in patients with node-positive (stage IIIC) uterine papillary serous carcinoma: A National Cancer Database study. Presenting Author: Jeff Feng-Hsu Lin, Magee-Womens Hospital of the University of Pittsburgh Medical Center, Pittsburgh, PA

Background: The surgical approach for interval debulking after neoadjuvant chemotherapy (NACT) for primary peritoneal, ovarian, or fallopian tube carcinoma has largely been extrapolated from experience with primary tumor reductive surgery (PTRS). It is unknown whether procedures considered mandatory in PTRS, such as hysterectomy, contribute to comparable removal of macroscopic disease in the NACT setting. Our study compared the difference in pathologic distribution of disease at interval debulking surgery versus primary tumor reduction. Methods: After IRB approval, patients who received NACT or PTRS were identified through the tumor registry and surgical database at a single institution from 2008-2012. Involvement of organs at the time of surgery was categorized as either macroscopic, microscopic and no tumor. Statistical analyses included Wilcoxon Mann-Whitney and Fisher’s exact tests. Results: Of the 163 patients identified, 111 (67%) received NACT and 54 (33%) underwent PTRS. Median age was 62 and the majority of patients had stage IIIC high-grade serous carcinoma (91%). Macroscopic ovarian involvement was more common at time of PTRS (92 % vs 63 %, p ⬍0.001). Gross uterine involvement was significantly less in the NACT group compared to PTRS, with the majority of specimens in the NACT group free of disease (Macroscopic 11 % vs 42%, no tumor 62% vs 44 %, p ⬍0.002). However, 27% of the NACT had microscopic uterine serosal disease. Macroscopic large bowel involvement was 50 % in the PTRS vs 26 % in NACT(p⬍0.005). There was no difference in disease involvement of the small bowel or omentum. Conclusions: The pathologic disease distribution at the time of interval tumor debulking is significantly different from that encountered during primary cytoreductive surgery.. NACT appears to reduce macroscopic large bowel and uterine tumor involvement and may negate the need for hysterectomy and/or large bowel resection at the time of interval debulking to achieve no gross residual.

Background: Uterine papillary serous carcinoma (UPSC) is an aggressive endometrial cancer that carries a 30-40% risk of nodal metastasis. Adjuvant systemic chemotherapy has become standard of care in advanced UPSC, but the role of additional adjuvant radiotherapy is unclear. This study aims to evaluate survival outcomes of multimodal therapy through the use of the National Cancer Data Base (NCDB). Methods: All patients diagnosed with surgically-staged FIGO stage IIIC uterine papillary serous carcinoma were identified in the NCDB from 1/1998 through 12/2010. Patients were divided into those who received chemotherapy only (CT) and both chemotherapy and radiation therapy (CT⫹RT). Overall survival was estimated using the Kaplan-Meier method. Univariate comparison by log rank test and multivariable analysis by Cox regression modeling were performed to identify and control for prognostic factors. Results: A total of 13,356 cases of uterine cancer were identified, of which 794 were UPSC. Of these patients, 387 underwent lymphadenectomy (median 14 nodes removed) with 75 patients (median age 65) found to have stage IIIC disease. Median follow up is 20.4 (range: 0-114) months. There were no significant differences were found between the RT and CT⫹RT group with regards to patient demographic, medical comorbidity, treatment facility or disease characteristics. The median overall survival was 23.2 (95% CI 14.5-31.9) and 40.3 (95% CI 31.5-49.1) months, (p⬍0.05) for the CT and CT⫹RT groups, respectively. Multivariate analysis controlling for age, race, income, Charlson-Deyo comorbidity index, treatment facility type, year of diagnosis, number of lymph nodes removed, number of positive lymph nodes and tumor size found radiotherapy independently predicted improved survival [HRdeath0.024 (95% CI 0.001-0.668)]. Conclusions: Patients with stage IIIC UPSC benefit from adjuvant radiotherapy in addition to adjuvant chemotherapy.

5586

5587


Impact of wait times on survival of women with uterine cancer. Presenting Author: Lorraine Elit, NCIC Clinical Trials Group, Hamilton, ON, Canada Background: Reducing cancer wait times have been a priority investment for Cancer Care Ontario since 2005. Our objective was to determine whether wait time from histologic diagnosis of uterine cancer to time of definitive surgery by hysterectomy impacted on all cause survival. Methods: Cases were identified in the Ontario Cancer Registry using ICD-09 codes 179 and 182. Excluded were women without histologic/cytologic confirmation of cancer prior to surgery, with no definitive surgery, or with wait times of ⱕ14 days or ⬎2 years. Survival was calculated using the Kaplan-Meier method from the day of hysterectomy. Factors were evaluated for their prognostic ability on survival using Cox proportional hazards regression. Wait time was evaluated as a continuous variable and dichotomized at selected cutpoints in the univariable analyses and in a multivariable model adjusting for significant patient factors identified using forward stepwise selection. Results: The final study population included 8,744 women. 51.9% had surgery by a gynaecologist and 69.9% had endometrioid adenocarcinoma. The optimal model is shown below. Multivariable analysis of factors prognostic for survival. Longer wait times remained a statistically significant negative prognostic factor for survival regardless of definition, univariably (p⬍0.002) and multivariably after adjusting for other significant factors (p⬍0.001). The final multivariable model is shown. 5-year (95%CI) survival for women with more than 12 week wait times was 61.4 (57.8-64.8)% versus 71.9 (69.9-73.8)% for women with less than 6 week wait time. Conclusions: The longer a woman waits from diagnosis of uterine cancer to definitive surgery negatively impacts her overall survival. Factor

Category

Charlson comorbidity score ⱖ3 versus ⱕ2 Previous cancer diagnosis Yes versus no Multiple cancer diagnoses Yes versus no Histology (reference is unknown) Sarcoma Serous Wait time Log (days)

HR (95% CI)

P value

2.09 (1.91-2.29) 1.13 (1.01-1.27) 2.28 (1.54-3.37) 2.45 (2.03-2.95) 1.54 (1.27-1.86) 1.18 (1.10-1.28)

⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001


Is uterine serous carcinoma a part of hereditary breast cancer syndrome? Presenting Author: Saeed Rafii, University of Birmingham, Birmingham, United Kingdom Background: Whilst the association between breast cancer and uterine serous carcinoma (USC) is attributed to tamoxifen treatment, few studies have reported that this increased risk is independent of tamoxifen. Methods: To further investigate the relationship between breast cancer and USC, we retrospectively studied 216 patients from 5 hospital trusts in Birmingham, UK who were diagnosed with USC between 1993 and 2012. We collected personal history of cancer in these cases before or after USC diagnosis. In addition FIGO staging, clinical and survival data were collected from our local cancer registry and patients’ clinical records. Results: In this case series, 56 patients (25.9%) had personal history of at least one cancer before and 18 patients (8.3%) had history of at least one cancer after the diagnosis of USC. Within the group of patients with the history of cancer before the USC, 38 patients (68%, 17.5% of all cases) had personal history of breast cancer prior to the development of USC, higher than the UK expected age standardised relative incidence of breast cancer (350 in 100,000, CRUK 2006-2008). Although 27/38 cases (71%) had endocrine treatment for their primary breast cancer, 11/38 patients (29%) did not have any tamoxifen treatment due to hormone receptor negative breast cancer. Additionally the median age of breast cancer diagnosis for the hormone receptor negative group was significantly lower than those patients who had hormonal treatment for their breast cancer (56 vs. 64 years, p :0.036) compatible with the younger age at diagnosis expected of the familial (BRCA mutated) or triple negative breast cancer. Of 18 patients with a second cancer after diagnosis of USC, 6 patients (33%) were diagnosed with breast/ovarian cancer. This group also had no treatment with tamoxifen. Conclusions: Lack of exposure to tamoxifen and younger age at diagnosis in this subgroup suggest that other factors such as a common underlying genetic predisposition may be responsible for the development of both malignancies. We propose that at least a subgroup of USC may be a part of hereditary breast cancer syndrome. This may have implications in prevention (prophylactic hysterectomy) or trials of targeted treatments (PARP inhibitors) for a subgroup of USC patients.


356s 5589

Gynecologic Cancer General Poster Session (Board #51E), Mon, 8:00 AM-11:45 AM

High-grade endometrial cancer: Revisiting tumor size and the lower uterine segment. Presenting Author: Kemi M. Doll, The University of North Carolina at Chapel Hill, Lineberger Comprehensive Cancer Center, Chapel HIll, NC

5590


Gene scoring model to predict recurrence in low- and intermediate-risk uterine endometrial cancer: Establishment of uterine print. Presenting Author: Tatsuyuki Chiyoda, Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan

Background: Tumor size is an independent poor prognostic factor in endometrial cancer, while tumor location has shown mixed results, with few studies addressing high-grade disease. We aim to determine if tumor size (TS) or lower uterine segment involvement (LUS) is associated with nodal disease and recurrence in high-grade endometrial cancer. Methods: In an IRB-approved, multi-institutional cohort study of patients with clinically early-stage, high-grade endometrial cancer (grade 3 and all nonendometrioid histologies), records were reviewed for demographic, pathologic, and treatment data. Recurrence as a function of tumor size and location were analyzed using logistic regression and exact tests for significance. Hazard ratios were calculated. Results: 208 patients with high-grade histology were identified from Jan 2005 to Jan 2012 with 188 patients having tumor location identified and 183 having tumor size reported. Both pelvic and para-aortic lymphadenectomy were completed in 100% of patients. There were 75 endometrioid (36.1%), 35 papillary serous (16.8%), 12 clear cell (5.8%), 26 carcinosarcoma (12.5%), and 60 (28.8%) with undifferentiated or mixed histology. Median follow up time was 17.2 months (0.2 – 67.6 mo) with 55 recurrences. LUS tumors were more likely to have pelvic and para-aortic nodal disease (OR 3.83, 95%CI 1.70 – 8.60, OR 5.13, 95% CI 1.96 – 13.45) and increased recurrence rates (HR 2.21, 95% CI 1.16-4.20) on univariate analysis. Tumors size ⱖ2cm was associated with pelvic nodal disease (27.4% vs. 0%, p ⫽ 0.01; OR 10.00, p ⫽ 0.01). TS was not independently associated with recurrence and patterns of failure did not significantly differ with LUS involvement. Conclusions: In patients with clinically early stage, high-grade endometrial cancers, TS and LUS tumor location are significantly associated with lymph node metastasis and advanced stage disease at the time of comprehensive surgical staging. Tumor location in particular is strongly associated with distant nodal disease and is a poor prognostic indicator for recurrence. Studies evaluating the role of adjuvant therapy based on tumor size and tumor location would be helpful in improving patient related outcomes.

Background: Endometrial cancers (ECs) classified as low-, intermediate-, and high-risk, based on clinical and pathological features (CPF: Lurain, 2007) associated with 5%, 15%, and 25% risk of recurrence, respectively. The need for adjuvant chemotherapy in intermediate-risk patients is controversial. We examined whether gene expression profiling can more accurately predict the prognosis of ECs, excluding the CPF-based high-risk group. Methods: Tumor specimens were obtained from 136 ECs including 14 recurrences, excluding high-risk cases. Gene expression profiles were achieved using a custom array consisting of 85 genes associated with EC recurrence and 20 internal controls that were previously screened. We established the gene scoring model (GSM) for recurrence by the logistic regression model in randomly selected 68 ECs including 7 recurrences, and evaluated the accuracy of GSM in other 68 ECs including 7 recurrences. This process was repeated 100 times. We calculated the mean accuracy of GSM and compared it with the accuracy of CPF. We also compared GSM and CPF with respect to progression-free survival (PFS) by use of the log-rank test. Results: Median age of all cases was 58 (29-86) years, and stage, histologic grade, and risk classification based on CPF were as follows: (I, 107; II, 15; III, 14), (G1, 69; G2, 57; G3, 10), and (low, 67; intermediate, 69). The median follow-up period was 1830 (1626-3444) days. The GSM was established based on the expression of 4 genes (PRCC, SPC25, PXDN, and LBXCOR1) and 10 internal controls. The area under the receiver operating characteristic curve of GSM to predict recurrence was 0.87 in 68 test cases. Based on the CPF, 68 cases were classified as 30 low-risk and 38 intermediate-risk, and the sensitivity and specificity of CPF was 86% and 48% each in the 68 test cases. When sensitivity of GSM was fixed at 86%, specificity of 67% was achieved, and 68 cases were classified as 42 risk (-) and 26 risk (⫹). PFS was significantly related with GSM (p ⫽ 0.006); however, it was not related with CPF (p ⫽ 0.09). Conclusions: GSM can predict the prognosis of ECs (low- and intermediaterisk) more precisely than CPF.

5591

5592


Analysis of plasma biomarker and tumor genetic alterations from a phase II trial of lenvatinib in patients with advanced endometrial cancer. Presenting Author: Yasuhiro Funahashi, Eisai Inc., Andover, MA Background: Lenvatinib is an oral receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFR␤. A phase 2 study in patients with advanced endometrial cancer following 1 or 2 prior platinumbased treatments was performed and is presented in a separate abstract. Here we report potential predictive markers of clinical benefit. Methods: Pre- and post-treatment plasma samples collected from 122 of 133 treated subjects were analyzed for 50 circulating cytokine and angiogenic factors (CAFs) using ELISA and multiplex assay platforms; 107 archival tumor tissues obtained from 133 enrolled subjects were analyzed for gene mutation (mut) (81 samples) and gene expression profiling (GEP) (64 samples). For GEP analysis, the NanoString nCounter platform was used to measure the expression level of approximately 300 genes identified preclinically as relevant. Correlation with clinical outcome measures including maximal tumor shrinkage (MTS), objective response rate (ORR), PFS, and OS was performed. Results: Clinical correlation identified baseline levels of 7 CAFs related to angiogenesis (Ang-2, IL-8, HGF, VEGFA, PlGF, Tie-2, and TNFa) that associated with survival. Only baseline levels of Ang-2 associated with greater MTS (R⫽0.36 [Spearman], P⬍0.001), ORR (61% vs 18%), mPFS (9.5 vs 3.7 mos), and mOS (23 vs 8.9 mos) as determined using a defined cut-off value for baseline Ang-2. In gene mut analysis, no significant correlations were observed among the genes tested. Mut in PIK3CA showed a trend toward shorter OS (p ⫽ 0.085). In GEP analysis, expression levels of approximately 90 genes correlated with clinical outcome. Combination of GEP and CAF signatures identified signaling pathways, including Ang-2, that associated with OS. Clinical and preclinical GEP analysis identified overlapping gene signatures involving MAPK and PI3K signaling pathways that contributed to lenvatinib resistance. Conclusions: Baseline circulating Ang-2 levels may potentially predict outcomes in patients with advanced endometrial cancer and require further examination. This may provide a basis for stratification of patients in future clinical trials. Clinical trial information: NCT01111461.


Statin use in uterine malignancies. Presenting Author: Lori Ann Spoozak, Albert Einstein College of Medicine, Bronx, NY Background: Statins, or 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors, are commonly used to manage hyperlipidemia. Epidemiologic studies have recently linked statins to improved cancer survival. Molecular pathways that explain this effect are not well defined, but may involve cell death and angiogenesis. Our aim was to determine the association between statin use and overall survival in a cohort of women with uterine malignancies. Methods: After IRB approval, a retrospective review of consecutive patients with uterine malignancies diagnosed between 01/2005 and 12/2009 at a single institution was performed. Age, race, diagnosis of hyperlipidemia, diabetes, hypertension, medication use including statins, beta-blockers, aspirin, pathology, and exposure to chemotherapy or radiation were abstracted from the time of initial diagnosis and treatment. Kaplan-Meier analysis, univariate, and multivariate Cox Proportional Hazard Regression were performed to assess the association between statin use, aspirin use, and survival. Results: Of 554 patients identified, 333 (60%) were not hyperlipidemic (NH), 165 (30%) were hyperlipidemic on statins (HS), and 56 (10%) were hyperlipidemic and not on statin therapy (HNS). The HS cohort was older, diabetic, hypertensive, used beta-blockers and aspirin. Stage, grade, and chemotherapy use were similar, but HS and HNS received more radiation (p⬍0.05). Both patients in the HS and HNS groups had improved overall survival compared to NH patients (p⫽0.04). Further stratifying our subgroups by aspirin use revealed that HS⫹aspirin users had significantly improved survival compared to other non-HS⫹aspirin users (p⫽0.01). In multivariate analysis, women who used statins had a 45% decreased hazard of death compared to NH women (HR ⫽ 0.55, 95% CI; 0.35, 0.87). Additionally, aspirin users had improved survival compared to non-users (HR ⫽ 0.47, 95% CI; 0.29, 0.76). Women using statins and aspirin had an 84% decreased hazard of death in comparison to other groups (HR ⫽ 0.16, 95% CI; 0.07,0.38, p⬍0.01). Conclusions: Statin and aspirin use are associated with improved overall survival in patients with uterine malignancy. Prospective evaluation of statin and aspirin use in uterine cancer is warranted.




Regional differences in therapy and clinical management of endometrial cancer: Findings of an international survey by the North-eastern German Society of Gynaecological Oncology (NOGGO). Presenting Author: Robert W. Kraetschell, Charité-Universitätsmedizin Berlin, Department of Gynecology, Campus Virchow Clinic, Berlin, Germany Background: We conducted an international survey to evaluate the differences in the systemic, radiotherapeutic and operative management of endometrial cancer (EC) in different regions of the world. Methods: In 2009 avalidated 15-item-questionnaire regarding surgical and adjuvant procedures of EC was sent to all German gynaecological clinics and in 2010 the English adapted questionnaire was set online as well as sent per post in most major gynaecological cancer societies. Results: 316 German institutions and 302 Institutions from 24 countries participated. We combined the different countries into regional groups: Central Europe (CE), southern Europe (SE), Asia and USA/UK. In Asian countries and in CE a lymph node dissection (LND) was performed routinely in 72.8% and in 55.6% of the cases, whereas in the USA/UK and in SE a LND was done mainly in selected cases when specific risk factors such as high-grade or non-endometrioidhistology applied (62.8% and 72.5%) than routinely (p ⬍ 0.001). A systematic pelvic and paraaortic LND was performed most frequently in CE 91.0%, in SE 76.9%, in Asia 70.9% and in USA/UK 68.6% (p ⬍ 0.001). A systematic LND with the intention of both adequate staging and for therapeutic value was performed in countries of central Europe to 74.6% and in Asia to 67.2%. In USA/UK the LND was seen merely as a staging instrument by 53.5% (p ⬍ 0.001). The LND was performed up to renal veins in CE in 86.8%, in Asia in 80.8%, in USA/UK in 51.2% and in SE in 45.1 %. A significant difference war found in the treatment for FIGO stage I (high risk factors (high grade, L1,V1)) and stage II disease between the countries: chemotherapy was applied in 84.8% of the participated centers in Asia,42.3% in SE, 21.2% in CE and only 13.6% in USK/UK (p⬍0.001).Vaginal brachytherapy was indicated as follows: USA/UK 84.1%, CE 78.8%, SE 78.8%, Asia 5.6% (p ⬍ 0.001). Conclusions: There is a large variety in the operative therapy and the clinical management of EC in different regions of the world. Future international prospective trials, will be necessary to improve and harmonize the evidence based treatment guidelines for EC- disease.

5595


A retrospective assessment of outcomes of chemotherapy-based versus radiation-only adjuvant treatment for completely resected stage I–IV uterine carcinosarcoma (UCS) with rhabdomyosarcoma (RMS) differentiation. Presenting Author: Vicky Makker, Memorial Sloan-Kettering Cancer Center, New York, NY Background: UCS with RMS differentiation are aggressive cancers with poor survival, and without an established standard treatment (txt). We aimed to determine the progression-free survival (PFS) and overall survival (OS) in patients (pts) who received either platinum-based chemo with or w/o radiation therapy (pelvic or IVRT), or RT alone (pelvic or IVRT). Methods: MSKCC EMR from 1990 to 2012 was reviewed for pt age, diag. date, primary surgery, residual disease at completion of primary surgery, FIGO stage, txt details, dates of progression, death, site(s) of first recurrence. Univariate analysis for PFS/OS utilized Kaplan Meier method. Differences between PFS/OS and categorical variables of stage ⫹ txt type were assessed using log-rank test. All analyses utilized SAS version 9.2. Pts who received chemo with or w/o RT or RT alone were included in the analysis. Results: 53 pts met study criteria. 41/53 (77.4%) pts received chemo: 30/41 (73.2%) paclitaxel-carboplatin (TC); 3/41 (7.3%) ifosfamide (I)platinum; 3/41 (7.3%) weekly cisplatin followed by TC; 2/41 (4.9%) other platinum-doublets; 3/41 (7.3%) IT. 34% of the chemo pts also received pelvic or IVRT. 12/53 (22.6%) pts received only pelvic RT⫹/-IVRT. FIGO stage: I ⫽16 (30%); II ⫽5 (9%); III ⫽14 (26%); IV ⫽18 (34%). Median PFS for the entire cohort: 11.7 mos (95% CI 6.4, 14.1). Median OS for the entire cohort: 21.8 mos (95% CI 14.9, 31.8). Median PFS by stage: 14.3 mos for early stage (stages I and II) vs 9.9 mos for late stage (stages III and IV), p⫽0.0217. Median OS by stage: not reached in the early stage cohort. Median OS for the late stage: 19.9 mos, p⫽0.0106. Median PFS by txt: 10.7 mos for the Pelvic RT⫹/- IVRT group vs 13.5 mos for chemo⫹/-Pelvic RT⫹/- IVRT group, p⫽0.5126. Median OS treatment: 23.9 mos for the chemo⫹/-Pelvic RT⫹/- IVRT group vs 17.4 mos for the Pelvic RT⫹/- IVRT group, p ⫽ 0.5191. Conclusions: PFS and OS outcomes in our cohort of pts with UCS with RMS differentiation were similar to survival outcomes among pts treated with platinum-based chemo on GOG 150 and GOG232B. The role of adjuvant RT in addition to chemo warrants further investigation.

5594

357s General Poster Session (Board #52E), Mon, 8:00 AM-11:45 AM

Early diagnosis program for cervical cancer in Tanzania: The “Vanda Project”. Presenting Author: Patrizia Serra, IRCCS, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy Background: In Sub-Saharan Africa cervical cancer represents 24% of all cancers and accounts for 23% of all cancer deaths in women. An early diagnosis program for breast and cervical cancer (Vanda Project) is ongoing in Mwanza and the surrounding lake area (12 districts with a population of 14,000,000). The aim of this project was to screen women aged 15-64 years living in the 12 districts. Methods: Women were invited to participate through local media and a mobile unit operating within the districts. A multidisciplinary team including medical oncologists was involved. Interventions consisted in Pap smear, clinical breast examination, breast self-examination training and training of district physicians to perform Pap smear and breast examination. Results: From May to December 2012, 2155 women from the districts of Shinyanga, Bukumbi, Kibara, Serengema and Musoma took part in the program: of these 91 (4%) had clinically evident cervical cancer. Age distribution classes were: ⬍ 18 years, 12% ; 18-35, 38%; 36-50, 41%; ⬎ 50, 9%. As expected a high stage distribution at diagnosis was observed: 30% stage III and 20% stage IV. Among the women with no clinical evidence of cancer, 408 samples were analyzed by cytology and 4% consisted of inadequate material. Of the remaining 392 samples, 85 (22%) were normal, 216 (55%) were infections (chiefly mycotic), 72 (18%) were precancerous lesions (50% H-SIL according to Bethesda classification) and 19 (5%) were positive for cancer (mainly stages III-IV). Precancerous lesions turned out to be cancer at histology in 44% of cases. 22% of precancerous lesions and 8% of clinically evident cancer were HIV-positive. Conclusions: This experience shows the high feasibility, good compliance and usefulness of a screening program for the early detection of cervical cancer in this high-risk population. Clinically detected cervical cancer by age and staging. Age range (years)Clinical cancer diagnosis Stage I < 18 ⴝ>18-35 >35-50 >50-60 >60 Total

5596

0 37 40 11 3 91

Stage II

Stage III Stage IV

0 0 0 0 7 16 11 3 2 19 12 7 0 2 4 5 0 0 0 3 9 (10%)37 (40%)27 (30%)18 (20%)


Long-term survival in advanced-stage uterine papillary serous carcinoma. Presenting Author: Laura L. Holman, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Advanced-stage (III/IV) uterine papillary serous carcinoma (UPSC) has a median overall survival (OS) of ~ 3 yrs. The study objective was to determine factors associated with long-term survival in advanced stage UPSC. Methods: We performed a retrospective review of pts diagnosed with stage III or IV UPSC between 1993 and 2012. Summary statistics were used to describe demographic and clinical characteristics. OS was estimated with the KaplanMeier estimator. Fisher’s exact test and the Wilcoxon rank sum test were used to compare pts surviving ⬎3 yrs with those surviving ⬍1 yr. Results: With a median follow-up of 2.2 years (range 0.06-13.2), 262 pts with advanced stage UPSC were identified. The probability of surviving ⬎3 yrs was 0.462, ⬎4 yrs was 0.310, and ⬎5 yrs was 0.228. Thirty-six (14%) pts survived ⬎3 yrs and 37 (14%) survived ⬍1 yr. There was no difference in median age of pts surviving ⬎3 yrs compared to pts surviving ⬍1 yr (60 vs 66, p⫽0.21). There was also no difference between groups in demographics or medical history. There were several significant differences in pathologic and treatment variables between groups (Table). Conclusions: Though rare, long-term survival in advanced stage UPSC is associated with mixed histology, combination treatment including chemotherapy, and complete response to primary therapy. Further study of the molecular basis for these differences has the potential to improve survival for all pts with this disease. Survived > 3 yrs % (Nⴝ36) Stage IIIA IIIB IIIC1 IIIC2 IVA IVB Histology Pure UPSC Clear Cell ⴙ UPSC Endometrioid ⴙ UPSC Undiff ⴙ UPSC Endometrioid ⴙ Clear Cell ⴙ UPSC Endometrioid ⴙ Undiff ⴙ UPSC Treatment Surgery ⴙ Chemo Neoadjuvant Chemo ⴙ/- Surgery Surgery ⴙ Radiation ⴙ/- Chemo Surgery Suboptimal Optimal Treatment response Complete response Partial response Progressive disease Recurrence Yes No

Survived < 1 yr % (Nⴝ37)

P 0.0474

19.4 (7) 5.6 (2) 27.8 (10) 22.2 (8) 0 (0) 25 (9)

5.4 (2) 0 (0) 16.2 (6) 18.9 (7) 2.7 (1) 51.4 (19)

27.8 (10) 11.1 (4) 33.3 (12) 0 (0) 19.4 (7) 5.6 (2)

43.2 (16) 13.5 (5) 32.4 (12) 5.4 (2) 0 (0) 5.4 (2)

69.4 (25) 2.8 (1) 25 (9)

40.5 (15) 24.3 (9) 21.6 (7)

5.6 (2) 80.5 (29)

5.4 (2) 54 (20)

88.9 (32) 5.6 (2) 2.8 (1)

18.9 (7) 8.1 (3) 51.4 (19)

33.3 (12) 66.7 (24)

59.5 (22) 40.5 (15)

0.0407

0.0017

0.29 ⬍0.001

0.0351


358s 5597

Gynecologic Cancer General Poster Session (Board #53C), Mon, 8:00 AM-11:45 AM

5598


Cridanimod and progestin therapy in hormone-resistant endometrial cancer. Presenting Author: Matthew J. Carlson, University of Iowa Hospitals and Clinics, Iowa City, IA

Disseminated tumor cells in bone marrow of patients with endometrial and cervical cancer. Presenting Author: Andrei F Taran, University of Tuebingen, Department of Gynecology and Obstetrics, Tuebingen, Germany

Background: Cridanimod is a novel small molecule that has been shown to increase progesterone receptor (PR) expression in rat endometrium. We hypothesize that cridanimod, in combination with progestin therapy, will increase PR expression and, thus improve survival in a mouse model of advanced, high grade endometrial cancer. Methods: Hec50co cells, established in our laboratory to represent genetically and phenotypically type II endometrial cancer, were injected into the peritoneal cavity of 96 athymic mice. These mice were randomly divided into 6 groups, receiving the following therapies: control (no therapy), medroxyprogesterone acetate (MPA) alone, cridanimod 1mg IM twice a week plus MPA, cridanimod 3mg plus MPA, cridanimod 6mg plus MPA, and adenovirus-mediated PR expression plus MPA. PR expression in tumor tissue and serum interferon (IFN) levels were assayed via Western blot and ELISA, respectively. Results: Kaplan-Meier survival analysis showed that the group receiving MPA plus 6 mg cridanimod twice a week had a significantly longer survival time than the control or MPA alone (62 ⫾ 7.0 days vs 38 ⫾ 5 or 33 ⫾ 3, respectively, p ⬍ 0.05). The group with MPA plus 3 mg cridanimod had a significantly longer survival than the group with MPA alone (56 ⫾ 8.0 days vs 33 ⫾ 3, p ⬍ 0.05). Western blot analysis showed that PR proteins were substantially higher in xenograft tumors from animals treated with cridanimod at doses of 3mg and 6mg when comparing to the control and MPA alone groups, ELISA data showed significant increases in IFN␣ and -␤ in cridanimodtreated mice in a dose-dependent manner. Conclusions: Combined progestin and cridanimod therapy significantly improved survival of mice with high-grade, advanced endometrial cancer. Cridanimod significantly increased PR expression, suggesting that the therapeutic benefit of combined therapy is mediated by up-regulation of PR, which is likely to be mediated through cridanimod induction of IFN␣ and IFN␤ expression. Further investigation is warranted to determine the utility of this promising agent.

Background: The presence of disseminated tumor cells (DTC) in the bone marrow (BM) of breast cancer patients is associated with poor prognosis. Several studies demonstrated that tumor cell dissemination may occur in gynecologic cancer and affect clinical outcome. The aim of our study was to evaluate the incidence of DTC and to assess their prognostic significance in patients with gynecologic malignancies. Methods: Bone marrow aspirates from 623 patients with primary endometrial (331), cervical (228), and vulvar cancer (64) undergoing surgery at the Department of Gynecology and Obstetrics, University Hospital, Tuebingen, Germany between November 2001 and May 2012, were included into the study. Disseminated tumor cells were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3 and by cytomorphology. Results: Disseminated tumor cells were detected in 18% of BM aspirates from patients with gynecological malignancies. Incidences of DTC in endometrial, cervical, and vulvar cancer were 21%, 16% and 16%, respectively. The presence of DTC was associated with a lower tumor grade in endometrial cancer For patients with vulvar cancer, no correlation with established clinicopathological factors was observed. In case of cervical cancer, BM positivity was correlated with International Federation of Gynecology and Obstetrics stage, nodal involvement and the presence of lymphangiosis carcinomatosa. For all analyzed tumor entities, no association between BM status and clinical outcome could be observed. Conclusions: Disseminated tumor cells are a common phenomenon in solid tumors. However, only in cervical cancer DTC postivity was associated with advanced disease. The consequences for DTC positive patients have to be determined.

5599

5600


L1-CAM as a predictor of survival in endometrial cancer: An analysis of The Cancer Genome Atlas (TCGA). Presenting Author: Thanh Hue Dellinger, City of Hope National Comprehensive Cancer Center, Duarte, CA Background: Despite a good survival rate for early-stage endometrial cancers (ECs), the prognosis for advanced-stage ECs remains poor, with no biomarkers and few therapeutic options currently in existence. L1-cell adhesion molecule (L1-CAM), a glycoprotein which functions in adhesion and migration of tumor cells, has been associated with a poor prognosis in Type I endometrial cancer (ASCO 2011 Abstract #5091). We evaluated the role of L1-CAM among both Type I and II ECs in TCGA. Methods: Partek Genomics Suit was used to define differentially expressed genes with p-values for clinical associations (ANOVA with linear contrast for discrete variables and linear regression for continuous variables). Differences in survival between “high” and “low” expression groups (defined by median expression) were compared using Cox regression analysis, with p-values calculated via log-rank test, using the ‘survival’ package in R. Results: Of 451 downloadable tumor samples, 335 tumors with both clinical and gene expression data were analyzed. Median age was 63 yrs. (range 31-90 yrs.). Stage I, II, III, and IV comprised 65%, 7%, 23%, and 5%, respectively. 82% were endometrioid; 16% (n ⫽ 52) serous. Grade 1, 2, and 3 comprised 24%, 27%, and 49%, respectively. Median follow-up was 19.5 months. High L1-CAM expression was found in older (p ⫽ 0.0005), suboptimally debulked (p⫽0.002), and African-American patients (p ⫽ 0.0003), and those with high grade (p ⫽ 0.008), serous histology (p ⬍0.00001), higher stage (p ⫽ 0.0004), positive peritoneal cytology (p ⫽ 0.007), deep myometrial invasion (p ⫽ 0.02), and positive pelvic (p ⫽ 0.003) and para-aortic lymph nodes (p ⫽ 0.002). High L1-CAM expression was associated with poor survival with a median overall survival of 17.2 months compared to 21.3 months for low L1-expressing endometrial tumors (HR⫽ 3.1, CI⫽1.3 -7.3, p ⫽ 0.007). Conclusions: L1-CAM expression is associated with poorer survival and high-risk clinicopathologic factors in endometrial cancer. Its prevalence in Type II ECs, such as high-grade, serous ECs, makes it a particularly attractive target for both novel biomarker discovery and therapeutic targeting.


Preoperative risk assessment model for identification of lymph node metastasis in early cervical cancer. Presenting Author: Seung-Hyuk Shim, Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea Background: The aim of this study was to develop a preoperative risk prediction model for lymph node metastasis in patients with early cervical cancer. Methods: The medical records of 504 patients with early cervical cancer who underwent hysterectomy and pelvic/paraaortic lymphadenectomy between 2007and 2012 in our center were retrospectively reviewed. According to the order of surgery performed, data between 2007 and 2010 were allocated to a model development cohort (n⫽314), and data between 2011 and 2012 were allocated to an external validation cohort (n⫽190). By using preoperative clinicopathologic data, magnetic resonance imaging (MRI) data, and positron emission/computed tomography (PET/CT) data, a multivariate logistic model was created. Based on this model, predictive nomogram was developed and externally validated. Results: Age, tumor size measured by MRI, and lymph node metastasis on PET/CT were found to be independent risk factors for nodal metastasis. Developed nomogram incorporating these three predictors showed good discrimination and calibration, with a bootstrap-adjusted concordance index of 0.772. Also, the validation set showed good discrimination with a bootstrap-adjusted concordance index of 0.783. Conclusions: We have developed a robust model to predict lymph node metastasis in patients with early cervical cancer. This new tool may be useful to clinicians and patients when deciding lymphadenectomy and maybe useful in designing clinical trials. Preoperative risk factors for lymph node metastasis by multivariate analysis. Age (yrs) Tumor size on MRI (cm) LNM on PET-CT

ORs

95% CI

P

0.972 1.40 4.027

0.946 -0.999 1.179 – 1.662 2.158 – 7.514

0.042 ⬍0.001 ⬍0.001

ORs, add ratios; CI, confidence interval; LNM, lymph node metastasis.




5602

359s General Poster Session (Board #53H), Mon, 8:00 AM-11:45 AM

Conservative management of young women with endometrial adenocarcinoma with grade 2-3 and/or superficial myometrial invasion. Presenting Author: Jeong-Yeol Park, Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea

Determination of the activated form of the progesterone receptor (PR) in endometrial cancer (EC). Presenting Author: Dinny Graham, Westmead Institute for Cancer Research, Sydney Medical School – Westmead, Sydney, Australia

Background: To estimate the oncologic and pregnancy outcomes after progestin treatment of young women with endometrial adenocarcinoma with grade 2–3 and/or superficial myometrial invasion. Methods: Medical records of 48 young women with endometrioid adenocarcinoma of the uterus with grade 2–3 and/or superficial myometrial invasion who were conservatively managed with oral progestin were reviewed. Results: Fourteen patients (29.2%) received daily oral megestrol acetate (median dose, 160 mg/day; range, 40 –240 mg/day) and 34 (70.8%) received daily oral medroxyprogesterone acetate (median dose, 500 mg/day; range, 80 –1000 mg/day). The median treatment duration was 10 months (range, 3–20 months). Complete responses were observed in 37 patients (77.1%) and the median time to complete response was 17 weeks (range, 9 –51 weeks). Complete response rates were 76.5%, 73.9%, and 87.5% for patients with grade 2–3 without myometrial invasion (n⫽17), patients with grade 1 and superficial myometrial invasion (n⫽23), and patients with grade 2-3 and superficial myometrial invasion (n⫽8), respectively (P ⫽ 0.731). Their recurrence rates after a median follow-up time of 48 months (range, 7–136 months) were 23.1%, 47.1%, and 71.4%, respectively (P ⫽ 0.104). None experienced disease progression or died of the disease. Nine patients gave birth to 10 healthy babies. Conclusions: Progestin treatment is safe for patients with grade 2–3 without myometrial invasion and patients with grade 1 and superficial myometrial invasion. However, it should be provided on an individual basis and must be applied cautiously in patients with grade 2–3 and superficial myometrial invasion.

Background: Endocrine treatments, in general have limited clinical efficacy in endometrial cancer. Upon ligand binding, PRs in normal tissue form discrete focal subnuclear distribution patterns (FDP), which are associated with DNA transcription. FDP are indicative of functionally activated PRs (APRs), and are observed in EC, independently of menopausal status. The feasibility of using an IHC technique to characterize the PR functional status has previously been reported in breast cancer and the APR phenotype in cell lines correlates with anti-progestin activity. The goal of this study is to determine if APR can be identified in EC and to determine if this IHC technique & APR phenotype could be developed as a companion diagnostic to predict anti-progestin efficacy in patients with EC. Methods: 72 archived primary EC specimens were processed with standard IHC for estrogen receptor (ER), PR & proliferation (Ki67). APR status was determined using commercially available antibodies specific to the A and B isoforms of the PR (PRA and PRB) with standard microscopy at 1000x magnification. Results: 56 (78%) tumors were of endometrioid histology. Endometrioid tumors were ER⫹ (68%) and PR⫹ (84%). Two PR nuclear distribution patterns were observed: an aggregated pattern (A) which is indicative of APR and a diffuse or finely granular pattern (D) indicative of an inactivated PR. This resulted in three tumor phenotypes: A cells only, D cells only, and a mix of A ⫹ D cells. APR was defined as any tumor with more than 5% A cells. An average of 49% of tumor cells were positive with PRA, 35% were positive for PRB. APR was present with PR A in 41% and with PR B in 47% of the PR⫹ endometrioid tumors. The APR status, for both PR A and PR B, was independent of PR positivity rate, PR staining intensity score and % Ki67 positive. APRpos phenotype was associated with a lower % ERposstaining. When observable, endometrial stromal and normal cells were PR positive (D pattern). Conclusions: APR can be identified using either PRA or PRB, in ~50 % of the EC samples; there was a pattern consistent with the presence of APR positive cells. The IHC technique to identify APR has the potential to be developed as companion diagnostic as a potential predictor of anti-progestin efficacy.

5603

5604


Neoadjuvant chemotherapy followed by chemoradiation in selected locally advanced squamous cervical cancer. Presenting Author: Juan Fernando Cueva, Complexo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain Background: Although there has not been a direct comparison between neoadjuvant chemotherapy followed by chemoradiation with chemoradiation alone, neoadjuvant chemotherapy is active in squamous cervical cancer. Methods: In this one arm phase II trial we accrued 25 patients from 2007 to 2012 diagnosed with squamous cervical cancer deemed poor candidates to initial chemoradiation (decided by a multidisciplinary committee). Patients had ⬎ 18 years of age, PS 0-1, adequate organ function an gave informed consent. They received neoadjuvant paclitaxel and cisplatin (80 and 33 mg/m2 respectively) on days 1,7, 15 of every 28 for two cycles and then external radiation in 1.8 Gy/ fraction with concurrent weekly cisplatin 40 mg/m2followed by brachytherapy in 5-6 applications. Dose intensity and toxicity was accrued, and both after neoadjuvant and chemoradiation patients were evaluated by RECIST 1.1 criteria for response with CT scan and pelvic MNR. Results: Baseline characteristics of the patients are listed in Table. 24 patients were evaluable for efficacy and safety. Response rate after neoadjuvant chemotherapy was 84 % (complete and partial responses in 24 and 60% of patients, respectively), without progression disease. Response rate after radiochemotherapy was 93 % (complete and partial responses in 52 and 41% of patients, respectively). After a mean of 29 months of follow up, 11 patients (45%) thus far have developed recurrent disease. Median progression-free survival and overall survival were 33 (23- 42) and 34⫹ m (29 – not reached). Treatment was well tolerated, without toxicities grade 3-4. Conclusions: Our weekly cisplatin-paclitaxel neoadjuvant regimen has been feasible and very effective in terms of dose delivery, tolerance and radiological responses without compromising definitive treatment with chemoradiation. If this approach is superior than the standard chemoradiation alone in this population should be explored in a randomized trial. Baseline characteristics of the patients Age Median (range) ECOG PS PS0 / PS1 Stage Ib2 bulky / IIb / IIIb / IIIc / IVa


Racial disparities in cervical cancer mortality over time. Presenting Author: Jose Alejandro Rauh-Hain, Massachusetts General Hospital, Boston, MA Background: The aim of this study is to examine changes over time in survival for African-American (AA) and white women diagnosed with cervical cancer (CeCa). Methods: Surveillance, Epidemiology, and End Results (SEER) Program data 9 for 1983-2007 were used for this analysis. Kaplan–Meier and Cox proportional hazards survival methods were used to assess differences in survival by race at 5-year intervals. Results: The study included 23,722 women; including 19,777 whites and 3,945 AA. AAs were older (51.4 vs. 49 years; p⬍0.001), had a higher rate of regional (38.3% vs. 31.7; p⬍0.001) and distant metastasis (10.5% vs. 8.5; p⬍0.001). AAs received less frequently cancer-directed surgery (53.1% vs. 65.7%; p⬍0.001), and more frequently radiotherapy (56.9% vs. 47.3%; p⬍0.001). AAs had a hazard ratio (HR) of 1.40 (95% CI, 1.31-1.49) of CeCa mortality compared to whites. Adjusting for SEER registry, marital status, stage, age, surgery, radiotherapy, grade and histology, AA women had a HR of 1.15 (95% CI, 1.07-1.24) of CeCa related mortality. AAs had a higher HR of all cause mortality and CeCa related mortality for all the five-year diagnosis cohorts (Table). After adjusting for the same variables, there was a significant difference in survival in the 1988-1992 group (HR 1.26; 95% CI 1.09-1.47). Conclusions: The present data indicates significant survival differences by race for women with invasive CeCa. After adjusting for SEER registry, marital status, stage, age, surgery, radiotherapy, grade and histology, only between 1988-1992 there was a difference in survival between the groups. Year diagnosis 1983-1987 1988-1992 1993-1997 1998-2002 2003-2007 All years

N 4,887 5,280 4,958 4,557 4,040 23,722

All-cause mortality, HR Unadjusted Adjusted 1.48 (1.35-1.61) 1.57 (1.43-1.72) 1.55 (1.29-1.72) 1.44 (1.29-1.62) 1.29 (1.21-1.59) 1.49 (1.43-1.57)

1.11 (1.00-1.23) 1.28 (1.16-1.42) 1.22 (1.08-1.37) 1.17 (1.03-1.34) 1.05 (0.90-1.23) 1.18 (1.12-1.24)

Cervical cancer mortality, HR Unadjusted Adjusted 1.51 (1.32-1.73) 1.47 (1.29-1.69) 1.39 (1.20-1.61) 1.29 (1.10-1.51) 1.28 (1.09-1.51) 1.40 (1.31-1.49)

1.12 (0.96-1.30) 1.26 (1.09-1.47) 1.15 (0.97-1.35) 1.08 (0.90-1.28) 1.03 (0.85-1.25) 1.15 (1.07-1.24)

N 51 ( 27 – 72) 1 / 24 1 / 10 / 7 / 4 / 3


360s 5605


Impact of socioeconomic status and degree of ethnic isolation on cervical cancer incidence among Hispanics and Asians in California. Presenting Author: Marie-Anne Froment, Stanford University, Stanford, CA Background: The incidence of cervical cancer in the United States has declined since the introduction of the pap smear. However, differences exist based on ethnicity and socioeconomic status (SES).This study aimed to evaluate the impact of nativity, neighborhood SES and enclave (degree of ethnic isolation) on the incidence of cervical cancer in California. Methods: Using data from the California Cancer Registry, comprising three of the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) program registries, information on all primary invasive cervical cancer diagnosed in California from January 1, 1990, through December 31, 2004 was obtained. We analyzed the influence of enclave, SES, and nativity on cervical cancer incidence. Results: Among the 22,189 invasive cervical cancer cases diagnosed between 1990 and 2004, 50% were non-Hispanic white (NHW), 39% Hispanic and 11% Asian women. Seventy percent (70%) of the invasive cervical cancer cases were squamous cell carcinoma (SCC), 19% were adenocarcinoma and 11% other histologies. Approximately half (51%) of patients presented with localized disease, 33% regional disease, 10% distant disease and 6% unknown. By ethnic group, US born women showed lower rates of SCC compared to foreign-born women. Seventy-six percent (76%) of invasive cervical cases were observed in high enclave neighborhoods, and seventy percent (70%) were noted in low SES neighborhoods. Hispanics living in low SES and high enclave had 12.7 times (95% CI; 11.2-14.3) higher rate of cervical cancer than those living in high SES, low enclave neighborhoods. For Asian women incidence rates were 6 times (95% CI; 4.9-7.5) higher in the low SES, high enclave neighborhoods compared to those living in high SES, low enclave neighborhoods. Conclusions: More efforts should be done to reach out to and increase pap smear screening for women living in high enclave neighborhoods to help decrease the incidence of invasive cervical cancer cases in these groups of women.

5607


Long-term survival following robot-assisted surgical treatment of early cervical cancer. Presenting Author: Amanda Lynn Jackson, The University of North Carolina at Chapel Hill, Chapel Hill, NC Background: To determine progression-free survival (PFS) and overall survival (OS) for patients with early stage cervical cancer surgically treated using robotic-assisted laparoscopy compared to open radical hysterectomy. Methods: A retrospective analysis of women that underwent a roboticassisted surgery (RAS) for early stage cervical cancer was performed. Surgical procedures included radical hysterectomy, parametrectomy, and trachelectomy from 2005 to May 2012. Patient demographics, clinicopathologic data, and disease status were analyzed. Comparison was made to open radical hysterectomies (ORH) from 2000 to May 2012. Survival statistics were analyzed using the Kaplan-Meier method. Results: 147 patients underwent RAS; 97 patients underwent ORH in our comparison group. Surgery was aborted in 8 RAS and 5 ORH due to extent of disease. The robotic surgical treatments included 121 (82.3%) radical hysterectomies, 14 (9.5%) trachelectomies, and 12 (8.2%) parametrectomies. In the RAS, the mean age was 44.3 (range 17-75); the mean body mass index (BMI) was 27.7 (range 16-50). Most patients presented with clinical stage IBI disease (79.9%). Squamous cell histology was most common (55.4%) followed by adenosquamous (36.7%). No significant differences were found between the RAS and ORH with regards age, BMI, surgical stage, grade, short and long-term complications, and comorbidities. The mean follow up time was 24.7 (range 0-82.1) months. Recurrence was documented in 3 patients after RAS and 11 patients after ORH; 3 deaths were recorded in the RAS group and 10 in the ORH. One patient had persistent adenocarcinoma in situ after robotic trachelectomy. Compared to ORH, there was a significantly better PFS in RAS (HR .312, CI 0 .099-0.98, p ⫽ 0.046) while no difference was seen in OS (p ⫽ 0.172). Conclusions: The results demonstrate that RAS is associated with lower rates of recurrence and no difference in overall survival. These findings provide further evidence that robotic-assisted surgical treatment is not associated with inferior results when compared to laparotomy or traditional laparoscopy. As robotic-assisted surgery is associated with a less steep learning curve, it may become the surgical approach of choice.

5606


Male workers’ influence on partners uptake of pap smear screening in a teaching hospital in Nigeria. Presenting Author: Idowu Emmanuel Olowokere, University College London Hospitals NHS Foundation Trust, Ibadan, Nigeria Background: Cervical cancer remains a major global health issue still claiming the lives of African women despite the availability of screening facilities. Male involvement has paid off in enhancing uptake of contraception in Africa as reported by several empirical studies. It may be worthwhile in encouraging women uptake of the screening services. This formed the basis for this study. Methods: The study adopted a cross sectional descriptive survey that involved 350 respondents. Their involvement was assessed using a structured questionnaire with cronbach reliability coefficient of 0.78. The study was analyzed using SPSS version 16 by computing the frequency, means and standard deviations. Chi-square was employed to test the significance of associations at p ⬍ 0.05. Results: The results showed that all (n ⫽ 350) male medical staff of the hospital were aware about cervical cancer and pap smear screening test for premalignant lesions of the cervix compared to 90% and 77% observed in paramedics and non-medical groups respectively. At least, an episode of Pap smear screening test had been done by the partners of 52.4% of the medical staff; while only 30.2% and 13% of the partners of paramedics and non-medical workers respectively had undergone the test. Among those whose partners had participated in screening; 78.9% (n ⫽ 95) of the men initiated the screening. Eighty two percent (82%, n ⫽ 95) paid for their wives’ transportation while 78.9% (n ⫽ 95) have at least once followed their partners to the screening centre. Chi square result showed that men with higher level of education are likely to support their partners to participate in screening for cervical cancer (p ⬍ 0.005). There was no significant association between religion and male support for Pap smear uptake (p ⬍ 0.407). Conclusions: The study showed that the medical male workers were more involved in facilitating partners screening for cervical cancer. This may not be unconnected with their knowledge of the consequences of late identification of the disease. The study therefore concluded that knowledge of cervical cancer and its consequences by men will enhance their involvement in encouraging partners to utilize screening facilities.

5608


Longitudinal quality of life (QOL) and sexual functioning in women undergoing pelvic exenteration for gynecologic malignancies. Presenting Author: Pamela T. Soliman, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Pelvic exenteration (PE) is en bloc resection of the pelvic organs including bladder, vagina, and rectum to treat central recurrence of a gynecologic malignancy. While this procedure has high morbidity, it is the only option for cure in some patients. The goal of this study was to assess QOL and sexual functioning in women who underwent PE with vaginal and/or bladder reconstruction. Methods: All patients were enrolled prior to PE. Surveys included the SF-12 (functional status), BIS (body image), SAQ (sexual functioning), SWD (satisfaction with decision), CES-D (depression), Stoma QOL, and DUFSS completed preoperatively (preop) and post-operatively at 4-6 wks, 6 mo, 1 yr, and 2 yrs. Descriptive statistics, chi-square, Mann-Whitney, and Kruskal Wallis tests were used to evaluate the data. Results: Between 2008 and 2012, 39 women participated. Median age was 56.7 yrs. Mean physical functional status scores (SF-12) declined through 6 mo postop, with improvements at 1 and 2 yrs (p⫽.002) but did not reach preop levels. SF-12 mental functioning scores declined immediately postop but returned to baseline by 6 mo. BIS was significantly worse at 1ys (p⫽0.02) and 2 yrs (p⫽0.025). Mean depression (CES-D) scores decrease but remained above the clinical cutoff of 17 at 6 mo. Poor sexual function was noted preop and did not improve. High scores for social support (DUFSS) remained constant. Stoma QOL improved in the first 2 yrs but not significantly. Pts reported high satisfaction with the decision to undergo PE, which did not change over time. Conclusions: While a majority of women remained satisfied with their decision to undergo PE, the procedure was associated with depression, worsening physical functioning and poor body image despite stable social support. Interventions are currently under development to improve QOL in this patient population. BIS (0-30) CES-D (0-60) DUFSS (0-40) Stoma QOL (20-80) SWD (0 – 36) SAQ Pleasure (0-18) Discomfort (0 to 6) SF-12 Physical function (0-100) Mental function (0-100)

Preop

4-6 wks

6 mo

1 yr

2 yrs

3 21 39 n/a

n/a n/a n/a 50 30 n/a

10.5 18 40 52 29 n/a

16.5

32.6 37.2

31.5 41.7

15 15.5 37 54 29 1.5 3 38.7 38.3

3 3 45.3 41.1

39.5 56.5 30 8 5 34.4 41.4




Adjuvant radiation therapy in node-positive vulvar cancer. Presenting Author: Eric Xanthopoulos, Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, PA Background: Adjuvant radiation (RT) has been demonstrated to improve overall survival (OS) in vulvar cancer patients with 2⫹ positive lymph nodes, but its role in patients with one positive lymph node is uncertain. We report on the largest and longest study of survival in patients with and without radiation following surgery in patients with vulvar cancer. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified node-positive women with squamous cell carcinoma of the vulva treated with and without external beam radiation following surgery. The Kaplan-Meier approach, log-rank tests and Cox modeling assessed OS. Results: All results are listed as women without vs with adjuvant radiation. From 1988 – 2008, 420 patients received surgery alone vs 753 women who received adjuvant radiation. Patient characteristics were well balanced across cohorts, including tumors ⱕ or ⬎ than 2 cm (p ⫽ 0.31), grade (p ⫽ 0.41), marital status (p ⫽ 0.20), provider type (p ⫽ 0.49), and AJCC stage (p ⫽ 0.35). Both groups also had similar incidence of biopsy of any kind (p ⫽ 0.40), lymph node dissection (p ⫽ 0.77), median number of nodes excised (p ⫽ 0.12), and type of surgery (p ⫽ 0.49). Median age (75 vs 70 y, p ⬍0.01) and race (94% vs 89% white, p ⫽ 0.01) were adjusted using Cox regression. Median survivor follow-up was 45 m (range 0 - 236 m). Adjuvant radiation was associated with survival across all node-positive patients (22 vs 29 m, p ⬍0.01), as well as in the subset of women with just one positive lymph node (37 vs 70 m, p ⬍0.01) or 2⫹ positive lymph nodes (14 vs 18 m, p ⬍0.01). On multivariable Cox regression, adjuvant radiation (95% CI 0.85 - 0.96), diameter (CI 1.28 - 2.01), marital status (CI 0.65 0.93), the number of positive nodes (CI 1.06 - 1.11), and the ratio of positive-to-excised nodes (CI 1.61 - 2.98) were all associated with survival (p ⬍0.01 for each). Conclusions: The largest cohort study of node-positive squamous cell carcinoma of the vulva suggests adjuvant radiation is associated with OS.Studies have reported that adjuvant radiation may provide a survival benefit in women with 2⫹ positive lymph nodes. Our findings suggest patients with one positive lymph node also may benefit from adjuvant radiation.

5611


Vulvar cancer: Presentation and treatment variation among races. Presenting Author: Jennifer Rosin, Creighton University, Omaha, NE Background: Vulvar cancer is the fourth most common gynecologic malignancy. We analyzed variation among races in treatment, histology and stage at presentation using the National Cancer Database (NCDB). Methods: Between 2000 and 2010, 51,157 women from 1338 hospitals across the US were reported to the NCDB with vulvar cancer. Differences were assessed using Chi square analysis. Results: Caucasian patients with vulvar carcinoma in situ received no first course treatment significantly less than African American or Hispanic patients (3% vs 6% and 7%, p⬍0.05). No treatment for stage I and II vulvar cancer was also significantly less than African American patients (1.4% vs 2.5%, p⬍0.05). African Americans overall chose radical surgery less often than Caucasians (13% vs 16%, p⬍0.05), but local tumor excision more (29% vs 24%, p⬍0.05). African Americans and Hispanics chose no surgery of primary sites significantly more than Caucasians (14% and 15% vs 9%, p⬍0.05). As expected, squamous cell carcinoma accounts for over 90% of vulvar cancer cases reported. However, Asian-Pacific Islanders had a significantly higher proportion of Extramammary Paget’s disease when compared to Caucasians, African Americans, or Hispanics (20% vs 4.3%, 0.6%, 3.2%. p⬍0.05). African Americans had the lowest proportion of Extramammary Paget’s compared to any other race for all stages (0.6%, p⬍0.05). African Americans presented as vulvar carcinoma in situ more often than any other race (33% vs 25-29%, p⬍0.05). Conclusions: This is the largest study analyzing racial differences in treatment, histology and stage at presentation in women with vulvar cancer. Caucasians were least likely to opt for no first course treatment overall. African Americans were most likely to choose no treatment and, when having surgery, preferred local excision over radical vulvectomy.

5610

361s General Poster Session (Board #54H), Mon, 8:00 AM-11:45 AM

Comparing intensity modulated radiotherapy and conventional external beam radiotherapy in cervical cancer. Presenting Author: Deleep Kumar Gudipudi, Indo-American Cancer Institute and Research Center, Road #14, Banjara Hills, Hyderabad, India Background: To compare Intensity-modulated radiation therapy (IMRT) with conventional external beam radiation therapy (CXRT) regarding morbidity, tumor response, and quality of life (QOL) in cervical cancer patients. Methods: Between 8/2009-2/2010, 50 patients (pts) with age range 20-85, with FIGO Stage IIA- IIIB were prospectively randomized 2:1 to CXRT and IMRT at Indo-American Cancer Institute. Both groups received concurrent chemotherapy (weekly cisplatin 30-40mg/m2) with external beam radiation (EBRT), 50Gy/25fractions followed by intracavitary brachytherapy at 21Gy/3fractions. Complications and QOL were evaluated during treatment and in follow-up with CTC 4.0 and EORTC QLQ-C30, and disease recurrence was based on pelvic exam. Analysis used Chi square(X2) at a significance level of 0.05. Results: Average time to completion was 49 and 48 days in CXRT and IMRT arms (p⬎.05). Four pts did not complete the treatment in the CXRT. Two months after completion 31/35 (89%) of CXRT and 15/15 (100%) of IMRT had complete response (p⬎.05). At 5 months, 30/35 (86%) of CXRT, and 14/15 (100%) of IMRT had no loco-regional disease (LRD); 1 IMRT pt died from distant metastasis (DM). At 18 months, 25/35 (72%) in CXRT and 14/15 (93.5%) in IMRT had no LRD or DM. Most common acute side effects in the CXRT were Grade 1 vomiting/ cystitis/diarrhea and Grade 2 nausea/skin reactions/proctitis. One pt developed vesicovaginal fistula (VVF) after 50Gy by EBRT. Most common acute side effects in the IMRT were Grade1 nausea/vomiting/cystitis/ proctitis/diarrhea. Two pts had grade 3 neutropenia in the 5th week of RT. QOL was better in IMRT (p ⬍.01) based on functional, symptom, single items, and global scales except for pain, insomnia, loss of appetite. Diarrhea, financial problems were worse in the CXRT (p⬍.05). Chronic complications such as radiation induced proctitis in 5 patients, and sub-acute intestinal obstruction in 2 patients during follow-up period in CXRT vs. IMRT (p ⬍ 0.001). Conclusions: IMRT is superior to CXRT with fewer chronic side effects and similar acute side effects and treatment responses. This is the first randomized clinical trial of these treatments in cervical cancer.

TPS5612


A phase I/II study of the vascular disrupting agent BNC105P in combination with gemcitabine-carboplatin in partially platinum-sensitive ovarian cancer patients in first or second relapse: An international collaborative group trial of ANZGOG and HOG. Presenting Author: Danny Rischin, Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia Background: BNC105P is a tubulin polymerization inhibitor and a vascular disrupting agent (VDA). In vivo exposure to BNC105P leads to selective damage of tumor vasculature in both primary and metastatic lesions, causing disruption of blood flow to tumors, hypoxia, and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells, including ovarian cancer cell lines. Pre-clinical data has demonstrated synergistic activity of BNC105P when combined with platinum or with gemcitabine, supporting the proposed study design. This study will determine the safety and efficacy of BNC105P in ovarian cancer when used in combination with gemcitabine-carboplatin. The target population is women with ovarian or primary peritoneal cancers who progressed 4 to 9 months after first-line platinum based chemotherapy, or 4 to 12 months after second line platinum based chemotherapy. Methods: A single arm phase I will be used to determine the phase II dose for the triplet combination (3-6 subjects per dose level, maximum of 24 subjects). Four dose levels of BNC105P (12-16 mg/m2) and gemcitabine (800-1000 mg/m2) will be assessed. The dose of carboplatin will be set at AUC 4. Enrolment to cohort 2 started in January 2013. The phase II component will consist of a 2-arm, randomized (1:1) study of BNC105P, gemcitabine and carboplatin versus gemcitabine and carboplatin alone. The primary endpoint for the phase II trial is objective response rate (ORR, according to RECIST 1.1 and/or GCIG CA125 criteria. An ORR of 40% or more with the experimental regimen would be considered worthy of further investigation, assuming an ORR of 20% with the control regimen. 110 phase II participants are planned (N ⫽ 55/arm). Treatment allocation will be balanced using minimization for the study site, target lesions according to RECIST (present vs. absent), progression free interval from last platinum based chemotherapy regimen (⬍6 months vs 6 months or more), and first relapse vs. second relapse. Biomarker (tissue and blood-borne) sampling and PK analysis will also be undertaken. Clinical trial information: NCT01624493.


362s TPS5613


A randomized double-blind phase III trial comparing vintafolide plus pegylated liposomal doxorubicin (PLD) versus PLD plus placebo in patients with platinum-resistant ovarian cancer (PROCEED). Presenting Author: R. Wendel Naumann, Levine Cancer Institute, Carolinas Medical Center, Charlotte, NC

TPS5614


PARAGON: Phase II study of aromatase inhibitors in women with potentially hormone responsive recurrent/metastatic gynecologic neoplasms: ANZGOG 0903. Presenting Author: Michael Friedlander, Prince of Wales Hospital, Sydney, Australia

Background: Folate receptor (FR) is expressed on the majority of epithelial ovarian cancers and FR expression appears to be a negative prognostic factor in this setting. Vintafolide (EC145) is a folate-conjugate designed to selectively deliver desacetylvinblastine monohydrazide (DAVLBH) to FRexpressing cells. 99mTc-Etarfolatide (EC20) is a technetium-labeled folate that identifies FR-expressing tumors. In a phase 2 study comparing vintafolide ⫹ PLD with PLD alone, the combination demonstrated a statistically and clinically significant delay in PFS (5.0 months) compared with PLD alone (2.7 months) in women with platinum-resistant ovarian cancer (Naumann et al, ASCO 2011). Data also indicated that 99mTcetarfolatide may have utility for selecting patients most likely to benefit from vintafolide therapy. Methods: This is an international, randomized, double-blind, placebo-controlled phase 3 study of PLD ⫾ vintafolide therapy compared in patients with primary or secondary platinum-resistant ovarian cancer (NCT01170650). Key eligibility criteria include: ⱖ18 years, pathology-confirmed epithelial ovarian, fallopian tube or primary peritoneal carcinoma, prior platinum-based chemotherapy, a RECIST v1.1 measureable lesion, and ECOG performance status 0 or 1. At baseline, patients undergo 99mTc-Etarfolatide imaging to identify FR-positive lesions and are subsequently randomized to the vintafolide ⫾ PLD. PLD (50 mg/m2) adjusted for Ideal Body weight is administered on day 1 of a 4-week cycle and treatment continues until the maximum allowable cumulative dose (550 mg/m2) is reached or until disease progression or intolerable toxicity. Vintafolide (2.5 mg) or placebo is administered on days 1, 3, 5, 15, 17, and 19 of a 4-week cycle and treatment can continue for up to 20 cycles or until unacceptable toxicity or disease progression. The primary objective is to assess PFS based on investigator assessment (RECIST v1.1) in FR positive patients. Secondary objectives include OS, safety/ tolerability, overall response rate, and disease control rate. Enrollment to the study is currently ongoing. Clinical trial information: NCT01170650.

Background: Many gynaecological cancers of different pathological type express estrogen and/or progesterone hormone receptors (ER/PR). Reports of tumour response and clinical benefit with hormonal therapies show variable rates of activity. There is a need to prospectively study the role of aromatase inhibitors in women with potentially hormone responsive recurrent gynaecological cancers to establish response rates, clinical benefit, quality of life (QoL) and identify predictors of response. Methods: PARAGON is phase II Gynecologic Cancer InterGroup trial lead by the Australia New Zealand Gynaecological Oncology Group, Cancer Research UK and the Belgian Gynaecological Oncology Group. The study is designed to facilitate research in rare tumours. The protocol allows postmenopausal women with recurrent gynaecological cancers to enrol into one of 7 subgroups; epithelial ovarian cancer (EOC) with only rising CA125 after first line chemotherapy, platinum resistant/refractory EOC, low grade EOC, endometrial carcinomas, endometrial stromal sarcomas, miscellaneous sarcomas and granulosa cell tumours and other sex cord stromal tumours. ER/PR positivity must be confirmed by immunohistochemistry. Each subgroup will enrol 25-50 patients with defined stopping rules based on response and reviewed by independent data monitoring committee (IDMC). Eligible patients receive 1 mg anastrozole daily until disease progression or unacceptable toxicity. Primary objective: clinical benefit (partial or complete response or stable disease). Secondary objectives: progression free survival, response duration, QoL, toxicity. Blood and tumour samples are being collected for translational studies and confirmation of ER/PR positivity. Recruitment commenced in 2011 in Australia, New Zealand and the United Kingdom. One hundred and fourteen of 350 planned patients have been enrolled to January 2013. In November 2012 IDMC recommended continuing recruitment to the EOC with rising Ca125 only and resistant/refractory subgroups based on review of activity outcomes for the first 25 patients. The trial will open in Belgium in April 2013. ACTRN12610000796088 Clinical trial information: 12610000796088.

TPS5615

TPS5616


Phase II clinical trial of six mercaptopurine (6MP) and methotrexate in patients with BRCA-defective tumors. Presenting Author: Shibani Nicum, Oxford University Hospitals NHS Trust, Oxford, United Kingdom Background: BRCA1 and BRCA2 genes are critical in homologous recombination DNA repair and have been implicated in familial breast and ovarian cancer tumorigenesis. Tumor cells with these mutations demonstrate increased sensitivity to cisplatin and poly(ADP-ribose) polymerase (PARP) inhibitors. 6MP was identified in a screen for novel drugs and found to selectively kill BRCA-defective cells in a xenograft model as effectively as the PARP inhibitor, AGO14699, even after these cells had acquired resistance to a PARP inhibitor or cisplatin (Issaeva 2010). Exploiting the genetic basis of these tumours enables us to develop a more tailored approach to therapy for patients with BRCA mutated cancers. This multi-center phase II single arm trial was set up to investigate the activity and safety of 6MP with methotrexate in patients with breast or ovarian cancer who are known to have a BRCA mutation. Methods: Two-stage Simon compromise design (Jung 2001, Jung 2004) with ␣⫽0.20, power⫽90% to detect an increase in activity from 10 to 20%. 1st stage: if ⱕ 3/30 evaluable patients respond at 8 weeks the trial will be stopped for futility; 2nd stage: if ⱖ9/65 evaluable patients respond at 8 weeks the treatment will be regarded as potentially effective and a phase III trial will be considered if the treatment appears safe and well-tolerated. 65 patients with BRCA defective cancer progressing after at least one prior chemotherapy or relapsed platinum resistant ovarian cancer, ECOG performance status 0-2 will be recruited and treated with daily 6MP (75mg/m2 ) and weekly methotrexate (20mg/m2) until progression. The starting dose was later reduced by 25% due to excess of expected toxicity. Patients with low TPMT activity or a low/low genotype are excluded due to the risk of increased toxicity. Prior treatment with a PARP inhibitor is permissible. Primary outcome: objective response at 8 weeks: complete, partial response or stable disease defined by RECIST 1.1. Secondary outcomes include safety, PFS, OS and quality of life. Of the 46 patients screened for TMPT activity between 15 Jun2009 and 05Dec 2012 from 12 UK sites, 31 patients were recruited. The pre-specified activity goal for the 1st stage was met and accrual into the 2nd stage continues. Clinical trial information: 2009-016846-16.


Dovitinib as second-line therapy in patients with fibroblast growth factor receptor 2 (FGFR2)-mutated or non-mutated advanced and/or metastatic endometrial cancer (EC): A single-arm, multicenter, phase II study. Presenting Author: Gottfried E. Konecny, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA Background: Despite the use of combination chemotherapy and introduction of novel targeted agents, the prognosis for advanced and/or metastatic EC is challenging. The occurrence of somatic activating FGFR2 mutations in EC suggests an opportunity for testing FGFR inhibitors. Dovitnib (DOV) is a potent receptor tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor and FGFR. The objective of the study is to investigate the efficacy and safety of DOV as second-line therapy in patients (pts) with advanced and/or metastatic EC. Methods: This multicenter, non-randomized, open label, single-arm, phase II study (NCT01379534) will enroll adult female pts (N~80) with either FGFR2 mutated (group 1) or non-mutated (group 2) histologically confirmed advanced and/or metastatic EC, who have documented radiological evidence of progressive disease (RECISTv1.1) after 1 prior line of chemotherapy, excluding adjuvant therapy. Eligible pts also need to have ⱖ1 measurable lesion (RECISTv1.1) and ECOG performance status ⱕ 2. Pts will receive oral DOV of 500 mg/day, on a 5-days-on / 2-days-off dosing schedule until disease progression, unacceptable toxicity, death, or discontinuation due to any other reason. Primary endpoint is 18-week progressionfree survival (PFS) rate (local review; RECIST v1.1) and secondary endpoints include overall response rate, disease control rate, duration of response, PFS, overall survival, safety, tolerability, pharmacokinetics, and pharmacodynamic effect of DOV on soluble plasma biomarker expression level. A 2-stage design with Bayesian interim monitoring (interim for futility analyses) will be used in each group. For stage 1, 20 pts will be enrolled into each group. If ⱖ 8 of the first 20 pts with measurable disease at baseline in either group are progression-free after 18 weeks of treatment, 20 additional pts will be enrolled into that group in stage 2. Preliminary results for each group will be evaluated in the interim analysis. As of 20 January 2013, 43 pts have been enrolled (12 with and 31 without FGFR2 mutations). Clinical trial information: NCT01379534.


Head and Neck Cancer 6000


Efficacy of cabozantinib (Cabo) in medullary thyroid cancer (MTC) patients with RAS or RET mutations: Results from a phase III study. Presenting Author: Steven I. Sherman, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Cabo extends progression-free survival (PFS) in patients (pts) with progressive, metastatic MTC (Schöffski, J Clin Oncol 30, 2012). Mutations in the RET oncogene are associated with most hereditary cases and ~half of sporadic cases of MTC. RAS gene mutations have recently been identified in subsets of RET wild type (wt) cases. Therefore, we investigated the association of RET (a prospectively defined endpoint) and RAS mutations (a post hoc analysis) with efficacy outcomes in the phase 3 study of cabo in MTC. Methods: Pts enrolled into the double-blind, placebo-controlled phase III trial were evaluated for the presence of somatic and germline RET mutations using Sanger and next generation methods. A subset of pts determined to be RET wt (44 pts) or RET unknown (41 pts) were then evaluated for tumor-associated mutations in KRAS, NRAS, and HRAS in codons 12, 13, and 61 by next generation sequencing. Impact of RET and RAS gene mutation status was evaluated with respect to PFS and tumor response rate (RR) according to RECIST. Results: RET status was determined in 65% of the study pts (215/330), of which 79% harbored an activating mutation, and 21% were RET wt. All RET mutational subgroups (RET mutated, RET wt, and RET unknown) showed hazard ratios indicating PFS benefit from cabo treatment, and demonstrated RRs between 22% and 32%. However pts harboring a RET mutation had longer median PFS on cabo (60 wks) than pts with wt RET (25 wks, PFS difference p⫽0.0001). Also, pts with the poor prognosis mutation RET M918T showed a longer median PFS on cabo treatment (61 wks) than pts with any other RET mutation (36 wks, PFS difference p⫽0.009). Patients with hereditary MTC had similar PFS to those with sporadic disease, and the presence of the common RET polymorphism G691S had no effect on either PFS or RR. Sixteen of 85 tested pts (5% of total study pts) with wt or unknown RET status were found to harbor a RAS gene mutation. The RAS-mutated pts showed a similar RR (31%) and PFS (47 wks) as RET mutated pts (32% and 60 wks). Conclusions: While hazard ratios indicate PFS improvement for all RET subgroups on cabo, the extent of benefit may depend in part on RET genotype. Cabo treatment benefit is also seen in pts harboring a RAS mutation. Clinical trial information: NCT00704730.

6002


Sym004, a novel strategy to target EGFR with an antibody mixture, in patients with advanced SCCHN progressing after anti-EGFR monoclonal antibody: A proof of concept study. Presenting Author: Jean-Pascal H. Machiels, Cliniques Universitaires St-Luc, Brussels, Belgium Background: Sym004 is a first-in-class drug mixture of two mAbs targeting non-overlapping epitopes on the EGFR. In preclinical models, Sym004 exhibited more pronounced EGFR internalization, degradation and tumor growth inhibition than cetuximab. Sym004 was investigated as monotherapy in palliative squamous cell carcinoma of the head and neck (SCCHN) patients (pts). Methods: SCCHN pts progressing after anti-EGFR mAbs for palliation were eligible. Documented clinical benefit (PR, CR or SD for at least 8 weeks according to RECIST) on an anti-EGFR mAbcontaining regimen followed by disease progression during or within 12 weeks after treatment cessation was required. The primary endpoint of this multicentre single arm trial was centrally evaluated progression-free survival (PFS), estimated by median PFS and 24 week progression free rate. Secondary endpoints included objective tumor response, safety, biomarkers and pharmacokinetics. Pts received weekly iv infusions of 12 mg/kg Sym004 until disease progression. Tumor evaluation was performed week 6, 12 and every 8 weeks thereafter. Results: Based on the statistical hypothesis, 26 pts were included, of whom 23 had progressed while on anti-EGFR mAb treatment. One of 19 evaluable pts was HPV positive and no EGFRvIII mutation was detected in 21 evaluable pts. No anti-drug antibodies were detected. Independent central review of CT/MRI scans from 20 evaluable pts showed tumor shrinkage in 8 pts (% decrease in sum of the largest diameters: 6.5, 7.1, 9.6, 10.2, 11.3, 13.6, 16.7, 27.1) and 14 pts had SD as best overall response. Median PFS was 82 days (95% CI: 41, 140) and 24 week progression free rate was 12% (95% CI: 1, 39). During treatment 25/26 (96%) pts developed skin rash with ⱖ grade 3 reported in 11/26 (42%) pts. Hypomagnesemia ⱖ grade 3 was reported in 10/26 (38%) pts. Sym004 treatment resulted in a marked down regulation of EGFR in centrally reviewed biopsies from skin and tumors. Conclusions: Sym004 demonstrated clinical activity in heavily pretreated, predominately HPV negative pts with advanced SCCHN previously progressing on or after anti-EGFR mAbs. No unexpected toxicities were reported. Clinical trial information: NCT01417936.

6001

363s Oral Abstract Session, Sun, 8:00 AM-11:00 AM

A randomized, open-label, phase II study of afatinib versus cetuximab in patients (pts) with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): Analysis of stage 2 (S2) following crossover. Presenting Author: Didier Cupissol, Centre Val d’Aurelle, Montpellier, France Background: This open-label trial assessed the efficacy of the irreversible ErbB Family Blocker afatinib (A) vs cetuximab (C) in R/M HNSCC pts following failure of platinum-containing therapy. In Stage 1 (S1), A and C had confirmed objective response rates (RECIST 1.0) of 16.1% vs 6.5% by investigator review (8.1% vs 9.7% independent central review [ICR]; Seiwert TY, et al. MHNCS 2012. Abs 235). S2 data after crossover are presented. Methods: In S1, pts were randomized 1:1 to oral A 50 mg/day or IV C 250 mg/m2/wk (400 mg/m2 IV loading dose) until progressive disease (PD) or intolerable drug-related adverse events (DRAEs). Pts could then crossover to the other treatment arm (S2), with treatment given until further PD or intolerable DRAEs. Tumor response in S2 (RECIST 1.0) was evaluated at 4 wks after crossover and every 8 wks thereafter. Results: 56% of pts crossed over into S2: 32 from A to C and 36 from C to A. Of these, 88% crossed over after PD and 12% after intolerable DRAEs. Baseline characteristics of S2 pts were similar in the A and C groups and treatment duration in S1 prior to crossover was comparable (A: 3.7 [0.2–15.7] months; C: 3.5 [0.0 –12.5] months). Median treatment duration in S2 was 2.1 (0.0 –7.6) months for A and 1.2 (0.0 –9.9) months for C. Tumor size decreases of ⱖ30% were observed in 1 pt in each treatment group (ICR). The disease control rate (DCR) for A was 33% vs 19% for C and the median progression-free survival time was 9.3 wks for A and 5.7 wks for C (ICR). The most frequently reported DRAEs (ⱖ20%) for A were rash/acne (56%), diarrhea (53%) and stomatitis (22%), and for C was rash/acne (44%). DRAEs of ⱖGrade 3 were seen in 47% of pts treated with A and 16% of pts treated with C. 12 A-treated patients had dose reductions to 40 mg and 1 pt had a further dose reduction to 30 mg; no C-treated pts had dose reductions. Conclusions: R/M HNSCC pts seem to benefit from sequential therapy with A/C or C/A, especially when using A treatment after C failure. Cross resistance is not universally present and further investigation of sequential treatment is warranted. Clinical trial information: NCT00514943.

6003


A phase II-III study comparing concomitant chemoradiotherapy (CRT) versus cetuximab/RT (CET/RT) with or without induction docetaxel/cisplatin/ 5-fluorouracil (TPF) in locally advanced head and neck squamous cell carcinoma (LASCCHN): Efficacy results (NCT01086826). Presenting Author: Maria Grazia Ghi, Medical Oncology Department, Venezia, Italy Background: This is the first phase III study directly comparing CRT vs CET/RT in LASCCHN. Primary endpoints of this study were to compare: 1) overall survival (OS) of induction vs. no induction arms; 2) Grade 3-4 in-field toxicity of CRT vs. CET/RT. Preliminary toxicity results of concomitant treatments (primary endpoint for this comparison) were reported at the 2012 ASCO meeting. Here we present response rate and survival data for the two concomitant treatments (CRT vs. CET/RT), irrespective of induction chemotherapy. Methods: Untreated patients with unresectable LASCCHN, stage III-IV, ECOG PS 0 –1 were randomized to a 2x2 factorial design: Arm A1: CRT (2 cycles of cisplatin/5fluorouracil concomitant to RT); Arm A2: CET/RT; Arm B1: 3 cycles of TPF followed by the same CRT; Arm B2:3 cycles of TPF followed by CET/RT. Results: A total of421 patients were randomized: 261 received CRT (131 Arm A1⫹ 130 Arm B1) and 160 received CET/RT (80 Arm A2⫹ 80 Arm B2). 82% were male; median age was 60y; PS of 0 (79%) or 1 (21%). Stage was III (32%) or IV (68%). Sites of disease were: oral cavity 20%, oropharynx 57%, hypopharynx: 23%. No significant differences were observed in patients’ characteristics distribution. At a median follow-up of 32.9 months, a total of 174 deaths occurred (204 required for final OS analysis). Data on activity and efficacy of CRT and CET/RT are shown in the Table. Conclusions: No significant differences were observed in response rate, progression free survival and OS between CRT and CET/RT. Pts are still being followed-up to assess OS of induction vs. no induction arms. Clinical trial information: NCT01086826. Complete response Partial response Complete ⴙ partial response Stable disease Progressive disease Median PFS (ITT analysis) – months Median OS (ITT analysis)-months

CRT

CET/RT

HR (95% CI)

36% 47% 83% 9% 8% 21.6 44.7

39% 49% 88% 6% 6% 20.7 44.7

1.05 (0.80-1.39) 0.86 (0.62-1.19)


364s 6004

Head and Neck Cancer Oral Abstract Session, Sun, 8:00 AM-11:00 AM

Adjuvant chemotherapy with S-1 after curative treatment in patients with head and neck cancer (ACTS-HNC). Presenting Author: Takahide Taguchi, Yokohama City University School of Medicine, Yokohama, Japan Background: To establish the efficacy of adjuvant chemotherapy with S-1 (tegafur gimeracil oteracil potassium) after curative treatment in patients with advanced squamous cell carcinoma of the head and neck (SCCHN), we conducted a randomized phase III study to investigate whether S-1 is superior to UFT (uracil/tegafur). Methods: Patients with SCCHN who had received curative treatment and were confirmed to be tumor-free were randomly assigned to receive UFT (300 or 400 mg/day for 1 year) or S-1 (80, 100, or 120 mg/day for 1 year). The primary end point was disease-free survival (DFS). Secondary end points were overall survival (OS), relapse-free survival (RFS), and safety. We estimated that 500 patients were needed to establish the primary end point. Results: From April 2006 through November 2008, a total of 526 patients (262 assigned to UFT; 264 assigned to S-1) were enrolled. The 3-year DFS rate was 66.0% in the UFT group and 64.1% in the S-1 group (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.66 to 1.16; [log-rank], P ⫽ .34). The 3-year OS rate was 75% in the UFT group and 82.9% in the S-1 group (HR, 0.64; 95% CI, 0.44 to 0.94; [log-rank], P ⫽ .022). The 3-year RFS rate was 63.6% in the UFT group and 68.2% in the S-1 group (HR, 0.81; 95% CI, 0.60 to 1.09; [log-rank], P ⫽ .16). There were no significant differences in 3-year DFS or RFS; however, the 3-year OS was significantly better in the S-1 group. The incidence of the following grade 3 or 4 events was significantly higher in the S-1 group: oral mucositis/stomatitis (2.4%), leukopenia (5.2%), neutropenia (3.6%), and thrombocytopenia (5.0%). Conclusions: S-1 was not demonstrated to be superior to UFT in terms of 3-year DFS; however, 3-year OS was significantly better with S-1 than with UFT. Clinical trial information: NCT00336947.

6006


Analysis of HPV and ERCC1 in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Presenting Author: Ranee Mehra, Fox Chase Cancer Center, Philadelphia, PA Background: We studied the association of human papillomavirus (HPV) and excision repair cross-complementation group 1 (ERCC1) tumor expression with clinical outcomes in patients (pts) with R/M SCCHN. Methods: Archival baseline specimens were obtained from pts on ECOG trials: E1395, phase III trial of cisplatin/paclitaxel (CP) vs. cisplatin/5-FU (CF), and E3301, phase II trial of docetaxel/irinotecan. HPV DNA was detected by in situ hybridization (ISH) with a wide spectrum HPV probe. Tumor p16 status was defined as positive if immunohistochemical staining for p16 was strong and present in ⬎80% of tumor cells. ERCC1 expression was measured (HistoRx PM-2000) and data analyzed using AQUA algorithms, after tissue was stained with ERCC1 ab (1:5000 HPA0297731, Sigma), and a wide-spectrum cytokeratin ab (Dako Z0622) for tumor mask. A prior determined cut point for nuclear staining was utilized. Fisher’s exact test and log-rank test were used to compare categorical variables and survival. Stratified logistic regression and Cox regression model were used to estimate odds ratio (OR) and hazard ratio (HR), respectively, adjusting for potential confounding factors. p-values were two-sided. Results: Tissue was evaluable from 65 tumors (T) for HPV, 66 for p16 (E1395 and E3301), and 43 for ERCC1 expression (E1395). 11 T were HPV⫹ (12 p16⫹), and 54 were HPV-/p16-. HPV⫹ tumors were similarly represented in all treatment groups (p⫽0.58). Objective response rates (RR): 67% for HPV⫹, 22% for HPV- (p⫽0.013); 60% p16⫹, 22% p16- (p⫽0.05). RR rates were calculated excluding cases with unevaluable/unknown responses. HR for OS was 2.66 (HPV, p⫽0.02) and 2.27 (p16, p⫽0.04), favoring HPV⫹/ p16⫹ pts. 18 T were ERCC1 high (H) and 25 ERCC1 low (L). HR for OS (H vs. L) was 1.96 (p⫽.11) RR: CF, 58% (L), 29% (H); CP, 33% (L), 56% (H). A test of ERCC1 by treatment interaction (p⫽0.12) suggested the effect of ERCC1 may be different for taxane vs. non-taxane regimens. Conclusions: This is the first study to show that HPV⫹/p16⫹ status is associated with a significant improvement in RR and OS among pts treated for R/M SCCHN. ERCC1 L was associated with a trend towards a better OS.

6005


E 1308: A phase II trial of induction chemotherapy (IC) followed by cetuximab with low dose versus standard dose IMRT in patients with human papilloma virus (HPV)-associated resectable squamous cell carcinoma of the oropharynx (OPSCC). Presenting Author: Shanthi Marur, The Johns Hopkins University, Baltimore, MD Background: HPV is associated with 60-80% of OPSCC. E2399 results showed IC followed by (f/b) paclitaxel (P)/3D RT (70Gy) improved 2-yr progression-free (PFS) for HPV⫹ compared to HPV- OPSCC. We studied a regimen with 20% radiation dose reduction to 54Gy in HPV ⫹ OPSCC patients (pts) with a clinical complete response (CCR) to IC. Methods: Stage III/IVA,B resectable HPV⫹ OPSCC were included. Eligible pts received IC q3 week x 3 with P 90mg/m2 days (D) 1,8, 15, cisplatin (CDDP) 75mg/m2 D1, and cetuximab (C) 400 mg/m2 D1, cycle 1 f/b C 250 mg/m2 weekly. Primary tumor and involved nodal response to IC were determined independently. Pts recieved IMRT 54Gy/27 fxs with weekly C for CCR vs. 69.3Gy/33 fxs with weekly C if ⬍CCR. Primary endpoint was 2-year PFS; secondary endpoints were toxicity, OS, response rate, QOL and correlative biomarkers. Results: From March 2010 to Oct 2011, 90 pts were enrolled (80 analyzable). Median age was 57 years, 95% men, 93% Caucasian, 91% PS 0, 46% never smokers, 84% not current smokers. Nodal stage: 39%-N2B, 29%-N2C, T stage: 23%-T1, 50%-T2, 16%-T3, 10%-T4. 96% received all 3 cycles of IC. Grade 3/4 toxicities included: rash (25%), neutropenia (11%). During CRT: oral mucositis (31%), dysphagia (17%), radiation dermatitis (8%). Response: Biopsy at primary site postbaseline measurements rendered 7/80 pts unevaluable (UE), 6/7 had investigatorreported CCR to IC. The centrally reviewed and investigator reported primary site CCR rate to IC was 63.8% ( 95% CI: 52.2%, 74.2%) and 71.3% (95% CI: 60.0%, 80.8%), respectively. Radiation: 73.8% (59/80 pts) received low dose IMRT/C to primary [54Gy (56), 52Gy (1), 40Gy (2)]. Best overall clinical response was 86% (CR ⫹PR⫹SD) with 14% UE. Rate of post-treatment neck dissection in low dose vs other RT gp is 13.4% vs 22.2% ( p value of 0.46), respectively. Median follow up is 11.8 months. Conclusions: Overall, IC with P, CDDP and C f/b low dose RT with C was well tolerated, with all pts responding and very low grade 3/4 toxicities. Data on PFS are premature. A 2 year PFS of 85% or better will be considered worthy of further study. Clinical trial information: NCT01084083.

6007


p16 expression as a human papillomavirus (HPV)-independent prognostic biomarker in non-oropharyngeal squamous cell carcinoma (non-OPSCC). Presenting Author: Christine H. Chung, The Johns Hopkins University, Baltimore, MD Background: p16 is an important tumor suppressor and cell cycle regulator that is commonly lost in HPV-negative (-) and upregulated in HPV-positive (⫹) OPSCC. While the role of p16 expression in OPSCC as a surrogate marker of HPV infection and its association with prognosis are well established, its significance has not been studied in non-OPSCC including oral cavity, hypopharynx and larynx, where HPV infection is rare. We hypothesize that p16 expression is a prognostic biomarker of favorable outcome (progression-free and overall survival) in non-OPSCC. Methods: p16 expression in non-OPSCC from RTOG 0129, 0234 and 0522 was determined by immunohistochemistry (p16 mouse monoclonal antibody, prediluted, MTM-CINtech, 9518) and considered positive if ⬎70% of the tumor cells demonstrated diffuse staining. The high risk HPV status in non-OPSCC from RTOG 0129 and 0522 was determined by in situ hybridization using a cocktail probe including HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 66. Hazard ratios from Cox models were expressed as positive/negative, stratified by trial, and adjusted for age, gender, T, and N stage. Results: p16 expression was positive in 14.1% (12/85), 24.2% (23/95) and 19.0% (27/142) of non-OPSCC from RTOG 0129, RTOG 0234, and RTOG 0522, respectively. HPV ISH was positive in 6.5% (6/93) and 6.9% (7/101) of non-OPSCC from RTOG 0129 and RTOG 0522, respectively. There was moderate agreement between p16 and HPV status (kappa⫽0.53). The hazard ratios for p16 expression are 0.63 (p⫽0.03) and 0.56 (p⫽0.01) for PFS and OS, respectively. In 0522, there was no interaction between p16 status and two treatment arms (RT⫹cisplatin⫹/cetuximab). In comparison of OPSCC and non-OPSCC, patients with p16(⫹) OPSCC have better PFS and OS than patients with p16(⫹) non-OPSCC, but patients with p16(-) OPSCC and non-OPSCC have similar outcomes. Conclusions: Similar to results in patients with OPSCC, patients with p16(⫹) non-OPSCC have better outcomes than patients with p16(-); however, the differential appears smaller than has been observed in HPV(⫹) OPSCC. Further studies are warranted to delineate the role of p16 expression as a prognostic biomarker in non-OPSCC and OPSCC. Clinical trial information: NCT00265941, NCT00047008, NCT00084318.




Multimodality determination of HPV status in head and neck cancers (HNC) and development of an HPV signature. Presenting Author: Zhixiang Zuo, University of Chicago Medical Center, Chicago, IL Background: Determination of HPV status is prognostically important, and various testing modalities are commonly used. Discordant results are occasionally observed and a gold standard (for research purposes) is E6/E7 mRNA expression. We aimed to evaluate accuracy of multiple research HPV tests compared to p16 expression/anatomic site, and developed a new HPV signature that we hypothesize will capture HPV-related oncogenic processes independent for all HPV types. Methods: HNCsamples from 136 patients were evaluated by: 1) nested E6 PCR (DNA) (Sotlar 2004), 2) qPCR for E6, E7 (HPV16), E6, L1 (HPV18) (mRNA), 3) p16 expression by IHC and/or mRNA. Results were correlated with anatomic site. A gene expression (GE) signature was developed based on Agilent 4x44Kv2 data and validated in a second cohort. In equivocal cases mutational status of TP53 was evaluated. Results: p16/CDKN2A expression was unreliable outside the oropharynx (OP) (81% false-positives in non-OP tumors, compared to 12% for OP tumors). Anatomic site as described by clinical reports was unreliable. In our cohort, 52 out 77 OP (67.6%) were HPV positive by DNA and RNA based approaches, 3 only by DNA. DNA and RNA based approaches appeared to be similarly accurate and concordant in 97% of samples. The newly developed HPV-GE signature was highly accurate, and allowed to reconcile discrepant cases, suggesting that the DNA-based approach overcalled HPV(⫹) in 2 tumors while the RNA based approach underreported HPV status in two cases. Expression levels of E6/E7 mRNA showed extensive variability in HPV(⫹) samples. Interestingly the HPV-GE signature suggested continuous/overlapping biology for a minority of cases. Two tumors (1 supraglottis/HPV18, 1 oropharynx/ HPV16) tested HPV(⫹) by DNA/RNA, p16/CDKN2A, and HPV-GE signature while at the same time having TP53 mutations. Conclusions: p16 should not be used outside the oropharynx and anatomic allocation may also be inaccurate. DNA and mRNA based approaches perform equally well and can be reconciled using the HPV-GE signature. The HPV-GE signature supports the hypothesis that HPV(⫹) and HPV(-) biology may overlap in a minority of cases.

6010


6009

365s Clinical Science Symposium, Mon, 11:30 AM-1:00 PM

The Cancer Genome Atlas: Integrated analysis of genome alterations in squamous cell carcinoma of the head and neck. Presenting Author: David N. Hayes, Lineberger Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC Background: Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer death in worldwide. Methods: The Cancer Genome Atlas (TCGA) is conducting DNA, RNA and miRNA sequencing along with DNA copy number profiling, quantification of mRNA expression, promoter methylation, and reverse-phase protein arrays on surgically resected samples from previously untreated patients with HNSCC. We report for the first time the integrated genomic alterations for 279 HNSCC patients. Results: The demographics of 279 patients enrolled in the study show a median age of 61 years (range: 19-90); 27% female, and history of tobacco smoking in 80%. Over 30 sites of significant somatic copy number alteration were identified as well as 15 significantly mutated genes at the false fiscovery rate of ⬍0.01, including: CDKN2A, TP53, PIK3CA, FAT1, MLL2, TGFBR2, HLA-A, NOTCH1, HRAS, NFE2L2, and CASP8. Evidence of the human papilloma virus (HPV) was observed by sequencing in up to 25% of samples. Integrated genomics data supported expected patterns including the predominant role of HPV type 16 infection in nonsmoking patients with tumors of the oropharynx which are wild-type for the tumor suppressor genes p16, Rb, and p53. In addition, striking atypical cases and viral infections will be presented as well as novel anti-correlation of HPV infection with focal copy number alterations including EGFR amplification and chromosome 11q. By contrast co-occurrence of HPV with focal deletions of TRAF3 and mutations of the oncogene PIK3CA will be described. Integrated tumor subtypes defined by gene expression, methylation, and miRNA will be presented in conjunction with associated mutations exclusive to tumor subtypes. For example, alterations of the “antioxidant response elements” transcription activators NFE2L2 and KEAP1 will be documented in association with the “classical” expression subtype of HNSCC, as has been shown in lung squamous cell carcinoma. By contrast, co-occurrence of CASP8 and HRAS will be documented in the “Basal” subtype. Conclusions: While, HNSCC is a heterogeneous tumor, coordinated tumor alterations are observed, including potentially targetable genes and pathways. Results presented on behalf of TCGA.

6011


Genomic profiling of kinase genes in head and neck squamous cell carcinomas to identify potentially targetable genetic aberrations in FGFR1/2, DDR2, EPHA2, and PIK3CA. Presenting Author: Michaela K. Keck, University of Chicago, Chicago, IL

An epithelial-mesenchymal transition (EMT) gene signature to predict resistance to EGFR inhibition and AXL identification as a therapeutic target in head and neck squamous cell carcinoma. Presenting Author: Robert Cardnell, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: Development of targeted therapies in head and neck squamous cell carcinoma (HNSCC) has been limited due to the lack of validated, oncogenic genetic aberrations. We determined mutations and copy number (CN) events in kinases in a 120 patient cohort in order to identify new potential treatment targets. Methods: Fresh frozen tumor (ⱖ70%) and matched normal tissue from 120 patients with treatmentnaïve, locoregionally advanced HNSCC were evaluated using targeted, massively parallel sequencing (Illumina HiSeq) for 60 cancer-relevant, targetable kinases (as well as PI3K related tumor suppressors). CN analysis was performed on the NanoString nCounter for 40 cancer relevant kinases. Mutations were modeled bioinformatically using the CHASM oncogenic driver prediction algorithm and reviewed for prior occurrence in COSMIC. Results: We identified somatic mutations in three potentially targetable receptor tyrosine kinases: 7 (5.8%) mutations were identified in DDR2, 3 (2.5%) mutations in FGFR2, and 4 (3.3%) mutations in EPHA2. Furthermore we identified multiple mutations in several PI3K family members including PIK3CA (N⫽22 (18,3%)) as well as PI3K related tumor suppressors (PTEN N⫽3 (2.5%)), INPP4B N⫽7 (5.8%)). Several mutations showed low CHASM scores consistent with oncogenic driver characteristics. We identified recurrent copy number aberrations in two kinases – FGFR1 (N⫽15 (13%), median CN:3.27 (3.03-15.662)), and EGFR (N⫽13 (11%), median CN: 3.73 (2.93-17.75)). Interestingly similar mutations/copy number events have been described in other cancer types including endometrial, and lung squamous cell carcinomas. Conclusions: We identified multiple novel mutations and copy number events in 45% of tumors: genetic aberration in FGFR1, FGFR2, DDR2, EPHA2, and the PI3K pathway are candidate oncogenic drivers that are potentially targetable. Results are corroborated by similar aberrations in other cancer types e.g. lung squamous cell carcinomas that are already being explored as therapeutic targets. Further validation and initiation of focused clinical trials in mutation pre-selected patients is indicated.

Background: Epithelial-mesenchymal transition (EMT) has been associated with EGFR inhibitor resistance in preclinical studies of head and neck squamous cell carcinoma (HNSCC). Recently, we developed an EMT signature that predicts EGFR inhibitor resistance in lung cancer. Using this signature, we explored the association between EMT and drug response in HNSCC, focusing on the tyrosine kinase Axl as a potential therapeutic target. Methods: We conducted an integrated molecular and drug response analysis in HNSCC. A 76-gene EMT signature previously developed and validated in lung cancer was tested in HNSCC cell lines (n⬎50) and patient tumors from The Cancer Genome Atlas (TCGA) (n⫽113) and a MDACC cohort (n⫽105). Reverse phase protein array (RPPA) and proliferation assays were used to measure protein expression and sensitivity to erlotinib and the Axl inhibitors SGI-7079 and TP-0930. Results: The EMT signature identified distinct epithelial and mesenchymal subsets of HNSCC among cell lines and patient tumors. RPPA experiments revealed higher protein levels of the receptor tyrosine kinase Axl, vimentin, and N-cadherin and lower expression of E-cadherin and beta-catenin in mesenchymal HNSCC (p-values ⬍0.02). Elevated Axl expression was also associated with significantly shorter overall survival in patients with locally advanced HNSCC (p⬍0.001 in TCGA cohort; p⫽0.003 MDACC). Consistent with previous studies, mesenchymal HNSCC cells exhibited resistance to erlotinib (IC50 ⬎10␮M); however, we discovered that mesenchymal HNSCC were highly sensitive to two Axl inhibitors, SGI-7079 and TP-0930 (IC50s ⱕ1.2␮M and 0.2uM, respectively). Conclusions: Our EMT gene expression signature identified discrete epithelial and mesenchymal subgroups of HNSCC. Mesenchymal HNSCC cells expressed higher levels of Axl protein and exhibited sensitivity to Axl inhibition, but resistance to erlotinib. These results highlight differences in drug response between epithelial and mesenchymal cancers and support Axl as a potential therapeutic target and predictive marker of EGFR inhibitor resistance in HNSCC. (Funded in part by 5 P50 CA097007-10)


366s 6012

Head and Neck Cancer Poster Discussion Session (Board #1), Sat, 1:15 PM-5:15 PM and 4:45 PM-5:45 PM

Effect of PDL-1 expression on prognosis in head and neck squamous cell carcinoma. Presenting Author: Maria Vasilakopoulou, Yale University, New Haven, CT Background: The recent demonstration that immunotherapeutic approaches may be clinically effective for cancer patients has renewed the interest for this therapeutic strategy. Engagement of programmed death-1 receptor (PD-1), expressed on activated T-cells, by its ligands, results in a negative regulatory effect, with inhibition of downstream cellular signaling events. Our aim was to investigate the expression and prognostic significance of immunoresistance molecule PDL-1 (the negative regulator programmed death-1-ligand 1) on an annotated HNSCC tissue microarray. Methods: A tissue array composed of 400 larynx cancers treated with surgery followed by radiotherapy was constructed. PDL-1 protein expression levels were assessed using automated quantitative protein analysis (AQUA). The objectives of this analysis were to determine the association of PDL-1 with efficacy outcomes ( overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) ). The univariate and multivariate Cox proportional hazards models were used to evaluate the relationship between PDL-1 and event-time distributions. Event-time distributions were estimated by the Kaplan-Meier method and compared by the log-rank test. Results: Mean follow-up time for the entire cohort was 39.34 months. Two-hundred thirty eight of 400 cases had sufficient tissue for AQUA analysis. High tumor PDL-1 expression was associated with favorable outcome for OS (P⫽0.029) and trended towards improved DFS (P⫽0.06) at 5 years. In multivariable analysis, adjusting for well-characterized prognostic variables, PDL-1 expression status retained its prognostic significance for OS and there was again a trend for PFS (p⫽0.05). Conclusions: This paradoxical result is in accordance with reported studies in HPV-associated HNSCC where PD-1(⫹) T cells were associated with favorable clinical outcome. It is possible that PDL-1 detection may reflect a previous immune response against tumors. Further work will determine whether PD-1/PD-L1 blockade induces tumor regression in HNSCC.

6015


Prognostication of survival from nasopharyngeal carcinoma by reduction of plasma Epstein-Barr viral DNA load at midpoint of radiotherapy course: A new paradigm of prognostication. Presenting Author: Anthony T. C. Chan, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, China Background: To test the hypothesis that prognostication of treatment outcome is feasible by biomarker response at mid-course of chemoradiotherapy (CRT)/ radiotherapy (RT), with respect to the plasma load of EpsteinBarr viral (EBV) DNA in nasopharyngeal carcinoma (NPC). Methods: 107 patients with stage IIB-IV NPC were prospectively studied. Plasma EBV DNA load was measured by quantitative PCR before therapy (pre-DNA), at completion of 4 weeks of CRT/RT (mid-DNA), and within 3 months of completion of therapy (post-DNA). The endpoints are post-DNA load, a recognized surrogate of survival, and clinical outcome. Results: 93% of patients had detectable EBV DNA before therapy (median load ⫽ 972 copies/ml). EBV DNA became undetectable in 55 (51%) patients at the end of week 4 of therapy. Detectable mid-DNA was associated with worse clinical outcome (median follow-up time, 6.2 years), for distant failure (HR 12.02, 95% CI 2.78-51.93; P⬍0.0001), progression-free survival (HR 4.05, 95% CI 1.89-8.67, P⬍0.0001), and overall survival (HR 3.29, 95% CI 1.37-7.90, P⫽0.0077). About three-quarters of all failures were associated with detectable mid-DNA, whereas about one-third of all failures were associated with detectable post-DNA. Patients with detectable mid-DNA which disappeared after RT continued to sustain a less favourable prognosis than those with undetectable mid-DNA. Stratification by tumor stage (II, III, IV) has no significant prognostic effect. Conclusions: Unfavorable EBV DNA response at mid-course of radiotherapy/chemoradiotherapy is an adverse prognosticator for treatment outcome, is linked to majority of all failures, and discriminates outcome better than tumor stage. The data could provide a basis for trial design that addresses alteration of therapy intensity during the latter phase of chemoradiotherapy, and adjuvant therapy.

6014


Postoperative detection of circulating EGFR transcripts as a surrogate marker for circulating tumor cells to predict tumor recurrence after adjuvant radio(chemo)therapy in locally advanced squamous cell carcinoma of the head and neck (LASCCHN). Presenting Author: Inge Tinhofer, Department of Radiooncology CCM/CVK, Charite University Hospital, Berlin, Germany Background: The prognostic role of circulating tumor cells (CTCs), occurring in up to 35% of LASCCHN patients, is still largely undetermined. In this prospective study we tested whether the detection of CTCs was associated with treatment outcome of adjuvant radio(chemo)therapy. Methods: Patients with LASCCHN (N⫽64) of the oropharynx (N⫽40), oral cavity (N⫽15), hypopharynx (N⫽3) or CUP (N⫽6) presenting after tumor surgery for adjuvant treatment were enrolled in this study. Peripheral blood samples were collected before start and at the end of adjuvant radio(N⫽22) or radiochemotherapy (N⫽42). Transcripts of epidermal growth factor receptor (EGFR) were detected using RT-PCR. Samples positive in at least 2 of 3 PCR replicates were considered CTC-positive, according to previous studies. CTC detection was correlated with failure-free (FFS) and overall survival (OS). Results: CTCs were detected in blood samples from 21 of 64 patients (33%) whereas all 30 samples from healthy donors used as control were negative. The CTC⫹ and CTC- patient cohorts were comparable with relation to sex, age, smoking history, T and N stage, tumor localization, type of adjuvant treatment and the median follow-up for OS and FFS. Detection of CTCs before or after adjuvant treatment was not predictive for OS. However, the presence of CTCs at the start of adjuvant radio(chemo)therapy identified patients with reduced FFS (CTC- vs CTC⫹ [% of patients without relapse at 2 years]: 89% vs. 60%, HR: 0.30, 95% CI: .08-.92, p⫽.037). Multivariate Cox regression analysis revealed that the prognostic value of the CTC status was not influenced by the T and N stage and independent of whether the adjuvant treatment consisted of radio- or radiochemotherapy. Conclusions: Persistence of CTCs after tumor resection as detected by EGFR transcripts was established as an independent marker for tumor recurrence in LASCCHN. Postoperative detection of CTCs might prove useful for risk stratification in future clinical trials for optimization of adjuvant treatment, especially for the poor-prognosis group of CTC⫹ patients.

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Association of the 3’-untranslated region KRAS-variant with cisplatin resistance in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Presenting Author: Joanne B. Weidhaas, Yale School of Medicine, New Haven, CT Background: A germline mutation in let-7 complementary site 6 (LCS6) within the KRAS 3’-untranslated region (rs61764370, the KRAS-variant: TG/GG) is known to associate with poor outcome and drug resistance in various cancers compared to the wild type allele (TT). We examine the prognostic significance of the KRAS-variant in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Methods: The KRASvariant was determined in 116 tumor DNA samples from HNSCC patients enrolled in 3 clinical trials and a tissue collection study using a previously validated PCR-based assay. Results: KRAS-variant status could be determined in 108/116 (93%) samples and an allele frequency of TG/GG was 28.7%. These results were correlated with patient demographics, p16/ human papillomavirus (HPV) status and clinical outcome. There was no association between p16/HPV status and the KRAS-variant status (Fisher’s exact test, p⫽1.0). The KRAS-variant was associated with poor progressionfree survival in patients treated with cisplatin⫹/-cetuximab (log-rank p⫽0.002) but this association was not observed in docetaxel/bortezomib treated patients (log-rank p⫽0.89). Conclusions: KRAS-variant is a potentially promising biomarker of poor prognosis and a predictive biomarker of cisplatin resistance in R/M HNSCC. Prospective validation is warranted. Clinical trial information: NCT00003809.




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367s Poster Discussion Session (Board #7), Sat, 1:15 PM-5:15 PM and 4:45 PM-5:45 PM

Assessment of early tumor response to induction chemotherapy (IC) in locally advanced squamous-cell carcinoma of head and neck (LASCCHN) with 18FDG PET-CT: A prospective trial. Presenting Author: Ulisses Ribaldo Nicolau, Hospital A.C. Camargo, São Paulo, Brazil

Positron emission tomography and stage migration for head and neck cancer. Presenting Author: Noam Avraham VanderWalde, Department of Radiation Oncology, University of North Carolina At Chapel Hill, Chapel Hill, NC

Background: Response to IC with triplet regimens adding taxanes to cisplatin and 5-fluorouracil (TPF), followed by chemoradiotherapy (CRT) for LASCCHN, is usually evaluated after 2 cycles of IC, based on bidimensional WHO or modified WHO criteria. Concerns regarding toxicity profile of TPF suggest a potential benefit of an early response evaluation approach that could select patients who would be spared from a toxic regimen and promptly started on an alternative treatment. The aim of this study is to assess the ability of evaluating early response after the first IC cycle based on a 40% decrease in standard-uptake value (SUV) measured by 18 FDG PET-CT on the 14th day. Methods: Patients with LASCCHN who underwent IC with TPF were prospectively evaluated. Staging procedure included locoregional and chest imaging, endoscopic examination and FDG PET-CT. At day 14 of first cycle, a second FDG PET-CT was performed and treating physicians were blinded for these findings. All cases were conducted according to the usual post-cycle 2 WHO or modified WHO criteria evaluation. Written informed consent was obtained from all recruited patients. Results: Between February 2010 and October 2012, 40 stage III/IV LASCCHN patients (34 oropharyngeal, 3 hypopharyngeal and 3 laryngeal) were recruited. With a median follow up of 11.4 months the actuarial 2 years overall (OS) and disease free survival (DFS) of all patients were 81.4% and 69.2%, respectively. Responders (any decrease of SUV) at day 14 PET CT had a better OS (90 vs. 27% - p⬍0,001) and DFS (76 vs. 0% - p⬍0,001) as compared to non-responders. Decrease of at least 40% in the SUV of primary tumor predicted a better DFS (100 vs. 51% p⫽0,007). Conclusions: These results suggest a potential role of early response evaluation with 18 FDG PET-CT in patients with LASCCHN undergoing IC. A SUV decrease of at least 40% predicts better DFS. An increase in the SUV predicts a poor prognosis.

Background: Positron emission tomography (PET) is often used for the staging of head and neck cancer (HNC). The purpose of this study is to explore the association between the increased utilization of PET and stage/survival in the managed care environment. Methods: Adult patients diagnosed with HNC (n⫽958) between 2000-2008, at 4 integrated health systems (Group Health Cooperative, Seattle; Health Alliance Plan/Henry Ford Health System, Detroit; Kaiser Permanente Colorado and Northwest, Portland) were identified via tumor registries linked to claims data. We compared AJCC stage distribution, patient/treatment characteristics, and survival between pre-PET era (2000-2004) vs. PET era (2005-2008), and those with PET vs. those without, during the PET era. AJCC stage was grouped into stage I/II (localized), stage III/IVa/IVb (locally advanced), and stage IVc (metastatic). Ordered logistic regression estimated the effects of PET utilization on upstaging. Kaplan-Meier estimates described overall survival (OS) differences between PET users and nonusers in the PET era. Cox proportional hazards regression evaluated the effect of PET use on survival. Results: There was a non-significant increase in stage III/IVa/IVb (40% to 44%) with a decrease in stage I/II (58% to 52%) between pre-PET era and PET era (p⫽0.11). During the PET era, patients with PET were more likely stage III/IVa/IVb and less likely stage I/II compared to patients without PET (III/IVa/IVb: 62% vs. 29%, I/II: 35% vs. 68%). On multivariate analysis those who were staged with PET were twice as likely to have locally advanced disease (OR 2.091; p⫽0.006). There was no difference in stage IVc. Patients with PET scans were more likely to receive chemotherapy with radiation and less likely to receive no treatment. 3-year actuarial OS for patients (all stages) with and without PET was 81% vs. 77% (p⫽0.261). 3-year actuarial OS for patients staged III/IVa/IVb with and without PET was 58% vs. 41% (p⫽ 0.001). Conclusions: HNC patients were more likely to be upstaged with the use of PET. There was an improvement in survival in stage III/IVa/IVb patients, but no difference in survival across all stages. This likely reflects selection bias and stage migration rather than improved outcomes among individual patients.

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Radiographic extracapsular extension (ECE) and treatment outcomes in locally advanced oropharyngeal carcinoma (OPC). Presenting Author: Benjamin H. Kann, Department of Radiation Oncology, Mount Sinai Medical Center, New York, NY

Sorafenib in recurrent and/or metastatic salivary gland carcinomas (RMSGCs): An investigator-initiated phase II trial (NCT01703455). Presenting Author: Laura D. Locati1, 1Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Background: Pathologic ECE (pECE) of tumor through lymph node (LN) is a poor prognosticator for OPC and typically diagnosed upon surgical LN removal. At our institution, experienced radiologists routinely identify ECE on pretreatment CT. The prognostic value of radiographic ECE (rECE) is less clear and may prove clinically useful. In this study, we evaluate rECE as an independent prognosticator in OPC. Methods: Retrospective review of 185 patients with locally advanced OPC treated in our department from 2006-2012. 109 patients had accessible pretreatment CT reports clearly stating the presence or absence of rECE. Patients were treated with definitive concurrent chemoradiation therapy (CCRT) (30%), induction chemo then CCRT (47%), or surgery with adjuvant CCRT (14%) or RT (9%). Kaplan-Meier survival analysis compared these cohorts for locoregional control (LRC), distant control (DC), and progression-free (PFS) and overall survival (OS); log-rank tests were performed for significance. Multivariate analysis was conducted via cox-regression. Results: Median follow-up of the 109 patients was 31 months (range: 1-80 months). 61 patients had rECE(⫹) and 48 had rECE(-) scans. There was no significant difference between the cohorts in terms of median age, stage, treatment type, smoking history, or tumor HPV status. There was a difference in nodal stage with 83% of rECE(⫹) patients having N2-3 disease versus 67% of rECE(-) patients (p⫽0.02). On univariate analysis, there were differences between the rECE(-) versus rECE(⫹) cohorts in OS (4yr: 92% vs 72%, p⫽0.01), PFS (4yr: 92% vs 62%, p⫽0.002), and DC (4yr: 98% vs 76%, p⫽0.006), with no difference in LRC (4yr: 95% vs 91%, p⫽0.35). On multivariate analysis factoring in age, smoking history, stage, and treatment type, rECE presence was a negative predictor of OS (hazard ratio, 0.26; 95% CI, 0.07 to 0.95) and PFS (hazard ratio, 0.23; 95% CI, 0.06 to 0.81), with DC approaching significance (hazard ratio, 0.13; 95% CI, 0.02 to 1.05). Conclusions: While pECE is an established risk factor for locally advanced OPC, this study suggests that rECE may be an independent poor prognosticator of PFS, OS and DC with potential importance in guiding clinical management.

Background: Palliative chemotherapy is the standard of care for RMSGCs. However its activity is usually poor especially in adenoid cystic carcinoma (ACC), while in histotypes other than ACC (non ACC) the response, if any, is of short duration. Some preclinical and clinical evidence suggest a rationale for the employment of anti-angiogenetic agents in RMSGCs, such as sorafenib. Methods: Subjects withproven RMSGC not amenable to surgery and/or radiotherapy were enrolled to receive sorafenib at 400 mg BID q28 days until disease progression, unacceptable toxicity or consent withdrawal. Primary endpoint was response rate (RR) (CR⫹PR) according to RECIST; secondary objectives included RR according to CHOI criteria, disease control rate (DCR) and toxicity. 37 subjects were required to test the null hypothesis that RR will be ⱕ 5% versus the alternative that RR ⱖ 20% within a two stage Simon design. At least 4 responders were necessary to reject the null hypothesis. Results: 19 ACC and 18 non ACC subjects were accrued from September 2010 to September 2012. 21 patients had received at least one chemotherapy regimen for RMSGC. Overall 6 PRs according to RECIST were recorded corresponding to a RR of 16% (95% CI 6,2-32,0) (11% in ACC and 22% in non ACC). PR according to CHOI was observed in 10 cases (of which only 2 were concordant with RECIST); no response was reported in 15 cases while CHOI response was not evaluable in 12 patients. A dramatic necrotic evolution of the disease, which resulted in cavitation of metastatic lesions in one case, was observed in two patients with mucoepidermoid cancer (MEC). SD was 57% lasting a median of 7 months (range 2-15⫹ months). At a median follow up of 10 months (range 3-28⫹ months): 5 patients are still receiving sorafenib; 15 are no longer being treated and 17 have died. AEs were generally consistent with previous sorafenib studies, except for one G5 toxicity due to meningitis (probably related to necrosis of a local relapse) and one G3 aspergillus abscess. Conclusions: Sorafenib is the first anti-angiogenetic agent to demonstrate some activity in RMSGCs, particularly in MEC. Molecular analyses, typifying MEC and ACC are ongoing. Clinical trial information: NCT01703455.


368s 6021


Phase II study of dovitinib (TKI258) in patients with progressive metastatic adenoid cystic carcinoma. Presenting Author: Patrick Michael Dillon, University of Virginia, Charlottesville, VA Background: Adenoid cystic carcinoma (ACC) is an uncommon malignancy of secretory glands for which there is no standard systemic therapy. At least 90% of ACC tumors carry a t(6;9)(q22–23;p23–24) chromosome translocation that results in overexpression of the MYB oncogene that in turn upregulates FGF2 and other growth factors. Dovitinib is a multiple receptor kinase inhibitor that could potentially block autocrine activation of the FGFR and VEGFR-mediated angiogenesis. In a mouse model, dovitinib suppressed the growth of low passage ACC xenografts. Methods: In this open-label, single-arm trial, patients (n⫽21) with metastatic ACC that progressed in the last 6 months were treated with dovitinib 500 mg/d, 5-days on/2-days off. The primary endpoint was objective response rate using a two-stage design to test a null and alternative rate of 1% and 18%, respectively, with 90% power and type I error ⬍5%. Secondary endpoints were progression-free survival, safety, quality of life, biomarker studies, and change in tumor growth rate. Results: All 21 patients (median age 54.3, range 29-74) had previous treatment with chemotherapy, radiotherapy or targeted agents. Median duration of treatment to date is 5.7 months (range 2-10 months) and is ongoing in 11 patients. Nine of 21 patients required dose reductions. Grade 3/4 drug-related adverse events included thromboembolism (4), hematuria (1), dehydration (1), pneumonia (2), hypertriglyceridemia (3), diarrhea (2), stomach pain (2), anxiety (1), transaminitis (3) and cytopenias (4). One death occurred unrelated to study drug. Among 19 evaluable patients, 2 had partial responses by RECIST criteria (1 with lung metastases and 1 with tracheal recurrence and stable bone metastases). Both experienced improvements in pain ratings and are free of disease progression at 8⫹ and 5⫹ months. Stable disease ⬎6 months was observed in 9 patients while 6 others with shorter follow-up have not progressed. Four patients progressed early (⬍4 months) and two are too early to assess. Conclusions: Dovitinib produces objective partial responses and prolonged tumor stabilization with acceptable toxicity in patients with progressive ACC. Clinical trial information: NCT01524692.

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A phase II study of everolimus in patients with aggressive RAI refractory (RAIR) thyroid cancer (TC). Presenting Author: Jochen H. Lorch, DanaFarber Cancer Institute, Boston, MA Background: We present results of an open label phase II study of the mTOR inhibitor Everolimus in patients (pts) with RAIR TC. Methods: Pts with metastatic, incurable RAIR TC who had shown radiographic progression within 6 months prior to enrollment received Everolimus 10mg orally once daily. Responses were monitored by CT’s every two months. The primary endpoint was progression free survival. Sequential biopsies were obtained in selected pts. Results: Enrollment to the differentiated TC (DTC) cohort finished in Jan 2013 and included 33 pts, among them 11 with Hurthle cell TC. Exploratory cohorts enrolled 10 pts with medullary [MTC] and 5 with anaplastic [ATC] with 2 added openings remaining for ATC. For the DTC cohort, median time on study to date is 10 months (mo) (⬍1-23⫹). 31 pts are evaluable at this time. PFS in the DTC cohort by Kaplan-Meier (K-M) analysis is 16.0 mo (95%CI 10-NR). Currently, disease stability for 6 and 12 mo or more was achieved in 18 and 10/31 pts, respectively, 11 pts remain on study. Median OS was not reached but 1 year survival by K-M analysis was 76%. One pt achieved a PR. 3 pts with DTC underwent sequential biopsies which revealed activation of autophagy while markers for apoptosis were not detected. Among 10 MTC pts, one achieved a PR and 9 pts had stable disease for 6 mo or more (6-33⫹). Among 5 ATC pts, 3 progressed, one has ongoing disease stability for 5 mo. One patient achieved a complete response that lasted for 18 mo and whole exome sequencing revealed somatic loss of function mutation affecting the Tuberous Sclerosis 2 (TSC2) protein, a negative regulator of mTOR activity [TSC2 (Q1178*) and FLCN (R17fs)]. Most common treatment-related adverse events were as anticipated and included fatigue, stomatitis and infections. Grade (gr) 3 events included infection 5, weight loss 3, leukopenia 3, thrombocytopenia 3, fatigue 3, hypophosphatemia 2, stomatitis 2, pneumonitis 1 and thrombosis 1pts. One pt had gr 4 hypercholesterinemia and one pt had gr 4 leukopenia. Conclusions: Everolimus has significant anti-tumor activity in pts with advanced TC. Activation of autophagy could account for high rate of disease stability. Sequencing may identify mechanistic basis and predictive markers for treatment response. Clinical trial information: NCT00936858.

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A phase II study of dasatanib (BMS 354825) in recurrent or metastatic ckit-expressing adenoid cystic (ACC) and non-ACC malignant salivary glands tumors (MSGT). Presenting Author: Stuart J. Wong, Medical College of Wisconsin, Milwaukee, WI Background: ACC is a rare disease, accounting for 1/3rd of MSGT, in which 90% of cases express the protein product of the ckit proto-oncogene. Dasatinib is a potent and selective inhibitor of five oncogenic PTKs/kinase families including ckit. We conducted a phase II study to determine the antitumor activity of dasatinib in ACC and non-ACC MSGT. Methods: In a two-stage design, adult patients (pts) with recent radiographic progressive, recurrent or metastatic ACC, ⫹ cKIT, were treated with dasatinib 70 mg PO BID. Pts with non-ACC MSGT of other histologic types, were treated as a separate cohort. Response was assessed every 8 wks by imaging using RECIST criteria. The study design stipulated enrollment of n⫽40 ACC patients (20 in stage I and 20 in stage II) and 25 non-ACC patients (14 in stage I and 11 in stage II). Results: Fifty-four pts were enrolled, 40 ACC and 14 non-ACC. One additional pt was a screen failure. Baseline data on 54 pts are: M:F ⫽ 28:26, median age 56.6 yrs (range 20-82), PS 0:1:2 ⫽ 24:28:2, prior radiation:chemotherapy ⫽ 44:21. The most frequent adverse events experienced (as % of pts, worst grade 2 or higher and at least possibly related to study drug) were: fatigue (28%), nausea (19%), headache (15%), lymphopenia (11%), dyspnea (11%), alanine aminotransferase increased (7%), anorexia (7%), vomiting (7%), alkaline phosphatase increased (6%), diarrhea (6%), and non-cardiac chest pain (6%). No grade 4 adverse events occurred and only 15 pts experienced a grade 3 adverse event (at least possibly attributed to study drug), primarily dyspnea (4 patients) and fatigue (3 patients). Significant cardiac toxicity was observed in one pt (grade 3 prolonged QT corrected interval). Among ACC pts, best response to dasatinib: 0 pts (0%) had PR, 21 pts (52%) had SD (range 2.8-13.8 months), 12 pts (30%) had PD, and 2 died prior to cycle 2. Median PFS was 4.8 mos. For 14 evaluable non-ACC pts, none had an objective response, triggering early stopping. 7 had SD (range 1.4-6.6 months), and 4 PD. Conclusions: Although there were no objective responses, dasatinib is well tolerated, with tumor stabilization achieved by 52% of ACC pts. Dasatinib demonstrated no activity in non-ACC MSGT. Clinical trial information: NCT00859937.

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Phase II study of everolimus and sorafenib for the treatment of metastatic thyroid cancer. Presenting Author: Eric Jeffrey Sherman, Memorial SloanKettering Cancer Center, New York, NY Background: Everolimus is an oral inhibitor of the mammalian target of rapamycin (mTOR). Unpublished work from the Fagin lab shows that mTORC1 is also required for the growth promoting effects of the oncoproteins RET/PTC, RAS and BRAF in rat thyroid PCCL3 cells. Further work shows synergy of mTORC inhibitors with RET kinase inhibitors in medullary thyroid cancer cell lines. Sorafenib is an oral kinase inhibitor with in vitro activity against multiple targets, including RAF, RET, VEGFR1, and VEGFR2 that is compendium approved for the treatment of radioactive iodine-refractory (RAIR) and medullary (MTC) thyroid cancer. Methods: The study was a single institution, two-stage phase II design. Primary objective was response rate initiated on 9/21/2010. Eligible patients (pts) had progressive, RAIR/fluorodeoxyglucose (18-F)-avid, recurrent/metastatic, non-anaplastic, thyroid cancer; RECIST measurable disease; and adequate organ/marrow function. Sorafenib was given at 400 mg orally twice a day and Everolimus at 5 mg orally once daily. 41 patients were enrolled; 36 were eligible for the primary endpoint of response and 3 were evaluable for toxicity only at the data cutoff date of 1/10/13. Seventeen patients are still actively on study. Mutational analyses of tissue is ongoing. Results: Of the 41 eligible pts, demographics: female- 44% (18); median age-61 years (35-79). Grade 4-5 adverse events at least possibly related to drug: grade 4- Alanine Aminotransferase Increase (1 pt): grade 4- Hyperglycemia (1 pt): grade 4-Pancreatitis (1 pt). Histology and response data by partial response, confirmed and unconfirmed, (PR), stable disease (SD) and progression of disease (POD) are in the table below. The median time on treatment is 167 days (range 1 to 797 days) at the cutoff date of 1/10/2013. Conclusions: The combination of sorafenib and everolimus shows promising results, especially in the Hurthle cell and medullary subgroups where data from studies at Ohio State have suggested very poor response to sorafenib alone. Clinical trial information: NCT01141309. Histology

No.

PR

SD

POD

Papillary Hurthle cell Follicular Poorly diff Medullary Total

8 9 2 8 9 36

4 (50%) 6 (67%) 1 (50%) 4 (50%) 4 (44%) 19 (53%)

3 (38%) 3 (33%) 1 (50%) 4 (50%) 4 (44%) 15 (42%)

1 (13%) 0 0 0 1 (11%) 2 (6%)




Re-differentiation of radioiodine-refractory BRAF V600E-mutant thyroid carcinoma with dabrafenib: A pilot study. Presenting Author: Stephen M. Rothenberg, Massachusetts General Hospital Cancer Center, Boston, MA Background: Resistance to radioactive iodine is a leading cause of mortality in differentiated thyroid carcinoma. The MAPK pathway is a major determinant of iodine uptake into thyroid carcinoma cells. Mutations in BRAF activate this pathway, resulting in resistance to radioactive iodine. A pilot study using the MEK1/2 inhibitor, selumetinib, (Ho, ASCO 2012) increased radioiodine uptake in a subset of thyroid cancers. Methods: This is a single institution, single arm pilot study investigating the potential for the BRAF inhibitor dabrafenib to induce radioiodine uptake in metastatic, BRAF-mutant, radioiodine-refractory papillary thyroid carcinoma (PTC). The primary endpoint is increased radioiodine uptake demonstrated on a 4mCi 131-I whole body scan. Patients with increased uptake receive 14 additional days of dabrafenib followed by treatment with 150mCi 131-I. Secondary endpoints include safety and tolerability and clinical benefit as measured by decreases in serum thyroglobulin and objective response rate per modified RESIST 1.1. Results: To date, 7 patients have been enrolled. All had negative 131-I scans within 14 months of enrollment. No dose adjustments for toxicity have been needed. One patient developed reversible hypophosphatemia and a second developed a benign skin lesion. 3 of 5 evaluable patients developed radioiodine uptake after 28 days of dabrafenib, and new radioiodine-avid lesions were demonstrated in all three after receiving a therapeutic dose of 131-I. All three patients demonstrated increases in thyroglobulin levels during treatment with dabrafenib. Conclusions: This initial data suggests that a subset of patients with radioiodine-resistant BRAF-mutant PTC demonstrate new iodine uptake following treatment with dabrafenib. Reuptake may correlate with increases in thyroglobulin, suggestive of re-differentiation. It is not yet known whether increased uptake of radioactive iodine will translate into a radiographic response. Two patients failed to convert to radioiodinesensitive disease; it is possible that BRAF inhibition was incomplete in these patients and/or determinants other than BRAF mutation status contribute to radioiodine sensitivity. Clinical trial information: NCT01534897.

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A phase II, multicenter, open-label, single-arm trial of famitinib in patients with advanced recurrent and/or metastatic nasopharyngeal carcinoma (NPC) after two previous treatment regimens. Presenting Author: Yan Huang, Sun Yat-sen University Cancer Center, Guangzhou, China Background: Famitinib is an oral, small molecular multiple tyrosine-kinase inhibitor (TKI), targeting stem cell growth factor receptor (c-Kit), platelet derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR). So far, few target therapies show acceptable efficiency in advanced recurrent and/or metastatic nasopharyngeal carcinoma (RM-NPC) patients. The primary object of this study is to determine the safety and efficacy of famitinib in patients with RM-NPC. Methods: This study recruited histologically diagnosed RM-NPC patients who failed more than two lines of systemic chemotherapy. Other eligible criteria included ECOG PSⱕ2, adequate organ function and no prior exposure to other c-Kit, PDGFR or VEGFR TKIs. The patients received famitinib orally at a dose of 25 mg once daily until the disease progression or intolerable toxicity. Results: From May 2011 to Sep 2012, 58 patients (Simon’s two-stage design, 28⫹30) were recruited at 8 sites in China. The clinical benefit rate (partial response or stable disease maintainedⱖ12 weeks, tumor response was evaluated every 4 weeks) is 32.8%, including 5 PR and 16 SD patients. Median PFS was 3.2 months. The most frequently observed hematologic toxicities included thrombocytopenia, leucopenia and neutropenia; non-hematologic AEs were hypertension, proteinuria, and hand-foot syndrome. All adverse events were generally mild-to-moderate (grade 1/2) and manageable with supportive treatment; grade 3/4 incidence was relatively low. Conclusions: This phase II study shows that famitinib demonstrates substantial clinical benefits in patients with advanced RM-NPC and the drug-related adverse reactions were most predictable and tolerable, no special toxicity was reported. Biomarker analysis for responder and non-responder is still ongoing and will be present at the meeting. Clinical trial information: NCT01392235.

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Identification of a gene expression profile associated with progression-free survival (PFS) in relapsed or metastatic (RM) head and neck squamous cell cancer (HNSCC) patients (pts) treated with first-line cetuximab and platinum therapy. Presenting Author: Paolo Bossi, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Activity of cetuximab (C) in head and neck squamous cell carcinoma (HNSCC) patients (pts) with PTEN loss or PIK3CA mutation treated on E5397, a phase III trial of cisplatin (CDDP) with placebo (P) or C. Presenting Author: Barbara Burtness, Fox Chase Cancer Center, Philadelphia, PA

Background: First-line chemotherapy with platinum and cetuximab is usually offered to RM-HNSCC pts. In the Extreme trial a median PFS time of 5.6 months was reported. However, a small fraction of pts achieves a prolonged PFS (⬎ than 12 months). Until now, no recognized predictive biological factor has been identified. Methods: A group of 14 pts treated with a first-line platinum and cetuximab with a PFS exceeding 12 months (long PFS) and a group of 26 pts with a PFS less than 5.6 months (short PFS) were selected. Tumor specimens of the recurrence (25 cases) or, if not available, of the primary tumor were collected. In order to identify molecular profiles deregulated between the 2 groups, a gene expression microarray analysis was performed using the Whole-Genome DASL assay and HumanHT-12_v4 BeadArray chips (lllumina). Results: The 2 groups were well balanced in regard to recognized prognostic factors (performance status, weight loss, prior radiotherapy, tumor grade, site of primary tumor, residual disease at primary tumor site). Mean PFS was 21 months in long (range 13-36) and 4 months in short PFS group (range 1-5). By class comparison analysis between the 2 groups, the expression pattern of 136 genes was found differentially expressed (FDR⬍0.05). In long PFS group, EGFR and genes associated to EGFR pathway including CDCP1 and EPGN were up regulated, as well as its ligand (EREG). Several members of the Kallikrein serine proteases gene family are present among the most upregulated genes in long PFS group, suggesting the involvement of extracellular-matrix remodelling. In addition to cellular morphology, pathways analysis showed an enriched modulation of genes belonging to cell-to-cell signalling, DNA replication/DNA repair and lipid metabolism. Conclusions: Our analysis suggests that a specific molecular signature may be associated with long and short PFS after platinum/cetuximab first line chemotherapy in RM-HNSCC pts. To our knowledge, it is the first study attempting to generate hypotheses in this field and further validation is required.

Background: Abnormalities in EGFR signaling targets are associated with C resistance but no biomarker of C resistance has been identified in HNSCC. We hypothesized that cases with loss of PTEN protein expression (PTEN null) or PIK3CA mutation would display C resistance in HNSCC. Methods: E5397 was a phase III trial of CDDP plus P or CDDP plus C and enrolled 117 eligible and evaluable pts. PIK3CA and PTEN were analyzed for 52 and 67 consented pts, respectively. PTEN expression (PTEN Cell Signaling Technology, Cat. 9559) was determined by automated quantitative analysis (AQUA) on the PM-2000 (HistoRx, New Haven) using a cutpoint generated in 5 HNSCC tissue microarrays, each consisting of HNSCC as well as positive (small intestine, median AQUA score 2833.2) and negative controls (breast and colon carcinoma, median AQUA score 205.5). A cutpoint of 570 provides 100% specificity, 100% sensitivity, and identified 30% of the HNSCCs as PTEN null, consonant with the literature. The 3 most common PIK3CA mutations (E542K and E545K in exon 9 and H1047R in exon 20) were determined by BEAMing (Inostics, Heidelberg, Germany). Response, overall survival (OS) and progression-free survival (PFS) were compared between PTEN null or PIK3CA mutated pts and all others. Log rank and multivariable Cox proportional hazards modeling were used to calculate p values. Results: 23/67 (34%) tumors were PTEN null and 2/52 (4%) had PIK3CA mutations (E542K and E545K). Both tumors with PIK3CA mutation had PTEN expression. No statistically significant differences in response, OS or PFS were noted in this small sample. However, among PTEN expressing/PIK3CA WT pts, median PFS increased to 4.2 months (m) for C (N⫽22) from 2.9 m for P (N⫽26) (Wald p⫽0.07), compared with 4.6 m for C (N⫽12) and 3.5 m for P (n⫽13) among the PTEN null/PIK3CA mutated (Wald p⫽0.60). Conclusions: The PTEN loss or PIK3CA mutation signature warrants further investigation as a predictor of C resistance.


370s 6029


PARTNER: A randomized phase II study of docetaxel/cisplatin (doc/cis) chemotherapy with or without panitumumab (pmab) as first-line treatment (tx) for recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Presenting Author: Lori J. Wirth, Massachusetts General Hospital, Boston, MA Background: PARTNER was a multicenter, randomized phase II estimation study evaluating 1stEline tx of R/M SCCHN with doc/cis ⫾ pmab. Methods: Patients (pts) were randomized 1:1 to doc/cis with pmab (Arm 1) or doc/cis alone (Arm 2). Arm 1 received 9 mg/kg pmab on day 1 of each 21-day cycle, and all pts received 1stEline doc/cis both at 75 mg/m2 on day 1 for up to 6 cycles. In Arm 1, pts could receive pmab monotherapy upon completion of 6 cycles of doc/cis until disease progression (PD). In Arm 2, pts could receive pmab as 2ndEline monotherapy upon PD. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. HPV status was determined using p16 INK IHC. No formal hypothesis was tested. Results: Baseline characteristics were balanced between arms. Of 103 pts, HPV status was evaluable in 66 (64%); 29% were HPV positive. Efficacy results are shown (Table). Worst grade 3/4 adverse events (AEs) were 73% in Arm 1 vs 56% in Arm 2. Conclusions: Median PFS was increased in both arms over historical doublet cytotoxic chemotherapy. PFS and ORR were higher in the pmab arm in the overall population, in the HPV positive (n⫽19) group, and in the HPV negative (n⫽47) group. There was an increase in grade 3/4 AEs with this regimen. The crossover design, with 57% of Arm 2 pts receiving pmab as 2ndEline monotherapy, confounds interpretation of OS. Clinical trial information: NCT00454779. All pts Median PFS,# mos (95%CI) Median OS, mos (95%CI) ORR,# % (95%CI) HPV negative Median PFS,# mos (95%CI) ORR,# % (95%CI) HPV positive Median PFS,# mos (95%CI) ORR,# % (95%CI)

Arm 1 (N ⴝ 52)

Arm 2 (N ⴝ 51)

6.9 (4.7 – 8.3) 12.9 (9.4 – 18.5) 44 (31 – 58) Arm 1 (N ⴝ 25) 7.3 (4.7 – 9.6) 52 (32 – 72) Arm 1 (N ⴝ 6) 8.1 (3.9 – NE) 67 (29 – 100)

5.5 (4.1 – 6.8) 13.8 (11.8 – 22.9) 37 (24 – 51) Arm 2 (N ⴝ 22) 5.3 (2.9 – 7.0) 27 (9 – 46) Arm 2 (N ⴝ 13) 5.7 (4.5 – 6.8) 54 (27 – 81)

HR (95% CI) 0.63 (0.40 – 1.00) 1.10 (0.71 – 1.72) HR (95% CI) 0.53 (0.27 – 1.02) HR (95% CI)

6030


Randomized phase II trial of cixutumumab (CIX) alone or with cetuximab (CET) for refractory recurrent/metastatic squamous cancer of head and neck (R/M-SCCHN). Presenting Author: Bonnie S. Glisson, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Preclinical evidence supports clinical investigation of IGF-1R inhibitors alone, or combined with EGFR inhibitors, in SCCHN patients (pts). CIX and CET monoclonal antibodies block ligand binding to IGF-1R and EGFR, respectively. CIX mono and CIX⫹CET combo were studied in pts with chemotherapy-refractory R/M-SCCHN. Methods: This open-label phase II trial randomized 97 pts with R/M-SCCHN, ECOG PS 0-2 and disease progression following (⬍90 days) platinum-based chemotherapy, to CIX 10 mg/kg alone (Arm A) or with CET 500 mg/m2 (Arm B) every 2 wks. Time to recurrence from last anti-EGFR exposure had to be ⬎90 days; pts were stratified by prior CET exposure. Primary endpoint was median PFS (RECIST assessments every 8 wks). Efficacy endpoints in the CET-naïve patients, immunohistochemical analysis of 10 relevant markers on tumor specimens, and cytokine/angiogenic factor profiling of blood samples obtained serially through treatment were also examined. Results: 47 Arm A and 44 arm B pts were treated: median age: 60.0 y (35 - 81), PS 0/1/2: 17.6%/62.6%/19.8%, male (80.2%), tumors originating mainly from oropharynx (67.1%), supraglottic (9.9%) and oral cavity (13.2%), with 33% moderately and 36.3% poorly differentiated tumors, previous therapy: 98.9% chemotherapy and 82.4% radiotherapy indicating no baseline differences. Most common tx-emergent AEs were fatigue (55.3 vs. 61.4%), dermatitis acneiform (6.4 vs 63.6%), nausea (29.8 vs. 34.1%), weight decreased (25.5 vs. 29.5%), hyperglycemia (25.5% vs. 29.5%), vomiting (21.3 vs. 20.5%), and headache (17 vs. 25%). Efficacy: See Table. Conclusions: Targeting IGF-1R alone with CIX or co-targeting IGF-1R and EGFR with CIX and CET did not result in improved PFS compared to historical data with CET alone in patients with chemotherapy-refractory R/M-SCCHN. The results of this study do not support CIX single-agent activity in this patient population. Therapy on both arms was feasible. There was no apparent exacerbation of CET toxicity by concurrent CIX exposure. Clinical trial information: NCT00617734. Endpoint Median PFS/OS months 6-month PFS Clinical benefit (CR/PR/SD)

CIX

CIXⴙCET

1.9/5.3 5.9% 19% (2%/0%/17%)

2.0/5.5 15.3% 38% (2%/7%/30%)

0.53 (0.16 – 1.71)

#Assessments by investigator review per modified RECIST 1.0. Pts with measureable lesions at baseline were included in the ORR analysis. HR: hazard ratio. NE: not estimable.

CRA6031


6032


Oral HPV infection in HPV-positive oropharyngeal cancer cases and their spouses. Presenting Author: Gypsyamber D’Souza, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

Differences in sexual practices and their role in gender, age, and racial disparities in HPV-positive HNSCC. Presenting Author: Carole Fakhry, Johns Hopkins University, Baltimore, MD


Background: Human papillomavirus associated head and neck cancers (HPV-HNC) have been steadily rising in the U.S., while HPV-unassociated HNCs have declined due to reductions in tobacco use. The trend of increasing HPV-HNC has been attributed to the sexual revolution, but not well explored. Individuals with HPV-HNC tend to be younger, white, and male and HPV-HNC is strongly associated with sexual behaviors. Methods: This analysis included 2270 men and 2261 womenfrom the 2009-10 National Health and Nutrition Examination Survey (NHANES) who answered a survey on demographic and behavioral risk factors. Participants also provided an oral rinse and gargle sample for HPV DNA analysis. Prevalence of sexual behaviors and oral HPV infection were calculated by gender, age cohort (18-29, 30-44, 45-59, 60-69), and race using NHANES samples weights to provide unbiasedestimates for the US population. Results: Men (85%) and women (83%) were similarly likely to have ever performed oral sex, but men had more lifetime oral and vaginal sexual partners and higher oral HPV16 prevalence (each p⬍0.001).Ever having performed oral sex was less common among 60-69 than 30-44 year old men (74% vs. 92%, p⬍0.001) and women (71% vs. 91%, p⬍0.001). Older individuals also had less lifetime sexual partners, but marginally higher oral HPV16 prevalence. Whites were more likely than blacks (90%vs69%, p⬍0.001) to have ever performed oral sex, to have more lifetime oral sex partners and higheroral HPV16 prevalence(each p⬍0.001). Prevalence ratios of ever performing oral sex for men vs. women (PR⫽1.03), 45-59 vs 60-69 year olds(PR⫽1.25), and whites compared to blacks (PR⫽1.32) were modest relative to more striking prevalence ratios for oral HPV infection andHPV-HNC(each PR⬎1.5). Conclusions: There are significant gender, age-cohort, and racial differences in oral sexual practices in a representative sample of the U.S population. Although men, younger age-cohorts, and whites have higher exposures to sexual behaviors of interest, the magnitude of these behavioral differences does not appear large enough to explain the observed disparities in oral HPV infection and HPV-HNC.




A preliminary cost-effectiveness analysis of human papillomavirus vaccination in males for the prevention of oropharyngeal cancer. Presenting Author: Donna M. Graham, Princess Margaret Cancer Center, Toronto, ON, Canada Background: Many western countries have established female human papillomavirus (HPV) vaccination programmes for prevention of cervix cancer. Efficacy against additional HPV-related disease is proven in both sexes, but cost-effectiveness of male vaccination remains controversial. Projected figures suggest incidence and prevalence of oropharyngeal cancer (OPC) in North America will exceed that of cervix cancer by 2020 due to HPV-related cases. Two cost-effectiveness analyses evaluating male HPV vaccination have included OPC, with contrasting results. The Canadian government recommends, but does not fund, male vaccination. In order to assess the value for money of male HPV vaccination in Canada with respect to OPC, we performed a preliminary cost-effectiveness analysis. Methods: Following extensive literature review regarding HPV-related OPC in Canadian males, healthcare cost and clinical effectiveness estimates were obtained from published studies. A Markov model was used to compare potential costs and effectiveness of HPV vaccination against no vaccination among males aged 12 years old. A 3-month cycle length was used with a ‘lifetime’ time horizon. The outcome of the analysis was the incremental cost per quality-adjusted life-year (QALY). Sensitivity analyses were conducted on variables such as vaccine uptake rate and efficacy. Results: Assuming 99% vaccine efficacy and 70% uptake, the use of HPV vaccine produced 0.05 more QALYs and saved $204 Canadian dollars (CAD) per person compared with no vaccine (QALYs and costs discounted at 5% per year). Assuming 50% vaccine efficacy and 50% uptake, use of HPV vaccine produced 0.01 more QALYs and saved $43 CAD. Based on a population of 12 year old males of 192,940 in 2012, male HPV vaccination may potentially save $8.3-39.4 million CAD for this cohort over its lifetime. Conclusions: Knowledge gaps exist regarding male HPV vaccination for OPC prevention. Due to practical limitations, including lack of identifiable precursor lesions in OPC, clinical trials to evaluate this issue may not be feasible. Without considering the effects of herd immunity, this preliminary analysis highlights potential savings from male vaccination.

6035


A phase III randomized trial of two cisplatin-based concurrent chemoradiation (CCRT) regimens for locally advanced head and neck squamous cell carcinoma (LAHNSCC). Presenting Author: Cristina P. Rodriguez, Oregon Health & Science University, Portland, OR Background: Excellent outcomes have been reported using both single and multiagent CCRT in LAHNSCC. This trial compares a 5FU/cisplatin regimen to single agent cisplatin CCRT. Methods: Patients (pts) with previously untreated stage III-IV, M0, LAHNSCC of the larynx, oropharynx (OP), oral cavity or hypopharynx received definitive once or twice daily radiation (70-74.4 Gy) and were randomized between concurrent chemotherapy with either Arm A: cisplatin 100mg/m2 on days 1, 22 and 43 or Arm B: cisplatin (20mg/m2/day) and 5-FU (1000mg/m2/day) as continuous 96 hour infusions weeks 1 and 4. ECOG performance status ⱕ 1, and adequate renal, liver and marrow function were required for entry. The primary endpoint was recurrence free survival (RFS). Results: Between 2/2008 and 10/2011, 69 pts were enrolled. An accrual of 126 pts was planned in order to demonstrate an improvement in 2-year RFS from 55% to 75%. The study was closed prematurely when a scheduled interim analysis confirmed markedly better outcomes in both arms and the futility of further comparison. Pt and tumor characteristics were well balanced in both arms. OP cancer was diagnosed in 83% of pts; 86% of the OP cancers were HPV/p16⫹. With a median follow up of 29.4 months, 2 yr KaplanMeier outcome estimates were similar between arms (Table). Pts on Arm A experienced more nephrotoxicity (26% vs. 3%; p⫽0.007) and ototoxicity (11% vs. 0%; p⫽0.042), but less Grade ⱖ2 radiation dermatitis (43% vs. 68%; p⫽0.038), neutropenia ⬍1000/mm3 (34% vs. 65%; p⫽0.012), and unplanned hospitalization (43% vs. 68% p⫽0.038). Treatment outcomes were inferior and feeding tube requirements greater in the HPV/p16 negative and actively smoking pts. Conclusions: Although these CCRT regimens produced similar outcomes, their toxicity profiles proved different and may serve to inform individual pt treatment. Tobacco use and HPV status had far greater impact on treatment outcomes than did the CCRT regimen. Clinical trial information: NCT00608205. Outcome RFS Overall survival Locoregional control Distant metastatic control Freedom from recurrence

All pts (Nⴝ69)

Arm A (Nⴝ35)

Arm B (Nⴝ34)

p (A vs. B)

89% 90% 99% 92% 91%

94% 96% 100% 94% 94%

85% 83% 97% 91% 88%

0.62 0.07 0.94 0.86 0.84

6034


Phase I study of weekly albumin-bound paclitaxel (ab-P) plus weekly cetuximab (Cet) plus intensity-modulated radiation therapy (IMRT) in patients with stage III/IVb head and neck squamous cell carcinoma (HNSCC). Presenting Author: Matthew G. Fury, Memorial Sloan-Kettering Cancer Center, New York, NY Background: There is a clinical need to improve the efficacy of standard Cet ⫹ concurrent RT for pts with stage III/IVB HNSCC. Taxanes have potent activity against HNSCC, and ab-P may offer therapeutic advantages in comparison with other drugs of this class. Methods: This was a single institution phase I study with a modified 3 ⫹ 3 design. 4 dose levels (DLs) of weekly ab-P were explored (30, 45, 60, and 80 mg/m2) during IMRT. Standard Cet (450 mg/m2 loading dose followed by 250 mg/m2 weekly) concurrent with IMRT (total dose, 70 Gy) was prescribed for all pts. The maximum-tolerated dose (MTD) would be exceeded if ⬎2/6 pts experienced DLTs at a given dose level. NCI CTCAE v.3 was used, and DLT monitoring extended until 2 wks after IMRT. Results: 25 eligible pts (20M, 5F) enrolled, with median age 58 years (range, 46-84) and median KPS 90 (range 80-100). Primary tumor sites were oropharynx, 20 (10 HPV pos, 5 HPV neg, 5 not done); neck node with unknown primary, 2; and larynx, oral cavity, and maxillary sinus, 1 each. Two pts never received ab-P and were deemed inevaluable. At DL 1 (ab-P, 30 mg/m2), there was one DLT (g.4 pneumonia) among 6 pts. At DL2 (ab-P, 45 mg/m2), there were 2 DLTs (g.4 cerebrovascular accident; g.3 decrease in L. ventricle ejection fraction/ CHF exacerbation) among 6 pts. At DL3 (ab-P, 60 mg/m2), there was 1 DLT (g.3 supraventricular tachycardia) among 6 pts. MTD was exceeded at DL4 (ab-P, 80 mg/m2) with 3 DLTS (g.3 neuropathy, g.3 dehydration, g.3 anemia) among 5 evaluable pts. For the entire study population, most common ⱖ g3 AEs were: lymphopenia 100%, functional mucositis, 56%, and pain in throat/oral cavity, 52%. There were no treatment-related deaths. Among 23 evaluable pts at a median follow up of 29 months, 2y PFS rate is 64% (95% CI: 41-80%) and 2y OS rate is 90% (95% CI: 66-97). Conclusions: The recommended phase II dose is ab-P 60 mg/m2 weekly when given concurrently with IMRT and standard weekly Cet. This regimen merits further study as an alternative to IMRT ⫹ Cet alone for pts who require a non-platinum regimen. This study was approved and funded by the NCCN from general research support provided by Celgene, Inc. Clinical trial information: NCT00736619.

6036


CAPRA: Safety, efficacy, and translational biomarkers of weekly everolimus, carboplatin, and paclitaxel as induction therapy for locally advanced head and neck squamous cell carcinoma (HNSCC). Presenting Author: Eric Raymond, Hôpital Beaujon, Clichy, France Background: ThePI3K/mTOR pathway is activated in ⬎50% of HNSCC with preclinical synergism between everolimus and carboplatin/paclitaxel. Methods: Patients (pts) with untreated locally advanced HNSCC with ECOG PS⬍2 received 9 consecutive weekly (w) cycles (cy) of CAPRA combining everolimus (30 mg/w at dose-level 1 then 50 mg/w at dose-level 2) with carboplatin (AUC2) and paclitaxel (60 mg/m2) followed by chemoradiotherapy. Endpoints were safety (CTCv3.0), antitumor activity (RECIST1.1), pharmacodynamic biomarkers on tumor biopsy. Results: A total of 50 pts with stage IV HNSCC (41 males, 9 females, median age 61) were enrolled. Among 7 patients included in the phase I, no dose-limiting toxicity was reported and the recommended dose (RD) of everolimus was 50 mg/w. Safety evaluation in 46 pts treated at RD for 325 cy and a mean number cy/pt of 7.1 (95%CI: 6.3-7.8) showed grade (Gr) 1-2 adverse events consisting of asthenia (50%), nausea/vomiting (28%), alopecia (26%), mucositis (24%), and constipation (20%). Hematological toxicities (Gr1-2/ 3-4) were neutropenia (35%/39%), anemia (61%/17%), and thrombocytopenia (54%/13%). Everolimus-related Gr3 toxicities were rashes (1pt), pruritus (1pt), dyspnea (1pt), hyperglycemia (2pts), and Gr1-2 hypercholesterolemia (23pts). There was no toxic death. Among 38 pts evaluable for antitumor activity, one pt experienced a complete response (2.6%), 29 pts a partial response (76.3%), and 8 pts a stable disease (21%) for an overall response rate of 79% (no progression reported). Interestingly, 20 major responses (⬎50% reduction tumor volume) were observed in large necrotic primary tumors/N3 involvement. Efficacy was not correlated to KRAS/BRAF/ PI3KCA/EGFR mutations. Significant decreases of Ki67/p-S6K activities were observed in post CAPRA biopsies compared to baseline. Conclusions: Weekly everolimus with carboplatin/paclitaxel as induction regimen was well tolerated with 11% grade 3 and no grade 4/5 toxicity. Translational data showed direct effects of everolimus in tumors. CAPRA yields high rate of objective responses in patients with locally advanced HNSCC. Clinical trial information: NCT01333085.


372s 6037

Head and Neck Cancer General Poster Session (Board #10A), Sat, 8:00 AM-11:45 AM

HPV prevalence in the different subsites of the oropharynx. Presenting Author: Per Attner, Karolinska University Hospital, Stockholm, Sweden Background: Oropharyngeal cancer patients are often reported as one group in articles and studies regardless that within the subsites of the oropharynx, there are differences regarding clinical features, treatment and HPV prevalence. To investigate these differences, we wanted to further analyze HPV prevalence in the different subsites of the oropharynx. Methods: We identified all patients diagnosed with oropharyngeal cancer in Stockholm County, Sweden, between 2000 and 2007, using the Swedish Cancer Registry, a registry unique in its reliability. Using the ICD 10 codes C01.9 (base of tongue cancer), C09.0-C09.9 (tonsillar cancer) and C10.0-C10.9 (oropharyngeal cancer) and C50.1-C50.8 (cancer of the soft palate). The two last subsites were grouped together into the group Other Oropharyngeal Cancer (OOC). We retrieved pre-treatment biopsies and tested for HPV-DNA using PCR, both with general primers and HPV16 specific primers. Results: We identified 474 patients diagnosed with oropharyngeal cancer in Stockholm County, Sweden between 2000 and 2007; 290 diagnosed with tonsillar cancer, 109 diagnosed with base of tongue cancer and 75 diagnosed with other oropharyngeal cancer. Of these 474 patients, pretreatment biopsies for HPV-testing were available for 400 patients (236, 95 and 69, respectively). In the tonsillar cancer group, 185 biopsies were HPV-DNA-positive (79%), in the base of tongue cancer group 71 (75%) and in the other oropharyngeal cancer group 17 were positive (25%) Conclusions: Tonsillar and base of tongue cancer share some similarities and HPV prevalence is similarly high in both groups. Other oropharyngeal cancer (OOC) does not share the high HPV-prevalence and it would then be preferred that the sub-sites of the oropharynx are reported separately.

6038


The results of first-line chemotherapy in 108 patients affected by recurrent or metastatic salivary gland malignacies (RMSGM). Presenting Author: Mario Airoldi, 2nd Medical Oncology Division, A. O. Città della Salute e della Scienza di Torino, Turin, Italy Background: Recurrent/metastatic salivary gland malignancies (RMSGM) are not manageable by means of surgery and/or radiotherapy; chemotherapy (CT) represents a palliative strategy without any curative purposes. In this abstract we report the results of CT in 108 cases of RMSGM. Methods: We enrolled 108 patients with radiologically documented progression of RMSGM. Five pts received cisplatin (DDP) 100 mg/sm d 1, q 3wks; 8 pts doxorubicin (DOX) 75 mg/sm d1, q 3wks; 30 pts vinorelbine (VNB) 30 mg/sm d. 1 and 8, q 3 wks; 9 pts DDP 60 mg/ sm ⫹ epirubicin (EPI) 60 mg/sm ⫹ 5-FU 600 mg/sm d.1, q 3 wks; 42 pts DDP 80 mg/sm d.1 ⫹ VNB 25 mg/sm d. 1,8 , q 3 wks, and 14 pts carboplatin (CBDCA) AUC 5.5 ⫹ paclitaxel (Taxol; TAX) 175 mg/sm d.1, q 3 wks. The maximum number of CT cycles was 6. Results: Patients characteristics were as follows: 65 males (60%) and 43 females (40%); median age: 57 yrs (range 20-74); 42 pts (39%) had ECOG PS⫽0 and 66 pts(61%) PS 1-2 (0-2); histological evaluation was as follow: adenocarcinoma 28 pts (26%), adenoid cystic carcinoma 63pts (58%), undifferentiated carcinoma 12 pts (11%) and malignant mixed tumors 5 pts (5%); the disease was local in 40 pts (37%), local ⫹ distant metastases in 30 pts (28%) and only metastatic in 38 pts (35%). Conclusions: DDP is the probably the most effective single drug scheme; our data suggest that VNB has superimposeable results with a better gastroenteric and renal toxicity profile. Single drug CT seems less effective than multi drug CT with DDP-based schemes. DDP⫹EPI⫹5-FU is as effective as DDP⫹VNB; CBDCA⫹TAX seems to have worse clinical outcomes than DDP combinations. The impact of CT on symptoms is quite good while on survival needs further investigations, moreover our data confirm the need of new biological target agents to improve clinical outcomes in RMSGM. Drug DDP DOX VNB DDPⴙEPIⴙ5-FU DDPⴙVNB CBDCAⴙTAX

6039


6040

Pts No.

ORR%

NC%

mPFS (m)

mOS (m)

5 8 30 9 42 14

20 20 20 33 33 14

60 25 30 22 33 45

4 3 5 7 7.5 5

6 5 8 9 10.5 8

General Poster Session (Board #10D), Sat, 8:00 AM-11:45 AM

Psychophysical functioning and quality of life in 94 patients affected by oropharyngeal cancer and treated with different therapeutic approaches. Presenting Author: Fulvia Pedani, 2nd Medical Oncology Division, A. O. Città della Salute e della Scienza di Torino, Turin, Italy

Validation of late oral health outcomes, an oral health subscale of the Vanderbilt Head and Neck Symptom Survey in post-radiation therapy head and neck cancer patients. Presenting Author: Leanne Kolnick, Deptartment of Medicine, Vanderbilt University Medical Center, Nashville, TN

Background: The treatment of oropharyngeal squamous cell carcinomas (OSCC) may heavily affect patient’s quality of life (QoL). Aim of our study was the evaluation of the impact of different treatments on physical and psychological functioning and on QoL of patients affected by stage III-IV disease. Methods: The enrolled sample was composed by 94 OSCC patients divided into 3 subgroups based on treatment modalities: surgery ⫹ adjuvant radiotherapy (S ⫹ RT: 30 patients), exclusive concomitant chemo-radiotherapy (CT ⫹ RT: 30 patients) and exclusive chemotherapy (CT) in 34 patients not suitable for surgery and/or radiotherapy. Psychooncological assessment included: Hospital Anxiety Depression Scale (HADS), Montgomery-Asberg Depression Scale (MADRS), Mini-Mental Adjustment to Cancer scale (MINI-MAC), EORTC QLQ C-30 questionnaire with the specific module Head and Neck 35 (H&N35). Results: The 60 patients primarily treated with S ⫹ RT or CT ⫹ RT presented superimposeable clinical and tumour characteristics while those treated with exclusive CT were affected by stage IV disease and in the 90% of cases underwent to previous treatment exclusive or combined treatment such as surgery, radiotherapy and chemotherapy. In the following table, data about physical and psychological functioning and on QoL of the 3 subgroups of patients are summarized. Conclusions: In stage III-IV OSCC treatments have a strong influence on QoL and coping styles. Patients treated with CT ⫹ RT were characterized by a lower percentage of self-reported anxiety and depression and higher EORTC Global QoL score. More than one third of patients treated with S ⫹ RT had overt symptoms of anxiety and depression. Stage IV patients treated with palliative CT had elevated level of anxiety, depression and low quality of life. Auto-evaluation is less effective in depression assessment. The role of concomitant psychological supportive care should be evaluated in these patients treated with different approaches.

Background: The Vanderbilt Head and Neck Symptom Survey (VHNSS) version 2.0 oral symptom subscale was developed to address potentially overlooked and underreported oral health issues. We report the validation of questions pertaining to xerostomia (4 items), dental health (4 teeth), dentures (1 item) and trismus (1 item). Methods: Between May 2011 and April 2012, 50 patients treated with chemoradiotherapy for head and neck cancer completed the 50-item VHNSS survey, underwent an oral health assessment by a dentist, salivary flow and inter-incisal opening (IIO) measurements. Results: Patient reported “problems with dry mouth” correlated with unstimulated salivary flow rates (-0.43, p ⫽ 0.002). “Cracked teeth” (-0.55, p ⫽ ⬍ 0.001) or “difficulty chewing due to teeth” (-0.43, p ⫽ 0.004) correlated with urgent or emergent dental care issues identified on exam. Using a cut off of ⬎4 on any of four the dental questions, we were able to identify 83% of patients with urgent or emergent dental issues. The ROC curve was useful (0.89, p⬍ 0.001) for separating patients with and without urgent/emergent dental issues. “Limitations” in jaw movement correlated with IIO (-0.43, p ⫽ 0.002). Small numbers of patients with dentures precluded meaningful analysis of this subsample. Conclusions: Clinically significant oral health issues pertaining to xerostomia, dental health and trismus may be identified using the oral health subscale of the VHNSS version 2.0. Patients who score ⬎ 4 on any of the teeth related items should be referred for immediate dental evaluation; and for trismus should be referred for physical therapy.

S ⴙ RT CT ⴙ RT CT

HADS Anxiety

HADS Depression

MADR Depression

EORTC Global QoL score

33.3% 22.2% 70.6%

30.5% 13.9% 67.5%

40.1% 40.1% 76.4%

71.42 76.05 49.04




Evaluation of potential predictive markers of efficacy of dacomitinib in patients (pts) with recurrent/metastatic SCCHN from a phase II trial. Presenting Author: Marie-Lise Audet, Centre Hospitalier Universitaire De Montréal, Hôpital Notre-Dame, Montreal, QC, Canada Background: Dacomitinib is an irreversible pan-HER TKI with preclinical (EGFRvIII⫹ cell lines, SCCHN xenografts) and clinical activity (phase II recurrent/metastatic SCCHN; Razak et al, Ann Oncol 2012). However, little is known about predictive markers of efficacy related to EGFR signalling in this setting. Methods: Of69 pts treated with 1st-line dacomitinib in a phase II trial for recurrent/metastatic SCCHN, 48 pts had archival tumor specimens obtained before treatment and 13 had paired biopsies (days 0 and 7 of therapy, FFPE and snap frozen). EGFRvIII and PTEN (IHC), HPV genotyping and human genomic mutations (Sequenom OncoCarta Panel – 19 genes, 238 mutations) were evaluated on archival tissue. IHC expression of AKT, CC3, EGFR, ERK, HER2, HER3, MET, Ki67, pAKT, pEGFR, pERK, pHER2 and pMET was evaluated in paired specimens. The presence/ absence or expression level of these markers was correlated with response (RR)/clinical benefit (CB), PFS and OS. Results: In pts with archival tissue, no statistically significant difference was found in RR/CB or PFS based on HPV, EGFRvIII, PTEN or presence of mutation. There was a trend to increased OS in HPV⫹ pts (HR 0.47, 95% CI 0.21–1.07, P⫽0.068). In paired biopsies, some expression variation was seen for cytoplasm AKT, membrane EGFR, nuclear ERK and pAKT. There was no correlation between basal expression of these markers and RR/CB or PFS. Variations in ratio to baseline of EGFR, pAKT, pERK and MET were qualitatively associated with RR/CB. No statistically significant correlations could be established for PFS, but there were interesting qualitative variations in the levels of expression of some molecules, eg, EGFR, pAKT. Conclusions: No predictive efficacy marker was identified. It cannot be determined if increased OS in HPV⫹ cases is due to prognostic or predictive effects. Paired biopsies demonstrated that dacomitinib was associated with variation in expression of multiple elements in signalling pathways linked to EGFR. Given the small number of paired biopsies, and large amount of data generated, descriptive study of cases is required. Further data will be presented at the meeting. Clinical trial information: 00768664.

6042


Phase II randomized trial of radiotherapy (RT), cetuximab (E), and pemetrexed (Pem) with or without bevacizumab (B) in locally advanced squamous cell carcinoma of the head and neck (SCCHN). Presenting Author: Athanassios Argiris, University of Texas Health Science Center at San Antonio, San Antonio, TX Background: We previously developed a novel regimen by the addition of Pem to RT and E (Ann Oncol 2011;22:2482). The current study evaluated PemE in the phase II setting and assessed the addition of B, an anti-VEGF monoclonal antibody, to PemE based on promising data with Pem/B (JCO 2011;29:1140) and E/B (Ann Oncol 2013;24:200) in recurrent/ metastatic SCCHN. Methods: Patients (pts) with previously untreated stage III/IV SCCHN of the oropharynx, larynx or hypopharynx, performance status (PS) 0-1, no history of bleeding, and adequate laboratory parameters were randomized after stratification for PS, stage and site to: RT 2 Gy/day to 70Gy, E 250mg/m2 weekly, after a loading dose of 400 mg/m2 1 week prior starting RT, and Pem 500mg/m2 every 21 days x 3 cycles (arm A, PemE), or the same regimen plus B 15mg/kg every 21 days x 3 cycles during RT followed by B maintenance x 8 cycles (arm B, B-PemE), with antibiotic prophylaxis. The primary endpoint was progression-free survival (PFS) with a target of 64% at 2 years; planned sample size was 80. Results: 79 pts were randomized of whom 77 were eligible and analyzable (arm A/B:36/ 41); oropharynx 65/larynx 12; HPV⫹ 38/HPV- 15/HPV unknown 24; stage IV 54/stage III 23. 31 pts were enrolled in community centers. Treatment delivery of E and Pem was similar between arms: E, median number of doses 8 (range, 5-11); Pem 3 (2-3); and B 3 (1-3). 5 deaths occurred: 3 due to progression; 1 from unknown cause; 1 pt died from hemoptysis after bronchoscopy within 4 weeks of the 8th cycle of B leading to elimination of B maintenance after the 6th pt was enrolled. 9 pts (2 HPV⫹) progressed. With a median follow-up of 18 months, the 2-year PFS was 81% vs 87% and the 2-year overall survival (OS) was 96% vs 86% for arm A vs B. Grade 3/4 acute toxicities for arm A vs B (N⫽59) : dermatitis 3/1 vs 4/1; mucositis 13/2 vs 13/0; neutropenia 7/4 vs 7/3; rash 6/1 vs 8/1; fatigue 1/0 vs 3/0; weight loss 2/0 vs 5/0. Conclusions: Both regimens are feasible in academic and community practice settings with expected toxicities. Preliminary efficacy results are very promising and better than projected, however, the addition of B does not appear to improve outcomes. Clinical trial information: NCT00703976.


Role of adjuvant radiation in patients with squamous cell carcinomas of the oral cavity. Presenting Author: Steven Maron, Yale School of Medicine, New Haven, CT Background: Although surgery is the initial treatment of choice for patients with stage III squamous cell carcinoma (SCC) of the oral cavity (OC), the role of adjuvant radiotherapy (RT) remains undefined. We evaluated the differences in outcome according to stage subsets and use of adjuvant RT. Methods: The Surveillance Epidemiology and End Results (SEER) database was queried for patients with SCCOC, treated with surgery (S), RT, or both (SRT); older than 21 years; and diagnosed between 2004 and 2009. Patients with extracapsular lymph node extension or multiple primary cancers were excluded. Overall Survival (OS) rates were estimated by the Kaplan-Meier method and compared using log-rank testing as well as Cox proportional hazards. Results: Among the 1,051 patients meeting eligibility criteria, the most common treatment was SRT (49.1%), followed by S alone (28.9%), and RT alone (22.0%). The 5-year OS ranged from 33.3% in T3N1 to 52.8% in T1N1. Compared to S alone, the addition of RT improved 5-year OS in the entire cohort from 39.5% to 51.1% (HR 0.69, 95% CI 0.54-0.87, p ⫽ 0.002). This benefit, however, was significant only for stage T3N0 with a trend towards improvement in the T3N1 group. No significant benefit was observed in T1N1 or T2N1 disease (Table). Conclusions: Stage III SCC of the oral cavity is a heterogeneous disease with significant differences in survival according to its subsets. Adjuvant RT was associated with improved survival for patients with stage T3N0 disease but not T1N1 or T2N1. The benefit of RT in T3N1 cases did not reach statistical significance likely due to the small number of patients. If confirmed in prospective studies, further subdivision of stage III SCC of OC may be necessary, and the indication for RT may be restricted to patients with T3 disease. Subgroup T1N1 T2N1 T3N0 T3N1

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Treatment (N)

5-year OS

HR (95% CI)

P value

S (87) RT (26) SRT (133) S (82) RT (75) SRT (195) S (114) RT (83) SRT (137) S (21) RT (47) SRT (51)

51.6% 38.7% 56.3% 33.1% 34% 46.6% 40.6% 18.3% 52.8% 27.0% 19.4% 49.6%

1.00 1.80 (0.90-3.57) 0.80 (0.49-1.33) 1.00 1.37 (0.88-2.15) 0.74 (0.50-1.10) 1.00 1.95 (1.32-2.89) 0.55 (0.36-0.84) 1.00 1.05 (0.52-2.12) 0.54 (0.26-1.14)

p⫽0.10 p⫽0.39 p⫽0.16 p⫽0.13 p⫽0.0009 p⫽0.006 p⫽0.89 p⫽0.11


Hospital variation in bronchoscopy and esophagoscopy rates during head and neck cancer diagnostic evaluation. Presenting Author: Gordon H. Sun, Robert Wood Johnson Foundation Clinical Scholars, Ann Arbor, MI Background: Hospital variation in bronchoscopy and esophagoscopy rates while diagnosing head and neck cancer may reflect professional uncertainty about the effectiveness of these procedures and a lack of clinical guidelines on best practices. Furthermore, high-volume hospitals have demonstrated better outcomes for select oncologic procedures. We examined the association between hospital case volume and diagnostic bronchoscopy and esophagoscopy rates. Methods: This retrospective cohort study used the 2006-2010 Michigan State Ambulatory Surgery Databases, capturing all outpatient surgical cases in Michigan. Eligible cases included head and neck cancer patients who underwent laryngoscopy, bronchoscopy, and/or esophagoscopy. The primary outcome measure was the likelihood that a patient who underwent laryngoscopy during head and neck cancer diagnostic workup also underwent either bronchoscopy or esophagoscopy. We used hierarchical, mixed-effect logistic regression to measure the association between the primary outcome and hospital case volume (⬍100, 100-999, or ⱖ1,000 cases/hospital) while adjusting for patientlevel variables such as age, sex, race, insurance status, and household income. Results: Of 17,828 head and neck cancer patients, 9,218 underwent diagnostic laryngoscopy. The 50 low-volume and 40 mediumvolume hospitals performed significantly more concurrent bronchoscopies and esophagoscopies compared to the 2 high-volume hospitals (both p⬍0.001). After adjusting for patient characteristics, medium-volume and low-volume hospitals respectively had 9.3-fold and 7.8-fold higher odds of performing esophagoscopy relative to high-volume hospitals (p⫽0.003), although the association with bronchoscopy was no longer statistically significant. Conclusions: The proportion of head and neck cancer patients undergoing diagnostic laryngoscopy with concurrent esophagoscopy, but not bronchoscopy, varies significantly by hospital volume. A robust discussion of the comparative effectiveness of comprehensive and selective endoscopy will require further research into whether endoscopic volume correlates with tumor staging, survival, and other outcomes data.


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6046


A phase II study of suberoylanilide hydroxamic acid (SAHA) in subjects with locally advanced, recurrent, or metastatic adenoid cystic carcinoma (ACC). Presenting Author: Priscila Hermont Goncalves, Karmanos Cancer Institute, Wayne State University, Detroit, MI

Health care-associated infections (HAIs) in head and neck carcinoma (HNC) patients treated with chemotherapy (CT) and/or radiotherapy (RT). Presenting Author: Aurora Mirabile, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Background: SAHA is a small molecule inhibitor of histone deacetylases (HDAC). Based on confirmed responses noted in 2 ACC patients treated with SAHA at our institution; we initiated this phase II trial. Methods: Patients with LA, recurrent or metastatic ACC and adequate organ function were eligible. Any prior number of chemotherapy regimens was allowed. Tumor tissue and blood were collected for correlative studies. SAHA was administered orally 400 mg daily for 28 days. The primary objective was to evaluate response rate (RR). Secondary endpoints included: time to tumor response (TTR); response duration (RD); progression-free survival (PFS); overall survival (OS); and adverse events (AE). 29 evaluable patients were needed in a Simon 2-stage optimal design to distinguish RR of at most 5% vs. at least 20%, with alpha ⫽ 0.15 and power ⫽ 0.90. Results: 30 evaluable patients (overenrolled by 1) were accrued from at 5 different centers between August 2010 and June 2012. Median follow up among the censored patients is 3.8 months for PFS, and 7.2 months for OS. 19 patients were female, 24 were Caucasian, median age was 53 years (range 21-73); 21 patients had a performance status of 1; 20 patients were chemo-naïve. The median number of cycles completed was 5 (range 1-27⫹). Lymphopenia (n⫽5), hypertension (n⫽3), oral pain (n⫽2), thromboembolic events (n⫽2) and fatigue (n⫽2) were the only grade 3 AEs that occurred in more than 1 patient. 5 patients were dose reduced due to AEs. At the time of data cut-off, 9/30/2012, 1 patient with lung metastasis had a PR, with RD of 11.2⫹ months. TTR was 7.7 months. SD was the best response in 25 patients. Median PFS is 12.7 months (90% confidence interval lower limit: 3.7 months). Median OS has not been reached. There were 6 patients with PFS ⬎ 1 year. The correlative studies results will be presented. Conclusions: SAHA shows promise in the treatment of ACC. We are awaiting genomic analysis of the tumors to study the basis of clinical benefit (PR and SD) of SAHA in ACC. Future drug combination studies in ACC are being considered focusing on the epigenetic mechanism of SAHA. Supported by 5U01CA062487/19. Clinical trial information: NCT01175980.

Background: HAIs are dangerous complications of HNC treatment. In lack of data we collected own data in a high volume HNCMOU, comparing them with those observed in other departments. Methods: HAIs recorded retrospectively among 2,288 hospital admissions at our HNCMOU observed from 2005 to 2009 were compared with 427 recent (2010-2012) hospital admissions. In the same period HAIs observed in ENT Surgical, Medical Oncology (MO) and Bone Marrow Transplantation (BMT) dept were recorded. Results: Between 2005 and 2009, 140 HAIs were observed in the HNCMOU: 49% Gram-, 35% Gram⫹, 16% fungi; 88% of P. Aeruginosa and all Enterobacteriaceae were sensible to meropenem and piperacillin/ tazobactam, methicillin-resistant S. aurei (MRSA) were 42% (Table). In the last 3 years infections and resistances rates increased with a similar pattern of bacteria: among 212 HAIs (43% Gram-, 32% Gram⫹, 24% fungi) the majority (39%) involved respiratory tract, 89% of P. aeruginosa and 92% of Enterobacteriacae were sensible to carbapenem and 89% and 51% were sensible to piperacillin/tazobactam. MRSA were 29%. We compared these data with HAIs occurred from 2005 to 2012 into other dept: most of HAIs in ENT Surgical dept were at surgical site (41%) due to Gram⫹ (45%), in BMT were sepsis (56%) due to Gram⫹ (51%) and in MO were urinary tract infections (39%) due to Gram – (70%). Conclusions: Gram- continue to represent the first cause of HAIs in HNC cancer patients treated with CT and/or RT, suggesting a peculiar pattern. This is paralleled by a rise in carbapenem resistance, while MRSA still represent a significant fraction. Respiratory tract

Surgical

Blood

Other

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Cetuximab with or without sorafenib in recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). Presenting Author: Jill Gilbert, Vanderbilt University Medical Center, Nashville, TN Background: For patients with R/M SCCHN, cetuximab, a monoclonal antibody against EGFR, is approved as a single agent and has a survival benefit when combined with chemotherapy. We hypothesized that addition of sorafenib, a multi-kinase inhibitor of targets including VEGFR, to cetuximab may have greater clinical benefit than cetuximab alone. Methods: This trial was designed as a blinded, randomized phase II, placebocontrolled study of cetuximab at 400 mg/m2 IV on day 1 followed by 250 2 mg/m IV weekly plus placebo bid (Arm A) or cetuximab at the same dose and schedule plus sorafenib 400 mg po bid (Arm B), each in 21 day cycles. After 19 patients were enrolled, the trial was amended to remove the placebo (and blinding) due to issues with placebo tablet solubility. Target sample size was 84 patients with 83% power to detect a 2-month increase in PFS, the primary study endpoint. Interim analysis was planned at midpoint, requiring hazard ratio ⬍ 1 to proceed to the second stage of study. Serum cytokine and tumor HPV ISH and p16 analyses were performed. Results: Of 56 patients (ages 26-74, 80% male) enrolled, 53 patients received treatment and 41 were evaluable for response. Of the patients who received therapy, 26 received cetuximab only (Arm A). For Arm A, the mean number of cycles delivered was 4.3 (range 1-16) and the mean for Arm B was 3.3 (range 1-11). The most common grade 3/4 AEs were fatigue (2 A, 1 B), hypertension (3 B), infusion reaction (both arms), and diarrhea (2 B). Arm A had 2 PRs and Arm B had 4 PRs. Median OS was 7 mo and 5.9 mo respectively. Median PFS was 3.1 mo for both arms. 24 patients had pre-treatment cytokine measurements. Of the 12 measured cytokines, high TGFB1 level was significantly correlated with inferior PFS (4.6 mo vs 1.6 mo), regardless of arm (p⫽0.015). 38 patients had tumors available for p16 staining (31 neg and 7 pos). 3 of 7 p16 pos were also HPV ISH pos. The p16 neg patients had significantly improved PFS (3.5 mo vs 1.6 mo) regardless of arm (p⫽0.032) but no difference in OS (p⫽1.0). Conclusions: Both arms demonstrated clinical activity although no significant difference was observed. However, a subset of patients with p16 neg tumors or low serum TGFB1 may have a greater benefit with cetuximabbased therapy. Clinical trial information: NCI-2012-02847.

Gram ⴙ N 49 (35%)

Site

Gram - N 69 (49%)

Fungi N 22 (16%)

Total 140

S. aureus 9 (15%) P. aeruginosa 18 (30%) Aspergillus species 2 (3%) 60 (43%) Corinebacterium species 3 (5%) Enterobacteriaceae 16 (27%) S. pneumoniae 3 ( 5%) H. influentiae 6 (10%) Others 3 (5%) S. aureus 5 (13%) P. aeruginosa 6 (15%) C. albicans 9 (22%) 40 (29%) Others 6 (15%) Enterobacteriaceae 5 (12%) C. species 5 (13%) C. glabrata 4 (10%) S. epidermidis 9 (26%) Enterobacteriacae 12 (34%) C. tropicalis 2 (6%) 35 (25%) S. aureus 4 (12%) P. aeruginosa 4 (11%) Others 4 (11%) S. aureus 4 (80%) G. vaginalis 1 (20%) 5 (3%)

6048


Impact of obesity on survival in patients (pts) with early-stage squamous cell carcinoma (SCC) of the oral tongue. Presenting Author: Neil M. Iyengar, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Obesity is a risk factor for several malignancies and an independent predictor of worse outcomes. In contrast, low body mass index (BMI) has been associated with increased risk of oropharyngeal cancers and poorer prognosis. In tongue SCC, impaired nutrition, smoking, and alcohol use impact BMI, and pre-diagnosis weight (wgt) loss negatively affects survival. The prognostic effect of obesity in tongue cancer is unknown. Methods: We conducted a singleinstitution, retrospective study of pts who underwent resection of T1/T2 SCC of the oral tongue. All pts underwent nutritional assessment prior to surgery. BMI was calculated from measured height and wgt at surgery and categorized as obese (ⱖ30), overwgt (25-29.9), or normal (18.5-24.9). The association between BMI and the primary endpoint, disease specific survival (DSS), was evaluated by Cox regression. The effect of BMI on the secondary endpoints, recurrence free survival (RFS) and overall survival (OS), was also assessed. Results: From 2000 to 2005, 155 pts (90 men, 65 women) of median age 57 (range 18-86) were included. Clinicopathologic characteristics were similar by BMI group. Obesity was significantly associated with adverse DSS compared with normal wgt in univariable (Table) and multivariable analyses (HR 2.87; 95% CI, 1.08-7.67; p⫽0.04). Obesity was also significantly associated with adverse RFS (HR 2.53; 95% CI, 1.12-5.74; p⫽0.03). Overwgt subjects may also have worse RFS (HR 1.74; 95% CI, 0.85-3.55; p⫽0.13). In pts without pre-diagnosis wgt loss (n⫽94), obesity was significantly associated with adverse OS (HR 2.70; 95% CI, 1.12-6.54; p⫽0.03). Conclusions: These data suggest that obesity is associated with a worse prognosis in tongue cancer, which may not have previously been appreciated due to confounding by pre-diagnosis wgt loss. Characteristic (n) Age BMI Normal (63) Overwgt (62) Obese (30) Stage T1 (109) T2 (46) Nodal metastases No (100) Yes (55) Race Non-Black (151) Black (4) Smoking Never (65) Former (48) Current (98)

HR

Univariable 95% CI

P

1.03

1.00 - 1.06

0.02

Ref 1.34 2.65

0.59 - 3.06 1.07 - 6.59

0.49 0.04

Ref 2.06

1.02 - 4.19

0.05

Ref 2.69

1.33 - 5.42

⬍0.01

Ref 5.87

1.76 - 19.55

⬍0.01

Ref 1.24 0.97

0.55 - 2.78 0.40 - 2.34

0.60 0.94




Validation of the Vanderbilt Head and Neck Symptom Survey Version 2.0. Presenting Author: Kenneth J. Niermann, Department of Radiation Oncology, Vanderbilt University, Nashville, TN Background: We previously reported the development and preliminary testing of the Vanderbilt Head and Neck Symptoms Survey version 2.0 (VHNSS 2.0 ) for assessment of symptom burden in head and neck cancer (HNC) patients who are undergoing or completed primary or adjuvant radiation based therapy (Cooperstein et al., Head and Neck, 2012, 24(6): 797-804). In addition to expanding items on existing domains, version 2.0 includes new domains such as dental health, mucosal sensitivity, and joint range of motion. Herein we report the results of initial validation of the instrument. Methods: 159 unique patients with HNC completed the 50 item VHNSS 2.0 as a part of one of three supportive care studies. Since each of these studies was prospective and longitudinal with repeated application of the VHNSS 2.0, we chose to utilize the first complete questionnaire for each patient for this analysis. Results: Patient characteristics: median age 57 (range 28-81 years), male 74.8%, Caucasian 91.8%, T3 or T4 46.5%, N2 or N3 66%, Site: pharynx 57.9%, oral cavity 15.1%, larynx 11.3%, 15.7%. Analysis identified 10 distinct clusters with 3 single items. The internal consistency of the clusters was good to excellent. Cronbach’s alpha coefficient, a statistical measure of reliability is shown in the Table. Conclusions: The VHNSS 2.0 is a robust, reliable measure of acute and late toxicities in patients undergoing radiation for HNC. These results provide a platform for administering appropriate interventions, which would ultimately provide for effective management of adverse oral health outcomes. Symptomatic clusters

# of items per cluster

Cronbach’s alpha

Mouth pain General pain Swallow solid Swallow liquid Nutrition Mucous Dry mouth Taste/smell Voice Teeth Hearing Trismus Neck/shoulder ROM

6 3 8 2 4 4 5 6 3 4 1 1 1

.90 .94 .92 .70 .83 .95 .92 .92 .89 .75 — — —

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375s General Poster Session (Board #11F), Sat, 8:00 AM-11:45 AM

Recombinant adenoviral human p53 gene combined radio- and chemotherapy after a tumorectomy in treatment of laryngeal carcinoma in advanced stage. Presenting Author: Fei Chen, Huaxi Hospital affiliated Sichuan University, Chengdu, China Background: To investigate the benefits of post-surgery using recombinant adenoviral human p53 gene (rAd-p53) combined with radio- and chemotherapy in treatment of laryngeal carcinoma in advanced stage. Methods: A total of 61 patients with a stage III or IV laryngeal cancer, 51 males and 10 females with an average age of 63.2, were randomly divided into three groups: G1, G2 and G3. The 18 G1 patients received no treatment after surgery. The patients in G2 (21 patients) and G3 (22 patients) received rAd-p53 followed by radio-and chemo-therapy, and only radio- and chemotherapy, respectively. The rAd-p53 was injected into the surgery wound bed at a dose of 2 x 1012 viral particles (VP) once per 3 days for 5 times. Radiotherapy was given at a total dose of 63-67 Gy in 7 weeks. The chemo-regimen included 5- Fu 500 mg/ m2 from day 1 to day 5 and DDP 30 mg / m2 from day 1 to day 3 in a treatment course of 21days for two courses. Results: All the study patients were followed up for at least 3 years. One patient in G2 lost to follow up. The local control rates (no recurrence) at 3 years were 38.9% (7/18), 75.0% (15/20), and 54.5% (12/22) for G1, G2, and G3, respectively. The 3-years progress free survivals (PSF) were 38.9%, 50.0%, and 45.0% for G1, G2, and G3, respectively. The 3-years overall survivals (OS) were 38.9%, 65.0%, and 45.0% for G1, G2, and G3, respectively. The three efficacy endpoints of G2 were significantly better than both G1 and G3. These efficacy measures of G3 were significantly higher than G1. Conclusions: Post-surgery chemo- and radiotherapy is necessary to increase the local control rate, prolong both PRF and OS. The rAd-p53 gene therapy can farther increase the efficacy measures.

6052


Neoadjuvant erlotinib, erlotinib-sulindac, or placebo: A randomized, doubleblind biomarker modulation study in operable head and neck squamous cell carcinoma (HNSCC). Presenting Author: Julie E. Bauman, University of Pittsburgh Cancer Institute, Pittsburgh, PA

Predictive values of (18)f-FDG PET standardized uptake value for adjuvant chemotherapy in patients with nasopharyngeal carcinoma. Presenting Author: Ching Chan Lin, Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan

Background: The epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) pathways are upregulated in HNSCC. Crosstalk potentiates growth, proliferation and invasion. Preclinical models show synergistic anti-tumor effects from dual blockade. We evaluated biomarker modulation in paired tumor specimens from a 3-arm phase 0 trial of erlotinib, a small molecule EGFR inhibitor; erlotinib ⫹ sulindac, a non-selective COX inhibitor; vs. placebo. Methods: Patients (pts) with untreated stage II-IVb HNSCC were randomized 5:5:3 to neoadjuvant erlotinib 150 mg daily (Arm 1, n ⫽ 19), erlotinib ⫹ sulindac 150 mg twice daily (Arm 2, n ⫽ 16), or placebo (n ⫽ 12). Pts were treated for 7-14 days. Tumor specimens were collected pre- and post-treatment. The primary endpoint was change in Ki-67 proliferative index. We hypothesized an ordering in Ki-67 downmodulation, with Arm 2 ⬎ Arm 1 ⬎ placebo. A Jonckheere-Terpstra test evaluated trend; a Wilcoxon test was applied to pairwise contrasts. We prepared tissue microarrays for IHC, to explore pharmacodynamic modulation of 21 EGFR and COX-2 pathway constituents including EGFR, Src, STAT3, Akt, EP2 and EP4. Results: From Dec 2005 – Dec 2008, 48 pts enrolled; 28 tumor pairs were evaluable for biomarker modulation. Class toxicities of EGFR inhibition, including acneiform rash and diarrhea, were observed on Arms 1 and 2. Compared to placebo, Ki-67 was reduced by erlotinib (p ⫽ 0.0005) or by erlotinib-sulindac (p ⫽ 0.0001). There was a trend in ordering of Ki-67 down-modulation, with greater effect from the addition of sulindac (exact Jonckeheere-Terpstra, Arm 1 vs. 2, p ⫽ 0.003). Among 21 protein candidates tested for association with Ki-67, only low baseline p-Src correlated with greater Ki-67 reduction in both erlotinib groups (R2 ⫽ 0.312, p ⫽ 0.024). Conclusions: Relative to placebo, brief neoadjuvant treatment with erlotinib or erlotinib-sulindac significantly decreased the proliferative index in operable HNSCC. Sulindac enhanced Ki-67 down-modulation. Efficacy studies of dual EGFR-COX inhibition are justified. Baseline p-Src warrants further study as a resistance biomarker for anti-EGFR therapy. Clinical trial information: NCT01515137.

Background: Concurrent chemoradiotherapy (CCRT) with or without adjuvant chemotherapy is the mainstay of treatment for locally advanced nasopharyngeal carcinoma (NPC). However the benefit of adjuvant chemotherapy has been controversial and search for adequate predictive factors is warranted. We conduct this study to evaluate the predictive values of mean standardized uptake value (SUV) measured in [(18)F]-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) for adjuvant chemotherapy in patients with locally advanced NPC. Methods: From January 2004 and July 2010, Data collection were performed in 108 NPC patients who underwent (18)F-FDG-PET before CCRT and adjuvant chemotherapy. The SUV was recorded for the primary tumor. All patients received intensity modulated radiotherapy. Concurrent chemotherapy was composed of cisplatin 100mg/m2 triweekly. Adjuvant chemotherapy was consisted of 3 cycles of cisplatin 75 milligrams/m2 and fluorouracil 1000 milligrams/ m2for 4 days. Results: The median follow-up was 41months. The optimal cutoff value was 8.35 for SUV. 63.8% of patients had lower SUV (n⫽69), and 36.2% had higher SUV (n⫽39). Patients with a lower SUV had a significantly better 3-year overall survival (OS), disease-specific survival (DDS), and distant relapse-free survival (DRFS), but showed no difference in local relapse-free survival. Multivariate analysis showed only stage, SUV and adjuvant chemotherapy were significant in terms of overall survival. In patients with higher SUV, those receiving adjuvant chemotherapy had significantly higher 3-year OS, DDS, and DRFS compared with those without adjuvant chemotherapy. However, in those with lower SUV, there was no difference of OS, DDS and DRFS between patients with and without adjuvant chemotherapy. Conclusions: SUV of (18)F-FDG-PET for primary tumor could identify NPC patients who benefit from adjuvant chemotherapy. OS(%)

P

DDS(%)

P

DRFS(%)

P

LRFS(%)

P

Lower SUV 95.1 vs 90.7 0.534 100 vs 95.1 0.308 95.7 vs 94.1 0.887 84.5 vs 90.5 0.541 (with vs without adjuvant chemotherapy) Higher SUV 88.2 vs 58.9 0.026 88.2 vs 58.9 0.026 85.2 vs 50.9 0.086 88.0 vs 65.5 0.098 (with vs without adjuvant chemotherapy)


376s 6053


Clinical outcomes of transoral robot-assisted supraglottic laryngectomy: An experience of a French cooperative evaluation group of transoral robotic surgery. Presenting Author: Philippe Ceruse, Centre Hospitalier Lyon Sud, Pierre-Benite, France Background: Transoral, minimally invasive organ preservation surgeries are being increasingly used for laryngopharyngeal carcinomas to avoid the toxicities of combined chemotherapy and radiation therapy regimens. This study investigates the efficiency, safety, and functional outcomes of transoral robot assisted surgery (TORAS) for supraglottic laryngectomy. Methods: Experience of TORA supraglottic laryngectomy for patients with supraglottic carcinomas is presented in a multicentric study of a case series with planned data collection between 2009 and 2012. Results: Eighty-six of 262 patients underwent TORA supraglottic laryngectomy for supraglottic carcinomas. Thirty-three percent of patients were started an oral diet within 24 hours. For 77% of the other patients, the median use of a feeding tube was 8 days (0-10 months). Nine percent of them had a definitive percutaneous gastrostomy feeding. For 87% of patients no tracheotomy was performed, for 23% of the others patients, the median use of tracheotomy was 8 days, 3% of them had a definitive tracheotomy. Aspiration was observed in 22% of the patients in the postoperative course and was responsible for the death of one patient. Sixteen percent of the patients had a postoperative bleeding. Fifty percent of the patients received adjuvant radiation therapy based on pathology results. Conclusions: TORA supraglottic laryngectomy is a safe procedure with good functional outcomes and fast recovery but adverse events are possible. Consequently this technique needs a good selection of the patients to reduce the risk of postoperative complications.

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Use of gene expression signature to discriminate oropharyngeal cancers according to HPV16 status. Presenting Author: Haitham Mirghani, Head and Neck oncology Institut Gustave Roussy, Villejuif, France Background: Strong evidence supports the hypothesis that high-risk human papillomavirus (HPV), particularly HPV16, is a causative agent for an increasing subset of oropharyngeal squamous cell carcinomas (OPSCC). These tumors have distinct oncogenic mechanisms and a more favorable prognosis than tobacco induced OPSCC. Although these differences emphasize the need for a specific therapeutic approach, HPV status is still not used to guide treatment. A better understanding of the molecular profile related to HPV16 induced OPSCC may help to develop personalized treatments. Methods: To identify an HPV16-related molecular signature, we compared the gene expression profile of 15 transcriptionally active HPV16positive and 15 HPV16-negative OPSCC. The study was conducted in two steps. First, a learning set of 16 OPSCC comprising 8 HPV16-positives and 8 HPV16-negatives OPSCC was analyzed in order to identify the signature. Potentially confounding factors of stage, sex and tobacco consumption were equally distributed in both groups. Secondarily, the robustness of this signature was further confirmed by blind case-by-case classification of an independent set of 14 OPSCC. Results: We identified a signature composed of 224 genes which discriminates HPV16-induced OPSCC from their tobacco induced counterparts. After the viral status was revealed, 13 out of 14 tumors were correctly classified according to tumor etiology, 1/14 was undetermined and none were misclassified. Interestingly, deregulated genes in HPV16-positive tumors are principally involved in innate immunity, in cell cycle regulation through the TP53/RB/E2F pathway, and autophagy through mTOR regulation. Well known targets of E6 and E7 proteins are also found to be deregulated. Conclusions: Our results demonstrate that a set of selected genes can distinguish OPSCC according to etiology. These genes shed light on HPV16 induced carcinogenesis since specific molecular pathways are deregulated. Further investigations are required for a better understanding of the differing natural histories and biological properties of these tumors. These properties may be exploited as a target of novel therapeutic agents in HPV-related OPSCC.

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Squamous cell carcinoma of the oral cavity (SCCOC) in young patients: The Dana Farber Cancer Institute experience. Presenting Author: Glenn J. Hanna, Beth Israel Deaconess Medical Center, Boston, MA Background: Young patients (ⱕ age 45) with SCCOC and limited tobacco and alcohol exposure represent a distinct clinical entity with a poor prognosis. These patients are poorly characterized. We report our institution’s experience treating these patients over the past decade. Methods: Patients ⱕ 45 years with SCCOC treated between 2001 and 2012 were identified retrospectively. Patient characteristics and treatment were recorded. Results: A total of 99 patients were identified (34 F and 65 M). Median age at diagnosis was 34 and 38 years, respectively (range 14 to 45 years). Thirty one (91.2%) women were never or former smokers with fewer than 10 pack-years, as compared with 50 (76.9%) men (p ⫽ 0.07). In women, 33 (97.1%) reported minimal to no alcohol use, compared with 52 (80%) men (p ⫽ 0.02). Oral tongue was the primary site in the majority of patients (30 F, 58 M). Surgical resection was the primary treatment modality (30, 88.2% F vs. 44, 68% M). Post-op radiation or chemoradiation was applied depending on stage and pathological findings. Stage: 53/99 (53.5%) presented with stage I or II disease and 46/99 (46.5%) had stage III or IV disease. Males on average had more advanced stage disease at presentation (33/65, 50.8%). Four of 7 women and 4 out of 18 men tested positive for human papilloma virus (HPV). Seven women (20.6%) and 13 (20%) men demonstrated evidence of local or locoregional recurrence with a median time to recurrence of 5 years and 0.67 years (range 1-10 and 0.08-11), respectively. Second primaries were rare (2, 5.88% F vs. 0, 0% M). Two women (5.9%) and 9 men (13.9%) died from recurrent disease. Overall, 4 (30.8%) women with stage III, IV disease demonstrated recurrence vs. 6 (18.2%) men (p ⫽ 0.35). Conclusions: In our experience, young patients with SCCOC have high cure rates that do not appear to be inferior to other sites in the head and neck area. Men and women are equally affected. Further clinical and genomic characterization for this group of patients is warranted.

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Radiotherapy (RT) potentiation with weekly (q1w) or standard every 3 weeks (q3w) cisplatin chemotherapy (CT) for locally advanced head and neck squamous cell carcinoma (HNSCC). Presenting Author: Yann Molin, University of Lyon, centre Léon Bérard, Lyon, France Background: Q3w CT is standard RT potentiation for HNSCC but its toxicity requires to look for new treatment’s modalities. The aim was to explore if q1w CT could be a safe and effective alternative. Methods: Patients (pts) treated by chemoradiation (CT-RT) for a HNSCC were retrospectively included. Study population was first described. Then overall (OS) and progression-free survival since the RT onset were performed. Survival distributions were estimated by Kaplan-Meier method and compared between CT groups using the Log-Rank test. Prognostic effect of CT group was explored using Cox model. Results: 266 pts treated between January 2004 and December 2008 were included: 170 and 96 pts respectively received q1w and q3w CT. At diagnosis, 46% had oropharynx lesions, 20% larynx, 17% hypopharynx and 14% oral cavity. 70% pts experienced surgery, 39% CT induction and a median dose of radiation of 64 Gy without any significant difference between CT groups. However, median age at diagnosis was significantly different between q1w and q3w CT (58 vs 54, p⬍0.001) as well as alcohol consumption (79% vs 68, p⫽0.047), stage at diagnosis (30%-60% stage III-IV vs 13% -80%, p⫽0.003), IMRT use (4% vs 13%, p⫽0.011) and median weight before RT (66 kg vs71kg, p⫽0.014). Q3w CT was more toxic than q1w in terms of weight loss (87% vs 75%, p⫽0.012), renal failure (50% vs 35%, p⫽0.022), worse CT plan completion (42% vs 66%, p⬍0.001). Moreover, grade 3/4 toxicities, such as mucositis (34% vs 13%, p⬍0.001) and dermatitis (7% vs 1%, p⫽0.012), were more frequent. More pts needed parenteral nutrition (10% vs 2%, p⫽0.008), analgesics (91% vs 70%, p⬍0.001), secondary hospitalization (31% vs 8%, p⬍0.001), RT interruption ⬎⫽ 3 days (8% vs 2%, p⫽0.037) and had long-term toxicities (24% vs 12%, p⫽0.014). With a median follow-up of 42 months 95% CI [36.8-48.8], a trend in favour of q3w CT was found:2-years OS of 83% (95% CI [73-90]) vs 74% (95% CI [66-80]), p⫽0.089. However, after adjustment on prognostic factors CT group was not significantly associated with OS nor with PFS. Conclusions: Q1w RT-CT is safer than q3w and may be as efficient. Follow-up data will be updated to reinforce efficacy results.




Induction chemotherapy (IC) with docetaxel/cisplatin/5-fluorouracil (TPF) followed by cisplatin-containing concomitant chemoradiotherapy (CRT) in fit patients with locally advanced head and neck cancer (LAHNC): The CONDOR study—A study of the Dutch Head and Neck Society. Presenting Author: Chantal Driessen, Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands Background: Standard treatment for patients (pts) with LAHNC is concomitant CRT containing cisplatin. In general 70% of the pts receive all planned cisplatin cycles. TPF IC is associated with survival benefit, but has never been studied in combination with standard CRT. We aimed to determine if TPF followed by cisplatin-containing CRT, in 2 different schedules, was feasible. Methods: In this multicenter randomized phase II trial LAHNC pts, PS 0-1, were treated with maximal 4 TPF courses (T 75 mg/m2, P 75mg/m2 and F 750 mg/m2 day 1-5) and thereafter randomized between P 100 mg/m2 on days 1, 22, 43 combined with conventional RT (arm A) or P 40 mg/m2weekly, maximally 6, combined with accelerated RT (arm B). Primary endpoint was feasibility, defined as receiving ⱖ 90% of the planned total radiation dose. Based on power analysis 70 pts were needed. Results: Following an interim-analysis, the study was early terminated after inclusion of 65 pts because only 32% of pts could be treated with the full cisplatin dose during CRT after TPF. 81,5% of pts was male, median age was 56 yrs and PS was 0 in 79% and 1 in 21%, primary site: oral cavity (23%), oropharynx (57%), hypopharynx (12%), larynx (8%). 3 pts did not start TPF; 6/62 pts were not randomized after TPF, due to death (1), toxicity (3) or severe PD (2). RR after TPF was CR 4%, PR 64% and SD 28% in the randomized pts. 27 pts were randomized in arm A and 29 in arm B. 97% of the pts received at least 90% of the planned total radiation dose. However, in arm A only 6 of the 27 pts (22%) and in arm B 12 of the 29 pts (41%) received the total planned chemotherapy part of the CRT. Most common grade 3-4 toxicity during TPF was febrile neutropenia (18%),and during CRT arm A vs arm B dehydration (26% vs 14% ), dysphagia (26% vs 24%), mucositis (22% vs 57%) and creatinin increase (19% vs 3%). After a median follow-up of 21 (7-42) months 66% of the pts was still alive. Conclusions: After TPF IC cisplatin-containing concomitant CRT is not feasible in LAHNC, because the total planned dose of cisplatin could only be administered in 32% of the pts due to severe toxicity. Clinical trial information: NCT00774319.

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A phase II study of radiation therapy (RT), paclitaxel poliglumex (PPX), and cetuximab (C) in locally advanced head and neck cancer (LA-HNC). Presenting Author: Seung Shin Hahn, SUNY Upstate Medical University, Syracuse, NY Background: RT ⫹ cisplatin in LA-HNC showed a survival benefit over RT alone, but with significant toxicity. Addition of C to RT demonstrated survival benefit without increased RT-related toxicity. PPX consists of paclitaxel linked to a biodegradable, water-soluble polymer of glutamic acid. PPX has a radiation enhancement factor of ⬇8 in a radiocurability murine model. This study addresses the combined use of intensity modulated RT (IMRT), PPX, and C in patients with LA-HNC. Methods: Eligible patients had untreated stage III/ IV squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, larynx, or unknown primary, ECOG PS 0-1, and adequate bone marrow function. Patients received C 400 mg/m2 day 1 and 250 mg/m2 weekly for 7 weeks. PPX was administered at 40 mg/m² weekly for 7 weeks. IMRT began on day 8 consisting of 69.96 Gy delivered in 2.12 Gy daily. Results: 38 patients with LA-HNC are included in this report and evaluable for response. 24 (63%) had CR and 14 (37%) had PR. HPV status is 21⫹, 11- and 8 unknown. Pre-therapy, 36 patients had nodal disease, 9 underwent neck dissection post-treatment and 1/ 9 patients had microscopic involvement by cancer. Locoregional tumor control occurred in 36/38 (95%) patients with two patients developing locoregional recurrence after completion of therapy. Two patients have died from metastatic disease and two patients are alive with distant metastases. Two additional deaths were unrelated to therapy (sudden cardiac death and COPD exacerbation with respiratory failure). The majority of adverse events (AEs) were grade 1/2 and consistent with known toxicities of individual agents. The most common grade 3 AEs were mucositis (n⫽28), radiation dermatitis (n⫽15), dehydration (n⫽8) and cetuximab rash (n⫽9). The median overall survival and progression free survival have not been reached. Updated numbers will be presented. Overall survival rate is 34/38 (89%) by intent-to-treat analysis, with a median follow up of 13 months. Conclusions: The combination of IMRT, PPX, and C is tolerable and shows promising clinical activity in patients with LA-HNC. An expansion cohort of HPV negative patients on this protocol is in progress. Clinical trial information: NCT00660218.

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Acupuncture for dysphagia after chemoradiation therapy in head and neck cancer: A randomized sham-controlled study. Presenting Author: Weidong Lu, Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA Background: Dysphagia is a common side effect following chemoradiation (CRT) in pts with head and neck cancer (HNC). The purpose of this pilot trial was to assess the feasibility of recruiting HNC pts and to collect preliminary data on the efficacy and safety of acupuncture on dysphagiarelated QOL. Methods: Pts were eligible if diagnosed with stage III-IV HNC, without evidence of distance metastasis, receiving curative-intent CRT. Pts were randomized to 12 sessions of either active or sham acupuncture, once every two weeks, over 24 weeks from during CRT to 20-week post-CRT. All study personnel and the pts were blinded; the treating acupuncturists were not. MDADI and other questionnaires were measured at baseline (end of CRT), end of acupuncture, and at six months follow-up (12-month post-CRT). Data were analyzed by repeated-measures ANOVA adjusting for baseline. Results: Accrual was completed in December 2011. Among 42 pts enrolled, 35 (83%) received at least 8 sessions of acupuncture, and 28 (67%) received all 12. Six pts withdrew due to time constraints. No serious side effects were observed. The mean MDADI total scores improved from baseline in both treatment arms [64.5 (SE⫹2.4) vs. 71.4 (SE⫾3.1), p ⫽ 0.048; 64.5 (SE⫾2.4) vs. 77.8 (SE⫾3.0), p⬍ 0.001]; the difference in improvement was not significant (p ⫽ 0.12). The median feeding tube duration did not differ between active and sham treatments (n ⫽ 39, median 125 days vs. 147 days, p ⫽ 0.93). Conclusions: Acupuncture is a safe and feasible treatment for HNC pts. There were improvements in QOL parameters from end of CRT to the time points examined that did not differ between the two arms. Efficacy of acupuncture to improve swallowingrelated QOL in HNC pts may require more frequent or longer duration of treatment. Clinical trial information: NCT00797732.

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Organ preservation with daily concurrent chemoradiotherapy using retrograde superselective intra-arterial infusion for stage III, IV oral cancer: Analysis of therapeutic results in 112 cases. Presenting Author: Kenji Mitsudo, Department of Oral and Maxillofacial Surgery, Yokohama City University School of Medicine, Yokohama, Japan Background: Retrograde superselective intra-arterial chemotherapy for oral cancer has the advantage of delivering a high concentration of the chemotherapeutic agents to the tumor bed, it can be used to provide daily concurrent chemoradiotherapy for patients with advanced oral cancer. The purpose of this study was to evaluate the therapeutic results and rate of organ preservation in 112 patients of stage III or IV (M0) oral cancer treated with retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy. Methods: Between August 2006 and July 2011, 112 patients with stage III or IV oral squamous cell carcinoma underwent intra-arterial chemoradiotherapy. Catheterization from the superficial temporal and occipital arteries was performed. And treatment consisted of superselective intra-arterial chemotherapy (docetaxel, total 60 mg/m2, cisplatin, total 150 mg/m2) and daily concurrent radiotherapy (total 60 Gy) for 6 weeks. Results: The median follow-up for all patients was 46.2 months (range, 10 –90 months). The median follow-up for living patients was 49.7 months (range, 36 –90 months). After intra-arterial chemoradiotherapy, primary site complete response was achieved in 98 (87.5%) of 112 cases. Thirty patients (26.8%) died. Using the Kaplan-Meier method, 3-year, and 5-year survival rates were 74.6% and 71.3%, respectively, while 3-year, and 5-year local control rates were both 79.3%. Grade 3 or 4 toxicities included mucositis in 92.0%, neutropenia in 30.4%, dermatitis in 28.6%, anemia in 26.8%, and thrombocytopenia in 7.1%. Grade 3 toxicities included dysphagia in 72.3%, nausea/vomiting in 21.4%, fever in 8.0%, and renal failure occurred in 0.9%, no patients died as a result of treatment toxicity. Conclusions: Retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy for Stage III, IV oral cancer provided good overall survival and local control rates, thus preserving organs and contributing to patients’ QOL.


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Is there an interaction between epidermal growth factor receptor (EGFR) inhibition and p16-status in patients (pts) with oropharyngeal squamous cell cancer: A retrospective analysis. Presenting Author: Tobenna Igewonu Nwizu, Cleveland Clinic Foundation, Cleveland, OH

Effect of early detection of recurrent disease by FDG PET/CT on management of patients with squamous cell cancer of the head and neck (HNSCC). Presenting Author: Lale Kostakoglu, Department of Radiology, Mount Sinai Medical Center, New York, NY

Background: Conflicting data exists about whether EGFR inhibition is more or less effective in pts with p16 positive or negative oropharynx cancer (OPC). We update results from two institutional clinical trials in pts with locoregionally advanced head and neck squamous cell carcinoma (LRA HNSCC) given chemoradiotherapy either with or without the oral EGFR inhibitor gefitinib (G), with specific attention to the subset of pts with p16-defined OPC. Methods: Between 1996-2000, 44 pts with LRA HNSCC were treated on a Cleveland Clinic IRB-approved protocol using concurrent cisplatin, fluorouracil and radiation without G (G- cohort). Between 20032007, 60 similar pts were treated using the same chemoradiotherapy regimen with the addition of G 250 mg daily for 2 years beginning on day 1 of radiation (G⫹ cohort). Available biopsy material from 64 OPC pts (23 G-, 41 G⫹) was retrieved and tested by immunohistochemistry for p16 (as a surrogate for human papillomavirus) positivity. Kaplan-Meier outcome projections were compared using the log-rank test. Results: With a median follow-up in excess of 7 years for all pts, survival and patterns of failure did not differ between the two trials. The 5-year overall survivals (OS) were 68% vs. 64% (p⫽0.73) and relapse-free survivals (RFS) 65% vs. 63% (p⫽0.85) in the G⫹ and G- cohorts respectively. OPC was more frequent in the more recently treated G⫹ cohort (68% vs. 53%). Excluding 14 pts for whom tumor was unavailable, OPC p16-positivity was also more frequent in the G⫹ cohort (74% vs. 63%). As expected, outcomes in the p16⫹ OPC pts were significantly better than in the p16- OPC pts including OS (66% vs. 58%, p⫽0.049) and RFS (69% vs. 56% p⫽0.027). However, in comparing the G⫹ and G- cohorts, the use of G did not significantly alter any survival outcome or pattern of failure in either the p16⫹ or p16- OPC pts. Conclusions: Although the retrospective nature of this analysis limits the strength of our conclusions, in the definitive management of LRA HNSCC, we could identify no effect of oral EGFR inhibition on any outcome. In subset analysis there was also no differential impact found in either the p16⫹ or p16- OPC pts. Clinical trial information: NCT00352105.

Background: Despite the increasing cure rates a substantial fraction of HNSCC patients (pts) will present with locoregional and/or distant relapse within 3 years of definitive therapy. The prognosis of HNSCC pts after failure of first-line therapy has been poor but recent changes in the biology of HNSCC, advances in surgical techniques and radiotherapy; and new drugs may lead to improved salvage therapy. Notably, the success of these developments are implicitly dependent on early diagnosis disease. Our objective was to compare the efficacy of surveillance FDG-PET/CT to that of high resolution CT (HRCT) and physical exam (PE/E) for detection of early relapse in HNSCC after completion of primary treatment. Methods: A retrospective analysis of FDG-PET/CT, neck HRCT and PE/E was performed in 99 curatively treated HNSCC pts during post-therapy surveillance (PTS) to compare the performance characteristics of the tests in the detection of early recurrence or metachronous cancer. Results: A total of 19/99 (20%) pts had recurrence during a median follow-up of 21mo (range:9-52). Median time to first PET/CT was 3.5mo. The median time to radiological recurrence was 6 mo (range:2.3-32). PET/CT detected more disease recurrences or second primaries and did so earlier than HRCT and PE/E. Sensitivity, specificity, PPVand NPV for detecting locoregional and distant recurrence or metachronous cancer : 100%, 87.3%, 56.5% and 100% for PET/CT vs. 61.5%, 94.9%, 66.7% and 93.8% for HRCT vs. 23.1%, 98.7%, 75% and 88.6% for PE/E. In all 19 pts with a true positive PET/CT there was a significant management change prompting either salvage or definitive surgery or initiation of systemic therapy. Of the 14 recurrent pts treated with curative intent, 11 were alive with no evidence of disease at a median follow up of 31.5 mo. Conclusions: FDG-PET/CT has a high sensitivity in the early detection of relapse or second primary cancer in HNSCC, associated with significant management implications. Given improvements in therapy and changes in HNSSC biology, appropriate modifications in the current recommended algorithms of the NCCN for PTS may be required to engage effective salvage or definitive therapies.

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A blood-based epigenetic test for early detection of nasopharyngeal carcinoma (NPC). Presenting Author: Yew-Oo Tan, Singapore Oncology Consultants, Singapore, Singapore

Treatment-associated mortality in head and neck cancer: Analysis of phase III trials. Presenting Author: Marina Shcherba, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY

Background: NPC is highly curable in early stages but 70% of NPC patients are diagnosed with advanced disease due to lack of effective screening. Genetic and epigenetic alterations involved in the pathogenesis of NPC are known. The higher order chromosomal structures reflecting aberrant transcriptional states of these genes can be measured via techniques such as chromosome conformation capture. Detection of these changes in peripheral blood may provide an accurate test for the early cancer detection. Methods: Blood samples have been collected from 84 patients with histologically confirmed NPC and 100 matched controls. Samples from 45 NPC patients and 68 controls have been analyzed. Fourteen genes known to be dysregulated in NPC were investigated. Potential higher order juxtaposition sites in the candidate genes were predicted using pattern recognition software. PCR primer sets were designed around the chosen sites to screen potential markers. Twenty-two markers showing predictability between NPC and control samples were analysed for optimal reproducibility using alternative primer sets. The optimal sets of markers were then tested amongst the complete set of samples. The dataset was processed by re-sampling using the synthetic minority oversampling technique. The overall sample was split into two groups (66% training set and 34% test set) in the classification. Results: Sixteen markers from 7 candidate genes were found to be optimal in differentiating between NPC and control samples in the first 103 samples. Using the multilayer perceptron (MLP) classification, the following results were obtained: Sensitivity 88.9%, 95% CI (79.2% - 98.6%); Specificity 72.7%, 95% CI (58.9% - 86.5%); PPV 72.7%, 95% CI (58.9% - 86.5%); NPV 88.9%, 95% CI (79.2% - 98.6%). The accuracy of the test was similar in detection of stage I and II NPC versus that of stage III or IV NPC. Conclusions: Using a PCR-based method to detect alterations in the cancer epigenome, the feasibility of developing a blood test of potential utility in early diagnosis of NPC was demonstrated. Analysis of larger numbers of patient samples and optimization of markers are ongoing. The performance characteristics of the test in the total population of 184 samples will be presented.

Background: Chemoradiotherapy is an accepted standard for patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). Although acute and long-term toxicities of this approach are known, little is known about early mortality associated with curative-intent treatment. Methods: We reviewed 45 phase III trials of curative-intent radiotherapy in SCCHN published from 2000-2012 for adequate reporting of early mortality defined as deaths during and within 3 months of therapy, regardless of attribution. We estimated pooled proportions of deaths during prescribed therapy using a random effects model of radiotherapy alone (RT), concurrent chemoradiotherapy (CCRT) and induction chemotherapy (IC) regimens. The relative risk of death during CCRT vs. RT and CCRT/IC vs. RT were estimated. Results: Although all trials reported early mortality statistics, definitions had wide variability, and only 34 trials (75%) met adequate reporting characteristics. Ten trials excluded enrolled patients who died prior to initiating therapy. Of studies reporting early mortality statistics, crude frequency of death during prescribed therapy was 2.7% (308/11362). The pooled estimated rates of death observed during RT alone was 1.7% (SE: 0.3, I2⫽89.2%) from 29 studies, while 2.8% (SE: 0.4, I2⫽64.9%, 19 studies) and 3.1% (SE: 0.5, I2⫽53.5%, 9 studies) for CCRT and IC regimens, respectively. The pooled relative risk for death in CCRT compared to RT treatment was 1.08 (95%CI: 0.78, 1.48, p⫽0.63, I2⫽0, 15 studies). The relative risk for death in CCRT or IC therapy compared to RT was 1.06 (95%CI: 0.77, 1.45, p⫽0.72, I2⫽0, 15 studies). When reported, most early deaths were attributed to infectious complications or cardiovascular events. Conclusions: Early death remains an uncommon but important complication of curative-intent radiotherapy in SCCHN that necessitates consistent reporting. Despite strict eligibility criteria and protocol-defined care, treatment-associated death occurs with all regimens, though no clear increase was observed with CCRT/IC regimens over RT alone. Early mortality should be considered during treatment planning, particularly for patients with considerable comorbidities.




An open-label single-arm, phase II trial of zalutumumab, a human monoclonal anti-EGFR antibody, in patients with platinum-refractory squamous cell carcinoma of the head and neck. Presenting Author: Vassiliki Saloura, University of Chicago, Chicago, IL Background: Treatment for patients with platinum-refractory metastatic squamous cell carcinoma of the head and neck (SCCHN) is limited. Cetuximab has been approved in the US in this patient population based on a phase II trial that demonstrated 13% response rate (RR) and 5.9 months median OS. A recently conducted phase III trial of zalutumumab, a human monoclonal IgG1k antibody against EGFR, versus best supportive care showed significant increase in PFS. Here, we present the results of a companion phase II trial in the same patient population. Methods: Patients with platinum-refractory recurrent or metastatic SCCHN received weekly infusions of zalutumumab starting at a loading dose of 8mg/kg. The dose was then reduced to 4mg/kg and individually titrated by increments of 4mg/kg every 2 weeks based on skin rash evaluation up to a maximum of 16mg/kg aiming at a grade 2 skin rash. Primary objective was OS. The analysis was based on the intent-to-treat principle and OS was estimated using the Kaplan-Meier method. Results: Between January 2008 till August 2011 90 patients were enrolled in 57 centers in the United States, Europe and South America. 23% of patients had WHO PS 2 and 74% had distant relapse metastases. Grade 3-4 adverse events (AEs) related to zalutumumab were observed in 19% of the patients and included skin rash (5%), hypomagnesemia (4%) and pneumonitis (1%). Infusion-related reactions occurred in 33% of patients. The frequency of all-cause grade 3-4 AEs was 62% and included infections (14%), gastrointestinal disorders (12%), hypokalemia (6%), dyspnea (9%) and anemia (6%). Two deaths secondary to cardiac arrest in a patient with history of myocardial infarction, and respiratory acidosis in a patient with a pleural effusion and hypomagnesemia were deemed related to zalutumumab. CR was observed in one (1%) patient and PR in four (5%) patients. The median PFS was 8.6 weeks (95% CI [8.0, 10.4]) and the estimated median OS was 5.3 months (95% CI [4.1, 7.1]). Conclusions: Zalutumumab showed reasonable efficacy in platinum-refractory recurrent or metastatic SCCHN patients and dosing titration based on skin rash evaluation was feasible. Clinical trial information: NCT00542308.

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Phase II trial of everolimus and erlotinib in patients with platinum-resistant recurrent and/or metastatic head and neck squamous cell carcinoma. Presenting Author: Erminia Massarelli, Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Head and neck squamous cell carcinoma (HNSCC) is characterized by epidermal growth factor receptor (EGFR) overexpression but treatments targeting EGFR have met with limited clinical success. We hypothesized that everolimus (EV), an mTOR inhibitor, potentiates the activity of erlotinib (ER), an EGFR tyrosine kinase inhibitor, in platinumresistant recurrent and/or metastatic HNSCC. Methods: This single-arm two-stage phase II clinical trial evaluated EV 5 mg and ER 150 mg orally daily in patients (pts) with platinum-resistant recurrent and/or metastatic HNSCC. Primary endpoints were response rate and 12-week progressionfree survival (PFS). Plasma biomarkers by multianalyte profiling (Luminex Corp) and ELISA at baseline (20 pts), 4 weeks (18 pts) and 12 weeks (16 pts) as well as p16 expression in baseline tumor tissue (29 pts) were assessed in correlation with clinical results. Results: Of the 36 evaluable pts (median age 61 years, 29 males, 19 with oropharynx primaries, 15 with ⱖ2 lines of chemotherapy, 17 with prior cetuximab), 3 (8%) achieved partial response at 4 weeks, one of which was confirmed at 12 weeks, while 27 (75%) pts achieved disease stabilization at 4 weeks, 11 of which were confirmed at 12 weeks. The 12-week PFS was 49%, median PFS was 11.9 weeks and median overall survival (OS) was 10.25 months. Grade 3 toxicities included mucositis (17%), fatigue (14%), skin (8%), diarrhea (8%), and 5 pts withdrew from trial secondary to toxicity. High neutrophil gelatinase-associated lipocalin(NGAL) levels at baseline were associated with worse OS (HR 4.59; 95%CI 1.36, 15.46; p⫽0.014) and at 4 weeks with worse PFS (HR⫽12.29; 95% CI 1.26, 119.87; p⫽0.03) and OS (HR⫽6.21; 95% CI 0.95, 40.62; p⫽0.057). High carbonic anhydrase-9 (CA-9) levels at 4 weeks were associated with worse OS (HR⫽1.18; 95% CI 1.001, 1.41; p⫽0.049), while decreased CA-9 levels at 4 weeks were associated with better PFS (p⫽0.77). Conclusions: Efficacy for the combination ofEV and ER is reasonable however plasma markers of tumor invasion and hypoxia are associated with worse outcomes, and further biomarker analysis may define subsets of pts with significant therapeutic benefit. Clinical trial information: NCT00942734.

6066


Genetic profiling of advanced RAI-resistant differentiated thyroid cancer and correlation with axitinib response. Presenting Author: Rebecca B. Schechter, The University of Chicago, Chicago, IL Background: The VEGFR inhibitor axitinib has demonstrated compelling antitumor activity in advanced RAI-resistant differentiated thyroid cancer (DTC). Biomarkers predicting which patients may benefit from axitinib are unavailable. We aimed to describe molecular markers in DTC that correlate with clinical outcome to axitinib. Methods: Pretreatment FFPE thyroid cancer blocks from patients treated with axitinib were collected and genomic DNA was isolated. The OncoCarta Mutation Panel was used to test for 238 mutations. Copy number of VEGFR1-3 and PIK3CA was determined using qPCR. Genomic DNA was analyzed for coding regions of VEGFR1-3 with custom primers. Clinical response to axitinib, including best response (BR) (RECIST) and progression free survival (PFS), was ascertained from corresponding patients. Fisher’s exact test and logistic regression models were used to correlate BR with molecular findings. Cox proportional hazards regression was used to correlate PFS with molecular defects. Results: A total of 22 pathology samples (11 primary, 11 metastatic) were identified. In patients with 2 samples (n ⫽ 4), results were concordant and only included once for analysis. Of 18 specimens, 4 tumors (22%) harbored BRAF V600E mutations, 2 (11%) had KRAS mutations (G12A, G13D) and 2 (11%) had HRAS mutations (Q61R, Q61K). One sample with mutated KRAS also had a PIK3CA (H1047R) mutation. qPCR showed increased copy numbers of PIK3CA in 6 (33%) tumors, VEGFR1 in 0 (0%) tumors, VEGFR2 in 4 (22%) tumors, and VEGFR3 in 6 (33%) tumors. VEGFR sequencing showed a possibly damaging non-synonymous SNP in VEGFR2 (G539GR) in 2 samples (11%), a possibly damaging SNP in VEGFR3 (E350VE) in 1 sample (6%), and a potentially novel mutation in VEGFR2 (T439IT) in 2 samples (11%). No significant relationship was seen between BR or PFS and the presence of molecular defects. Conclusions: While DTC is genetically heterogenous, primary and metastatic lesions showed identical alterations. Molecular evaluation of DTC specimens did not predict clinical response to axitinib but data were limited by small sample size. We did identify molecular changes in VEGFR that should be further explored. This study was supported by Pfizer, Inc.

6068


The association between severe treatment-related lymphopenia and progression-free survival in patients with newly diagnosed squamous cell head and neck cancer. Presenting Author: Jian Li Campian, Johns Hopkins Medical Institute, Baltimore, MD Background: Severe treatment-related lymphopenia (TRL) occurs in 50% of glioblastoma and pancreatic cancer patients and is associated with early death from tumor progression. We sought to determine if similar findings were seen in head and neck squamous cell carcinoma (HNSCC). Methods: Eligible patients for this retrospective study had: 1) HNSCC cancer diagnosed in 2007-2009, 2) good performance status, 3) platinum-based chemoradiation, and 4) follow-up at Johns Hopkins. Serial total lymphocyte counts (TLC), overall survival (OS) and progression-free survival (PFS) were analyzed accounting for known prognostic factors. Results: Fifty-six adults met eligibility criteria: median age: 57 years, female: 21%, HPV⫹: 61%, surgery prior to chemoradiation: 16%, stage IVA-IVB: 77%, T stage 3-4: 40% and N stage 2b-3: 56%. Changes in TLC are shown below (Table). 14/56 patients (25%) had tumor recurrence and 9 (16%) died of their tumor. HPV⫹ patients had longer PFS (p⫽0.01) and OS (p⫽0.006) than HPV- patients. 10/22 HPV- patients had disease progression and 7 died. HPV- patients who developed grade III-IV TRL two months after beginning chemoradiation had a strikingly higher hazard rate for disease progression than those whose TLC remained higher (multivariate analysis HR 6.2, 95%CI: 1.1-35.2; p⫽0.039). Too few events occurred in the HPV⫹ cohort for analysis. Conclusions: TLCs were normal before chemoradiation. However, two months after chemoradiation ~60% of patients had severe TLC regardless of HPV status. HPV- patients with severe TRL were much more likely to have disease progression than those without TRL. Prospective studies are needed to confirm these findings which are similar to those reported in other cancers. Preservation of the immune system during chemoradiation may be important to improving PFS and OS.

Overall HPV- (nⴝ22) HPVⴙ (nⴝ34)

Median TLC: Baseline

Median TLC: 2 months post-RT

% with TLC 2 years achieved with cabozantinib in subjects with metastatic medullary thyroid carcinoma on a phase I study. Presenting Author: Ezra E.W. Cohen, The University of Chicago Medicine and Biological Sciences, Chicago, IL Background: Metastatic medullary thyroid cancer (MTC) carries a median survival of about two years (Modigliani et al. 1998; Roman et al. 2006). Cabozantinib inhibits three primary pathways implicated in MTC pathogenesis and progression: MET, vascular endothelial growth factor receptor-2 (VEGFR2), and RET. A phase I study was initiated in September 2005 in patients (pts) with advanced solid tumors. Methods: 85 pts, including 37 with MTC were enrolled to evaluate safety, pharmacokinetics, and to determine maximum-tolerated dose (MTD). Once the MTD of 140 mg freebase (equivalent to 175 mg malate salt) was determined, 20 metastatic or locally advanced MTC pts were enrolled in an MTD expansion cohort. 10/37 MTC pts achieved a confirmed partial response (cPR) (Kurzock et al. 2011). We report here on long-term disease control (DC), defined as cPR or progression-free at ⱖ 24 months (m), in the MTC cohort. Results: After a minimum follow-up period of 52 m, 11 of 37 pts (30%) experienced DC, and have remained progression-free for ⬎ 24 m. Time from diagnosis and time since development of metastatic disease was similar in patients with (11) or without (26) long term DC. As of 04 Dec 2012, 5 of these 11 pts remain on treatment for a median time of 55 m (53-73m). A best response of cPR was associated with long-term benefit: 4/5 pts continuing on treatment achieved cPR, one achieved SD. The adverse event profile of cabozantinib was generally predictable and adverse events were managed with symptomatic treatment and dose modifications. The median final dose for pts with long-term DC was 60 mg (range 20-140), with a median number of dose reductions of 2 (range 0E4). Reasons for dose reductions in two or more pts experiencing long-term DC included diarrhea (7), palmarplantar erythrodysaesthesia syndrome/rash (6), mucositis/stomatitis (3), anorexia (3), nausea (2), and vomiting (2). Conclusions: Treatment with cabozantinib demonstrates long-term DC in a cohort of pts with metastatic MTC. Cabozantinib offers an important new treatment option for patients with progressive, metastatic MTC. Clinical trial information: NCT00215605.

6092


Sequential TKI treatments for iodine-refractory differentiated thyroid carcinomas. Presenting Author: Christelle de la Fouchardiere, Centre Léon Bérard, Lyon, France Background: Tyrosine kinase inhibitors (TKI) are currently used to treat patients with advanced iodine-refractory differentiated thyroid cancers (DTC) but none has been approved by the FDA or the EMA until now. Sometimes, patients are treated with off-label TKI when a clinical trial is not available or in second- and third-line therapy. Methods: We hereby report the efficacy of “off-label” sorafenib and sunitinib treatments as first-, second- and third-line therapy in metastatic DTC patients from the French TUTHYREF (TUmeurs THYroïdiennes REFractaires) network. Primary endpoints were progression free survival (PFS) and tumor response according to sequential TKI treatment. Secondary endpoint was organspecific metastatic site analysis. Results: 45 patients with advanced iodine-refractory DTC treated with off-label TKI were included in this study (26 men, mean age: 62 years). 22 had papillary, 10 had follicular and 13 had poorly DTC. 24/45 patients were treated with two and 3/45 with three lines of TKIs. Sorafenib was the most frequently used (57%) followed by sunitinib (21.5%) and vandetanib (21.5%). Partial response (PR) rate was of 29% in the 21 patients who received first-line sorafenib therapy whereas PR was observed in 57% of the 7 first-line sunitinib patients. There was no PR with second- (n⫽24) and third-line (n⫽3) treatments. However, median progression free survival (PFS) was similar in second- as compared to first-line sorafenib or sunitinib treatment (6.7 vs. 7.6 months, HR 0.85 (95CI 0.45-1.61) p⫽0.6). Liver metastases were the most responsive to treatment (n⫽7; mean of -30%), followed by lung (n⫽57; mean of -19%) and lymph node (n⫽43; mean of -13%) metastases. Bone (n⫽14) and pleural (n⫽9) lesions were the most refractory to treatment (mean of -1% and -5%, respectively). Conclusions: Due to the small number of patients, we could not recommend a specific treatment sequence (sorafenib then sunitinib) over another (sunitinib then sorafenib). But TKI therapy appears to be beneficial in refractory DTC patients even in second- and third-line therapy, with similar PFS and stable disease as best response. Bone and pleural metastases were the most refractory and liver lesions the most responsive to treatment.


386s 6093


6094


Survival and prognostic factors of radioiodine refractory pulmonary metastatic differentiated thyroid carcinoma (DTC). Presenting Author: Johanna Wassermann, Department of Nuclear Medicine, Pitié-Salpêtrière University Hospital, Paris, France

Combination lapatinib and capecitabine in advanced, incurable squamous cell carcinoma of the head and neck (SCCHN). Presenting Author: Jared Weiss, Lineberger Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC

Background: The challenging key point of management of radioiodine refractory DTC patients is to define those who could benefit from experimental drugs in clinical trials. Methods: We reviewed clinical and pathological data of patients with refractory pulmonary metastatic DTC treated in our center from 1990 to 2011. Survival was estimated with the method of Kaplan-Meier. Associated prognostic factors were studied in Cox model based analyses. Results: Among 167 pulmonary metastatic DTC, 46% (n⫽76) met a criterion of radioiodine refractory disease: at least one metastases without I131 uptake: 61% (n⫽46); progressive disease despite I131: 22% (n⫽17) and absence of complete response despite a cumulated dose ⬎600mCi: 17% (n⫽13). There were 63% of female (n⫽48) and the median age was 64 years (range 18-87). The initial treatment was total thyroidectomy in 92% (n⫽70), lymph node dissection in 71%, (n⫽54) and radioiodine therapy in 100% of patients. Pathological features were papillary histology in 61% (n⫽46), follicular histology in 29% (n⫽22) and poor differentiated histology in 10% (n⫽8). pT stage was 1ab, 2, 3, and 4 in 11%, 13%, 63% and 13% respectively, pN stage after lymph node dissection was 0, 1a and 1b in 33%, 7% and 60% respectively. Metastasis were present at diagnosis in 45% (n⫽34) of cases. The refractory feature was established at the time of diagnosis and in the follow-up in 18% and 82% of cases respectively. When the disease was considered as refractory, the median overall survival was 5.5 years. The refractory feature at the initial diagnosis was the only independent prognostic factor correlated with poor survival (p⬍0.001). Conclusions: Patients who are considered as radioiodine refractory at the initial diagnosis of DTC have poor prognosis and should be considered for clinical trials in case of progression.

Background: In an era of increasing use of platinum-based induction chemotherapy and chemoradiotherapy, most metastatic/recurrent SCCHN patients (pts) have received multiple chemotherapeutic agents prior to being diagnosed with incurable disease, at which point PS is often poor, pts are often refractory to multiple agents, and standard therapies (Tx) are unacceptably toxic and inconvenient. Methods: We conducted a phase II study of 44 pts with metastatic/recurrent SCCHN with a primary endpoint of median OS. Pts received capecitabine 1,000 mg/m2 BID for 14/21 day cycles, with lapatinib at 1,250 mg daily for a total of four cycles. In the absence of disease progression or unacceptable toxicity, pts received maintenance Tx with lapatinib. Prior exposure to any chemotherapy other than capecitabine and lapatinib was allowed, as long as it was as part of therapy delivered with curative intent. Results: 36 of 44 planned patients are assessable at this time. 69% had prior resection, 75% prior radiation and 61% prior chemotherapy, of whom 18 (50%) had received prior platinum. Median age was 62, 11 pts (31%) had PS 0, 22 pts (61%) pts had PS1 and 3 pts (8%) had PS2. Median number of cycles given was 4; 14 pts have gone on to maintenance Tx. The most common grade 3-4 adverse events have included dehydration, diarrhea, and hand-foot syndrome, each occurring in 11% of pts. 2 patients did not have RECIST evaluable disease. Of the remaining 34 patients, 6 pts had PR and 1CR, for an ORR of 21% (24% in assessable pts). As of 1-31-13, 20 pts are alive, 2 are lost to followup, and 14 are deceased. Conclusions: The combination of capecitabine and lapatinib is tolerable and active in metastatic/recurrent head neck cancer, including pretreated patients. OS data, not yet mature, will be required to determine if this regimen is worthy of further testing. Clinical trial information: NCT01044433.

6095

6096


Survival in patients with HPV-positive oropharynx squamous cell carcinoma with distant metastases. Presenting Author: Katharine Andress Rowe Price, Mayo Clinic, Rochester, MN Background: Prognosis for patients (pts) with locally-advanced, HPVpositive oropharynx squamous cell carcinoma (HPV⫹OPSCC) is significantly better than for pts with HPV-negative head and neck squamous cell carcinoma (HNSCC). Historic survival of pts with metastatic HNSCC is 6-9 months with palliative therapy. However, the prognosis and survival of pts with HPV⫹OPSCC with distant metastases is not known. Methods: Pts with HPV⫹OPSCC with distant metastatic disease were identified from databases from the departments of surgery, radiation, and medical oncology. Demographic and clinical data was abstracted from the medical record. All pts had confirmed HPV/p16⫹ disease. Results: Fifteen pts with metastatic HPV⫹ OPSCC were identified. The median age was 57 years (range 42-78, 15 male). The median pack-year smoking was 0 (range 0-120). Primary site included 10 tonsil and 5 tongue base. At diagnosis, one pt had stage III and 14 had stage IV disease (IVA: 9, IVB: 2, IVC: 3). T- and N-stage included T1 (1), T2 (10), T3 (3), T4 (1) and N1 (1), N2a (1), N2b (9), N2c (3), N3 (1). Extracapsular extension was seen in 8 pts, absent in 2, and unknown in 5. Seven pts had lymph node (LN) involvement at level IV/V. Initial therapy for locally-advanced disease included surgery followed by adjuvant radiation (RT) in 1 pt and chemoRT in 8, and definitive chemoRT in 3 pts. Three pts were metastatic at initial diagnosis. Of 6 pts with an isolated metastatic site, 3 pts are alive ⬎ 2 years from diagnosis of metastasis (median 1.97 years, range 0.49-2.29). Palliative therapy included surgery (3), RT (9), platinum chemo ⫹/- cetuximab (8), cetuximab alone (2) or with a taxane (2). The most common sites of metastasis included bone (6), lung (5), and LNs (5). The 1-year survival rate after diagnosis of metastatic disease was 92%. The median time to diagnosis of metastatic disease after definitive therapy was 0.47 years (95% CI 0.19-1.29); 75% of pts who developed metastatic disease did so within 1 year of definitive therapy. Of note, 2 of the 15 pts developed a secondary immune-mediated malignancy (melanoma and non-HIV associated Kaposi’s sarcoma). Conclusions: The survival of pts with metastatic HPV⫹OPSCC is significantly better than that of historic controls.


Superselective intra-arterial chemotherapy for oral cancer by subcutaneous implantation of an intra-arterial catheter and an infusion reservoir: A new chemotherapy method to improve the quality of life and curative effect. Presenting Author: Masatoshi Ohmae, Rinku General Medical Center, Izumisano, Osaka, Japan Background: We have developed a superselective intra-arterial chemotherapy (iaCT) approach for oral cancer, in which intra-arterial catheter is retrogradely inserted via the superficial temporal artery (STA) and/or occipital artery (OA). This approach increases chemotherapy efficiency but remarkably decreases activities of daily living (ADL) because the catheter penetrates the skin over the approaching artery (STA/OA). Methods: This study assessed our new outpatient iaCT approach involving implantation of an intra-arterial catheter connected to a subcutaneous infusion reservoir. We included 10 patients who had oral cancer treated using outpatient iaCT: tongue carcinoma, 7; cheek mucosal carcinoma, 1; upper gingival carcinoma, 1; palatal carcinoma, 1. In this approach, the STA or OA or both were percutaneously dissected out, a catheter was inserted, and the catheter tip was superselectively placed in the tumor-feeding artery. The extra-arterial catheter portion was implanted through a subcutaneous tunnel and was connected to a subcutaneous infusion reservoir implanted around the mastoid process. The patients were discharged after catheterization, and the chemotherapeutic agent was intra-arterially administered at the Outpatient Chemotherapy Center of Rinku General Medical Center once or twice a week. Intra-arterial infusion was repeated 6 times per course. Results: The response rate was 100%, i.e., 8 cases of CR and 2 of PR; patients with PR underwent surgery.Their ADLs were scarecely disturbed exept for ambulatory visits. Conclusions: In this approach, the catheter is completely implanted subcutaneously; therefore, usual catheter-related issues (e.g., infection, catheter fall out) rarely occur. Because this leads to very good ADLs, outpatient chemotherapy can be safely performed. Consequently, the quality of life (QOL) improves and medical expenses decrease.Our new outpatient iaCT approach improves QOL of and curative effects for oral cancer patients if the ambulatory convenience and the performance status are good.


Head and Neck Cancer TPS6097


TPS6098


Phase II study of de-intensification of radiation and chemotherapy for low-risk HPV-related oropharyngeal squamous cell carcinoma. Presenting Author: Bhishamjit S. Chera, Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC

Phase II study of dalantercept, a novel inhibitor of ALK1-mediated angiogenesis, in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Presenting Author: Antonio Jimeno, University of Colorado, Denver, Aurora, CO

Background: The prognosis is excellent for low-risk human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (OPSCC). Current standard chemoradiotherapy (CRT) regimens cure most patients but cause significant acute (mucositis) and long-term toxicities (xerostomia and dysphagia). Toxicity is primarily determined by the dose of radiotherapy and the intensity of chemotherapy. The aim of this study is to evaluate the pathological complete response (pCR) rate of low-risk HPVassociated OPSCC after de-intensified CRT. Methods: The major inclusion criteria are: 1) T0-T3, N0-N2c, M0, 2) HPV or p16 positive, and 3) ⬍/⫽ 10 pack-years smoking history. Patients receive 60 Gy of intensity modulated radiotherapy (IMRT) with concurrent weekly intravenous cisplatinum (30 mg/m2). CT scans are obtained 4 to 8 weeks after completion of CRT to assess response. All patients have a surgical resection of any clinically apparent residual primary tumor or biopsy of the primary site if there is no evidence of residual tumor and a selective neck dissection to encompass at least those nodal level(s) that were positive pre-treatment, within 4 to 14 weeks after CRT. Longitudinal assessments of quality of life (EORTC QLQ-C30 & H&N35, NDII), patient reported outcomes (PRO-CTCAE, EAT-10), and swallowing evaluations (modified barium swallow) are obtained prior to, during, and after CRT. The primary endpoint of this study is the rate of pCR after CRT. The null hypothesis is that the pCR rate for de-intensified CRT is at least 87%, the historical rate (based on the reported 3-year local regional control rate of 87% in the RTOG 0129). Power computations were performed for N⫽40, with a type I error of 14.2% if the true pCR rate is 0.87. The study will be done in 3 stages with 15⫹15⫹10 patients with interim analyses at 15 and 30 patients. The trial will be stopped if the pCR rate is ⬍/⫽ 9/15 and 21/30. The null hypothesis will be accepted if the pCR rate is ⬎/⫽ 33/40. Clinical trial information: NCT01530997.

Background: Despite advances in the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN), the prognosis remains poor with a need to develop novel therapeutic strategies. Targeting angiogenesis in SCCHN is an active area of clinical research. Activin receptor-like kinase 1 (ALK1) is a type 1 receptor in the TGF-ß superfamily which is selectively expressed on activated endothelial cells. ALK1 binds bone morphogenetic proteins (BMP) 9 and 10 (ligands for ALK1) and is primarily involved in the maturation stage of angiogenesis. Dalantercept is a human ALK1-Fc receptor fusion protein that binds BMP9/10 and acts as a ligand trap. In preclinical tumor models, dalantercept demonstrated a decrease in tumor vascularization and delayed tumor growth. In a completed phase I study, dalantercept demonstrated anti-tumor activity in patients with advanced solid tumors including SCCHN. Methods: An open label, multi-center, multiple dose, phase II study to evaluate dalantercept in patients with advanced SCCHN is ongoing. Dalantercept is being administered every three weeks via SC injection in a total of 45 patients to assess safety, tolerability, and efficacy. 13 patients were enrolled at the 0.6 mg/kg dose level. To date, 6 out of 30 planned patients have received dalantercept at the 1.2 mg/kg dose level. Key inclusion criteria are tumors arising from the oral cavity, oropharynx, hypopharynx, or larynx, at least one prior platinum-containing regimen, ECOG performance status ⬍/⫽ 1, and measurable disease. Exclusion criteria include prior anti-angiogenesis therapy, significant pulmonary, cardiovascular, or bleeding risk. The primary efficacy endpoint is RR. Secondary endpoints include PFS, OS, TTP, DOR, DCR, and PD biomarkers on tumor and serum specimens including BMP9/10 and ALK1 expression. Clinical trial information: NCT01458392.

TPS6099

TPS6100

General Poster Session (Board #18A), Sat, 8:00 AM-11:45 AM


Seamless phase II/III trial design with survival and PRO endpoints for treatment selection: Case study of RTOG 1216. Presenting Author: David Ira Rosenthal, The University of Texas MD Anderson Cancer Center, Houston, TX

Pharmacodynamic study of neoadjuvant vemurafenib (VEM) in patients (pts) with BRAF mutated, locally advanced papillary thyroid cancer (PTC). Presenting Author: Maria E. Cabanillas, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: Clinical trial results from phase II trials to select an experimental treatment arm for separate phase III trial comparison can require years. Cancer clinical trials also now aim at both survival and PRO/functional outcomes, especially in head and neck (HN) studies. We developed a unique seamless phase II/III trial design to save on sample size and trial duration. The initial multi-arm phase II trial selects the most effective regimen among multiple experimental arms by first comparing each of the new treatments to a common control arm, using chosen endpoints, such as progression free survival. The winner will be tested for overall survival in the phase III study. Methods: We propose a phase II/III design to test the efficacy of experimental arms of postoperative radiation (RT) ⫹ docetaxel or RT ⫹ docetaxel ⫹ cetuximab in patients with HN squamous cancer. These are compared to the control arm of RT ⫹ cisplatin in the phase II part. Only one arm will be selected to go on to phase III depending on efficacy (PFS), PRO and safety outcomes. One experimental arm must be sufficiently better than the common control arm and the winner not having increased toxicity or functional cost to be selected for phase III inclusion. If not, the trial is halted for futility. Patients in the phase II selected arm and the control arm are included in phase III testing. Group sequential method is used to design each component. Separate interim efficacy and futility analyses are built in such that each endpoint can be monitored as in separate phase II, III trials. Once sample sizes are derived, operating characteristics for the seamless II/III design are evaluated through simulations under the null and various alternative hypotheses. Savings on sample size and time are compared to typical separate phase II and III designs and to the design testing only the arm of RT ⫹ docetaxel ⫹ cetuximab in phase II. Conclusion: The phase II/III RTOG 1216 HNC trial offers cost effectiveness, operational efficiency and scientific innovation.

Background: BRAF mutations are found in 40% of pts with newly diagnosed PTC but much more prevalent in recurrent PTC, ranging from 78-86%, suggesting they play an active role in tumor progression. Activating mutations in BRAF result in constitutive activation of MEK and subsequently ERK. ERK mediates activation of nuclear transcription factors coordinating expression of genes involved in proliferation and survival of malignant cells. PTC usually has an excellent prognosis, especially in younger pts and in pts who respond to the only effective treatment: surgery followed by radioactive iodine (RAI). However, more advanced stage disease at diagnosis, older age, and lack of RAI avidity are associated with a high rate of recurrence and distant metastasis, imparting a worse overall survival. Long-term outcomes depend highly on initial surgery outcome. Pts at highest risk of recurrence and death are those with gross residual disease after surgery and macroscopic tumor invasion. VEM is an inhibitor of the activated form of the BRAF serine-threonine kinase enzyme. The drug is FDA approved for the treatment of advanced melanoma and is currently being studied in a phase 2 trial in metastatic BRAF-mutated PTC. This is a neoadjuvant trial to determine if pharmacodynamic changes in the tumor correlate with response to drug. Methods: Pts with primary or recurrent BRAF mutated PTC who are planned for surgical resection are eligible. Pts will undergo baseline core biopsy prior to starting VEM 960mg bid. After 56 days of treatment they will undergo surgery and post-treatment specimen will be collected. Pts with widely metastatic PTC may continue VEM. The primary endpoint is to determine whether changes in ERK phosphorylation responses after treatment with VEM correlate with clinical response at day 56 in pts with locally advanced, BRAF mutated PTC. Secondary endpoints include assessments of safety of neoadjuvant VEM, response by RECIST, rate of surgical complications, persistent disease at the surgical site at 1 year, and mechanisms of resistance to VEM. The trial began enrolling pts in December 2012, with a total of 22 pts planned. This trial has no sponsor. Clinical trial information: NCT01709292.


388s TPS6101

Head and Neck Cancer General Poster Session (Board #18C), Sat, 8:00 AM-11:45 AM

Potentiation of cetuximab by inhibition of Tregs in metastatic squamous cell cancers of head and neck. Presenting Author: Gautam Gopalji Jha, University of Minnesota, Minneapolis, MN Background: There are few effective treatment options for patients with metastatic squamous cell cancers of head and neck (HNSCC). The only significant advance in the last few decades has been approval of cetuximab, a monoclonal antibody directed against the overexpressed epidermal growth factor receptor (EGFR). Despite its high specificity for EGFR, cetuximab as single-agent has resulted in response rates of only 13% and PFS of less than 2 months. Recent evidence suggests that cetuximab may induce tumor cell killing through an immune-mediated ADCC and not through blockade of EGFR signaling. Cetuximab binds EGFR on tumor cells making them targets for natural killer (NK) cell-mediated lysis. The effectiveness of cetuximab is limited by the tumor mediated immunesuppression that inhibits NK and other effector cells. This local and possibly generalized immune suppression is primarily mediated by regulatory T cells (Tregs) which inhibit NK cells and other effector cells. HNSCC tumors are highly immunosuppressive and characterized by marked and persistent elevation of inhibitory Tregs. The myelosuppression and immunosuppression caused by cyclophosphamide is dose dependent, and at lower doses cyclophosphamide has been shown to selectively deplete Tregs, restore NK cell activity and paradoxically induce auto-immunity. Objectives: To assess potentiation of clinical response by tracking PFS, OS and HRQOL and immune augmentation in tumor biopsies and blood samples. Methods: The current pilot study (n⫽15) will assess the hypothesis that Tregs, which are elevated in HNSCC, can be suppressed with cyclophosphamide and that this suppression can lead to improved anti-tumor responses mediated by cetuximab. Eligibility: Metastatic HNSCC progressed on initial chemotherapy or not a candidate for platinum Treatment: Daily oral cyclophosphamide 50 mg bid and weekly cetuximab (SOC). Patients will have blood collected for immune monitoring at weeks 0, 3, 6, 12 and pre and post treatment biopsies at week 0, 6. T cell subsets, NK cell function, Tregs, MDSC will be assessed at tumor site and in blood for immune response. Restaging CT scans will be done pretreatment and at weeks 6, 12. Clinical trial information: NCT01581970.


Health Services Research 6500


6501

389s Oral Abstract Session, Mon, 8:00 AM-11:00 AM

Randomized trial of a web-based intervention to address barriers to clinical trials. Presenting Author: Neal J. Meropol, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH

Participation in cancer pharmacogenomic studies in 8,456 patients registered to Cancer and Leukemia Group B (Alliance) clinical trials. Presenting Author: Lynn G. Dressler, Mission Health, Fullerton Genetics Center, Asheville, NC

Background: Cancer patients (pts) have knowledge and attitudinal barriers to participation in clinical trials (CT). We developed PRE-ACT (Preparatory Education About Clinical Trials), a tailored, interactive, web-based intervention to address these barriers and improve preparation for consideration of CT as a treatment option. Methods: We conducted a prospective, randomized, multicenter, phase III clinical trial of PRE-ACT vs. control (general text about CT excerpted from NCI materials). All assessments and interventions were conducted online. Cancer pts ⬎18 years old were enrolled before initial oncologist consultation. Pts completed a baseline assessment including CT knowledge (19-item); CT attitudes (28-item); preparation for decision making (10-item); and validated measures of preferences for shared decision making and quality/length of life. PRE-ACT pts received a summary of their preferences and a list of their top CT barriers. Based on ranking of individual barriers, pts were presented with a video library of 30-90 second clips addressing their top barriers (10 maximum). After the educational intervention a follow up survey reassessed CT barriers and preparation. Results: 1255 pts were randomized; median age 59 (range 20-88); 58% female; 12% non-white / 2% Hispanic; 76.4% some college education. 1081 pts completed baseline and post-intervention assessments. The control and PRE-ACT groups both had improved knowledge, reduced attitudinal barriers, and improved preparation (p⬍.0001 for all comparisons). PRE-ACT was more effective than control in improving knowledge (p⫽.0006) and attitudes (p⬍.0001). Furthermore, pts in the PRE-ACT arm were more satisfied with the amount (p⫽.002) and format (⬍.0001) of information, and felt more prepared to consider CT (p⫽.0003). Conclusions: This large-scale randomized trial of a tailored, web-based, video intervention demonstrates that educational information delivered online before the oncologist visit can significantly reduce knowledge barriers and attitudinal barriers and improve preparation for consideration of clinical trials. Both text and PRE-ACT are effective, with greater improvements and satisfaction in the PRE-ACT group. Clinical trial information: NCT00750009.

Background: Clinically annotated specimens from cancer clinical trial participants offer an opportunity for discovery and validation of pharmacogenomic findings. This observational study assessed patient (pt) and institutional factors that may contribute to participation in pharmacogenomic components of prospective cancer clinical trials. No trial in the study used pharmacogenomic results to guide therapy, but germline DNA was collected from consenting pts for future study of potential heritable variations associated with clinical outcome. Methods: Pt demographic data (age, sex, diagnosis, self-reported race) and institutional characteristics (CALGB/CTSU site, diversity, accrual rate) were evaluated for 8546 pts enrolled in 7 CALGB phase III trials with a pharmacogenomic component. Participation was defined as pt consent specific to this component documented in the CALGB database. Results: Most pts (81%) enrolled on the clinical trials consented to participate in the pharmacogenomic component. In a multivariable analysis, site (CALGB vs CTSU), selfreported race (non-white vs white) and institutional diversity (% minority cancer pts on national trials) were significantly associated with participation. Pts from CALGB sites were more likely to participate than pts at CTSU sites (OR 2.09, CI 1.60-2.73, p⬍0.0001). Non-white pts were less likely to participate than white pts (OR 0.48, CI 0.41-0.56, p⬍0.0001). A significant interaction between site and race was observed (OR 0.41, CI 0.37-0.47, p⬍0.0001). As institutional diversity increased, likelihood of participation in the pharmacogenomic component decreased for both white (p⫽0.0001) and non-white pts (p⫽0.054). Conclusions: Pharmacogenomic studies are achievable in the context of multicenter cancer clinical trials, but optimization of pt and institution participation is needed. Institutional factorsappear to be more important than pt demographics. To promote equitable pt benefit, prospective studies should be conducted to understand barriers and incentives to participation in pharmacogenomic research at the patient, clinician and institutional levels.

6502

6503



A population-based analysis of outcomes in cancer patients who do not satisfy clinical trial eligibility criteria (CTEC). Presenting Author: Winson Y. Cheung, British Columbia Cancer Agency, Vancouver, BC, Canada

Impact of copayment elimination on annual and biennial screening mammography utilization among rural U.S. women. Presenting Author: Jeffrey M. Peppercorn, Duke Cancer Institute, Durham, NC

Background: Trials have stringent inclusion and exclusion criteria to maintain internal validity. However, study findings are often applied to patients in routine practice who do not meet CTEC. Our aim was to characterize the outcomes and magnitude of treatment benefit in these patients. Methods: Patients diagnosed with stage III colon cancer from 2006 and 2008, referred to 1 of 5 regional cancer centers in British Columbia, and assessed for adjuvant chemotherapy (AC) within 12 weeks of surgery were analyzed. Patients were considered trial-eligible (TE) if aged 18 to 79 years, ECOG 0/1, CEA ⬍10, did not receive prior chemotherapy or radiation, and had adequate blood counts and normal cardiac, liver and kidney function. All other patients were deemed trialineligible (TI). Results: A total of 820 patients were identified: median age was 69 years (range 60-76), 423 (52%) were men, 365 (45%) were ECOG 0/1 and 592 (72%) received AC. Among patients treated with AC, 370 (63%) were TE and 222 (37%) were TI. Compared to TI patients, those who were TE were younger (63 vs 70 years, p⬍0.01) and more likely to receive combination regimens rather than single agent AC (56 vs 33%, p⬍0.01). Outcomes were significantly different among patients who were TE, TI, and those who did not receive AC (Table). In multivariate analyses that adjusted for known prognostic factors such as age, ECOG and T and N stages, both TI patients and those not treated with AC had worse outcomes than TE patients (HR for colon cancer death 1.32, 95%CI 0.86-2.02 and 2.77, 95%CI 1.92-3.99, respectively, p trend ⬍0.01; HR for all cause death 1.24, 95%CI 0.85-1.80 and 2.95, 95%CI 2.17-4.00, respectively, p trend ⬍0.01). Conclusions: In this population-based cohort, colon cancer patients who did not fit CTEC were frequently treated with AC. Outcomes in this TI group were inferior to those in the TE group, but they were better than the subset that did not receive AC. Broadening CTEC to include a segment of the TI population should be considered as there appears to be benefit in selected individuals.

Background: Early detection of breast cancer through mammography screening leads to earlier stage at diagnosis and improved survival. Previous research has shown that rural American women are less likely to receive screening mammography compared to their urban counterparts. Copayments for mammography are a potential barrier to screening, and elimination of copayments may improve screening rates. We examined annual (aSMU) and biennial (bSMU) screening mammography utilization and the impact of copayment elimination among rural U.S. women. Methods: Using the insurance claims database of the National Rural Electric Cooperative Association (NRECA), which insures over 100,000 electrical workers and their families nationally, we identified all women ages 40 to 64 with no prior history of invasive breast cancer or DCIS (based on ICD-9 codes) and captured claims for aSMU and bSMU between 1999 and 2009. Changes in screening over time were assessed for the periods before and after NRECA elimination of copayments for screening mammography in January, 2006. Chi-squared tests were used to compare aSMU and bSMU rates by age group. All p-values are two-sided. Results: During this time period, over 20,000 women ages 40 to 64 received health insurance through NRECA each year. From 1999 to 2009, aSMU increased from 38.1% to 49.5%, while bSMU increased from 57.2% to 68.1%. Screening increased significantly following elimination of copayments in 2006 (p ⫽ 0.0004). Specifically, for the period 2006-2007 compared to 20042005, the percentage of women undergoing at least biennial screening increased from 60.9 to 68.8% (p ⬍ 0.0001), with absolute differences in screening by age ranging from an increase of 5.3% among women 40-45, to 10% among women 60 – 64. Conclusions: Evaluation of insurance claims data from rural US populations reveals that a large percentage of rural women ages 40 to 64 do not undergo even biennial breast cancer screening. Elimination of copayments improves both annual and biennial screening rates in all age groups, but does not eliminate all barriers. Further investigation is ongoing to understand financial and non-financial barriers to screening and attitudes towards current screening recommendations.

Group TE and received AC TI and received AC No AC

5-year CSS rate

P value

5-year OS rate

P value

82% 75% 57%

⬍0.001

74% 65% 35%

⬍0.001

CSS, cancer specific survival; OS, overall survival.


390s

Health Services Research

6504


6505


Association between high-cost imaging and hospice use at the end of life of cancer patients. Presenting Author: Michaela A Dinan, Duke Clinical Research Institute, Durham, NC

Use of high-intensity surveillance in patients following a diagnosis of stage I-II non-small cell lung cancer. Presenting Author: Jason D. Wright, Columbia University College of Physicians and Surgeons, New York, NY

Background: Use of high cost imaging modalities can inform prognosis and potentially de-escalate unnecessary care at the end of life of cancer patients, but it may also be associated with increased health care expenditures. This analysis investigated the association of hospital-level use of advanced imaging studies with aggressiveness of care near death, as measured by hospice enrollment. Methods: Using SEER-Medicare, patients who died from common solid tumors between 2002 and 2007 were identified and hospital-level utilization of CT, MRI and PET scans were categorized into quartiles. Patients were assigned to the hospital at which they spent the majority of their inpatient days during the last 6 months of life. Multivariate-adjusted logistic regression models based on tumor type were constructed to correlate imaging use with late as well as all hospice admissions, defined as enrollment within 3 days and 18 months of death, respectively. Results: A total of 7,876 breast, 31,933 lung, 12,877 colorectal and 9,137 prostate cancer patients were included. High cost imaging varied across tumor types with rates being highest for lung cancer (mean of 2.29 CT, 0.58 MRI and 0.21 PET scans per patient) and lowest for prostate cancer (mean of 1.25 CT, 0.41 MRI, and 0.01 PET scans per patient) in the 6 months before death. Overall hospice use was least frequent in colorectal cancer (50% of patients) while late hospice admission was most common in lung cancer (11% of patients). Hospitals within the top quartile of imaging use generally had decreased odds of hospice utilization and higher likelihood of late hospice enrollment across most cancer types (Table). Conclusions: In this large cohort, receipt of care near end of life in hospitals with the highest rates of advanced imaging use was associated with lower use of and later enrollment to hospice. High cost imaging is not correlated with de-escalation of aggressive care.

Background: The incidence of stage I and II lung cancer has been increasing due to the reported benefits of CT screening in high risk individuals. Guidelines suggest continued surveillance following diagnosis, however the extent to which this is done is unclear. We examined the patterns and predictors of surveillance imaging in patients following a diagnosis of stage I-II non-small cell lung cancer (NSCLC). Methods: The SEER-Medicare database was used to identify patients with stage I-II, NSCLC who underwent curative intent surgical resection from 2000-2006.Three surveillance periods (6-18, 18-30, 30-42 months) after diagnosis were identified. Use of imaging was quantified for each period and logistic regression models developed to examine predictors of thoracic imaging during all 3 surveillance periods. Results: Between 2000-2006 5269 patients were identified. During the first year of surveillance use of chest CT (48% in 2000 to 78% in 2006) and PET (2% to 23%) increased while use of bone scan (12% to 6%) and chest radiography (87% to 71%) decreased over time. Similar trends were noted for surveillance periods 2 and 3. During the study, surveillance imaging was performed in all 3 surveillance periods in 38% of the cohort. Yearly surveillance imaging increased with time; 21% of patients diagnosed in 2000 vs. 78% diagnosed in 2006 underwent testing in the first 3 years of follow-up (P⬍0.0001). In a multivariable model, in addition to year of diagnosis, patients with high socioeconomic status (OR⫽1.96; 95% CI, 1.51-2.55 compared to low SES) were more likely to undergo yearly surveillance imaging, while Hispanics (OR⫽0.42; 95% CI, 0.21-0.85) and older patients (OR⫽0.52; 95% CI, 0.43-0.63) were less likely to undergo testing. Conclusions: The use of costly diagnostic imaging of uncertain value is increasing rapidly for patients with localized NSCLC. Non-clinical factors including high socioeconomic status and white race are among the strongest predictors of use of high intensity surveillance.

Odds of any and late hospice enrollment in the top imaging quartile (*ⴝsignificant). Cancer type Breast Lung Colorectal Prostate

6506

Any hospice enrollment CT MRI PET 1.00 0.74* 0.88* 0.61*

0.77* 0.79* 0.85* 0.69*

0.77* 0.78* 0.87* 0.73*

Late hospice enrollment CT MRI PET 1.54* 1.78* 1.57* 1.41*

0.90 1.11* 1.03 1.31*

1.17 1.07 1.29* 1.24*


Financial distress, communication, and cancer treatment decision making: Does cost matter? Presenting Author: Yousuf Zafar, Duke University Medical Center, Durham, NC Background: Financial distress (FD) increases the burden of living with cancer. Even insured patients may experience considerable FD, but little is known about whether patients want to include cost discussions in treatment decision-making. Methods: This is an ongoing cross-sectional study of insured adults with solid tumors on anticancer therapy for ⱖ1 month. Consecutive patients were surveyed, in person, at a referral center and 3 rural oncology clinics. Participants were asked about FD (via a validated measure), out-of-pocket (OOP) costs, discussion of costs with their doctor, and decision-making. Medical records were reviewed for disease and treatment data. Logistic regression assessed the relationship between FD and cost communication. Results: 119 participants (85% response) had a median age of 60 years (range 27-86). 54% were men, 29% non-white, and 96% completed high school. 81% had incurable cancer. 58% had private insurance. Median income was $50,000/yr. Median OOP costs were $480/mo. The mean FD score (6.7, SD 2.5) corresponded to moderate FD. 19% reported high/overwhelming FD. Overall, 48% (n⫽57) expressed any desire to discuss costs with their doctor, but only 21% (n⫽25) had actually done so. Of the 19% with highest FD, 36% (n⫽8) had discussed costs with a doctor, and 68% (n⫽15) expressed any desire to discuss costs. The most common reasons for not discussing costs with doctors were: “no problems with costs” (n⫽47); “want best care regardless of cost” (n⫽36); and “doctors shouldn’t have to worry about costs” (n⫽19). Of those who discussed costs with their doctor, 48% (n⫽12) felt the discussion helped decrease costs. 54% (n⫽64) wanted their doctors to account for costs in cancer treatment decision-making; 20% (n⫽24) always wanted costs considered in decision-making. High FD was the only variable associated with greater willingness to discuss costs (adjusted OR 2.81; 95%CI 1.05-7.50; p⫽0.04). Conclusions: FD was prevalent among insured cancer patients. A large proportion wanted costs discussed with doctors and included in treatment decision-making. Discussing finances may lower costs, but the discussion rarely occurs. Communication and decisionmaking present a potential focus for intervening on FD.

6507


Choosing mastectomy over lumpectomy: Factors associated with surgical decisions in young women with breast cancer. Presenting Author: Shoshana M. Rosenberg, Harvard School of Public Health, Boston, MA Background: Few studies have comprehensively evaluated surgical decisions in young women with breast cancer. Young women have unique medical and psychosocial concerns, and identifying factors associated with surgical choices in this population can inform their decision-making process. Methods: As part of an ongoing multi-center cohort study enrolling women diagnosed with breast cancer at age 40 or younger, we evaluated 277 women with stage I-III disease who indicated they had a choice between mastectomy and breast conserving surgery (BCS). Logistic regression was used to identify predictors of choosing mastectomy vs. BCS. Independent variables with a p-value ⱕ 0.15 in bi-variate analyses were included in the final multivariable model. Results: 172/277 women (62%) had either a single or bilateral mastectomy as their definitive surgery. Median age at diagnosis was 37 (range: 17-40). Most women were married (75%), had stage I or II disease (90%), and estrogen receptor (ER) positive tumors (65%); approximately 14% were carriers of a BRCA 1 or 2 mutation. In the multivariable analysis (Table), having a mutation, nodal involvement, HER2-positivity, tumor grade, lower BMI, having 2 or more children, anxiety, and decisional involvement by the patient were all associated with mastectomy. Age, race, marital status, tumor size, having a first degree relative with breast or ovarian cancer, ER status, fear of recurrence, and depression were not significantly associated with having a mastectomy. Conclusions: Despite being candidates for BCS, many young women choose to have a mastectomy. Our results suggest potential targets for interventions such as anxiety reduction and fostering fully informed shared decision-making. Significant predictors of mastectomy versus BCS. OR (95% Cl) Mutation positive Any nodal involvement HER2 positive Grade (refⴝ1) 2 3 Number of children (refⴝ0) 1 >2 BMI Anxiety Decisional involvement (refⴝshared) Mainly patient’s decision Mainly doctor’s decision

10.17 (3.25-31.79) 1.88 (1.01-3.52) 2.41 (1.20-4.82) 3.02 (1.03-8.89) 1.78 (0.62-5.08) 1.44 (0.62-3.34) 2.20 (1.06-4.54) 0.92 (0.88-0.97) 2.19 (1.12-4.29) 2.07 (1.14-3.76) 0.86 (0.31-2.38)




Beyond Jeopardy!: Harnessing IBM’s Watson to improve oncology decision making. Presenting Author: Peter Bach, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Electronic decision support is increasingly prevalent in clinical practice. Traditional tools map guidelines into an interactive platform. An alternative method builds on experience-based learning. Methods: Memorial Sloan-Kettering (MSK), IBM and WellPoint teamed to develop IBM Watson – a cognitive computing system leveraging natural language processing (NLP), machine learning (ML) and massive parallel processing – to help inform clinical decision making. We made a prototype for lung cancers using manufactured and anonymized patient cases. We configured this tool to read medical language and extract specific attributes from each case to identify appropriate treatment options benchmarked against MSK expertise, anonymized patient cases and published evidence. Treatment options reflect consensus guidelines and MSK best practices where guidelines are not granular enough to match treatments to unique patients. Analysis and building accuracy is ongoing and iterative. Results: 420 manufactured and 525 anonymized patient cases trained the initial models. Early results show accuracy improvement in NLP and ML in identifying treatment options (Table). All treatment plans were guideline adherent. A proportion of cases showed the need to incorporate tailored treatment plans reflecting MSK’s practice beyond guidelines – e.g. 11% of cases required addressing a site of critical metastasis before initiating guideline supported treatment. Conclusions: IBM Watson is extracting information from free text medical records that supports building ML models to assist in selecting treatments for persons with lung cancers. This tool can select treatment options from consensus guidelines, and, through ML, it will identify personalized treatment plans. Training is ongoing to improve individualized decision making and optimize the web-based tool that connects with IBM Watson. Batch 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Activity

Cases run

% Accurate*

# Elements

NLP

25† 25† 49† 25† 25† 25† 25† 300† 300‡

12 36 67 36 52 36 52 40 44 49 52 63 68 70 75 77

11 11 11 13 13 13 16 29 29 29 29 29 29 29 29 29

ML

6509

391s Clinical Science Symposium, Tue, 11:30 AM-1:00 PM

Off-label and compendia use of chemotherapy in patients with metastatic cancer. Presenting Author: Dawn L. Hershman, Columbia University College of Physicians and Surgeons, New York, NY Background: In 2012, ASCO Identified opportunities to improve the quality and value of cancer care by reducing inappropriate and/or prolonged use of chemotherapy The NCCN compendium is recognized as an authoritative reference for insurance coverage for drug indications without FDA approval. We evaluated FDA-approved, compendia and unapproved use of chemotherapy. Methods: We useddata from the SEER-Medicare database to identify patients with metastatic cancer who received chemotherapy. For each tumor, drugs with ⬎3 claims were identified. Each drug was classified as having an FDA-approved indication, an indication based on NCCN compendia guidelines or neither of these. The number of claims for each drug was calculated. Logistic regression was used to assess the factors that Results: Between 1998-2007, 37,351 subjects were identified as having received chemotherapy; of these, 24,876 (66.6%) received only FDA approved drugs, and 12,475 (33.4%) received at least one unapproved drug. Of those who received an unapproved drug, 8,669 (69%) received a drug with a compendia listing. Therefore, of the total population, 10% received a drug that was neither FDA nor compendia approved. The mean number of unapproved claims was 10.3 (SD⫽15.2) and the mean number of drugs was 1.3. Unapproved use was highest in subjects with prostate and lowest in patients with colon cancer. In a multivariate analysis, unapproved use decreased with increasing age and ⬎2 comorbid conditions. Compared to prostate cancer, the odds of having an unapproved drug was lower for breast (OR⫽0.27), colon (OR⫽0.08), lung (OR⫽0.65), ovary (OR⫽0.38), uterus (OR⫽0.49) and myeloma (OR⫽0.60). No patients with colon or prostate cancer received compendia-approved drugs. Over 90% of unapproved use for breast, ovary and lung cancer were compendia-approved. Costs associated with unapproved/compendia use will be presented. Conclusions: A large fraction of patients who use chemotherapy receive FDA-unapproved drugs; however, the majority of those drugs are acknowledged by NCCN. A better understanding of the costs and benefits of compendia-approved drugs is warranted to reduce the costs of cancer care.

* NLP: % cases with all attributes correctly extracted; ML: % cases with appropriate treatment recommendation(s) first. † Blind test. ‡ Retest using same data.

CRA6510

Clinical Science Symposium, Tue, 11:30 AM-1:00 PM

Impact of oncology drug shortages. Presenting Author: Zeke Emanuel, Perelman School of Medicine and The Wharton School, University of Pennsylvania, Philadelphia, PA


6511

Clinical Science Symposium, Tue, 11:30 AM-1:00 PM

For-profit hospital ownership status and use of brachytherapy after breastconserving surgery. Presenting Author: Sounok Sen, Yale School of Medicine, New Haven, CT Background: Because the benefits of adjuvant radiation therapy (RT) for breast cancer decrease with increasing age, the use of newer and more expensive RT modalities such as brachytherapy in the treatment of older women has been questioned. In particular, patients and policy makers may be concerned that for-profit hospitals might be more likely to use therapies with higher reimbursements. Among both younger and older Medicare beneficiaries with breast cancer, we examined whether hospital ownership status is associated with use of adjuvant brachytherapy. Methods: Using the Centers for Medicare and Medicaid Services Chronic Condition Warehouse database, we conducted a retrospective study of female Medicare beneficiaries aged 66-94 years old receiving breast-conserving surgery for invasive breast cancer in 2008 and 2009. We assessed the relationship between hospital ownership and receipt of brachytherapy, as well as overall RT (i.e. brachytherapy or whole breast irradiation) using hierarchical generalized linear models. Results: The sample consisted of 35,118 women, 8.0% of whom had undergone surgery at for-profit hospitals.Among patients who received RT, those who underwent surgery at for-profit hospitals were significantly more likely to receive brachytherapy (20.2%) than patients treated at not-for-profit hospitals (15.2%; OR for profit vs. not-for profit: 1.50; 95% CI: 1.23-1.84; p⬍0.001). Among women 66-79 years old, there was no relation between hospital profit status and overall RT use. However, among women age 80-94 years old, receipt of surgery at a for-profit hospital was significantly associated with higher overall RT use (OR: 1.22; 95% CI: 1.03-1.45, p⫽0.03) and brachytherapy use (OR: 1.66; 95% CI: 1.18-2.34, p⫽0.003), but not whole breast irradiation use (OR: 1.14; 95% CI: 0.96-1.36, p⫽0.13) Conclusions: Medicare beneficiaries undergoing breast-conserving surgery at for-profit hospitals were more likely to receive brachytherapy, a newer, less proven, and more expensive technology. Among the oldest women, who are least likely to benefit from RT, care at a for-profit hospital was associated with higher overall RT use, with this difference largely driven by the use of brachytherapy.


392s 6512

Health Services Research Poster Discussion Session (Board #1), Sun, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

Determining value of high cost cancer therapies and discussing cost of cancer care: The patient perspective. Presenting Author: Saurabh Rajguru, University of Wisconsin Hospital and Clinics, Paul Carbone Comprehensive Cancer Center, Madison, WI Background: A trend in cancer treatment is the growing number of high-priced therapies which offer marginal clinical benefits. This has led ASCO to issue guidelines stressing the importance of discussing treatment costs with patients. There are many identified barriers which limit communication of cost including oncologists’ fears that patients may view this discussion as inappropriate. We attempted to assess cancer patients’ views on discussion of treatment costs with their oncologists, as well as, their views on high-cost drugs (HCDs), including the belief that there is a cohort of patients who would forgo high-priced treatment even if there was no out-of-pocket expense. Methods: We surveyed patients with advanced prostate cancer. The survey consisted of demographic information and an 11-item questionnaire. We also gave them a hypothetical scenario in which they were asked how much they would be willing-to-pay (WTP) for a $100K drug that would improve survival on average by four months with minimal side-effects (modeled after Provenge). The survey was administered to patients in clinic prior to their visit. Results: Of the patients approached, 169 responded (88% response rate). Seventeen percent stated they would not want treatment with HCDs even if they had no out-of-pocket expenses (more likely to be older (⬎70) and have an annual household income of ⬎$60K). Another 21% stated they would accept treatment only if they had no out-of-pocket expenses. The median WTP for the hypothetical drug was $20K. Most patients (79%) agree that a discussion of costs with their physician is appropriate and 69% would want to have this discussion. Most patients (82%) agree that prognosis is important when making treatment decisions however 66% of patients did not know their cancer stage. Only 37% agree that the oncologist or the patient should consider the country’s healthcare costs when making treatment decisions. Conclusions: Prostate cancer patients clearly want to have discussions regarding costs-of-care with their oncologists. There is a group who would forgo treatment with high-cost drugs that yield only modest survival benefits. Their motivation is unknown, but is hypothesized to reflect a value-based judgment.

6514


6513


Adoption of robot-assisted surgery and its impact on treatment patterns for newly diagnosed localized prostate cancer. Presenting Author: Ya-Chen T. Shih, University of Chicago, Chicago, IL Background: With the rapid increase of robotic surgical systems in hospitals, it is important to understand the impact on treatment patterns for localized prostate cancer. The objective of this study is to determine whether the presence of robotic surgical systems independently influenced rates of surgery, radiation, and active surveillance for localized prostate cancer. Methods: We conducted an observational study using National Cancer Database (NCDB) state-level data, 2002-2010. Our study cohort includes patients newly diagnosed with clinical stage I-III prostate cancer from 48 states and Washington D.C. in the United States. The number of robotic systems installed in each state over time was obtained from publicly available information on-line. We characterized the state-level treatment pattern as the proportion of patients having surgery, radiation and active surveillance as their first course of treatment. Results: Between 2002 and 2010, the average number of robotic surgical systems per state increased from 2 to 26.3, while the unadjusted rate of surgery increased from 37.5% to 52.4%, radiation therapy decreased from 43.3% to 30.2%, and active surveillance increased from 7.0% to 9.3%. For every 10 additional robotic systems installed in a state, there would be a 2.5% increased rate of surgery (p⬍0.01), accompanied by a 1.3% (p⫽0.04) and 1.0% (p⬍0.01) decrease in the rate of radiation and active surveillance, respectively. Subgroup analyses suggest that the robotic adoption crowding out effect on radiation and active surveillance was driven primarily by men with stage I-II prostate cancer. If the adoption trajectory for robotic systems continues, the increased cost of treating localized prostate cancer in 2012 will be close to $27 million. Conclusions: During a period of rapid acquisition of robotic surgical systems, we found the number of robotic systems available at the state-level is significantly and directly associated with a higher rate of surgery for localized prostate cancer, and lower rates of radiation therapy and active surveillance.

6515


Impact of Medicaid reimbursement and eligibility policies on receipt of cancer screening. Presenting Author: Michael T. Halpern, RTI International, Washington, DC

The cost per patient of deviations from evidence-based standards of oncology care. Presenting Author: Arlene A. Forastiere, Eviti, Inc., Philadelphia, PA

Background: State Medicaid programs cover receipt of cancer screening services. However, coverage of cancer screening tests does not guarantee access to these services. Medicaid beneficiaries are less likely to be screened for cancer and more likely to present with advanced stage cancers. State-specific variations in Medicaid program eligibility requirements and reimbursements for medical services may affect cancer screening rates among Medicaid enrollees. This study examined how eligibility and reimbursement policies affected receipt of breast, cervical, colorectal, and prostate cancer screening. Methods: We examined 2007 Medicaid data for individuals age 21-64 enrolled in fee-for-service Medicaid for at least 4 months from 46 states and the District of Columbia. We examined the association of state-specific Medicaid cancer screening test and office visit reimbursements, income and financial asset eligibility requirements, physician copayments, and frequency of Medicaid eligibility renewal on receipt of cancer screening. Analyses used multivariate logistic regressions with generalized estimating equations to control for correlation between beneficiaries within a state. Results: Increased Medicaid screening test reimbursements were significantly associated with small increases in receipt of colonoscopy, mammograms, and PSA tests. Increased reimbursements for office visits were associated with increased receipt of colonoscopy, FOBT, Pap tests, and mammograms. Greater asset thresholds for Medicaid eligibility increased the likelihood of all screening tests except FOBT. Beneficiaries in states requiring more frequent (⬍12 month) renewal of Medicaid eligibility were more likely to receive FOBT, PSA, or mammograms, but less likely to receive Pap tests. Conclusions: Increasing Medicaid reimbursement rates and asset policies was generally associated with increases in cancer screening. As proposed Medicaid eligibility expansions will almost certainly increase the number of enrollees in this program, it is crucial to provide adequate reimbursements and develop eligibility policies to promote cancer screening and thereby increase early cancer detection among this underserved population.

Background: Practice variation contributes to the high cost of healthcare and wasteful spending; by contrast, adherence to evidence-based (EB) clinical guidelines is advocated to improve quality and potentially lower cost. We sought to estimate the average cost per patient associated with unjustified deviations from EB national standards for use of chemotherapy, supportive drugs, and radiotherapy. Methods: The ITA Partners/eviti, Inc. database of oncology treatment plans (TPs) reviewed for payers for adherence to national guideline recommendations (e.g. ASCO, ASTRO, NCI, NCCN Compendium, FDA) was used to calculate the variance in cost between submitted TPs with unwarranted deviations from EB standards and EB care. For prospective reviews, the final EB treatment given was known and for retrospective reviews, the variance was estimated based on the EB alternative with the lowest cost. AWP pricing was used to calculate chemotherapy and supportive drug costs, and Medicare pricing for radiotherapy. First order savings were calculated. An annual trend of 8% was applied from the mid-data period to 2013 (Milliman Client Report 2010). Results: From March 2009 to March 2012, a total of 2775 consecutive patients had TPs submitted and of these, 730 patients had unjustified, non-EB TPs. All cancer types, stage and treatment intent (curative, non-curative) were included. The cost of EB treatment was less than the submitted TP for 622 (85%) patients, more for 9 (1%), and zero (could not be taken due to payer plan definitions) for 99 (14%). Descriptive statistics for the cost per patient of non-EB TPs trended to 2013 showed: mean $25,579, median $13,882, standard deviation $40,958. Conclusions: In this unselected population comprising all cancers, 26% had TPs that did not conform to EB standards or could not be medically justified. Our conservative estimate of the average per patient overspend (first order) on inappropriate treatment validates the potential for quality care to lower cost and deliver huge value to patients, physicians, and payers. 95% CI Chemotherapy Radiation therapy Combined

Mean

Lower bound

Upper bound

$27,873 $13,660 $25,579

$24,475 $8,685 $22,585

$31,271 $18,636 $28,574




6517

393s


The financial burden of cancer care: Do patients know what to expect? Presenting Author: Fumiko Chino, Duke University School of Medicine, Durham, NC

Impact of Medicare Part D on out-of-pocket pharmaceutical costs for patients with cancer. Presenting Author: Sheetal Mehta Kircher, VA Ann Arbor Healthcare System, Ann Arbor, MI

Background: Patients receiving cancer treatment can experience significant financial distress (FD), but little is known about whether patients are adequately informed about costs of care. Methods: This is a planned interim analysis of an ongoing cross-sectional study of insured adults with solid tumors on anticancer therapy for ⱖ1 month. Consecutive patients were surveyed, in person, at a referral center and 3 rural oncology clinics. Participants were asked about subjective FD (via validated measure), out-of-pocket costs, expected burden, and willingness to accept high out-of-pocket costs. Medical records were reviewed for disease and treatment data. Logistic regression assessed the relationship between FD, expected burden, quality of life (QOL), and willingness to accept high out-of-pocket costs. Results: Among 119 participants (85% response), median age was 60 years (range 27-86), 54% were men, 29% were non-white, 96% had completed high school, and 40% were retired. 81% had incurable cancer. Median income was $50,000/yr. Median out-ofpocket costs were $480/mo. 19% reported high/overwhelming FD. Median time on treatment was 200 days. Compared to anticipated levels of personal financial burden at the start of treatment, 40% were experiencing a higher degree of burden, 24% were experiencing a lower degree of burden, and 32% were experiencing the same degree of burden. In adjusted analyses, both high/overwhelming FD score (OR 4.79; 95% CI 1.64-13.95; p⫽0.004) and a lower QOL score (OR 0.81; 95% CI 0.67-0.99; p⫽0.035) were associated with a higher than expected financial burden. The following were not associated with higher than expected financial burden: age, gender, education, cancer stage, cost as a proportion of income, time on treatment, or willingness to accept high out-of-pocket costs. Conclusions: A large portion of insured patients faced out-of-pocket costs that were greater than expected. Those who were least prepared for financial burden reported higher FD and lower QOL. Since patient characteristics could not identify those at highest risk for unexpected cost burden, future research should focus on how to identify patients at risk and better prepare them for potential treatment-related financial burden.

Background: As federal policy, Medicare Part D was designed to reduce OOP costs for Medicare beneficiaries, but the extent to which this occurred for patients with cancer has not been measured. The aim of this study is to quantify the impact of Part D eligibility on out-of-pocket (OOP) cost for prescription drugs for cancer patients. Methods: Differences-in-differences analyses were used to estimate the effects of Medicare Part D eligibility on OOP pharmaceutical costs, by comparing 4-year periods before and after Part D implementation. Analyses were based on data from the publicly available Medical Expenditure Panel Survey, a nationally representative, all-payer sample of the United States non-institutionalized civilian population. Our analysis compared per-capita OOP burden between Medicare beneficiaries (age 65⫹) with cancer to near-elderly patients age 55-64 years old with cancer. Statistical weights provided with the dataset were used to generate nationally representative estimates. Results: Overall, 2,147 near-elderly individuals with cancer and 5,296 individuals with Medicare and cancer were included in the analysis (total n⫽7,443), representing over 88 million people with cancer in 8 years of study. As expected, prescription drug coverage more than doubled among individuals with Medicare from before Part D (34.4%) to after (77.8%); in contrast, prescription drug coverage among the near-elderly remained stable before vs. after Part D (72.0% vs. 71.1%). The mean per-capita OOP cost for Medicare beneficiaries with cancer before Part D was $935 (SE ⫾30) and decreased to $616 (⫾25) after implementation of Medicare Part D—a decline of 34%. Compared with changes in OOP pharmaceutical costs for non-elderly patients with cancer over the same period, implementation of Medicare Part D was associated with a further reduction of $159 (⫾73) per person with cancer. Conclusions: The implementation of Medicare D has significantly reduced OOP prescription drug costs for seniors with cancer, beyond trends observed for younger patients. Further analyses will examine OOP cost patterns for patients with cancer with specific sociodemographic and clinical characteristics.

6518

6519



Patient, public, and oncologists’ attitudes toward rationing medical care. Presenting Author: Keerthi Gogineni, Hospital of the University of Pennsylvania, Philadelphia, PA

When using patient-reported outcomes in clinical practice, the measure matters: Results from an RCT. Presenting Author: Claire Frances Snyder, The Johns Hopkins University, School of Medicine, Baltimore, MD

Background: Lowering health care costs is critical. Patients with cancer (PT) and oncologists (MD) regularly make decisions regarding interventions with potentially marginal benefit but substantial expense. What are the attitudes of PT, the public (GP), and MD on ways to control costs? Methods: In 2012, surveys were completed by 326 adult PT (Response Rate (RR)⫽72%), a random sample of 891 U.S. adults (RR⫽50%) and 245 MD (RR⫽55%). Results: A majority thought Medicare spending was a big or moderate problem (76% PT; 75% GP; 97% MD) and that Medicare could spend less without causing harm (66% PT; 70% GP; 74% MD). Respondents attributed rising costs to multiple factors including drug companies charging too much (94% PT; 90% GP; 94% MD) and insurance company profits (88% PT; 88% GP; 83% MD). Many also thought physicians and hospitals provided unnecessary tests and treatments (RX) (69% PT; 81% GP; 70% MD). Regarding solutions, most supported refusing to pay for expensive care if an equally effective, less expensive alternative was available or if therapy did not improve survival or quality of life (QOL). Few respondents were willing to refuse payment for RX that extend life by 4 months. Conclusions: The majority of those sampled view Medicare costs as a substantial problem and pharmaceutical and insurance companies as significant contributors. The GP in particular believe physicians and hospitals add considerably to the cost problem. A majority favor not paying for more expensive RX when cheaper ones are equally effective or if RX do not improve survival or QOL. MD were accepting of an independent oversight panel however this was met with resistance by PT and the GP. Currently, Medicare and other payers do not consistently follow such practices.

Background: Patient-reported outcomes (PRO) assess patients’ perspectives on the impact of diseases and treatments. There is increasing interest in having patients complete PRO questionnaires and using the data clinically to identify and address patients’ issues. There are many different PRO questionnaires, and this study investigated whether one PRO is more appropriate than others for clinical use. Methods: This controlled trial randomly assigned patients to complete 1 of 3 PRO questionnaires: six domains from the Patient Reported Outcomes Measurement Information System (PROMIS), the EORTC QLQ-C30, or the Supportive Care Needs Survey-Short Form (SCNS). Breast or prostate cancer patients, ⬎⫽21 years old, undergoing treatment, with oncologist visits at least monthly were eligible. Patients completed their assigned PRO questionnaire via computer either in the clinic or via the web prior to their clinic visits for the duration of active treatment. The results were provided to their clinicians for use during visits. After treatment ended, patients completed a 13-item feedback form to assess the impact of the questionnaire on their care (e.g., easy to complete, promoted communication, improved care quality). We hypothesized that there would be no difference in the proportion of patients who strongly agreed/agreed to all 13 items in the feedback form by questionnaire arm. Results: Of 294 eligible patients approached, 224(76%) enrolled (mean age 66, 78% white, 28% breast, 72% prostate). Of these, 181 patients (81%) responded to the feedback form, with 116 patients (52%) completing all 13 items. Of the 116 patients with complete data, subjects in the QLQ-C30 arm were most likely to strongly agree/agree to all items (82%), followed by PROMIS (62%), and SCNS (56%) [p⫽.05]. Among the 181 patients with at least partial data, the proportions strongly agreeing/agreeing to all items were 74% for QLQ-C30, 61% for PROMIS, and 52% for SCNS [p⫽.03]. Conclusions: In a randomized trial comparing the benefits of PROs applied in clinical practice, we found significant differences among the 3 PRO questionnaires. Future applications of PROs for patient care should select the most appropriate PRO measures for the purpose and setting.

Support for cost-lowering options (%) Refuse to pay if there is a less expensive, equally effective RX Make patients who can afford more pay more Refuse to pay if RX does not prolong life or improve QOL Independent expert panel decides which RX to cover Refuse to pay if RX does not extend life but adds convenience Refuse to pay if RX extends life by 4 months Refuse to pay if RX does not extend life but reduces pain Refuse to pay if RX extends life by 2.5 years

PT nⴝ326

GP nⴝ891

MD nⴝ245

78 56 52 33 27 20 5 1

86 58 57 46 32 28 10 8

90 52 80 64 59 12 33 ⬍1


394s 6520

Health Services Research Poster Discussion Session (Board #9), Sun, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

Multitrial evaluation of longitudinal tumor measurement (TM)-based metrics for predicting overall survival (OS) using the RECIST 1.1 data warehouse. Presenting Author: Sumithra J. Mandrekar, Mayo Clinic, Rochester, MN Background: We previously reported that alternative cutpoints and alternate categorical metrics to RECIST standards provided no meaningful improvement in OS prediction. Here, we sought to identify and validate continuous, longitudinal TM-based metrics for predicting OS. Methods: Data from 13 trials (1739 patients with sufficient imaging-based measurements from breast, lung or colon cancer) were randomly split (60:40) into training and validation datasets and landmarked at 12-weeks (w). Multiple candidate metrics that capture tumor curve trajectory were considered: first slope (or % change) from baseline to 6 w, last slope (or % change) from 6 w to 12 w, and indicator of increase (⬍5% (includes no increase or a decrease) vs. ⱖ5%) from the prior assessment (baseline to 6 w, 6 w to 12 w). Multivariable Cox models stratified by study and number of baseline target lesions (⬍3 vs. ⬎3) and adjusted for baseline tumor burden (ratio of the sum of lesions/number of lesions) were fit for each tumor type. Predictive ability was assessed via concordance (c)-index (0.5: no association to 1.0: perfect association), and hazard ratios/p-values (HR/p). Results: Patients whose tumor size increased by at least 5% from the prior assessment, as well as whose tumors showed a positive slope (or % change) from 6 to 12 w (indicating tumor growth) had worse OS. The first slope (or % change) metric was less consistent, with an initial decrease in slope suggesting worse OS in some cases. Predictive ability of these metrics varied across tumor type with poorest prediction in Breast (Table). Conclusions: Continuous TM-based metrics performed no better than categorical RECIST metrics for OS prediction. HR (p) from slope based model Breast Metric First slope (mm/w) Last slope (mm/w) >5% vs. 30 days before death (nⴝ366)

IPC86 Race White Asian Black Hispanic Other Receives low-income insurance subsidy

Odds ratio

95% Confidence interval

P value

1.086 1.211 1.689 2.475

0.994 – 1.186 1.105 – 1.329 1.527 – 1.868 2.170 – 2.822

0.07 ⬍0.01 ⬍0.01 ⬍0.01 ⬍0.01

0.786 1.554 0.981 1.219 1.741

0.610 – 1.013 1.382 – 1.747 0.846 – 1.138 0.866 – 1.717 1.620 – 1.872

0.06 ⬍0.01 0.80 0.26 ⬍0.01

⬍0.01


Impact of a decision support tool on quality measures. Presenting Author: Peter G. Ellis, UPMC CancerCenters, Pittsburgh, PA Background: UPMC CancerCenter received their ASCO QOPI certification after the Spring 2011 measurement period with a QOPI Certification Overall Quality Score of 78.2%. The results, however, demonstrated a number of metrics performing below QOPI mean scores. Physicians and staff performed an analysis of root causes for these underperforming metrics and identified a combination of steps to improve these metrics and the overall score. Methods: Interventions to ensure high capture of Core Metric #9 (staging within 30 days of diagnosis), #10 and #11(treatment intent and discussion with patient) were imbedded into the clinical pathways program (Via Oncology Pathways) used by the UPMC CancerCenter physicians beginning in February 2011. These data points were charted by physicians when utilizing the Via Pathways Portal and automatically displayed on the regimen order sets that are generated by that Portal. These order sets were used as official orders and therefore placed into the patient charts. Results: UPMC CancerCenter’s QOPI Certification Overall Quality Score improved by 7 percentage points to 85.39% for the Fall 2012 measurement period (as compared to Spring 2011). All of the 24 certification metrics for Fall 2012 were similar or improved as compared to Spring 2011. Core Metrics #9 and #10 improved by 18 and 22 percentage points, respectively Conclusions: Improvements in quality measures such as ASCO QOPI can be gained through targeted analysis of root cause and application of new interventions such as clinical pathways decision support. We feel that decision support tools such as pathways programs may be an important source of data for e-QOPI type programs and should be considered.

* Also adjusted for neighborhood income, comorbidity, and chemotherapy use.


424s TPS6644

Health Services Research General Poster Session (Board #24D), Mon, 1:15 PM-5:00 PM

TPS6645


Overcoming health care disparities in cancer treatment by instituting a patient navigation program. Presenting Author: Tarek Elrafei, Jacobi Medical Center, Bronx, NY

Predictors of accrual success for cooperative group trials: The Cancer and Leukemia Group B (Alliance) experience. Presenting Author: David Hirsch Gordon, Alliance for Clinical Trials in Oncology, Chicago, IL

Background: Cancer health disparities affecting low-income and minority patients are well documented. Causes of poor outcomes include treatment delays coupled with social and financial barriers. Navigation interventions have been more commonly applied in cancer screening and in early diagnosis programs than in improving adherence to treatment among those with barriers to care. This report examines the early impact of patient navigation on adherence to prescribed cancer treatment. Methods: We put into place a Patient Navigation Program as a pilot project (supported by an Avon Foundation grant) at our public safety net hospital. Health care coverage: 58% Medicaid, 23% uninsured or undocumented. Navigator duties included care coordination, appointment reminders, patient education materials, translation services, and transportation arrangement. During a 4 month period new medical oncology practice patients felt to be at high risk received navigated care. Data collected prospectively included patient characteristics, cancer type, time from referral to first RT, and compliance with visits; this was compared with usual care historical controls immediately prior to the 4 month period. Results: Patient Navigation Program patient characteristics: N ⫽ 52 patients (22 breast cancer, 6 prostate cancer, 5 lung cancer and 19 patients with other cancers). Mean age ⫽ 55; 48% Black, 38% Hispanic, 8% Asian, 6% White. Adherence to visits, and time to first RT results are seen in the Table. Conclusions: In the first 4 months of its initiation, this Patient Navigation Program has been associated with observed improvements in adherence to chemotherapy and follow up physician visits, but no impact on time to 1st RT to date. These results document that a Patient Navigation Program can help overcome barriers to good cancer care while identifying RT as an area for further improvement.

Background: Clinical trials that fail to meet accrual waste patient, physician, and institution resources. We explored factors that predict for poor accrual to cooperative group trials in order to improve trial design and target resources to support or increase accrual when needed. Methods: Twenty trial characteristics were collected for Cancer and Leukemia Group B (CALGB) trials that closed between 06/01/02 and 06/01/12. We evaluated accrual in two ways: (1) logistic regression applied to accrual success/ failure as a binary outcome; (2) treated the ratio of actual to expected accrual rate as a continuous response and applied linear regression to the square root of the ratio. Results: 110 trials (phase III⫽27, phase I/II⫽83) were examined. 89 (80.9 %) met the accrual goal, 21 (19.1%) did not. For trials that met their accrual goal, time to accrual ranged from 0.5 to 8.8 years and was non-normally distributed, with 57% accruing within 3 years and 83% accruing within 5 years. Phase III trials took longer to accrue (univariate p⬍0.001) but were not less likely to meet accrual goal (p⫽0.30). Provision of study drug was an important predictor of success in both analyses performed (borderline significant in success/failure analysis); having at least one agent provided by the study was significantly associated with better accrual. Factors not found to affect accrual included: Time from concept approval by CALGB to study activation, research-only biopsies, and estimated rarity of disease being studied. Conclusion: Provision of drug as a predictor of accrual success has not been previously reported, and will need to be confirmed. This factor is likely a surrogate for physician and patient eagerness to have access to a drug not otherwise available.

MD visits (n ⴝ 2021) Infusion visits (n ⴝ 1656) Time to first RT (n ⴝ 25)

TPS6646

Navigated care adherence

Usual care adherence

97% 90% 32 days

86% 79% 30 days


Chemotherapy for malignancies in the post solid organ transplant (SOT) setting: A single institute experience. Presenting Author: Omar Al Ustwani, Roswell Park Cancer Institute, Buffalo, NY Background: Management of advanced malignancies in SOT recipients is not well defined. These patients need immunosuppressive agents to avoid graft rejection. Simultaneous administration of chemotherapy and immunosuppressive agents may increase treatment toxicities. We reviewed data of SOT recipients treated at Roswell Park Cancer Institute (RPCI) for different malignancies to assess their tolerance to treatment and outcomes. Methods: Between 2000-2012, 126 SOT recipients were seen at RPCI for management of cancer. Patients with superficial skin cancer and PTLD or other malignancies not qualifying for therapy were excluded. Adverse events were documented per CTCAE 4.0. Results: 40 patients were included for the review. Median age was 61.5 (29-79) years, and 50% were male. Types of SOT were: 17 liver, 16 kidney, 4 heart, 2 lung and 1 liver/kidney. Types of cancers were: 12 GI, 9 breast, 6 lung, 4 AML/myeloma, 3 head & neck, 2 GYN, 2 skin requiring therapy and 2 GU. Median lag time between SOT and cancer diagnosis was 14.5 years (2m-39y). 13/36 (36%) of solid tumors were metastatic at diagnosis. At the time of analysis, 9/34 (26%) of patients with documented outcome were alive. Of all patients, median overall survival was 28.5m. 31/40 (78%) received chemotherapy and 9/40 (22%) had hormonal therapy alone. In the chemotherapy group, patients received a median of 1.8 lines of therapy (1-6), 4/31 (13%) were given definitive chemotherapy⫹RT and 8/31 (26%) received chemotherapy in the neoadjuvant/adjuvant setting. Treatment delays were necessary in 10/31 (32%), and dose omission or reduction in 13/31 (42%). The most common hematologic adverse events (AEs) were anemia (25/31, 80%) and thrombocytopenia (19/31, 61%). Febrile neutropenia (G3) occurred in 5/31(16%). The most common non-hematologic AEs were fatigue (23/31, 74%) and hepatic dysfunction (19/31, 61%). The most common G3/4 hematologic AEs were neutropenia (9/31, 29%) and leukopenia (7/31, 23%) while non-hematologic G3/4 AEs were diarrhea and fatigue (4/31 each, 13%). Conclusions: SOT patients tolerate chemotherapy relatively well but AEs, dose reductions and delays occur. Treating physicians should be careful when dosing chemotherapy in these cases.


Leukemia, Myelodysplasia, and Transplantation 7001

Oral Abstract Session, Tue, 8:00 AM-11:00 AM

Impact of baseline mutations on response to ponatinib and end of treatment mutation analysis in patients with chronic myeloid leukemia. Presenting Author: Michael W. N. Deininger, Division of Hematology and Hematologic Malignancies and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT Background: BCR-ABL kinase domain mutations frequently cause tyrosine kinase inhibitor (TKI) failure in chronic myeloid leukemia (CML). Ponatinib, a potent oral pan-BCR-ABL TKI, has shown preclinical activity against all single mutants tested, including T315I. The impact of baseline (BL) mutations on response to ponatinib (45 mg once daily) and end of treatment (EOT) mutations in pts discontinuing treatment were evaluated in the phase II PACE trial. Methods: Heavily pretreated chronic phase (CP) CML pts (93% received ⱖ2 prior TKIs, 60% ⱖ3) resistant or intolerant to dasatinib or nilotinib (N⫽203) or with T315I confirmed at BL (N⫽64) were enrolled. The primary endpt was major cytogenetic response (MCyR). Min follow up at analysis (9 Nov 2012) was 12 mos (median 15 [0.1-25]). Sanger sequencing was done at one central laboratory. Results: At BL, no mutations were detected in 51% of pts, 1 mutation in 39%, and ⱖ2 mutations in 10%; 26 unique mutations were observed. Responses were observed regardless of BL mutation status. MCyR rates were: 56% overall, 49% in pts with no mutations, 64% 1 mutation, 62% ⱖ2 mutations; 57% in pts with mutation(s) other than T315I, 74% T315I only, 57% T315I ⫹ other mutation(s). Responses were seen against each of the 15 mutations present in ⬎1 pt at BL, including T315I, E255V, F359V, Y253H. 99 pts discontinued, 56 had EOT mutations assessed. 5 pts lost a mutation, 46 had no change, 5 gained mutations (Table). 11 pts lost MCyR (none with T315I); of the 6 discontinuing, 4 had EOT mutations assessed and no changes from BL were seen. Conclusions: Responses to ponatinib were observed regardless of BL mutation status. No single mutation conferring resistance to ponatinib in CP-CML has been observed to date. Data with a minimum follow up of 18 mos, including pts with advanced disease, will be presented. Clinical trial information: NCT01207440. Relevant mutation history

BL mutation(s)

EOT mutation(s)a

E255V T315I T315I T315I Y253H

None None T315I F359V V299L/F359V

E255V [10%]b T315I/F359V [100%/90%]c T315I/M351T [100%/40%]b T315I [100%]d Y253H/F359V [100%/100%]d

Gained mutation ⫽ bold; % of transcripts with mutation ⫽ [%]. Reason for discontinuation: bOther. cAE. dProgressive disease.

a

7003


Final results of a phase I study of idelalisib (GSE1101) a selective inhibitor of PI3K␦, in patients with relapsed or refractory CLL. Presenting Author: Jennifer R. Brown, Dana-Farber Cancer Institute, Boston, MA Background: Signals through PI3K-delta regulate activation, proliferation and survival of B cells, critically influence homing and retention of B cells in lymphoid tissues, and are hyperactive in many BEcell malignancies. Idelalisib (GS-1101) is a first-in-class, selective, oral inhibitor of PI3K␦ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells. Methods: Pts with relapsed/refractory CLL were treated continuously with single-agent oral idelalisib from 50E350 mg/dose (QD or BID). Response evaluated by investigators per Hallek (2008) and Cheson (2012). Results: 54 pts (9F/45M) median (range) age 63 (37E82) years enrolled with: bulky lymphadenopathy (80%), refractory disease (70%), extensive prior therapies (median: 5, range: 2E14), unmutated IgHV (91%), del17p and/or TP53 mutation (24%), del11q (28%), NOTCH1 mutation (17%). The median (range) exposure was 9 (0E41⫹) months. 25 (46%) pts completed the primary study, 23 (43%) enrolled into an extension study. ORR was 30/54 (56%, 2 CR, 28 PR). Of the 28 PR, 22 met Hallek (2008) and 6 met PR with lymphocytosis Cheson (2012). 44/54 (81%) showed a lymph node response (ⱖ50% reduction in the nodal SPD). 21/54 were SD and 3/54 NE. The median (range) time to first response was 1.9 (0.9-12.9) months. Median PFS was 17 months and median DOR was 18 months. Idelalisib treatment resulted in resolution of splenomegaly (14/20, 70%) and normalization of cytopenias: anemia (17/25, 68%); thrombocytopenia (27/34 79%), neutropenia (15/15, 100%). Most common AEs independent of causality (any Grade/ⱖGr 3) included fatigue (31%/2%), diarrhea (30%/6%), pyrexia (30%/4%), rash (22%/0%), upper respiratory tract infection (22%/0%), pneumonia (20%/ 19%). 2% of pts had ⱖGr 3 ALT/AST elevation. 15% of pts discontinued due to AEs, 7% potentially treatment-related. There were no dose-limiting toxicities. Conclusions: Idelalisib shows substantial clinical activity and a favorable safety profile in heavily pretreated, refractory and highErisk pts with CLL. Phase 3 trials with idelalisib in combination with rituximab or bendamustine/rituximab are ongoing. Clinical trial information: NCT01539512, NCT01569295.

7002

425s Oral Abstract Session, Tue, 8:00 AM-11:00 AM

A randomized study of lenalidomide (LEN) with or without EPO in RBC transfusion dependent (TD) IPSS low and int-1 (lower risk) myelodysplastic syndromes (MDS) without del 5q resistant to EPO. Presenting Author: Andrea Toma, Hopital Henri Mondor-APHP, Universite Paris 12, Creteil, France Background: ESAs, the first line treatments of anemia in non del 5q lower risk MDS, yield only 40-50% responses. LEN gives RBC transfusion independence (TI) in about 25% of ESA resistant (or relapsing) TD lower risk MDS without del 5q (Raza, Blood, 2008), and a gene expression signature can predict response (Ebert, Plos Med 2008). We randomized in this patient population LEN alone and LEN⫹EPO. Methods: In this prospective multicenter open-label phase II study (NCT01718379), lower risk MDS patients without del 5q, with TD (ⱖ4 RBC units during the previous 8 weeks (w)) with ESA resistance or relapse after a response were randomized between LEN alone, 10mg/d x 21 d/4 w (L arm) or LEN (same schedule) ⫹ EPO beta, 60 000 U/w (LE arm). The primary endpoint was erythroid response (HI-E, IWG 2006 criteria) after 4 treatment cycles. Secondary objectives included identification of biomarkers of response. Results: Between July 2010 and June 2012, 132 patients (pts, 66 / arm), median age 73 (range 46-88), M/F: 88/44 were enrolled. Median TD was 6 RBC units/8w (range 2-18). IPSS was Low in 45% and Int-1 in 55% pts. Pretreatment characteristics did not differ between the 2 groups. All but 3 pts, who withdrew consent (2L⫹1LE), were evaluable for response. In this ITT population, HI-E was obtained in 15 pts (23.4%) in L arm and 26 (40.0%) in LE arm (RR⫽ 1.7, p⫽ 0.043, chi2 test), and TI in 9 (14.1%) versus 16 (24.6%) pts (RR⫽1.7, p⫽ 0.13). In the 99 pts who completed 4 treatment cycles, 41 achieved HI-E, including 15/49 (30.6%) in L arm versus 26/50 (52.0%) in LE arm (p⫽ 0.03), and TI in 9 (18.4%) versus 16 (32.0%) pts (RR⫽ 1.7, p⫽0.12). Side effects (cytopenias and 1 DVT/arm) were similar in the 2 arms. A 29-gene expression profile signature predicting HI-E to L or LE, different from that previously published, was identified and a polymorphism in the CRBN gene (Kosmider, submitted) was significantly associated with HI-E in the entire cohort (p⫽0.034). Conclusions: LEN ⫹ EPO yielded a significantly better erythroid response than LEN alone in lower risk MDS patients with anemia resistant to ESA alone. A gene expression signature and a CRBN gene polymorphism correlated with the erythroid response. Clinical trial information: NCT01718379.

7004


Obinutuzumab (GA101) plus chlorambucil (Clb) or rituximab (R) plus Clb versus Clb alone in patients with chronic lymphocytic leukemia (CLL) and preexisting medical conditions (comorbidities): Final stage 1 results of the CLL11 (BO21004) phase III trial. Presenting Author: Valentin Goede, German CLL Study Group, Dept. I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne, Germany Background: Chemoimmunotherapy (CIT) is standard of care in young and physically fit patients (pts) with CLL. Development of CIT for older and less fit CLL pts is ongoing, but data from phase III trials are sparse. CLL11 is the largest trial to evaluate three treatments in previously untreated CLL pts with comorbidities: Clb alone, GA101 ⫹ Clb (GClb), R ⫹ Clb (RClb). The final analysis of CLL11 stage 1 efficacy and safety results is presented here. Methods: Treatment-naïve CLL pts with a Cumulative Illness Rating Scale (CIRS) total score ⬎6 and/or an estimated creatinine clearance (CrCl) ⬍70 mL/min were eligible. Pts received Clb alone (0.5 mg/kg po d1, d15 q28 days, 6 cycles), GClb (100 mg iv d1, 900 mg d2, 1000 mg d8, d15 of cycle 1, 1000 mg d1 cycles 2-6), or RClb (375 mg/m2 iv d1 cycle 1, 500 mg/m2 d1 cycles 2-6). Primary endpoint was investigator-assessed progressionfree survival (PFS). Results: Median age, CIRS score, and CrCl at baseline were 73 years, 8, and 61.1 mL/min for stage 1a (Clb vs GClb, 356 pts) and 73 years, 8, and 62.1 mL/min for stage 1b (Clb vs RClb, 351 pts, triggered by a different event rate). Key efficacy and safety results are shown in the Table.Grade 3-4 infusion-related reactions with GClb occurred at first infusion only. Management required splitting the first dose over 2 days. Conclusions: CIT with GClb or RClb significantly prolongs PFS vs Clb alone. The results demonstrate that GClb and RClb are very active in CLL and superior treament options in this population. GClb vs RClb will be compared in stage 2 analysis with more follow-up available. Clinical trial information: NCT01010061. Total stage 1 Nⴝ589 Median observation time, months Overall response rate, % Complete responses, % Median PFS, months HR, CI, p Grade 3-5 adverse events during treatment, % Infusion-related reaction Neutropenia Infections

Stage 1a Clb GClb Nⴝ118 Nⴝ238

Stage 1b Clb RClb Nⴝ118 Nⴝ233

13.6 14.5 30.2 75.5 0 22.2 10.9 23.0* 0.14, 0.09-0.21, ⬍.0001 41 67

14.2 15.3 30.0 65.9 0 8.3 10.8 15.7 0.32, 0.24-0.44, ⬍.0001 41 46

15 11

21 34 6

15 11

4 25 8

* Still immature, ⬍ 20% at risk at time of median.


426s 7005

Leukemia, Myelodysplasia, and Transplantation Oral Abstract Session, Tue, 8:00 AM-11:00 AM

7006


A phase II study of the selective phosphatidylinositol 3-kinase delta (PI3K␦) inhibitor idelalisib (GS-1101) in combination with rituximab (R) in treatment-naive patients (pts) >65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Presenting Author: Susan Mary O’Brien, The University of Texas MD Anderson Cancer Center, Houston, TX

Multi-institutional study of allogeneic bone marrow transplantation using myeloablative busulfan (Bu)/fludarabine (Flu) conditioning and shortcourse, single-agent graft-versus-host disease (GVHD) prophylaxis with high-dose, post-transplantation cyclophosphamide (PTCy). Presenting Author: Christopher George Kanakry, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD

Background: PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3K␦ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective oral inhibitor of PI3K␦. When combined with R in 19 relapsed/refractory patients with CLL, the ORR was 78% (Coutre, ASH 2012). Methods: Treatment-naive pts ⱖ65 yrs with CLL or SLL were treated with R 375 mg/m2 weekly x 8 and idelalisib 150 mg bid continuously for 48 weeks (primary study). Pts completing 48 wks w/o progression could continue to receive idelalisib on an extension study. Responses and progression were based on investigator assessment using IWCLL criteria (Hallek, Blood 2008). Results: Data is presented here on the first 50 of 64 pts enrolled, 48 CLL/2 SLL, median age 71 yrs (range: 65-89), M/F 70/30 (%), Rai stage III/IV 10/32 (%), nodes ⱖ5 cm in 16%, WHO 0/1/2 in 34/64/2 (%); del(17p) in 6 pts and del(11q) in 13 pts. 32 pts completed 48 wks (18 discontinued, 11 due to AE, 4 due to death and 3 other); 30 pts entered the extension study and 26 remain on treatment. The median time on treatment was 16 months (range 0.8-27.5). The ORRwas 96% with 4% nonevaluable; median time to response was 1.9 mos (range 1.0-6.5). There have been no on-study relapses. The Kaplan-Meier estimated PFS is 91% at 24 mos. Of note, 6/6 pts with del(17p) responded (1 CR, 5 PR) and 3 remain on treatment for more than 21 months. 13/14 (93%) pts with thrombocytopenia and 12/12 (100%) pts with anemia at baseline responded. Of 20 pts with B symptoms at baseline, 13 (65%) were asymptomatic by 8 wks. Most frequent AEs (total%/ ⱖG3%) were diarrhea (including reported as colitis) (46/16), pyrexia (42/4), chills (34/0), fatigue (34/2), rash (34/10), pneumonia (30/20) and nausea (28/0). Elevated ALT/AST was seen in 60%, Gr ⱖ3 in 22%. Conclusions: Idelalisib ⫹ R is highly active, resulting in durable disease control in treatment-naïve older pts with CLL. These results support the further development of idelalisib in frontline CLL. Clinical trial information: NCT01203930.

Background: The clinical efficacy of 1) myeloablative BuFlu and 2) PTCy as GVHD prophylaxis have been independently shown in multiple singlecenter studies. Here, we sought to combine these two promising strategies in the context of a multi-institutional clinical trial. Methods: IV Bu was given in pharmacokinetically adjusted doses to achieve a targeted steady-state concentration. PTCy at 50mg/kg on Days ⫹3 and ⫹4 was administered as sole GVHD prophylaxis. Ninety-two patients (median age 49, range 21-65) receiving HLA-matched allografts (49% related and 51% unrelated) were enrolled at three institutions: 42 at Johns Hopkins, 38 at Fred Hutchinson, and 12 at MD Anderson. Diagnoses included 37 patients with de novo AML (40%), 16 with secondary AML (17%), 15 with acute lymphoblastic leukemia (16%), 13 with myelodysplastic syndrome (14%), 5 with chronic myelogenous leukemia (5%), two with chronic myelomonocytic leukemia (2%), three with non-Hodgkin lymphoma (3%), and one with multiple myeloma (1%). Twenty-five patients (27%) were not in remission by morphologic criteria at the time of allogeneic transplantation and an additional 17 patients (18%) had flow cytometric, cytogenetic, or molecular evidence of disease. Results: Five patients (5.4%) had primary graft failure. The cumulative incidences of grades 2-4 and 3-4 acute GVHD were 51% and 16%, respectively, and the cumulative incidence of chronic GVHD was 14%. GVHD was the primary cause of death in two patients, and one patient died of veno-occlusive disease. The 100 day and 1 year non-relapse mortality were 9.8% and 16%, respectively. Relapse occurred in 24% of these high-risk patients. At 1 year, the EFS was 64% and the OS was 72%. For the 50 patients in complete remission without MRD, at 1 year the EFS was 77% and the OS was 78%. Conclusions: This multiinstitutional trial confirms the efficacy of high-dose PTCy as single-agent GVHD prophylaxis and demonstrates that it can be safely and effectively combined with the myeloablative BuFlu conditioning regimen. Clinical trial information: NCT00809276.

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Long-term safety and survival outcomes after TK-expressing donor lymphocyte infusion (TK-DLI) in allogeneic hematopoietic stem cell transplantation (HSCT). Presenting Author: Fabio Ciceri, Hematology and BMT Unit, San Raffaele Scientific Institute, Milan, Italy

Impact of allogeneic hematopoietic stem cell transplant (HSCT) on patients harboring the spliceosome mutation SRSF2. Presenting Author: Betty Ky Hamilton, Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH

Background: Suicide gene therapy (SGT) was firstly applied to allogeneic HSCT, addressing the need for modulation of graft vs host disease (GvHD) reactions while preserving graft vs leukemia (GvL) effect of alloreactive T cells. HSV-TK gene insertion in donor T-cells modulates alloreactivity by selectively destroying dividing alloreactive cells involved in GvHD. Methods: Long-term safety and survival was assessed in 128 pts entering worldwide 10 phase I-II trials that used TK-DLI to improve GvL, immune reconstitution (IR) and GvHD control. In all, 57 pts received TK DLI at our Institution: 23 to treat relapse after HLA-identical HSCT (Ciceri, 2007) and 34 to improve IR after haploidentical HSCT (Ciceri, Bonini, 2009). Results: SGT was feasible, safe and effective in promoting a dynamic and specific modulation of alloreactivity. TK-DLI clinical benefit, defined by chimerism, tumor response and/or IR, was achieved by 65 pts (51%). Grade 2 to 4 GvHD (n⫽28, 22%) was fully controlled by SGT. TK-DLI engrafted in 51 pts (90%) and, being detectable at low frequency up to 14 yrs, no SGT-related adverse events occurred. In HLA-identical setting (n⫽23; median follow-up, 15 yrs), 11 pts (48%) had disease response and 2 pts (9%) were alive in complete response (CR). In haploidentical setting (n⫽34; median follow-up, 7 yrs), 25 pts (73%) had IR and 9 pts (26%) were alive in CR. All pts were monitored according to guidelines on long-term survivors (Majhail, 2012). There were no major infections, while 3 pts had a second tumor. Immunity against TK-DLI was reported exclusively after HLA-identical allo-HSCT indicating that TK-DLI is not limited by SGT-specific immunity after haploidentical HSCT. Conclusions: Long-term follow-up confirms the high benefit to risk ratio of TK-DLI. A phase III trial is ongoing in haploidentical HSCT (NCT00914628). Clinical trial information: NCT00423124.

Background: Molecular predictors of outcome are increasingly important in determining optimal therapy for myeloid neoplasms. Mutations (mut) in spliceosome genes U2AF1 and SRSF2 predict poor outcome in MDS and related diseases. The purpose of this study was to investigate the role of HCT on the prognostic impact of U2AF1 and SRSF2 in myeloid malignancies. Methods: 123 patients (pts) with MDS (33%), AML (51%), MPN (10%), and MDS/MPN (5%) receiving an allogeneic HCT from 2003-2012 for whom genomic DNA was available from a time when the disease was active, were evaluated for mut in U2AF1 and SRSF2 by direct sequencing. Data were analyzed using competing risks methods (relapse and nonrelapse mortality, NRM), proportional hazards (overall survival, OS) and logistic regression models (GVHD). Results: Median time of follow up was 38 months (range 1.5-108). Median age at HCT was 51 yrs (range 18-71). 53 (43%) pts were in remission and 70 (57%) had active disease prior to HCT. 20 (16%) pts had low, 48 (39%) intermediate and 32 (26%) high risk cytogenetics respective to their disease, (per CALGB criteria for AML, IPSS-MF for MPN and IPSS-R for MDS), with missing data on 23 (19%) pts. 89 (72%) had myeloablative transplants, and 34 (28%) received reduced intensity regimens. 54 (44%) had related, 52 (42%) unrelated and 17 (14%) cord blood donors. SRSF2 mut were detected in 13 (11%) pts and U2AF1 in 2 (2%) pts. Due to the low incidence of U2AF1 mut in our cohort, further analysis was focused on SRSF2. There were no significant differences in baseline characteristics between mut and wild-type (wt) pts except SRSF2 mut tended to occur in older AML pts (median age 64 vs 50 yrs, p⫽0.0004). SRSF2 mut and wt had similar OS (p⫽0.95), relapse (p⫽0.28), NRM (p⫽0.45) and rates of acute (p⫽0.41) and chronic (p⫽0.67) GVHD. Results were similar, adjusting for factors such as age, disease type, cytogenetics, comorbidity, transplant type and stem cell source. Conclusions: SRSF2 has previously been associated with dismal outcomes in MDS pts, with 5 yr-OS of ⬍20%. In this cohort of transplanted pts, SRSF2 mut had similar outcomes to wt, suggesting HSCT may compensate for the adverse impact of SRSF2.




Incidence of posttransplantation lymphoproliferative disorder (PTLD) following allogeneic blood or marrow transplantation (alloBMT) using posttransplantation cyclophosphamide (PT-Cy) for graft-versus-host disease (GVHD) prophylaxis. Presenting Author: Jennifer Ann Kanakry, Johns Hopkins School of Medicine, Baltimore, MD Background: Immunosuppression to prevent graft rejection and GVHD is associated with an increased incidence of PTLD in the first year after alloBMT. AlloBMTs using partially HLA-mismatched or unrelated donor grafts, particularly when coupled with selective T-cell depletion approaches and/or anti-thymocyte globulin therapy, are associated with PTLD rates of 4-8%. The incidence of PTLD after umbilical cord blood alloBMT ranges from 2-7%. We evaluated the incidence of PTLD associated with the use of PT-Cy as GVHD prophylaxis at Johns Hopkins Hospital. Methods: After IRB approval, the Blood and Marrow Transplant Research database was queried for adult patients (age ⬎ 18) who received PT-Cy as GVHD prophylaxis. Medical records from the first year after alloBMT, including clinical notes, pathology reports, and laboratory assays for Epstein-Barr virus (EBV), were reviewed. Results: From 2000-2011, 765 alloBMT patients received PT-Cy (50 mg/kg/day on days 3 and 4 after alloBMT) as GVHD prophylaxis. Of these, 734 patients had 1-year follow-up or death. In patients receiving myeloablative conditioning and HLA-matched grafts (n⫽289, 117 unrelated donors), PT-Cy was the sole GVHD prophylaxis. Other patients undergoing alloBMT received mycophenolate mofetil and tacrolimus in addition to PT-Cy. These included recipients of HLA-matched (n⫽63) or haploidentical (n⫽352) grafts who were conditioned with reduced intensity regimens, as well as recipients of HLA-haploidentical grafts who received myeloablative regimens (n⫽30). Forty-one patients with CD20(⫹) tumors received rituximab after alloBMT as part of a clinical protocol. There were no cases of PTLD. Conclusions: The absence of PTLD in this series, even among high-risk recipients of haploidentical or unrelated donor grafts, suggests that PT-Cy is less associated with PTLD than other GVHD prophylaxis strategies. We hypothesize that multiple mechanisms may account for the lack of PTLD with PT-Cy, including destruction of B cells that harbor EBV, sparing of EBV-specific memory T cells, and rapid immune reconstitution.

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Allogeneic transplantation for myelofibrosis: Benefit of dose intensity. Presenting Author: Uday R. Popat, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX Background: We did a prospective study of busulfan (bu) and fludarabine (flu) conditioning in patients with myelofibrosis. After observing a high relapse rate in the initial cohort, we increased the intensity of conditioning regimen for subsequent patients, hypothesizing that increased dose intensity delivered with PK guidance will reduce relapse rate without increasing non relapse mortality (NRM), thereby improving overall outcome. Methods: Patients with intermediate or high risk MF were eligible if they had adequate organ function and at least 9/10 matched related or unrelated donor. Of the 46 consecutive patients, 15 (bu low group) received IV busulfan 130 mg/m2 x 2 (day -3,-2). Of the remaining 31 (bu high group), 27 received IV busulfan dose to a target daily AUC of 4000 ␮mol.min x 4 (day -5 to -2) and 4 patients received a fixed dose of 100 mg/m2 x 4 (days -5 to -2). All patients received fludarabine 40mg/m2x 4 (day -5 to -2). Results: 23 males and 23 females with a median age of 58 years (27-74) had intermediate (25) or high-risk (21) disease. Donors were matched sibs (19), matched unrelated (23), or mismatched unrelated (4). With a median follow-up of 2.1 years (range 0.1-6 years), 3-year overall survival(OS), event-free survival (EFS), cumulative incidence (CI) of non-relapse mortality (NRM), and CI of relapse were 69%, 50% , 13%, and 37%, respectively. Multivariate Cox regression analysis showed that Bu-high dose (HR 0.41; p⫽0.04) and peripheral blood CD 34 count (HR 1.7; p⫽0.03) were significantly associated with EFS, and high CD-34 count was significantly associated with OS (HR 1.87; p⫽0.04). Table shows details of 3-year outcomes of low-dose and high-dose group. All patients engrafted with a median time to neutrophil engraftment of 13 (0-27) days and a median time to platelet engraftment of 24 (0-268) days. Cumulative incidence (CI) of grade II-IV, grade III, IV acute GVHD, and Chronic GVHD were 22%, 5%, and 39%, respectively. Conclusions: Higher dose busulfan, delivered with pharmacokinetic dose adjustment, reduces relapse without increasing non-relapse mortality, resulting in better EFS in patients with MF. Clinical trial information: NCT00475020. @ 3 years OS EFS CI of relapse CI of NRM

Bu-High (nⴝ31)

Bu-low (nⴝ15)

75% 61% 29% 10%

60% 27% 53% 20%

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Impact of monosomal karyotype and FLT3 status on post-transplant relapse in acute myeloid leukemia (AML). Presenting Author: Antonio Martin Jimenez, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Relapse remains the major cause of treatment failure in AML patients (pts) undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). We aimed to identify prognostic factors for relapse and leukemia free survival (LFS) after allo-HCT in AML pts. Methods: We retrospectively analyzed 987 consecutive pts who underwent their first allo-HCT for AML between January 2001 and June 2012. 124 pts had monosomal karyotype (MK⫹), 440 had other cytogenetic abnormalities (core-binding factor [CBF] n⫽67; MK-, n⫽373). 113 pts had diploid cytogenetics and FLT3 mutations (CN-FLT3⫹), 235 were diploid without FLT3 mutations (CN-FLT3-); FLT3 data was unavailable for 75 CN pts. Pts were stratified based on disease status at HCT: complete remission (CR, n⫽627) and active disease (n⫽360). Results: In this cohort, median age was 52 years (range: 19 – 76) and 191 pts (20%) had secondary AML (sAML). Conditioning intensity was non-myeloablative in 230 pts (23%). On multivariate analysis in pts with CR at HCT (adjusted for age, donor type and conditioning intensity) factors that predicted inferior LFS included: sAML (HR⫽1.5, 95% CI⫽1.1-2.2, p⫽0.009), ⬎⫽CR2 vs. CR1 (HR⫽1.6, 95% CI⫽1.2-2.1, p⫽0.002), CN-FLT3⫹ (HR⫽1.7, 95% CI⫽1.1-2.5, p⫽0.02), MK- (HR⫽1.4, 95% CI⫽1.1-2.0, p⫽0.04) and MK⫹ disease (HR⫽2.1, 95% CI⫽1.4-3.2, p ⬍0.001). Three-year LFS rates for CNFLT3⫹ and MK⫹ were 45.3% and 34% vs. 53.3% for CN-FLT3- pts. For pts with active disease; CN-FLT3⫹ (HR⫽2.6, 95% CI⫽ 1.5-4.2, p⬍0.001) and MK⫹ (HR⫽2.3, 95% CI⫽ 1.5-3.5, p⬍0.001) predicted worse 3-year LFS: 10% and 6% vs. 30.8% in pts with CN-FLT3- . For CR pts, cumulative incidence of relapse (CIR) was higher for those with CN–FLT3⫹ (HR⫽1.9, 95% CI⫽1.1-3.1, p⫽0.01) and MK⫹ disease (HR⫽2.1, 95% CI⫽1.23.5, p⫽0.005). Among active disease pts, CN-FLT3⫹ (HR⫽2.5, 95% CI⫽1.4-4.3, p⫽0.002) and MK⫹ (HR⫽1.9, 95% CI⫽1.2-3.0, p⫽0.009) also predicted for higher CIR. Conclusions: Although pts with CN-FLT3⫹ and MK⫹ represent a high risk group for decreased LFS with increased relapse incidence after allo-HCT, they may still enjoy LFS of 30% - 45% if transplanted in CR. Post-transplant strategies to minimize the risk of relapse should be investigated in this setting

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Response rate and bridging to hematopoietic stem cell transplantation (HSCT) with quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory AML after second-line chemotherapy or previous bone marrow transplant. Presenting Author: Jorge E. Cortes, The University of Texas MD Anderson Cancer Center, Houston, TX Background: FMS-like tyrosine kinase 3 internal tandem duplication (FLT3ITD) in acute myeloid leukemia (AML) is associated with early relapse after chemotherapy and poor survival. Relapse after HSCT or failure of salvage chemotherapy in FLT3-ITD AML is rarely associated with subsequent HSCT or durable survival. Quizartinib, an oral FLT3 inhibitor, shows promising activity; a Ph 2 study (n⫽333) of quizartinib monotherapy (Levis et al, ASH 2012) reported that quizartinib often bridged patients (pts) to HSCT. Methods: 136 FLT3-ITD(⫹) and 40 FLT3-ITD(-) pts, relapsed/refractory after HSCT or 1-second line regimen, were included. The response category of composite complete remission (CRc) comprised complete remission [CR] ⫹ complete remission with incomplete platelet recovery [CRp] ⫹ complete remission with incomplete hematologic recovery [CRi]. Results: Quizartinib was discontinued for HSCT in 47/136 FLT3-ITD(⫹) pts (35%), with 44/47 having at least a PR (2 CRp, 24 CRi, 18 PR). Median overall survival (OS) was 41.5 wks for pts with CRc prior to HSCT and 29 wks for pts with PR. The 1y survival rate was 39% for both response groups. Pts with a CRc (n⫽36) or PR (n⫽20) but no HSCT, respectively, had a median OS of 24.5 and 20.9 wks and 1y survival rates of 25% and 5%. Of 27 pts with OS ⬎52 wks, 17 (63%) had HSCT. Quizartinib was discontinued for HSCT in 14/40 FLT3-ITD(-) pts (35%), with 13/14 having at least a PR (1 CR, 1 CRp, 7 CRi, 4 PR). Median OS was not yet reached for pts with CRc, and was 40.7 wks for pts with PR. The 1y survival rate was 78% for pts with CRc and 50% for pts with PR. 8 of these 14 pts had detectable ITD mutation but the level was below the prespecified 10% cutoff. Conclusions: Of clinical significance in these heavily pretreated pts who had failed salvage chemotherapy or HSCT, approximately 1/3 were successfully bridged to potentially curative HSCT, with encouraging 1y survival rates. To extend the potential benefits of FLT3 inhibitor therapy in combination with allogeneic HSCT, studies of maintenance quizartinib to prevent relapse post HSCT are ongoing. Clinical trial information: NCT00989261.


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Leukemia, Myelodysplasia, and Transplantation Poster Discussion Session (Board #5), Sat, 8:00 AM-12:00 PM and 12:00 PM-1:00 PM

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Efficacy and safety of cladribine: Subcutaneous versus intravenous administration in hairy cell leukemia. Presenting Author: Tarek Yakout Mohamed, Cairo Oncology Center, Giza, Egypt

Use of tumor genomic profiling to reveal mechanisms of resistance to the BTK inhibitor ibrutinib in chronic lymphocytic leukemia (CLL). Presenting Author: Betty Y Chang, Pharmacyclics, Inc., Sunnyvale, CA

Background: Hairy cell leukemia (HCL) is rare B-cell lymphoproliferative disorder. Its treatment has evolved from splenectomy with time to failure (TTF) of 19 months to Cladribine that increased complete remission (CR) rate to 90%, with only small percentage of patients relapsing at 30 months. Cladribine (CDA) is originally administered intravenously as continuous infusion for 7 days; Subsequently, it was administered subcutaneously. This study aims at comparing efficacy and toxicity of Subcutaneous (SC) versus Intravenous (IV) administration of CDA in treatment of HCL. Methods: This retrospective study included HCL patients presented to National Cancer Institute and Nasser Institute, Cairo, Egypt, during period 2004-2010. Included patients received CDA as 1st or 2nd line with minimum follow up of 12 months. All files were reviewed for baseline clinical & laboratory parameters, route of administration, response, adverse events and survival. Results: This study included 49 eligible patients, 41 patients received CDA as 1st line treatment, while 8 patients as 2nd line. Eighteen patients were treated by continuous IV infusion whereas 31 patients by SC injections. Both groups were comparable regarding baseline clinical and laboratory parameters with no statistically significant difference. At median follow up period of 33.5 months, complete remission rate was 94% in IV group versus 97% in SC group (p⫽0.691); median TTF for IV group was 52.9 months while that for SC group was not reached (p⫽0.035). The median time to achieve CR in both arms was similar. By analyzing different factors affecting TTF using multivariate analysis, route of administration proved to be the only statistically significant factor (P⫽0.006). Regarding adverse events, there was no difference between both groups in hematological toxicities. IV route was associated with a significant higher incidence of mucositis (p⫽0.02) and viral infections (p⫽0.01). Hepatotoxicity and neurotoxicity were higher in SC group but difference was not statistically significant. Conclusions: SC administration of cladribine is an alternative route to IV in treatment of HCL with similar response rate, longer time to treatment failure and better tolerability.

Background: Ibrutinib interacts covalently with cysteine 481 of Bruton tyrosine kinase (BTK), resulting in targeted inhibition of B cell receptor signaling. Early trials of ibrutinib mono- or combination therapy enrolled 246 CLL patients receiving a median of 14 months of ibrutinib. 20 patients (8%) experienced progressive disease (PD), including 8 patients with Richter’s transformation. Here we examine changes to the CLL genome in 3 patients that acquired resistance to ibrutinib. Methods: Ibrutinib resistance was defined as patients achieving partial response (PR) or better lasting ⱖ 6 months, then developing PD without Richter’s transformation. RNAseq and whole exome sequencing (WES) followed by comparative genome analysis was performed at baseline and after PD and confirmed by Sanger sequencing. RNAseq and WES data were aligned using TopHat and BWA software. Single nucleotide variations (SNVs) were identified using SAMtools mpileup. Results: Compared to patients who relapsed from conventional chemotherapy, minimal genomic changes were acquired in ibrutinib resistant patients, reflecting relative genomic stability. SNVs were discovered in 3 patients specific to the relapse sample (Table). 2 out of 3 patients had distinct SNVs that each encode a cysteine-to-serine substitution at position 481of BTK (C481S). Homologous cysteine residues in BMX, ITK, TEC and BLK were wild-type (WT). Ibrutinib inhibited recombinant C481S 25 fold less potently than WT, and could not covalently bind C481S expressed in cells. The third patient had WT BTK, but acquired a potential gain-of-function mutation encoding a R665W substitution in PLCg2, a substrate of BTK, consistent with constitutive PLCg2 activation. Conclusions: Although rare, the acquisition of C481S BTK and R665W PLCg2 mutations in the setting of resistance confirms BTK as an important pharmacologic target of ibrutinib, and suggests mechanisms of ibrutinib resistance.

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A comprehensive prognostic index for patients with CLL. Presenting Author: Natali Pflug, Department I of Internal Medicine and Center of Integrated Oncology Cologne Bonn, University of Cologne, Cologne, Germany Background: Besides clinical staging, a number of biomarkers predicting OS in CLL have been identified. The multiplicity of markers, limited information on their independent value, and a lack of understanding of how to interpret discordant markers are major barriers to use in routine clinical practice. We developed an integrated prognostic index using the database of the German CLL Study Group (GCLLSG), which was subsequently validated in a cohort of untreated CLL patients (pts) from the Mayo Clinic. Methods: The analysis was based on a dataset collected between 1997 and 2006 in 3 GCLLSG phase III trials. The external validation was performed on a series of newly diagnosed CLL pts managed at Mayo Clinic. Results: The GCLLSG dataset (1,948 physically fit pts at early and advanced stage; median age: 60 yr (range 30-81); median observation time 63.4 mo) was used as a training dataset. 7 parameters were identified as independent predictors for OS: sex, age, ECOG status, del 17p, del 11q, IGHV mutation status, thymidine kinase and ␤2-microglobulin. By using a weighted grading a prognostic index was derived separating four different pts groups: low risk (score 0 - 2), intermediate risk (score 3-5), high risk (score 6-10) and very high risk (score 11-14) with significant different OS rates (95.2%, 86.9%, 67.7% and 18.7% OS after 5 yr for the low, intermediate, high and very high risk group respectively (p⬍0.001). This prognostic index was validated in a cohort of 676 newly diagnosed, untreated pts from the Mayo Clinic (median age 61.5 yr (range 32 - 89); median observation time 47.0 mo). The 4 risk groups were reproduced with 98.3%, 95.4%, 75.4% and 10.8% OS after 5 yr. The prognostic index predicts OS independent of Rai/Binet stage and provides accurate estimations regarding time to first treatment (TTF). C-statistic is 0.75. Conclusions: Using a multi-step process including external validation, we developed a comprehensive prognostic index combining clinical, serum, and molecular information into a single risk score for pts with untreated CLL. The prognostic index provides more accurate prediction of both TTF and OS. To our knowledge it is the first prognostic model in CLL to reach the C-statistic threshold (c ⬎ 0.70) necessary to have utility at the level of the individual.

Study

RXn

Duration Best on ibrutinib response

PCYC-04753 Ibrutinib 560 mg daily 575 days PCYC-1102 Ibrutinib 420 mg daily 581 days PCYC-1108 Ibrutinib 420 mg daily ⫹ 388 days bendamustine/rituximab x 6 cycles

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PR PR CR

Mutation C481S BTK R665W PLCg2 C481S BTK


Which treatment options impact outcomes in elderly chronic lymphocytic leukemia patients with high prevalence of comorbidity? Presenting Author: Sacha Satram-Hoang, QD Research, Granite Bay, CA Background: Therapy selection in chronic lymphocytic leukemia (CLL) patients is based on disease severity as well as patient characteristics such as age and comorbidity. While treatment outcomes are mostly available from clinical trial data in younger patients, less is known about the effect of comorbidities on outcomes in elderly CLL patients in the real-world setting. Methods: The linked Surveillance, Epidemiology, and End Results (SEER)Medicare database was utilized in this retrospective cohort analysis of 3,366 first primary CLL patients. Patients were diagnosed between 1/1/1998-12/31/2007, were ⬎66 years, continuously enrolled in Medicare Part A and B with no HMO coverage in the year prior to diagnosis and received first-line treatment with any oral or infused therapy. CLB is covered by Medicare Part D and data for its use were only available from 2007-2009 in the dataset. Cox regression with backward elimination and propensity score weighted Cox regression estimated the relative risk of death. Date of last follow-up was 12/31/2009. Results: There were 153 CLB, 606 R-mono, 702 R⫹IV Chemo, and 1,905 IV Chemo-only patients. CLB and R-mono patients were older at diagnosis with mean age of 77 compared to R⫹IV Chemo (73 years) and IV Chemo-only (76 years; p⬍.0001). Patients administered R-mono had a higher comorbidity burden and more advanced disease compared with other treatment groups. In the survival analysis we compared CLB to R-mono during the time period 2007-2009 and R⫹IV Chemo to IV Chemo-only during the time period 1998-2009. The adjusted multivariate survival analysis revealed a significant mortality risk reduction with R⫹IV Chemo compared with IV Chemoonly patients (HR, 0.72; 95% CI, 0.62-0.84) while a non-significant mortality risk reduction was noted with R-mono compared to CLB patients (HR, 0.47; 95% CI, 0.21-1.05). Older age and increasing comorbidity score were significantly associated with higher mortality. Conclusions: These findings suggest that chemo-immunotherapy is more effective than chemotherapy in an elderly population with a high prevalence of comorbidity. This extends the conclusions from clinical trials in younger, medically fit patients.




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Update on a phase I study of the selective PI3K␦ inhibitor idelalisib (GS-1101) in combination with rituximab and/or bendamustine in patients with relapsed or refractory CLL. Presenting Author: Jacqueline Claudia Barrientos, Hofstra North Shore-LIJ School of Medicine, Hyde Park, NY

Updated results of a phase I first-in-human study of the BCL-2 inhibitor ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presenting Author: John Francis Seymour, Peter MacCallum Cancer Center, Melbourne, Australia

Background: PI3K-delta signaling is critical for proliferation, survival, homing and tissue retention of malignant B cells. Idelalisib is a first-inclass, selective, oral inhibitor of PI3K␦ that has shown considerable monotherapy activity in pts with heavily pretreated CLL. Methods: This phase I study evaluated idelalisib continuously given at 150 mg BID in combination with rituximab (R, 375 mg/m2 every wk x 8), bendamustine (B, 70 or 90 mg/m2 x 2, every 4 wks x 6) or BR (every 4 wks x 6) for relapsed/refractory CLL. Pts still on treatment after 48 weeks were eligible to continue idelalisib on an extension study. Clinical response was evaluated according to published criteria (Hallek 2008; Cheson 2012). Results: 52 pts (23F/29M) with a median (range) age of 64 (41-87) years were enrolled. Adverse disease characteristics included bulky lymphadenopathy (62%), refractory disease (50%), multiple prior therapies (median 3, range: 1-14) with 96% receiving prior R and 44% receiving prior B. As of 14 Jan 2013, the median (range) treatment duration was 18 (1-33) months. 31/52 (60%) pts enrolled into the extension study; of those, 24/52 (46%) pts are continuing idelalisib treatment on the extension study. The ORR was 81%, with 1 CR, and a median (range) time to response of 1.9 (1.5-8.3) months. The 2-year PFS and OS were 62% and 85%, respectively. At 2 years follow up, 71% of responses were still enduring. There was no difference in outcomes for pts with ⬍3 prior treatments (n⫽21) vs ⱖ3 prior treatments (n⫽31). The most common TEAEs (any Grade/ⱖGr 3, independent of causality) included pyrexia (44%/6%), diarrhea (40%/14%), cough (31%/2%), fatigue (29%/2%), nausea (29%/0%). Pneumonia (any Gr/ⱖGr 3) occurred in 15%/12% and rash was seen in 15%/0%. 10% of patients experienced ⱖGr 3 ALT/AST elevation based on laboratory values. Conclusions: A lack of overlapping toxicities allowed idelalisib to be co-administered with R, B, or BR, and all 3 combination regimens were highly active, resulting in durable tumor control in pts with heavily pretreated relapsed/refractory CLL. Phase III trials evaluating the efficacy of idelalisib in combination with R or BR are ongoing. Clinical trial information: NCT01088048.

Background: Targeting BCL-2 is a promising strategy for treating CLL, including disease refractory to fludarabine (F), or with (del(17p). ABT-199 is a selective BCL-2 inhibitor with ⬎500-fold higher affinity for BCL-2 (Ki⬍0.10 nM) than for BCL-XL (Ki⫽48 nM). Methods: Objectives of this Ph I dose-escalation study include evaluations of safety, pharmacokinetics and preliminary efficacy of ABT-199 in patients (pts) with R/R CLL. A single oral dose was given followed by 6 days off drug, before continuous once daily dosing. After cohort 1, the initial dose was reduced and daily dosing modified to include a 2 or 3 step dose-escalation to the target dose for each cohort. Results: As of January 11, 2013, 56 pts have been enrolled; median age 67 y (range 36-86); 41 males; median 3.5 prior therapies (range 1-10). 16 (29%) had del(17p) and 18 (32%) F-refractory CLL. Median follow up is 6.3 months (range 0.03-16.5); 7 pts have been on study for more than 1 yr. 13 pts discontinued; 7 due to PD, 6 for other reasons: tumor lysis syndrome (TLS; 2), other illness (2), thromboembolic event (1), consent withdrawal (1). The most common non-hematological AEs (⬎15% pts) were nausea (36%), diarrhea (30%), fatigue (25%), upper respiratory tract infection (23%), and cough (16%). Grade 3/4 AEs occurring in ⬎ 5 pts were neutropenia 21(38%), thrombocytopenia 6 (11%) and TLS 5 (9%). TLS occurred in 3/3 pts in cohort 1 and 2/53 pts with the modified stepped dosing schedule (DLTs). Additionally, 1 fatal AE occurred within 48 hrs of dose-escalation to 1200 mg in a pt with laboratory evidence of TLS (DLT). 46 of 54 pts (85%) evaluable for efficacy achieved a response to ABT-199; 7 (13%) a CR or CR with incomplete count recovery and 39 (72%) a PR (30 confirmed by consecutive scans). 14/16 (88%) and 12/16 (75%) of pts with del(17p) and F-refractory CLL, respectively, achieved at least a PR. Conclusions: ABT-199 is highly active achieving a 85% overall response rate in R/R CLL, independent of high risk markers such as del(17p) and F-refractory disease. Additional dosing and scheduling modifications are currently being explored to minimize the risk of TLS. Clinical trial information: NCT01328626.

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Aberrant NFAT2 signaling in chronic lymphocytic leukemia. Presenting Author: Jonas S. Heitmann, Department of Hematology, Oncology and Immunology, University of Tuebingen, Tuebingen, Germany Background: CLL is a malignancy of mature B cells and constiututes the most common leukemia in adults. It is characterized by a progressive accumulation of clonal B cells, which coexpress CD19, CD23 and CD5. NFAT is a family of highly phosphorylated transcription factors residing in the cytoplasm of resting cells. Upon dephosphorylation by calcineurin, NFAT proteins translocate to the nucleus where they orchestrate developmental and activation programs in diverse cell types. In this study, we investigated the significance of NFAT signaling in B-CLL. Methods: NFAT2 expression and aberrant nuclear translocation in CLL cells (n⫽30) was assessed by Western Blotting and immunofluorescence. In addition, NFAT2 mRNA levels were measured by qRT-PCR and its DNA binding capacity was assessed using an electrophoretic mobility shift assay. Transcriptional activity of NFAT2 proteins in CLL cells was further analyzed by determining the expression of several well characterized NFAT target genes. Results: We detected a profound overexpression of NFAT2 mRNA and protein in all CLL samples. Using qRT-PCR we found that CD19⫹CD5⫹ CLL cells exhibited a significant overexpression of NFAT2 as compared to CD19⫹ B cells isolated from healthy donors (8-200fold). This overexpression of NFAT2 in CLL cells could also be confirmed on the protein level. We could further demonstrate that even under resting conditions significant amounts of NFAT2 protein had translocated to the nucleus in CLL cells, whereas virtually all NFAT2 was in the cytoplasm in non-malignant B cells. Nuclear NFAT2 in CLL cells was able to bind DNA but its transcriptional activity with respect to several apoptosis-regulating genes (i.e. Spp1, Pdcd1) was severely compromised. Conclusions: These results provide strong evidence that the Ca2⫹/NFAT signalling axis is constitutively activated in CD5⫹CD19⫹ CLL cells. Reduced expression of several apoptosis regulators which are known target genes of NFAT2 links deregulation of this signaling cascade to CLL progression. Further investigation is warranted to investigate the therapeutic potential of modulating Ca2⫹/ Calcineurin/ NFAT signaling in CLL.


Immunopharmacodynamic response to blinatumomab in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). Presenting Author: Andrea Schub, Amgen Research (Munich) GmbH, Munich, Germany Background: Blinatumomab is an anti-CD19/anti-CD3 bispecific T cell engager (BiTE) that induces target cell-dependent, polyclonal T cell activation and proliferation, resulting in redirected lysis of CD19⫹ target cells. Methods: In a phase 2 study, adult patients (N⫽36) with relapsed/ refractory B-precursor ALL received continuous blinatumomab IV infusion for 28 days in ⱕ5 treatment/consolidation cycles. Whole blood and serum samples were collected throughout treatment and analyzed for lymphocyte subpopulations, cytokines, granzyme B, and blinatumomab serum concentrations. Results: Lymphocytes in all patients responded in a similar fashion. After infusion start, peripheral B cell counts dropped to ⱕ1 B cell/␮L in ⬍1 week and remained undetectable throughout treatment. Peripheral T cells showed a redistribution characterized by swift disappearance within the first 2-6 hrs and subsequent recovery to baseline within several days. Otherwise, T cell counts remained at least stable in most patients. In some patients even an expansion of the T cell compartments was observed, most likely due to specific proliferation of activated T cells but could not be defined as prerequisite for treatment efficacy. During the first infusion days, a significant proportion of T cells newly expressed the activation marker CD69, and the T cell effector molecule granzyme B was detectable in serum. Additionally, a transient cytokine release dominated by IL-10, IL-6 and IFN-␥ was observed in most patients shortly after first infusion start, which was alleviated or absent in subsequent cycles. Blinatumomab serum steady state concentrations (mean⫾SD) were 198⫾61 pg/mL and 694⫾236 pg/mL at doses of 5 and 15 ␮g/m²/d, respectively, which is comparable to those from previous studies. Conclusions: Immunopharmacodynamic response to blinatumomab was characterized by B cell depletion, T cell activation and redistribution, and release of granzyme B and cytokines, suggesting T cell engagement according to the expected BiTE mode of action. The tested pharmacodynamic markers did not allow for predictive differentiation between patients achieving a hematologic response and those who did not. Clinical trial information: NCT01209286.


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Effect of quizartinib (AC220) on response rates and long-term survival in elderly patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia. Presenting Author: Giovanni Martinelli, Seragnoli Institute of Hematology, Bologna University School of Medicine, Bologna, Italy Background: Advanced age and FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Quizartinib (AC220), an oral FLT3 inhibitor active against ITD mutant and wild type FLT3, has shown promising activity in Ph 1 and 2 studies. Methods: Patients (pts) in a Ph 2 open label study (N ⫽ 333) of quizartinib monotherapy included 154 aged ⱖ60 y with known FLT3-ITD status and AML relapsed in ⬍1 y or refractory to 1st line chemotherapy. Median duration of treatment was 14.2 wks (range 0.1–70.6 wks) for FLT3-ITD(⫹) pts and 9.5 wks (range 1.1–77.0 wks) for FLT3-ITD(-) pts. The composite complete remission (CRc) rate included complete remission (CR), complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete hematologic recovery (CRi). Results: Of 110 FLT3-ITD(⫹) pts, 63 (57%) had a CRc (3 CR, 4 CRp, 56 CRi). Of 44 FLT3-ITD(-) pts, 16 (36%) had a CRc (2 CR, 1 CRp, 13 CRi). Median overall survival (OS) in FLT3-ITD(⫹) pts was 25.3 wks and 16/110 (15%) survived ⬎52 wks. The median age of these pts surviving ⬎52 wks was 69.5 y (range 66 – 80 y) and median OS was 76.3 wks (range 56.9 –96.0 wks). All of these pts responded to quizartinib (2 CR, 2 CRp, 8 CRi, 4 partial remission [PR]). 2 pts were still alive ⬎1 ½ y (OS 93.0 and 96.0 wks). Median OS in FLT3-ITD(-) pts was 19.1 wks and 6/44 FLT3-ITD(-) pts (14%) survived ⬎52 wks. The median age of these pts was 70.0 y (range 65–77 y) and their median survival was 76.6 wks (range 54.9 –98.4 wks). 5 of these pts responded to quizartinib (1 CR, 3 CRi, 1 PR). Conclusions: These data for an FLT3-targeted agent show encouraging survival in a subset of elderly pts with relapsed/refractory FLT3-ITD(⫹) AML. Clinical trial information: NCT00989261. Efficacy in elderly relapsed/refractory AML pts.

Cumulative CRc, n (%) CRcⴙPR, n (%) Median CRc duration, wk (95% CI) Median overall survival, wk (95% CI)

FLT3-ITD(ⴙ) (Nⴝ110)

FLT3-ITD(-) (Nⴝ44)

63 (57) 86 (78) 12.1 (6.3, 15.7) 25.3 (21.3, 30.0)

16 (36) 20 (56) 10.8 (8.1, 26.1) 19.1 (12.0, 29.4)

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BH3 profiling as a predictive biomarker for response to cytarabine-based treatment of acute myelogenous leukemia. Presenting Author: William E. Pierceall, Eutropics, Inc., Cambridge, MA Background: Acute myelogenous leukemia (AML) is the most frequently diagnosed of the leukemias with approximately 13,000 new cases per year in the U.S. Although intense therapeutic discovery efforts have been directed towards AML, cytarabine-based treatment remains unchanged as the standard-of-care (SOC). As patient response to SOC is variable, segregating patients based on biomarker-driven predicted response may lead to improved clinical outcomes. One personalized diagnostic approach that may provide actionable information in patient management is BH3 profiling, a surrogate functional biomarker assay that assesses cell mitochondrial response to pro-apoptotic signaling. Methods: Blinded to outcomes, we profiled an AML cohort (n⫽63) treated with cytarabine-based therapy using a panel of BH3 peptides with response as a primary endpoint. Peripheral blood mononuclear cell (PBMC) or bone marrow aspirate (BM) specimens were obtained from newly diagnosed AML patients and viably preserved. Specimens were assayed by flow cytometry following cell permeabilization and incubation with potentiometric JC-1 mitochondrial dye and individual BH3 peptides. Results: Mann-Whitney analysis indicates BH3 profiling biomarkers are correlated with response to induction therapy. Among BH3 peptides, BIM was highly significant (p⫽2X10-6; CI[0.73,0.94]) with a notable sensitivity/specificity profile (AUC⫽0.84; p⫽2X10-10). Multivariate analysis indicates improved profiles for BIM ⫹ patient age (AUC⫽0.89; CI[0.81,0.97])and BIM ⫹ patient age ⫹cytogenetic status (AUC⫽0.91; CI[0.83,0.98]). When patients were stratified by cytogenetic status, BIM was significant for both intermediate (p⫽0.0017; AUC⫽0.88; CI[0.71,1.04]) and unfavorable (p⫽0.016; AUC⫽0.80; CI[0.60,1.00]), demonstrating that the predictive power of the assay is independent of cytogenetics. Conclusions: Here, BH3 profiling predicts patient response to cytarabine-based treatment regimens with accuracies of 90%. Thus, patients may potentially benefit from being given alternate therapies while at the same time spared the toxicities, cost, and time lost associated with a therapy less likely to exhibit response.

Abbreviations: CRc ⫽ composite complete remission; PR ⫽ partial remission.

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Efficacy and safety of quizartinib (AC220) in patients age > 70 years with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia (AML). Presenting Author: Alexander E. Perl, University of Pennsylvania, Philadelphia, PA Background: Advanced age and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in AML are each associated with early relapse after standard chemotherapy and poor survival. Quizartinib, an oral FLT3 inhibitor active against ITD mutant and wild type FLT3, has shown promising activity in Ph 1 and 2 studies. Methods: We provide detailed analysis from a Ph 2 study (N ⫽ 333) of quizartinib monotherapy, focusing on patients (pts) aged ⱖ 70 y with AML that relapsed and/or was refractory to prior therapy. Results: A total of 83 pts age ⱖ70 y included 60 (72%) FLT3-ITD(⫹) and 23 (28%) FLT3-ITD(-). Median duration of treatment was 14.6 wks for FLT3-ITD(⫹) pts and 5.9 wks for FLT3-ITD(-) pts. Composite complete remission (CRc) rate included complete remission (CR), complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete hematologic recovery (CRi). Of 60 FLT3-ITD(⫹) pts, 32 (53%) had a CRc (1 CR, 3 CRp, 28 CRi). Of 23 FLT3-ITD(-) pts, 10 (43%) had a CRc (2 CR, 1 CRp, 7 CRi). 12/27 FLT3-ITD(⫹) pts (44%) and 5/10 FLT3-ITD(-) pts (50%) refractory to prior therapy responded to quizartinib, and 12/83 (14%) survived ⬎1 y. The most common (ⱖ10%) Grade 3 or 4 treatment-related adverse events (TRAEs) were febrile neutropenia (22%), anemia (20%), transient QT interval prolongation (17%; no Grade 4), and thrombocytopenia (12%). 15 pts (18%) had TRAEs resulting in discontinuation. Conclusions: Because AML in the elderly, particularly in those aged ⱖ70 y, is genetically heterogeneous and often follows a myelodysplastic syndrome, there is a wide assumption that it may be less amenable to FLT3-targeted therapy than AML in younger pts. Our data argue against these conclusions and show that pts aged ⱖ70 y with chemotherapy-resistant AML have preserved high response rates, and promising survival to quizartinib. Clinical trial information: NCT00989261. Efficacy in relapsed/refractory AML pts > 70 Y. FLT3-ITD(ⴙ) (Nⴝ60) FLT3-ITD(-) (Nⴝ23) Cumulative CRc, n (%) CRcⴙPR, n (%) Median CRc duration, wk (95% CI) Median overall survival, wk (95% CI)

32 (53) 41 (68) 13.9 (8.0, 16.5) 21.0 (17.0, 25.4)

10 (43) 12 (52) 8.3 (4.1, 26.1) 19 (7.6, 28.9)

Abbreviations: CRc, composite complete remission; PR, partial remission.

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Phase II study of combination of hyperCVAD with ponatinib in frontline therapy of patients (pts) with Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (ALL). Presenting Author: Elias Jabbour, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Combination of chemotherapy with TKIs was evaluated and appears to be effective in Ph⫹-ALL. Ponatinib is a more potent inhibitor and suppresses the T315I clones, a common cause of relapse in pts with Ph⫹- ALL. Clinical trials of ponatinib have demonstrated its high activity and limited toxicity in pts with Ph⫹-leukemia failing 2-3 TKIs and in those with a T315I mutation. Combinations of chemotherapy regimens and ponatinib may be associated with better response rates and higher likelihood of eradication of MRD. Methods: In this phase II trial, pts with newly diagnosed Ph⫹ ALL receive ponatinib 45 mg po QD for the first 14 days of cycle 1 then continuously for the subsequent 7 cycles. Pts in CR receive maintenance with ponatinib 45 mg po QD and vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. MRD monitoring is conducted. Results: To date 20 pts with untreated Ph⫹ ALL have received a median of 6 cycles; 5 pts are receiving maintenance in CR. Median age is 49 years. Median WBC at diagnosis was 2.45 x 109/L. All pts were in CR after 1 cycle. 15 of the 17 pts (88%) known to be Ph⫹ by cytogenetic analysis at baseline achieved CCyR after 1 cycle; 1 had mCyR only and 1 had no cytogenetic analysis at CR, both of them achieved CCyR after cycles 2; 3 had a diploid karyotype at the start. To date, 17 pts (85%) have achieved MMR, of whom 11 (55%) have achieved CMR at a median of 10 weeks from initiation of treatment. MRD assessment by flow cytometry is negative in 18 (90%) pts at a median of 3 weeks. Median time to neutrophil and platelet recovery for cycle 1 was 18 and 22 days, and 16 and 22 days for subsequent cycles, respectively. Grade ⱖ3 toxicity included increase of LFT’s/hyperbilirubinemia in 8 pts, thrombosis in 3, skin rash in 2, pancreatitis in 1, and pericardial effusion in 1. With a median follow up of 6 months, 19 pts are alive and in CR; 1 pt died in CR from an unrelated cardiac event. 1 pt has undergone an allogeneic transplant. The 1-year PFS and OS rates were 100% and 95%, respectively. Conclusions: The combination of hyperCVAD with ponatinib is safe and highly effective in achieving molecular remissions in pts with Ph⫹ ALL. Clinical trial information: NCT01424982.




Rate of complete hematological response of elderly Phⴙ acute lymphoblastic leukemia (ALL) patients by sequential use of nilotinib and imatinib: A GIMEMA protocol LAL 1408. Presenting Author: Cristina Papayannidis, Institute of Hematology, Bologna, Italy Background: We have explored if the administration of two TKIs, Nilotinib (NIL) and Imatinib (IM) can improve the results without increasing the toxicity in the elderly Ph⫹ Acute Lymphoblastic Leukemia (ALL) patients. We investigate the type and number of BCR-ABL kinase domain mutations developing during and after the study. Methods: We have designed a study (ClinicalTrials.gov. NCT01025505) in which patients more than 60 years old or unfit for intensive chemotherapy and SCT where treated with two TKIs, NIL 400 mg twice daily, and IM 300 mg twice daily, alternating for 6 weeks for a minimum of 24 weeks (study core) and indefinitely in case of response. The 6-weeks rotation schedule was respected, irrespectively of temporary discontinuations. The primary end-point was the rate of Disease Free Survival (DFS) at 24 weeks (4 courses of treatment); the secondary end points included the evaluation of CHR, CCgR and CMR rates. Results: 39 patients have been enrolled in 15 Italian hematologic Centers (median age 66 years, range 28-84). Among these, 8 patients were unfit for standard chemotherapy or SCT (median age 50 years, range 28-59). 27 patients were p190, 5 were p210 and 7 were p190/p210. After 6 weeks of treatment, 36 patients were evaluable for response: 34 were in CHR (94%) and 2 in PHR (6%). 23 patients have already completed the study core (24 weeks), 87% were in CHR and 17 are currently continuing therapy in the protocol extension phase. Thus, the OS at 1 year is 79%, and 64% at 2 years. Overall, 1 patient was primarily resistant and 13 patients have relapsed, with a median time to relapse of 7.6 months (range 0.8-16.1 months), for a DFS of 51.3% at 12 months. Conclusions: In this small cohort of Ph⫹ ALL elderly/unfit patients, the rates of relapse and progression were not likely to be different from the rates observed with Imatinib alone. Acknowledgements: ELN, AIL, AIRC, PRIN. Clinical trial information: NCT01025505.

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Variations in FLT3 ligand levels during the course of AML treatment. Presenting Author: Michael Richard Grunwald, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD Background: FLT3 ligand (FL) is a hematopoietic growth factor expressed in many tissues. AML patients who are administered myeloablative therapy exhibit a marked and transient rise in plasma FL concentrations. Furthermore, the presence of high concentrations (1000 pg/mL) of FL impedes the efficacy of FLT3 tyrosine kinase inhibitors in vitro. However, the behavior of FL concentrations throughout the course of AML treatment remains unknown. This pilot study was undertaken to track the relationship between AML therapy and FL levels over time. Methods: Ten AML patients were enrolled in an IRB-approved procurement protocol. Blood samples were collected at weekly intervals for one year, and plasma was isolated by centrifugation. Plasma FL and stem cell factor (SCF) concentrations were measured by ELISA. Results: We observed four distinct patterns in FL fluctuations. First, in all cases where induction or consolidation chemotherapy resulted in an aplastic bone marrow (nine patients), FL concentrations rose markedly and consistently to levels ⬎1000 pg/mL following the administration of chemotherapy. Second, in three of four patients whose leukemia was refractory to induction chemotherapy, FL concentrations remained below 500 pg/mL during induction. Third, in two patients receiving the FLT3 TKI sorafenib, FL concentrations did not rise above 500 pg/mL while on this medication. Fourth, in one patient receiving the hypomethylating agent 5-azacitidine, FL concentrations remained below 100 pg/mL throughout the course of therapy. SCF concentrations did not vary throughout the course of chemotherapy. Conclusions: An “FL surge” was seen when cytotoxic chemotherapy resulted in aplasia. This FL surge was not seen with sorafenib or 5-azacitidine. In addition, the FL surge was attenuated in three patients whose leukemia was refractory to chemotherapy. These observations give rise to two new hypotheses regarding FL: 1) It is possible to maintain lower FL levels with targeted agents than with chemotherapy; and 2) Residual leukemia appears to inhibit the FL surge, providing indirect evidence of cross-talk between leukemia and the stromal microenvironment. This inhibition may be the explanation for why AML patients develop pancytopenia early in relapse.

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Use of Axl, a therapeutic target in AML, to mediate stroma-induced chemoresistance. Presenting Author: Isabel Ben Batalla, II. Medical Clinic & Institute of Tumor Biology, Campus Forschung, University Hospital Hamburg-Eppendorf, Hamburg, Germany

SWOG S0919: A phase II study of idarubicin and cytarabine in combination with pravastatin for relapsed acute myeloid leukemia (AML). Presenting Author: Anjali S. Advani, Cleveland Clinic Taussig Cancer Institute, Leukemia Program, Cleveland, OH

Background: Axl, the receptor for Growth Arrest-specific protein 6 (Gas6) plays a role in AML pathobiology (Blood Suppl. Nov 2011; 118: 940). Here, we investigated whether Axl represents a therapeutic target in AML. Methods: Gas6 levels were measured by ELISA and immunohistochemistry. Axl expression was detected by flow cytometry. Co-cultures of (murine) BM stroma cells (primary, OP9, S17) with Mv4-11 and OCI-AML5 cell lines were performed. Results: We found (i) higher expression of Axl in AML BM compared to healthy BM donors (66.20 ⫾ 10.87 vs. 0.65 ⫾ 0.10 %; n⫽8/6; p⬍0.05); (ii) Axl expression by 68 ⫾ 31% of AML blasts and (iv) higher expression of Axl by CD34⫹CD38- AML stem cells compared to healthy CD34⫹CD38- BM stem cells (58.43 ⫾ 4.63 % vs. 6.00 ⫾ 2.01 %; n⫽7/6; p⬍0.05). The Axl inhibitor BGB324 dose-dependently inhibited proliferation of primary AML cells with a mean IC50 of 1.8 ␮M. Sensitivity to BGB324 (i.e. a lower IC50) correlated with Axl expression on leukemia cells (Pearson’s r ⫽ -0.9656, p⬍0.05). Combination therapy with BGB324 and cytarabine exerted an additive therapeutic effect and BGB324 could chemosensitize cytarabine-resistant AML cells. Analyses of BM sections revealed that Gas6 expression was low in AML cells, similar to healthy hematopoietic cells while it was abundantly expressed in AML BM stromal cells with fibroblastic/mesenchymal morphology (BMDSCs). Gas6 expression was considerably lower in control BMDSCs (86 ⫾ 14 % vs. 20 ⫾ 20 %; n⫽5/7; p⬍0.05) thus suggesting a possible paracrine interaction between AML cells and BMDSCs leading to Gas6 upregulation in the stroma compartment. Co-culture experiments indicated specific upregulation of murine (m)Gas6 in BMDSCs via leukemia-cell derived IL-10 and M-CSF. This stroma-derived Gas6 could mediate chemoresistance of AML cells in co-culture, which was abrogated by sAxl or by BGB324. Thus, interaction between stroma-derived Gas6 and Axl⫹leukemia cells forms a chemoprotective niche for leukemia cells. In line with these findings Axl blockade chemosensitizes Mv4-11 cells for treatment with doxorubicine in vivo. Conclusions: Axl represents a therapeutic target in AML and Axl inhibition by BGB324 holds potential to treat chemosensitive and chemoresistant AML.

Background: Inhibition of cholesterol synthesis and uptake sensitizes AML blasts to chemotherapy (Blood 104: 1816, 2004). A prior Phase 1 study demonstrated the safety of high dose pravastatin given with idarubicin and cytarabine in patients with AML and also reported an encouraging response rate (Blood 109: 2999, 2007). SWOG S0919 therefore evaluated the complete remission (CR) rate in a larger number of pts with relapsed AML treated with the pravastatin dose arrived at in the Phase 1 trial. Methods: Pts were treated at SWOG institutions from Aug 2009 through Nov 2012. Pravastatin was supplied by Bristol-Meyers Squibb. The protocol was approved by each institution’s review board. Eligibility: age ⱖ 18 yrs, relapsed AML, cardiac ejection fraction ⱖ 45%, CR/ CR with incomplete count recovery (CRi) following most recent chemotherapy lasting ⱖ 3 months, no prior hematopoietic cell transplant. Treatment: oral pravastatin 1280 mg Days 1-8, idarubicin 12 mg/m2/d IV Days 4-6, and cytarabine 1.5 g/m2/d continuous IV infusion Days 4-7. Pts achieving a CR could receive 2 cycles of consolidation. CR and CRi were defined by IWG criteria. Fifty eligible pts were to be accrued. If ⱖ 21 pts achieved CR or CRi, the regimen would be considered sufficiently effective (critical level ⫽ 4.8% if true CR rate ⫽ 30% and power of 90% if true CR rate ⫽ 50%). Results: The study closed to accrual on Nov 1, 2012 after meeting the defined criterion for a positive study. Thirty-six pts with a median age of 59 yr (range 23-78) were enrolled. Seventeen pts (47%) were male and the median WBC was 2800/ uL (range 700-110,600). The median time from initial dx to registration was 18 mo (range 5-136). Relapse status: 1st: 17 pts (47%), 2nd: 15 (42%), 3rd: 2 (5.5%), and 4th: 2 (5.5%). Eighteen pts have died, 3 during treatment. The response rate was 75% (95% CI 58-88%; 20 CR, 7 CRi); and the median overall survival was 10 mo. The p-value comparing 75% to 30% (null response rate) is 3.356 x 10-8. Duration of last CR (ⱕ 6 months) and prior high dose cytarabine exposure did not affect response to protocol treatment. Conclusions: The CR/ CRi in this relapsed population is encouraging. We plan to evaluate the efficacy of this regimen in higher-risk patients. Clinical trial information: NCT00840177.


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Activity and tolerability of SL-401, a targeted therapy directed to the interleukin-3 receptor on cancer stem cells and tumor bulk, as a single agent in patients with advanced hematologic malignancies. Presenting Author: Arthur E. Frankel, Scott & White Cancer Research Institute, Temple, TX Background: SL-401 is a novel biologic targeted therapy directed to the interleukin-3 receptor (IL-3R). IL-3R is overexpressed on cancer stem cells (CSCs) and tumor bulk relative to normal hematopoietic cells in a wide range of hematologic malignancies including AML and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Since SL-401 targets both leukemia blasts and CSCs, tumor regression and improvement in long-term outcome is expected. The clinical activity and side effect profile of SL-401 were evaluated in a multicenter Phase I/II trial of patients with advanced hematologic cancers. Methods: Eighty-one patients with advanced hematologic cancers, including relapsed or refractory AML (n ⫽ 59) and heavily pretreated BPDCN (n ⫽ 4), have been enrolled. Patients received a single cycle of SL-401 via 15-minute IV infusion to determine the maximum tolerated dose (MTD) and assess antitumor activity. Results: A single cycle of SL-401 demonstrated single agent activity in relapsed or refractory AML patients, including 2 durable CRs of 8 and 25⫹ months duration and multiple cases of blast reductions. SL-401, when delivered at therapeutically relevant doses, was associated with ⬎ 3-fold greater median overall survival (OS) in AML patients who received 2⫹ prior lines of treatment relative to historical results. In addition, 3 heavily pre-treated patients with BPDCN, an uncommon malignancy that expresses high levels of IL-3R and is ultrasensitive to SL-401 (IC50 values in the femtomolar [10-15 M] range), had CRs, with durations of 5, 3⫹ and 1⫹ months. The MTD was 16.6 ␮g/kg/day; the dose-limiting toxicities of hypoalbuminemia and edema, which are manifestations of capillary leak, occurred at 22.1 ␮g/kg/day. Other ⱖ Grade 3 adverse events included transient transaminase elevations. There was no treatment-related myelosuppression. Conclusions: SL-401 was well tolerated and demonstrated single agent activity in patients with relapsed or refractory AML and BPDCN. Based on these findings, single agent SL-401 given in multiple cycles will be advanced into pivotal studies of AML (3rd-line) and BPDCN. Clinical trial information: NCT00397579.

7031


Phase II study of orally administered rigosertib (ON 01910.Na) in transfusion-dependent lower-risk myelodysplastic syndrome (MDS) patients. Presenting Author: Azra Raza, Columbia Presbyterian Medical Center, New York, NY Background: Rigosertib, a novel small molecule inhibitor of PI3-Kinase and PLK pathways is currently evaluated (IV infusions) in a phase III trial in higher risk MDS patients who have failed hypomethylating agents. A previous phase I study found good bioavailability and activity of orally administered rigosertib in transfusion-dependent MDS patients (ASH 2011). Here we report preliminary results from an ongoing phase II study. Methods: This is a randomized, two-arm study of oral rigosertib (560 mg bid) administered either intermittently (2 out of 3 weeks) or continuously. Transfusion-dependent patients must have received at least 4 units RBC transfusions over 8 weeks before randomization, and can receive transfusions and erythrocyte stimulating agents (ESAs) while on study. Results: Twenty nine MDS patients (25 intermediate-1 and 4 low risk per IPSS classification) have been randomized as of December 17, 2012. Overall oral rigosertib was well tolerated except for a high incidence (5 of 9 patients) of grade 2⫹ urinary side effects (dysuria, hematuria, cystitis, and urinary urgency), in the continuous dosing arm. Accordingly, the protocol was amended to allow all patients to be treated with intermittent dosing, with option of dose interruption/reduction resulting in a much lower frequency of urinary side effects (4/20 patients with urinary grade 2⫹ toxicity). Fifteen patients (none of them with del5q cytogenetic) have been treated with intermittent dosing for at least 8 weeks. Seven (47%) patients achieved transfusion independence (no RBC transfusion for at least 8 consecutive weeks), which lasted 8 to 27 ⫹ weeks. Six of 7 responding patients were refractory to prior treatment with ESAs and 5 of these 7 patients received concomitant ESAs, suggesting an effect of rigosertib on ESA resistance. Conclusions: Preliminary results of this phase II study indicate that intermittent dosing of rigosertib administered orally is well tolerated and active in producing transfusion independence in approximately 50% transfusion dependent, lower risk MDS patients. The contributing role of rigosertib and ESAs in these transfusion responses is being investigated. Clinical trial information: NCT01584531.

7030


Exploratory analysis of the effect of ruxolitinib on bone marrow morphology in patients with myelofibrosis. Presenting Author: Hans-Michael Kvasnicka, University of Frankfurt, Frankfurt, Germany Background: Myelofibrosis(MF) is characterized by splenomegaly, burdensome symptoms, progressive bone marrow (BM) fibrosis, and shortened survival. Ruxolitinib (Rux), an oral, FDA-approved JAK1/JAK2 inhibitor, has demonstrated improvements in spleen volume, symptoms, and survival in patients (pts) with MF. This study was conducted to explore possible effects of long-term Rux treatment on BM morphology in MF. Methods: Trephine biopsies were obtained at baseline, 24 (67 pts), and 48 (17 pts) months (mo) from the cohort of MF patients treated at MD Anderson Cancer Center who participated in a phase I/II trial of Rux (NCT00509899). The clinical outcomes from this trial have been published previously [Verstovsek, NEJM 2010]. Two of the authors (JT and HMK) independently evaluated the World Health Organization (WHO)-defined BM fibrosis grade (0-3). Reviewers were blinded to pts characteristics and outcomes and consensus decided discordant scores. For demonstrative purposes, WHO BM fibrosis grading was also determined for a control cohort of pts treated with hydroxyurea (HU) for 24 (31 pts) and 48 (20 pts) mo. Changes in BM fibrosis grade vs. baseline were calculated for 24 and 48 mo, and categorized as improvement, stabilization, and worsening for each patient. Results: A higher percentage of Rux-treated pts showed stabilization or improvement of BM fibrosis at both 24 and 48 mo than the HU-treated pts. Worsening was greater in the HU-treated cohort at both time points. Conclusions: This exploratory analysis of long-term exposure to Rux in MF provides the first indication that JAK inhibitor therapy may be able to meaningfully retard advancement of BM fibrosis. A comparable effect was not seen with long-term HU therapy. Additional research is needed to further elucidate these findings. Clinical trial information: NCT00509899. Direction of changes in 24 mo 48 mo WHO-defined BM fibrosis grade versus baseline* HU Ruxolitinib HU Ruxolitinib No. of pts Stabilization Improvement

31 52% 10%

67 57% 15%

20 35% 0%

17 53% 24%

No. of pts† Worsening

23 52%

50 38%

17 76%

15 27%

* Not a formal comparison. †Pts with baseline BM fibrosis grade 3 were excluded from this calculation because they could only stabilize or improve.

7032


The origin of GPI-AP deficient cells in MDS, MPD, and aplastic anemia and its significance in predicting leukemic transformation. Presenting Author: Jeffrey J. Pu, Penn State Hershey Cancer Institute, Hershey, PA Background: PNH is a clonal disorder originating from a multipotent hematopoietic stem cell (HSC) acquiring a PIG-A gene mutation. PIG-A mutation lead to glycosylphosphatidylinositol-anchor protein (GPI-AP) deficiency, which contributes to many manifestations of PNH. About 25% of MDS and MPD, and 60% of AA also harbor small population of PNH-like cells. It was observed that 1) 10-20% AA harboring PNH-like cells eventually transform into PNH; but MDS and MPD seldom evolve to PNH; 2) AA harboring PNH-like cells may have a better response to immunosuppressive therapy; and 3) PIG-A mutation frequency significantly increased in some human cell lines with genomic instability. However, the clinical significances of these PNH-like cells in MDS, MPD, and AA are unclear. Methods: We prospectively recruit MDS, MPD, and AA patients. Peripheral blood flow cytometry is used to identify GPI-AP deficient blood cells, a proaerolysin-resistant CFC assay is used to select GPI-AP deficient progenitor cells, a novel T cell enrichment assay with proaerolysin selection is used to expand GPI-AP deficient T cells, and RT-PCR assay and DNA sequencing assay are used to identify and analyze particular gene expression deficiency in GPI-AP biosynthesis. Results: Our preliminary data shows that PNH-like cells in AA arise from multipotent HSC harboring PIG-A mutation; in MDS initiated at progenitor harboring PIG-A mutations and are transient; and in MPD caused from PIG-Y gene transcriptional silencing. Interestingly, the PIG-A mutation frequency in 4 MDS harboring PNH-like cells were 10~100 times higher than healthy controls. Furthermore, these 4 MDS and 3 MPD harboring PNH-like cells rapidly transformed into acute myelogenous leukemia. Conclusions: The origins and the clonality of PNH-like cells are different among MPD, MDS, and AA. This may explain why AA often evolves into PNH, but MPD and MDS seldom transform into PNH. PNH-like cell population in MPD and MDS is a marker of genomic instability and may predict a risk of leukemic transformation.




Survival and cause of death in patients with refractory anemias. Presenting Author: Yue Zhang, Yale School of Medicine, New Haven, CT

7034

433s


Costs of allogeneic hematopoietic cell transplantation using reduced intensity conditioning regimens. Presenting Author: Nandita Khera, Division of Hematology/ Oncology, Mayo Clinic in Arizona, Phoenix, AZ

Background: Despite its common occurrence, there are few large populationbased studies on low-grade myelodysplastic syndromes (MDS). We evaluated the outcomes for the two low-risk MDS subtypes. Methods: The Surveillance, Epidemiology and End Results (SEER) database was searched for patients with refractory anemia (RA) or RA with ringed sideroblasts (RARS), diagnosed between 2001 and 2009 with complete demographic information. Incidence rates were calculated from SEERStat 7.1. Overall survival (OS) and disease-specific survival (DSS) were calculated from diagnosis to death from any cause and death from MDS or acute leukemia, respectively. Univariate survival was estimated by the Kaplan-Meier method and curves compared by log rank. Univariate and multivariable Hazard ratios (HR) were calculated by Cox Proportional Hazards. Results: Among the 6,505 patients who met the inclusion criteria, there were 3,866 (59%) RA and 2,639 (41%) RARS. Age-adjusted incidence rates per 100,000 population for RA and RARS were 0.55 and 0.44 respectively. Medians OS for RA and RARS were 39 and 48 months respectively. Although RARS was associated with improved 5-year OS compared to RA (41.3% vs 37.7%; HR 0.86; 95% CI 0.81-0.92, p ⬍ 0.0001), there were no differences in 5-year DSS (74.2% vs 76.3%; HR 1.01, 95% CI 0.90-1.14, p ⫽ 0.41). Altogether, 2,112 deaths were accrued among RA patients and 1,352 among the RARS subclass. The number of deaths due to MDS or acute leukemia were 610 (28.8%) in RA and 457 (33.8%) in RARS. Acute leukemia was the cause of death in 190 (9.0%) RA patients and in 143 (10.6%) of RARS patients. Cardiovascular disease accounted for 25% of total deaths in RA and RARS. After adjusted for age, gender, race and year of diagnosis, RARS was associated with increased OS (HR 0.81; 0.760.87; p ⬍ 0.0001) but not DSS (HR 0.95; 0.84-1.07, p ⫽ 0.41). Conclusions: Both RA and RARS are indolent diseases with a high 5-year DSS and death occurring mostly from other causes, particularly cardiovascular disease. Although RARS was associated with better 5-year OS compared to RA, there were no differences in 5-year DSS.

Background: Reduced intensity (RIC) conditioning regimens have allowed older patients and those with comorbidities to receive hematopoietic cell transplantation (HCT). Methods: We analyzed medical costs from the beginning of conditioning to 100 days after HCT for 484 patients who underwent a RIC allogeneic HCT at Fred Hutchinson Cancer Research Center (FHCRC; n⫽147) and Dana Farber Cancer Institute (DFCI; n⫽337) from 1/2008 to 12/2010. Costs up to 2 years after HCT were analyzed for DFCI (n⫽311) as most patients receive their post-transplant care there. Multiple linear regression was used to analyze the association between clinical variables and costs. Results: Disease distribution and transplant characteristics were comparable between the two sites, though significant differences were seen in age distribution (88% FHCRC patients ⱖ 50 years vs. 80% at DFCI, p⫽0.04) and pre-transplant performance scores (63% patients with Karnofsky scoreⱖ 90 at FHCRC vs. 47% at DFCI; p⫽0.006). Median costs for first 100 days in 2010 $ at FHCRC and DFCI were $129 000 (range 31,000-352,000) and $96,000 (3,000-614,000) respectively, p⫽0.0002, but differences were not significant in multivariate analysis. Inpatient costs accounted for 42% of early costs at FHCRC and 87% at DFCI.Significant predictors for early costs included a diagnosis of lymphoma/ myeloma (17% decrease in costs; p⫽0.01), donors other than matched related (50 -100% increase; p⬍0.001), relapse (17% increase, p⫽0.04) and ⱖ grade II acute GVHD (37% increase; p⬍0.001). Median costs between d100 and 2 years were $39,000 (0-976,000) at DFCI. 39% of the 2 year costs occurred after first 100 days. There was no association of late costs with pre-transplant variables, and only death was associated with higher costs (138% increase; p⫽0.005). Conclusions: After adjustment for pre and post HCT variables, the overall costs of the RIC allogeneic transplants were similar between the two institutions despite different management approaches (inpatient vs. outpatient conditioning) and accounting methodologies. Use of unrelated/ alternative donors, relapse and acute GVHD were predictors for higher early costs while only death was associated with higher late costs.

7035

7036



Outcomes of hematopoietic stem cell transplant recipients admitted to the medical intensive care unit. Presenting Author: Duc Quang Tran, Emory University Winship Cancer Institute, Atlanta, GA

Cutaneous complications in hematopoietic cell transplant recipients: Impact of biopsy on patient management. Presenting Author: Oana Valeria Paun, Case Western Reserve University, Cleveland, OH

Background: Outcome results for hematopoietic stem cell transplant (HSCT) patients admitted to intensive care unit (ICU) and prognosis is infrequently reported during recent years, especially in view of increasing use of unrelated donors, increasing use of transplant maneuver in older patients using reduced intensity conditioning regimens and improvement in supportive care. We assessed our institutional survival outcomes and evaluated predictors of mortality in HSCT recipients admitted to ICU. Methods: Among the 390 HSCTs performed from March 2011 until July 2012, we retrospectively evaluated 34 HSCT patients admitted to ICU. 22 patients received mechanical ventilation (MV) or vasopressor support and were analyzed separately. All previously defined predictors of mortality were evaluated. SPSS version 20 was used for statistical analysis. Results: 9% of all HSCT patients were admitted to ICU. 65% of patients received allogeneic transplants. Major underlying hematological malignancies were AML/MDS (29%) and myeloma (24%). 41% were admitted for respiratory failure and 23.5% for sepsis. Median age was 55.5 (range: 27-76). Median length of ICU stay was 7 days (0-42) and median APACHE II score was 20 (9-39). 30 day and 60 day mortality rates are 47% and 62% among all patients; 54% and 68% among MV patients or receiving vasopressors. Predictors for day 30 mortality on univariate analysis among all patients were APACHE II score ⱖ26 (p⫽0.05). Predictors for day 60 mortality were APACHE II score ⱖ31 (p⫽0.001) and multiorgan failure (p⫽0.009). Among patients receiving MV or vasopressors, APACHE II score ⱖ31 is the only significant predictor of mortality (p⫽0.011). On multivariate analysis, APACHE II score ⱖ31 at day 30 hazards ratio (HR) 3.777 (95%CI 1.041-13.69; p⫽0.043) and at day 60 HR 3.789 (95%CI 1.07-13.45; p⫽0.039) are significant predictors of mortality. Conclusions: Significant predictors identified on multivariate analyses were APACHE II score ⱖ31 at day 30 and day 60. Interestingly, type of transplant is not a significant predictor of mortality. Future studies with larger patient samples and longer follow up are required for further understanding of prognosis in these patients.

Background: Although skin biopsies are recommended for diagnostic purposes in hematopoietic cell transplant (HCT) recipients, their utility in directing management of post transplant cutaneous eruptions remains uncertain. Little evidence was found in support of this procedure either from a diagnostic or prognostic perspective. Methods: We retrospectively evaluated 351 consecutive HCT recipients transplanted at our institution between January 2005 and December 2011; 156 patients underwent 388 cutaneous biopsies. Results: The group that underwent cutaneous biopsy after transplantation and the group that was spared the procedure were homogenous with regards to age and gender. The pre-biopsy diagnosis and final diagnosis differed in 213 episodes (55%) as determined by histologic evaluation. Biopsy results led to a change in therapy in 61 of 388 (16%) biopsied rashes. With regards to therapy changes, 24 of 61 (39%) occurred in response to a clinical diagnosis of GVHD. In this situation the most frequently noted change was augmentation or addition of systemic immunosuppression (19 of 24). Changes in systemic therapy occurred with similar frequencies with respect to concordance or discordance between clinical and histopathologic diagnosis (p ⫽ 0.12). We used classification and regression tree analysis to develop an algorithm to predict the biopsy yield as expressed by change of management. This is a non-parametric decision tree learning technique that produces a classification tree based on a categorical dependent variable, formed by a collection of rules based on variables in the modeling data set. Conclusions: Cutaneous biopsy findings often changed the clinical dermatologic diagnoses of HCT recipients; however, the impact of biopsy results on treatment decisions was less profound; altered diagnoses in patients who underwent biopsy often did not lead to therapy changes. Skin biopsies of post-transplant patients may not be mandatory for either diagnostic or therapeutic reasons, but in carefully chosen circumstances can yield extremely important data. A prospective study should be undertaken in order to evaluate current practice data and to validate our decision making analysis tree.


434s 7037

Leukemia, Myelodysplasia, and Transplantation General Poster Session (Board #34E), Sun, 8:00 AM-11:45 AM

Impact of oral mucositis on outcomes of multiple myeloma patients treated with high-dose melphalan conditioning and autologous stem cell transplantation (ASCT). Presenting Author: Graziella Chagas Jaguar, Hospital A.C. Camargo, São Paulo, Brazil Background: High-dose melphalan is the standard conditioning regimen for patients with multiple myeloma (MM) undergoing ASCT. However, this therapy is commonly associated with severe oral mucositis (OM). Low-level laser therapy (LLLT) has been reported as an effective method in preventing this complication. The aim of this study was to define the potential impact of OM on outcomes in patients with MM undergoing ASCT and receiving preventive LLLT. Methods: We describe a retrospective cohort of 79 consecutive patients with MM who received high-dose melphalan conditioning. All patients received prophylactic LLLT application performed daily from the beginning of the conditioning regimen up to day ⫹2. The patients continued receiving LLLT in case of OM grade ⱖ 2 until complete remission of the lesions. OM severity was assessed daily using WHO scale from the beginning of conditioning until hospital discharge. We examined the relationship between worst OM grade and clinical outcomes, including days with oral pain, days of total parenteral nutrition, days of LLLT and days with neutropenic fever. Results: Of 79 patients, 55 (69.62%) experienced OM grade 0-1, 16 (20.25%) experienced OM grade 2, 7 (8.86%) grade 3 and 1 (1.26%) grade 4. Patients with OM grade 0-2 had statistically fewer days of oral pain compared with grade 3-4 (0.88 and 6.25 days, respectively, p ⫽ 0.0001). The worst OM grade was also significantly (p ⬍ 0.05) associated with days of narcotic therapy and length of LLLT. Severe OM was not associated with febrile days or the use of parenteral nutrition. Conclusions: Severe OM is associated with worse clinical outcomes. In this transplantation setting, severe OM was not common as previously reported in literature, probably due to LLLT. Controlled randomized trials should be performed to confirm the real benefit of LLLT in this scenario as well as the pharmacogenomics and pharmacokinetic studies to better understand interpatient variability of melphalan exposure and toxicity.

7039


Comparison of four different strategies of stem cell mobilization in patients with multiple myeloma. Presenting Author: Jeffrey Michael Sivik, Penn State Hershey Cancer Institute, Hershey, PA Background: There is no consensus among institutions for the optimal strategy of peripheral blood stem cell (PBSC) collection for autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM). Methods: We retrospectively analysed the outcomes of PSBC collection in MM patients using the following mobilization regimens: cyclophosphamide 5,000 mg/m2 ⫹ etoposide 1,000 mg/m2 ⫹ G-CSF 5 mcg/Kg/day (Group A, n ⫽ 49); cyclophosphamide 2,000-3,000 mg/m2⫹ G-CSF 5 mcg/Kg/day (Group B, n ⫽ 25); G-CSF 16 mcg/Kg/day (Group C, n ⫽ 21); G-CSF 16 mcg/kg/day ⫹ plerixafor 0.24 mg/Kg (Group D, n ⫽ 128). Results: The median number of PBSC collected was 28.1 (range, 2.1-134), 4.5 (0.1-39.7), 4.0 (0-7.3) and 8.4 (0.2-41.2) million CD34⫹/kg in groups A, B, C and D, respectively (p ⬍0.001). The mean number of collection days was 1.3, 2.2, 2.4, and 1.3 in groups A, B, C, and D, respectively (p ⬍0.001). Febrile neutropenia occurred in 16 (32.7%), 1 (4%), 0, and 0 patients in groups A, B, C, and D, respectively. One patient who received CTX 3 g/m2 died of septic shock during the neutropenic phase. Failure to collect PBSC, defined as ⬍2x106 CD34⫹ cells/Kg for a planned single ASCT or ⬍4x106 for planned tandem ASCTs, was observed in 2/49 (4%), 5/25 (20%), 4/21 (19%), and 9/128 (7%) patients in groups A, B, C, and D respectively (p⫽0.037). Conclusions: Plerixafor ⫹ G-CSF provided the greatest benefit to risk ratio for PSBC collection in MM patients.

7038


Comparison of allogeneic stem cell transplantations in chronic myeloid leukemia before and after the era of tyrosine kinase inhibitors. Presenting Author: Muhit Ozcan, Ankara University Faculty of Medicine, Department of Hematology, Ankara, Turkey Background: In this retrospective study we aimed to evaluate the rates and the clinical outcomes of allo-HSCT in CML following the advent of TKIs. Methods: We compared the transplantations (Txs) performed prior to 2002 (old era), the first year of TKIs, with the Txs during and after 2002 (new era). Results: Between 1989 and 2012 inour Tx unit a total of 189 allo-HSCTs were performed in 185 CML patients (second Tx for 4 patients). The ratio of Tx for CML among the whole Tx group decreased from 40 % to 12 % after 2002. The ratio also dropped to less than 5 % after 2008 and increased again to 15% in 2012. Time from diagnosis to Tx was longer in the old era than in the new era (9.2 months vs 15.4 months, p⬍.0001). The ratio of patients with advanced disease (accelerated or blastic phase) was higher in the new era. Although the progression free survival (PFS) was shorter in the new era than in the old era (median 13.8 months vs 37.1 months, p⫽0.09), overall survival, Tx outcomes and survival curves did not change. Conclusions: AlloHSCT rates sharply decreased after the TKIs, but a slight increase in recent years have been observed compatible with the TKI’s failure in years. Despite the fact that patients who underwent allo HSCT in the new era had more challenging disease biologically, overall survival was not affected possibly due to post-Tx interventions such as use of TKI alone or with donor lymphocyte infusion. Features Median age (range), years Gender (M/F), n Donor Median age (range), years Gender (M/F), n Related or unrelated, n TKIs use at pre-Tx Myeloablative/reduced IC Stem cell source BM/PB/CB Immune-supression CsA-Mtx/CsA-MMF/other Disease status at pre-Tx CP1/³CP2/AP/BC Engraftment kinetics Neutrophil (>0.5x10e9/L), d Platelet (>20x10e9/L), d Tx response, CR (%) Tx related mortality (%) Median PFS Median OS

7040

Prior to 2002 (nⴝ128)

During and after 2002 (nⴝ61)

P

34 (14-48) 73/55 32 (9-56) 72/50 128/0

34 (18-57) 35/26 32 (0-65) 31/50 54/7

0.4 0.9 0,8 0,5 ⬍.0001

0 118/10 64/64/0

43 (70 %) 44/17 19/40/2

⬍.0001 0.009

120/4/4

45/15/1

⬍.0001

116/4/7/1

32/13/5/11

⬍.0001

16 (0-34) 15 (11-59)

16 (0-54) 14 (0-69)

0.8 0.3

86.7 32.8 37.1 Not reached

91.8 31.1 13.8 Not reached

0.2 0,8 0.09 0.3


Efficacy and cost of peripheral blood stem cell (PBSC) mobilization with low-dose cyclophosphamide (LD-CY) compared with plerixafor (P) in multiple myeloma (MM) patients (pts) treated with novel induction therapies. Presenting Author: Lubna Chaudhary, West Virginia University, Morgantown, WV Background: Efficacy and cost effectiveness of P vs. LD-CY mobilization in MM pts treated with novel induction therapies is not known. Methods: We analyzed the mobilization outcomes of 107 consecutive pts who underwent a planned, single autograft within 1-year of starting induction therapy with novel agents (thalidomide, lenalidomide, bortezomib) between 20032012. Pts undergoing mobilization with LD-CY/G-CSF (1.5gm/m2) (n⫽74) were compared against those receiving P/G-CSF (0.24mg/kg) (n⫽33). Efficacy of PBSC mobilization was assessed by evaluating peak peripheral blood (PB) CD34⫹ cell counts, CD34⫹ cell yield on day1 of collection, total CD34⫹ cell collection, and total number of apheresis sessions. Mobilization failure was defined as failure to collect ⱖ2 x106 cells/kg body weight. Mobilization costs were calculated per patient in both groups. Centers for Medicare and Medicaid Services reimbursement rates and Red Book Average Wholesale Price were used for cost determination. Results: At baseline, the LD-CY and P cohorts were well balanced. Compared to LD-CY, P use was associated with higher median peak PB CD34⫹ cell count (68/␮l vs. 36/␮l, p⫽0.048), CD34⫹ yield on day 1 of collection (6.9 x106/kg vs. 2.4 x106/kg, p⫽0.001), and total CD34⫹ cell yield (11.6 x106/kg vs. 7x106/kg, p⫽0.001). Median numbers of apheresis sessions were 2 in each group (p⫽0.17). In pts with prior lenalidomide use, mobilization failure rate in the LD-CY group was higher compared to the P group (20% vs. 0%, p⫽0.01). P group had a higher number of pts collecting ⱖ10x106/kg CD34⫹ cells (60.6% vs. 31%, p⫽0.01). Rate of infectious complications, transfusion requirements and hospitalizations was similar in both groups. The average total cost of mobilization in the P group was significantly higher compared to the LD-CY group ($28,980 vs. $19,627, p-value⬍0.0001). Conclusions: Our data indicates that although associated with a significantly higher total mobilization cost, plerixafor produced a more robust PBSC mobilization, without any collection failures.




Day 100 peripheral blood absolute monocyte/lymphocyte count prognostic score and survival in diffuse large B-cell lymphoma post-autologous peripheral blood hematopoietic stem cell transplantation. Presenting Author: Ana I. Velazquez, Mayo Clinic, Rochester, MN Background: Prognostic factors for diffuse large B-cell lymphoma (DLBCL) at day 100 post-autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT) have not been evaluated. We previously reported that absolute monocyte (AMC)/lymphocyte count (ALC) prognostic score (AMLCPS) at diagnosis of DLBCL patients is a prognostic factor of survival, stratifying patients into three risk groups: low- (AMC⬍630/␮L and ALC⬎1000/␮L), intermediate- (AMC ⱖ 630/␮L or ALC ⱕ 1000/␮L) and high-risk (AMC ⱖ 630/␮L and ALC ⱕ 1000/␮L) (Leukemia 25: 1502-9, 2011). Therefore, we evaluated day 100 AMLCPS as a prognostic factor of survival by landmark analysis from day 100 post-APBHSCT in DLBCL patients. Methods: DLBCL patients that achieved complete response by day 100 post-APBHSCT qualified for the study. From 2000 to 2007, 134 consecutive DLBCL patients were evaluated. Overall survival (OS) and progression free survival (PFS) were calculated using Kaplan-Meier analysis. Results: The median follow up from day 100 for the cohort was 5.5 years (range: 0.17-12.17 years) and for living patients (N⫽93) was 6.9 years (range: 2.5-12.17 years). Day 100 AMLCPS was able to stratify patients into three risk groups low-, intermediate-, and high-risk for OS [low: median OS ⫽ not reached, 5-year survival rate ⫽ 94% (95%CI 83.3%-98.1%); intermediate: median OS ⫽ not reached, 5-year survival rate ⫽ 70% (95%CI 58.0%-79.8%); high: median OS ⫽ 2.2 years, 5-year survival rate ⫽ 13% (95%CI 3.4%-40.5%); p⬍0.0001] and PFS [low: median PFS ⫽ not reached, 5-year progression free rate ⫽ 87% (95%CI 74.5%-94.3%); intermediate: median PFS ⫽ 10.9 years, 5-year progression free rate ⫽ 67% (95%CI 55.4%-77.5%); high: median PFS ⫽ 1 year, 5-year progression free rate ⫽ 13% (95%CI 3.4%-40.5%); p⬍0.0001]. The day 100 AMLCPS was balanced in relation to the International Prognostic Index (IPI; p⫽0.22), infused CD34⫹ stem cells (p⫽0.92), and disease status pre-APBHSCT (complete remission versus partial response; p⫽0.11). Conclusions: The day 100 AMLCPS is a simple biomarker that can help identify DLBCL patients post-APBHSCT with poor clinical outcomes.

7043


Incidence of engraftment fever post autologous transplant for lymphomas and analysis of risk factors. Presenting Author: Avinash Pandey, Advanced Centre for Treatment, Research, and Education in Cancer, Tata Memorial Center, Navi Mumbai, India Background: Engraftment fever (EF) is a phenomenon observed in some patients undergoing autologous transplant (ASCT). We analyzed our data to evaluate the incidence and risk factors associated with EF. Methods: Seventy-nine patients underwent ASCT (53-Hodgkin’s and 26- Non Hodgkin’s) from August 2007 – January 2013. All except 5 received LACE (Lomustine, Ara-C, Cyclophosphamide and Etoposide) conditioning regimen. EF was defined as onset of fever with rising white cell count for which no infectious cause was ascertained. Patients of EF and non-EF groups were compared for the following variables to determine risk factors. These included histology, number of lines of chemotherapy regimens pretransplant, complete remission (CR) at transplant, peripheral blood CD 34 count on day 1 of collection (PBCD34-D1), CD 34 cell dose collected and infused and number of days of stem cell collection. Results: The median age at transplant was 23.5 years with 57 males and 22 females. Time to neutrophil and platelet engraftment was 10 and 13 days respectively. EF was seen in 35 patients (44 %) at a median of 9 days. Short course of methylprednisolone (n⫽28) or hydrocortisone (n⫽3) was given to which all responded. On univariate analysis, PBCD34-D1 ⬎ 50/uL (P ⫽ 0.037), CD 34 cell dose infused ⬎5.9x106/kg (P⫽0.012),CD34 cell dose collected ⬎ 7.2 x 10 6 /kg (P⫽0.032) , those receiving ⱕ 2 lines of chemotherapy regimens before transplant (P⫽0.04), those who had ⱕ 2 days of stem cell collection (P⫽0.002) and patients in CR at transplant (P ⫽ 0.015) were associated with risk of developing EF. On multivariate analysis, patients in CR at transplant and those who had ⱕ 2 days of collection had higher risk of EF. Conclusions: The incidence of EF is high. Patients with lesser days of stem collection and those in CR at transplant have significant risk of developing EF.

7042

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Primary payer status and outcomes after autologous hematopoietic stem cell transplant: A national perspective. Presenting Author: Abu Ahmed Zahidur Rahman, Cape Fear Valley Hospital, Fayetteville, NC Background: With healthcare cost in rise, it is of interest to explore variation in healthcare delivery outcome with different payment source. This study was aimed to analyze relationship between payment source and outcome following autologous hematopoietic stem cell transplant (AutoHSCT) in a national database. Methods: We identified all hospitalizations with AutoHSCT (n⫽1,673) from Nationwide Inpatient Sample (NIS), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality 2010 database using the ICD 9 procedure codes 41.04 and 41.07. Based on sample weights an estimated 8,444 AutoHSCT procedures were performed nationwide in 2010. Patients were stratified on the basis of payer status: Medicare (27%), Medicaid (12%), private insurance (60%), and uninsured (0.8%). Multivariable logistic regression models were used to determine the association of primary payer status and outcomes. Results: Patients had a mean age of 54 (⫾13) years, 39% were women and 69% were whites. In-hospital mortality occurred in 1.1%, 2.9% and 3.3% of AutoHSCT patients with primary payer status of private insurance, Medicaid and Medicare respectively. AutoHSCT patients with primary payer status of Medicaid and Medicare had a statistically significant higher chance of in-hospital mortality compared to patients with private insurance (adjusted odds ratios and 95% confidence intervals, 2.68; 1.54-4.65; P ⬍0.001 and 1.90; 1.21-2.99; P⫽0.005 respectively). Length of stay was longer for Medicare patients (20 ⫾ 11 days) and Medicaid patients (20 ⫾ 12 days) compared to private insurance (18 ⫾ 8 days; P ⬍0.001). Medicare and Medicaid patients also accrued higher hospital charges (USD 175,221 and USD 166,453), compared to private insurance patients (USD 157,120; P ⬍0.001). Conclusions: In this national study Medicaid and Medicare patients had an independent risk for in-hospital mortality compared to private insurance patients. Medicaid and Medicare patients also had longer length of hospital stays and accrued higher hospital charges. This may mandate a closer look into the current resource utilization strategies to reduce such disparities among patients undergoing AutoHSCT.

7044


The impact of sarcopenia on transplant-related complications and number of days spent in the hospital in patients with lymphoma. Presenting Author: Megan Veresh Caram, University of Michigan, Ann Arbor, MI Background: Sarcopenia, a state of abnormally low muscle mass, has been found to be associated with more treatment-related complications and shorter overall survival in patients with different cancers. Sarcopenia can be reliably assessed with routine computerized tomography (CT). The objectives of the study were to determine whether sarcopenia is associated with the number of complications and the number of days spent in the hospital in patients undergoing autologous hematopoietic stem cell transplantation (autoSCT) for lymphoma. Methods: Adult patients treated for non-Hodgkin’s or Hodgkin’s lymphoma with autoSCT between 2/2005 – 6/2/2012 at the University of Michigan (U-M) Bone Marrow Transplant (BMT) Program were eligible for inclusion if a CT of the abdomen was performed within 60 days prior to autoSCT. Total psoas area and lean psoas area were calculated for each patient with cross-sectional area and density measurements taken at the level of the fourth lumbar vertebra using algorithms programmed in the Analytic Morphomics Lab at U-M. All analyses were completed using Poisson regression models controlling for age, gender, body mass index, Hematopoeitic-Cell Transplant Co-morbidity Index (HCT-CI), and Karnofsky performance status (KPS). Results: Total and lean psoas area were calculated in the 121 patients who met inclusion criteria. Men with greater psoas muscle measures experienced fewer complications and spent fewer days in the hospital during the autoSCT admission compared to men who were sarcopenic (complications ␤ ⫽ -0.206, p⫽0.001; hospital treatment days ␤ ⫽ -0.043, p⫽0.029). Sarcopenia did not play a role in outcomes in women. A strong association existed between sarcopenia and re-admission days within 100 days following autoSCT among both men (␤ ⫽ -1.183, p⬍0.0001) and women (␤ ⫽ -0.805, p⬍0.0001). Conclusions: Muscle mass is independently associated with complication rates and duration of hospitalization in patients undergoing autoSCT for lymphoma. CT-determined psoas muscle mass may be a valuable addition to other indices used to guide optimal treatment selection and serve as a potentially modifiable host factor to improve transplant-related outcomes.


436s 7045


MEDI-551, an anti-CD19 antibody active in chronic lymphocytic leukemia (CLL) patients previously treated with rituximab. Presenting Author: Mehdi Hamadani, Osborn Hematopoietic Malignancy and Transplant Program, West Virginia University, Morgantown, WV

7046


Management of chronic myeloid leukemia in chronic phase (CML-CP) by American Hematology-Oncology Physicians (AHOP’s): Diagnostic and treatment preferences after first-line imatinib (2010-2012). Presenting Author: James M. Foran, Mayo Clinic Cancer Center, Jacksonville, FL Background: In CML-CP there is perceived complexity in risk stratification at diagnosis, and in testing for BCR-ABL kinase domain mutation (KD mut, including T315I) at relapse. We sought to understand AHOP practices in the context of NCCN and European LeukemiaNet guidelines. Methods: Between 2010 and 2012, we studied time dependent practice preferences of n⫽1,335 AHOP’s using a proprietary, live, case-based market research tool. A core case scenario and variations based on available diagnostic & treatment options were constructed. Preference data were acquired using blinded audience response technology. All responses for each scenario were obtained contemporaneously prior to any display of summary respondent selections. All sources of research support were double blinded. AHOP’s were presented with a scenario of 59-year old CML-CP patient, then indicated preferred management from up to 9 relevant available/ emerging diagnostic or therapeutic options following relapse after 1st-line imatinib. Results: The majority of AHOP’s in 2012 either did not calculate (52%), or were unfamiliar (21%) with Sokal or Hasford risk stratification score. Diagnostic preferences following relapse from 2010-12 are noted in Table (distribution over time, p⬍0.0001). If T315I was then detected in scenario, we noted marked differences in subsequent treatment preference in 2012 vs. 2011, respectively: decreased AlloBMT (16% vs. 32%); & increased 2nd-line dasatinib (26% vs. 14%) or bosutinib (12% vs. 8%) vs. nilotinib (8% vs. 20%) despite lack of efficacy for each in T315I. Preference increased slightly for ponatinib (16% vs. 14%), but not for omacetaxine (2% vs. 6%). Conclusions: Most AHOP’s do not apply risk stratification. Increasing preference for KD mut panel testing at relapse conforms to guidelines, although not all AHOP’s test. Heterogeneity in T315I treatment suggests uncertainty or unfamiliarity with newer agents, and evidence-based efforts are needed to improve awareness.

Background: Anti-CD20 mAb therapy has provided survival advantage to patients (pts) with CLL; but pts invariably relapse after anti-CD20 therapy and new approaches are needed. The CLL cells of most pts express CD19, which are upregulated following anti-CD20 therapy. MEDI-551, an affinityoptimized anti-CD19 antibody, destroys malignant cells by Ab-dependent cellular cytotoxicity (ADCC) once bound to CD19. Methods: The activity and toxicity of single-agent MEDI-551 in CLL pts with prior rituximab administration was assessed in a phase 1/2, open-label, dose-escalation and expansion study (NCT00983619). Response was assessed using the 2008 Intl Working Group criteria. B-cell depletion was assessed with flow cytometry and confirmed with biomarker analyses (BAFF). Safety assessments included laboratory parameters and adverse events (AEs and serious AEs [SAEs]). Results: Of 91 pts with refractory B-cell malignancies included in the study, 26 had CLL. CLL pts had received a median of 6 prior therapies: 89% with chemotherapy, 27% with single-agent biologics. Within 3 cycles of MEDI-551 (3 mos), ⬎60% of assessable pts achieved CD20⫹ B-cell depletion to ⬍20 cell/uL. Decreases in circulating CD20⫹ and CD22⫹B cells were associated with concomitant increases in serum BAFF concentrations. Of 20 pts evaluable for response, 4 achieved partial response and 13 had stable disease. Commonly reported AEs were generally grade 1/2 and included infusion reactions (62%), nausea (23%), pyrexia (23%), and neutropenia (23%). Six SAEs were noted in 3 pts: 1 had infusion reaction and general health deterioration, another had subarachnoid hemorrhage (SAH), and a third had dyspnea, pyrexia, and back pain. Only infusion reaction was considered treatment related. Two treatmentunrelated events of general health deterioration and SAH resulted in death. Conclusions: Single-agent activity with a manageable toxicity profile was seen in CLL pts treated in this phase 1/2 study of MEDI-551. An ongoing phase 2 study of MEDI-551 in combination with bendamustine in relapsed CLL patients (NCT01466153) is evaluating clinical response to MEDI-551 and chemotherapy. This study was sponsored by MedImmune, LLC.

Yes—KD mut panel Yes—T315I only None Refer to Center of Excellence, or Other

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7048


Association of prior epidemiologic exposures with cytogenetic risk in adult acute myeloid leukemia (AML). Presenting Author: Laura Elizabeth Finn, Mayo Clinic, Jacksonville, FL Background: In addition to secondary AML (sAML), important lifestyle and environmental exposures associated with increased risk of AML development have been identified in recent case-control studies including obesity (BMI⬎30kg/m2), smoking, regular acetaminophen use, and rural/farm habitat. The association of these exposures with AML cytogenetic risk groups is unknown. We therefore evaluated relevant exposures in a cohort of 301 AML patients with confirmed central cytogenetics analysis diagnosed and treated at Mayo Clinic FL and AZ since 1995. Methods: Documented patient exposures were extracted from central electronic medical records, including: prior chemotherapy/radiation or hematologic malignancy, occupation, select medications, “toxins” (esp. benzene) and solid organ transplantation (SOT). Standard cytogenetic risk categories (including intermediate abnormal) were applied. The association of epidemiologic exposures with cytogenetic risk was evaluated on multivariable analysis using logistic regression models. Results: sAML was significantly associated with cytogenetic risk groups, as was prior SOT, healthcare occupation, farm habitat and toxin exposures [see Odds Ratios (OR), Table). In contrast, prior radiation for epithelial malignancies, smoking and BMI were not independently associated with specific cytogenetic risk categories. Conclusions: Specific epidemiologic exposures are significantly associated with AML cytogenetic risk categories suggesting a unique clinical phenotype. This supports a link to leukemogenesis and requires validation in a controlled prospective therapeutic study. N

Poor risk (OR)

P value

Intermediate abnormal risk (OR)

P value

Normal and good risk (OR)

P value

sAML

166

2.62

0.0002

1.09

NS

0.40

0.0002

Prior heme malignancy Radiation

147 41

2.33 0.82

0.001 NS

0.95 1.41

NS NS

0.40 0.97

0.003 NS

BMI

301

1.01

NS

1.16

NS

0.90

NS

Tobacco

169

0.85

NS

1.23

NS

0.96

NS

Health care worker

23

0.64

NS

6.36

⬍0.0001

0.23

0.01

Metformin

20

1.78

NS

1.73

NS

0.31

0.048

9

0.61

NS

3.20

0.098

0.53

NS

Farm habitat

14

2.74

0.078

0.86

NS

0.36

NS

Toxin

22

2.89

0.026

0.33

0.10

0.74

NS

Exposures

SOT

Mutation testing

2010 nⴝ395

2011 nⴝ268

2012 nⴝ672

60% 17% 9% 15%

65% 15% 7% 13%

72% 13% 15% 1%


Analysis of the cardiovascular risk profile of Phⴙ leukemia patients treated with ponatinib. Presenting Author: Hanna Jean Khoury, Emory University, Winship Cancer Institute, Atlanta, GA Background: Coronary artery disease (CAD), peripheral arterial occlusive disease and cerebrovascular disease have been observed in pts treated with BCR-ABL tyrosine kinase inhibitors (TKIs). While uncommon, these events can be serious complications of BCR-ABL TKI therapy. Methods: The cardiovascular (CV) profile of ponatinib (45 mg/day) was evaluated in 449 pts with chronic myeloid leukemia (CML) or Ph⫹ acute lymphoblastic leukemia (Ph⫹ ALL) resistant or intolerant to prior TKIs in the phase 2 PACE trial. At analysis (23 July 2012), median follow-up was 12 (0.1-21) mos. Myocardial ischemic events including myocardial infarction (MI), CAD, and angina were analyzed. Results: Myocardial ischemic serious adverse events (SAEs) (14 MI, 5 CAD, 2 angina) were reported in 21/449 pts (5%). 10 of these 21 pts had active cardiac disease at entry characterized by prior MI (4 pts), coronary revascularization (4 pts), or documented CAD; 5 had MI reported on study. 5/21 pts had other cardiac disease at entry (eg, valvular or pericardial disease); 5 had MI on study. Thus, 10/14 MIs occurred in 15 pts with known cardiac disease. 6/21 pts had no history of cardiac disease, but 5/6 had ⱖ1 CAD risk factor; 4 MIs occurred in these pts, all had risk factors. Of 21 pts with myocardial ischemic SAEs (13 CP-CML, 6 AP-CML, 2 BP-CML/Ph⫹ALL), mean age was 67 (42-87), and median duration since diagnosis was 12 (1-20) yrs. They were heavily pretreated (67% TKI use ⱖ5 yrs) with multiple CAD risk factors at entry (71% ischemia, 57% hypertension, 38% hypercholesterolemia, 33% diabetes [62% BMI ⬎25]); 81% had ⱖ2 risk factors, 95% had ⱖ1. Median time to onset and duration of SAE was 160 (9E402) and 7 (1E98) days, respectively. At analysis, 18/21 pts had the SAE reported as resolved (managed by dose interruption [50%] or no dose change [33%]), and 13/21 pts remained on study. Response rates for the subset of 21 pts with cardiac SAEs were major cytogenetic response 77% in CP-CML; major hematologic response 67% in AP-CML. Conclusions: In this uncontrolled study in heavily pretreated pts, these CV SAEs occurred mostly in pts with preexisting cardiac disease, and were primarily managed with satisfactory outcomes. Pts with preexisting CV co-morbidities should be monitored. Clinical trial information: NCT01207440.




Frequency of rare cytogenetic abnormalities at relapse in acute myeloid leukemia (AML) with FLT3 internal tandem duplication (ITD) and normal karyotype at diagnosis: Evidence for genomic instability? Presenting Author: Theodore Stewart Gourdin, University of Maryland, Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD Background: FLT3-ITD mutations are present in AML in 30% of patients, most commonly with a normal karyotype, and are associated with short disease-free survival. In vitro and in vivo studies of FLT3-ITD cell lines and patient samples have demonstrated DNA double-strand break repair by an alternative highly error-prone form of non-homologous end-joining (ALT NHEJ), resulting in illegitimate ligation of non-contiguous DNA breaks, causing DNA deletions and translocations that may contribute to disease progression. To look for clinical evidence of genomic instability, we reviewed cytogenetic changes at relapse. Methods: Charts of patients with cytogenetically normal AML with FLT3-ITD treated at the University of Maryland Greenebaum Cancer Center were reviewed along with metaphase analysis results at diagnosis and relapse. Results: Cytogenetic data were available from first and, when applicable, subsequent relapses for 12 patients with cytogenetically normal AML with FLT3-ITD who relapsed, including 5 following allogeneic hematopoietic stem cell transplantation (allo HSCT). Ten patients acquired cytogenetic changes, many of them rare translocations and inversions (Table). Conclusions: AML with FLT3-ITD and normal karyotype at diagnosis has a high frequency of rare cytogenetic abnormalities at relapse, providing clinical evidence for genomic instability. These data may support the potential therapeutic role of inhibitors of ALT NHEJ repair proteins, such as PARP1 and DNA ligase IIIa, in AML with FLT3-ITD.

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Rapid identification of drug-resistant BCR-ABL(ⴙ) leukemia. Presenting Author: Ronald J. Rieder, BioSense Technologies, Inc., Woburn, MA

46,XY,t(2;14)(p23;q24)[2]/46,XY[18] 46,XX,t(4;4)(q21;q35)[7]/46,XX[13] 46,XX,t(5;13)(q31;q12)[20]* 46,XX,inv(9)(q22q32)[20] 46,XY,t(9;22)(q34;q11.2)[4]/46,XY[8] 46,XY,inv(10)(p11.2q21.2)[12]/46,XY[8]* 46,XY,t(10;13)(q10;q10)[9]/46,XY[9]//46,XX[2]* 47,XY,⫹21[10]/46,XY[10]* 46,X,t(X;10)(q13;q24),t(3;14)(p21;q11.2),t(12;17)(p12;q12)[15]//46,XY[5]* 45,XX,der(2)t(2;?)(q21;?),del(3)(q12),der(6)t(6;?)(p22;?),der(7)t(7;?) (p15;?),-17,-22,⫹mar[19]/46,XX[1]

Background: Approximately 20% of patients with chronic myeloid leukemia and most patients with BCR-ABL-positive acute leukemia demonstrate resistance to imatinib mesylate resulting in treatment failure or suboptimal patient outcomes. We hypothesize that monitoring the development of cellular stress in BCR-ABL cells incubated with tyrosine kinase inhibitors (TKI) can be used as an early marker for determining the effects of the drugs on the cancer cells enabling rapid identification of drug-resistance and facilitating change to more effective therapies. Methods: The dielectric permittivities of non-leukemic peripheral blood mononuclear cells (PBMCs) and BCR-ABL cell lines known to be resistant (K562R and BaF3/ T315I) or sensitive (K562 and HL60/BCR-ABL) to different TKIs were measured in the presence of imatinib (IMT), dasatinib (DAS), nilotinib (NIL), or ponatinib (PON) using the Z-Sense differential impedance sensing platform to record any changes in cellular stress. We also performed similar measurements on PBMCs from newly diagnosed CML patients exposed in vitro to the same TKIs. Results: Non-leukemic PBMCs showed no significant background levels when incubated with the following TKI concentrations: IMT (5 mg/mL), DAS (5 mg/mL), NIL (2.5 mg/mL), and PON (5 ng/mL). Normalized dielectric responses for all drug-resistant cell lines showed no change in value similar to control runs where no drugs were added. In contrast, all responses obtained for cell lines sensitive to these same TKIs were immediate and continuously decreased in value over time compared with resistant cell lines (p⬍0.01). All sensitivities were confirmed by MTT assay. Notably, the response of BaF3/T315I cells to PON was easily distinguished from the responses to IMT, DAS, and NIL. Of significance, all responses of BCR-ABL(⫹) patient blood to the four TKIs measured prior to commencing therapy were qualitatively similar to sensitive cell line measurements and subsequently confirmed to respond to IMT therapy. Conclusions: Drug-sensitive BCR-ABL(⫹) cells can be readily distinguished from drug-resistant cells without cell culturing in less than 60 minutes by monitoring the development of cellular stress in response to TKI drugs using differential impedance sensing.

7051

7052^

Karyotypes at relapse (*after allo HSCT).


Effect of dose-optimized imatinib (IM) 800 mg on deep molecular responses (CMR 4.5) and prediction of survival: Results from the randomized CML-study IV. Presenting Author: Rüdiger Hehlmann, III. Medizinische Universitätsklinik, Medizinische Fakultät Mannheim der Universität Heidelberg, Mannheim, Germany Background: Since complete molecular remission (CMR 4.5) defines a subgroup of patients who may stay in remission even after discontinuation of treatment, we analysed whether CMR 4.5 is reached faster with dose optimized IM 800 mg and whether the achievement of CMR 4.5 at specified points in time results in better survival than the achievement of less deep remissions. Methods: Confirmed CMR 4 and CMR 4.5 are defined as ⱕ 0.01% BCR-ABL IS or ⱖ 4 log reduction and ⱕ 0.0032% BCR-ABL IS or ⱖ 4.5 log reduction, respectively, from standardized baseline as determined by real-time PCR in 2 independent analyses. Details on CML-Study IV have been published (Hehlmann et al., JCO 2011). Cumulative incidences were estimated under consideration of competing risks. Landmark analyses were performed to evaluate the prognostic impact of different remissions at 4 years on survival. Results: Of 1551 randomized patients with newly diagnosed chronic phase CML 1525 were evaluable. Median age was 52 years, 88% were EUTOS low risk, 12% high risk. 113 patients were transplanted (73 in first chronic phase), 246 received 2nd generation TKI. 152 patients have died. After a median observation time of 67.5 months, 6-year OS was 88.2%.CMR 4.5 was reached after a median of about 76.1 months with IM 800 and 107.3 months with IM 400. EUTOS low-risk patients reached all remissions faster than high-risk patients. Independent of treatment approach CMR 4.5 at 4 years predicted OS significantly better than complete cytogenetic remission (p⫽0.043), but not significantly better than major molecular remission (MMR) or CMR4. After a median observation of 3.9 years 1 of 626 patients with CMR 4 has progressed. Only six of the 394 patients with CMR 4.5 have died after a median observation time of 3.0 years, no patient has progressed. An additional finding was that achieving MMR at 3 and at 6 months predicts faster achievement of CMR 4.5. Conclusions: We conclude that dose optimized IM 800 induces CMR 4.5 faster than IM 400 and that CMR 4.5 at 4 years is associated with a survival advantage. Dose optimized IM 800 may provide an improved therapeutic basis for treatment discontinuation in patients with CML. Clinical trial information: NCT00055874.


Nilotinib versus imatinib in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): ENESTnd 4-year (y) update. Presenting Author: Richard A. Larson, The University of Chicago, Chicago, IL Background: In the 3-y follow-up (f/u) of ENESTnd, NIL demonstrated superior rates of molecular response and reduced progression to accelerated phase/blast crisis (AP/BC) vs IM. Here, we report results with a minimum f/u of 4 y. Methods: 846 adults with newly diagnosed Philadelphia chromosome–positive CML-CP were randomized to receive NIL 300 mg twice daily (BID; n ⫽ 282), NIL 400 mg BID (n ⫽ 281), or IM 400 mg once daily (QD; n ⫽ 283). Results: NIL continued to demonstrate higher rates of major molecular response (MMR; ⱕ 0.1% BCR-ABLIS), MR4 (ⱕ 0.01%IS), and MR4.5 (ⱕ 0.0032%IS) vs IM (Table). No new progressions have occurred on treatment on any arm since the 2-y analysis. NIL had significantly lower rates of progression to AP/BC on treatment (n ⫽ 2, 3, and 12 on NIL 300 mg BID, 400 mg BID, and IM, respectively) and when including f/u after discontinuation (n ⫽ 9, 6, and 19 on NIL 300 mg BID, 400 mg BID, and IM, respectively) and higher overall survival (OS) vs IM. By 4 y, half as many pts acquired new BCR-ABL mutations on study with NIL vs IM (n ⫽ 12, 11, and 22 on NIL 300 mg BID, 400 mg BID, and IM, respectively). Since the 3-y analysis, 2 new mutations (1 pt with T315I on NIL 300 mg BID; 1 pt with F317L on IM) were reported. Safety profiles of both drugs were consistent with previous ENESTnd analyses. By 4 y, peripheral arterial occlusive disease (PAOD) events were reported in 4 and 5 pts in the NIL 300 mg BID, and 400 mg BID arms, respectively. No pt in the IM arm had a PAOD event. Conclusions: ENESTnd 4-y data continue to demonstrate the superiority of NIL over IM for achieving deeper responses with lower risk of progression, supporting the use of NIL as frontline therapy in CML-CP. Clinical trial information: NCT00471497.

Response by 4 y, % (P value vs IM) MMR MR4 MR4.5 4-y freedom from progression to AP/BC,a % (P value vs IM) On core treatment On core or extension treatment or during f/u after discontinuation 4-y OS,a % All deaths Pts with BCR-ABL mutations acquired on study, n Any T315I a

NIL 300 mg BID (n ⴝ 282)

NIL 400 mg BID (n ⴝ 281)

IM 400 mg QD (n ⴝ 283)

76 ( ⬍ .0001) 56 ( ⬍ .0001) 40 (⬍ .0001)

73 ( ⬍ .0001) 50 ( ⬍ .0001) 37 (.0002)

56 32 23

99.3 (.0059) 96.7 (.0497)

98.7 (.0185) 97.8 (.0074)

95.2 93.1

94.3 (.4636)

96.7 (.0498)

93.3

12 4

11 2

22 3

Kaplan-Meier estimate.


438s 7053^


Switching patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with residual disease on long-term imatinib (IM) to nilotinib (NIL): ENESTcmr 24-mo follow-up. Presenting Author: Nelson Spector, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Background: The 12-mo results of ENESTcmr demonstrated that switching pts on IM with sustained BCR-ABL positivity to NIL leads to faster, deeper molecular responses (MRs)vs remaining on IM. These deeper molecular responses (MR4.5 [BCR-ABL ⱕ 0.0032%IS] or greater) are a prerequisite to enter most treatmentfree remission studies. Here, we report 24-mo f/u of ENESTcmr. Methods: Philadelphia chromosome–positive CML-CP pts (N ⫽ 207) who achieved a complete cytogenetic response, but had detectable BCR-ABL transcripts after ⱖ 2 y on IM, were randomized to receive NIL 400 mg twice daily (BID; n ⫽ 104) or continue their IM dose (400/600 mg once daily [QD]; n ⫽ 103). Results: By 24 mo, significantly more pts achieved confirmed undetectable BCR-ABL (by RQ-PCR with ⱖ 4.5 log sensitivity in 2 consecutive samples) with a switch to NIL vs continuing IM (22.1% vs 8.7%; P ⫽ .0087). The increase in the rate of undetectable BCR-ABL from mo 12 to 24 was higher for pts on NIL vs IM (9.6 vs 2.9 percentage points). In pts without MR4.5 at baseline (BL), MR4.5 was achieved by 24 mo in 42.9% vs 20.8% of pts (NIL vs IM; P ⫽ .0006). In pts without major molecular response (MMR; ⱕ 0.1%IS) at BL, MR4.5 was achieved by 24 mo in 29.2% vs 3.6% of pts (P ⫽ .016). No progressions to accelerated phase/blast crisis or deaths occurred on study since the 12-mo f/u. Event-free survival at 24 mo was 96.6% vs 92.8% in the NIL and IM arms, respectively. Discontinuations due to adverse events occurred in 11.5% and 2.9% of pts in the NIL and IM arms. The NIL safety profile was consistent with prior switch studies. Conclusions: By 24 mo, significantly more pts achieved deeper responses (MR4.5and undetectable BCR-ABL) with switch to NIL vs remaining on IM, and the difference between arms in these endpoints increased between 12 and 24 mo. Clinical trial information: NCT00760877. NIL IM 400 mg BID 400 or 600 mg QD (n ⴝ 104) (n ⴝ 103) P value Confirmed undetectable BCR-ABL (ITT), % By 12 mo 12.5 5.8 By 24 mo 22.1 8.7 MR by 24 mo (in pts without the response of interest at BL), % MR4.5 (n ⫽ 94) (n ⫽ 91) 42.9 20.8 Undetectable BCR-ABL (n ⫽ 101) (n ⫽ 100) 31.7 17.0 MR by 24 mo (in pts without MMR at BL), % MMR (n ⫽ 24) (n ⫽ 28) 83.3 53.6 MR4.5 (n ⫽ 24) (n ⫽ 28) 29.2 3.6

7055

.108 .0087 .0006 .0106 .0342 .016


7054^


Impact of early molecular response to nilotinib (NIL) or imatinib (IM) on the long-term outcomes of newly diagnosed patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): Landmark analysis of 4-year (y) data from ENESTnd. Presenting Author: Giuseppe Saglio, University of Turin, San Luigi Gonzaga Hospital, Orbassano, Italy Background: ENESTnd demonstrated the superiority of NIL to IM in pts with newly diagnosed CML-CP, such as higher rates of molecular response (MR) and reduced risk of progression to accelerated phase (AP)/blast crisis (BC). This landmark analysis of ENESTnd is based on BCR-ABL transcript levels at 3 mo, with 4 y of follow-up. Methods: Rates of major MR (MMR; BCR-ABLIS ⱕ 0.1%), MR4.5 (BCR-ABLISⱕ 0.0032%), progression to AP/BC, overall survival (OS), and progression-free survival (PFS) in pts in the NIL 300 mg twice daily (BID; n ⫽ 282) and IM 400 mg once daily (QD; n ⫽ 283) arms of ENESTnd were evaluated based on 3-mo BCR-ABL levels (ⱕ 10% vs ⬎ 10%). Results: More pts treated with NIL than IM achieved BCR-ABL ⱕ 10% at 3 mo (91% vs 67%; Table). Other factors associated with MR at 3 mo included Sokal risk, spleen size, chromosomal abnormalities, white blood cell count, and median dose intensity (for NIL). On both arms, pts with BCR-ABL ⱕ 10% at 3 mo had significantly higher rates of MMR and MR4.5and significantly improved PFS and OS than pts with BCR-ABL ⬎ 10% at 3 mo. Of the pts with BCR-ABL ⬎ 10% at 3 mo, 2 on NIL (8%) and 14 on IM (16%) progressed to AP/BC on study. Half of these progressions occurred between 3 and 6 mo. Analyses of outcomes based on BCR-ABL levels at 6 mo were similar to findings based on 3-mo data. Conclusions: BCR-ABL levels ⱕ 10% at 3 mo were associated with superior outcomes, including higher rates of MR4.5 by 4 y and lower risk of disease progression. More pts treated with NIL than IM achieved this early level of MR. Clinical trial information: NCT00471497. NIL 300 mg BID (n ⴝ 258)a BCR-ABL level at 3 Mo

Pts, % Median dose intensity during first 3 mo, mg/day Sokal score, % Low Intermediate High MR4.5 by 4 y, % P value 4-y PFS, % P value 4-y OS, % P value

IM 400 mg QD (n ⴝ 264)a BCR-ABL level at 3 Mo

< 10%

> 10%

< 10%

> 10%

91 600

9 474

67 400

33 400

39 36 26

29 29 42

46 36 18

24 32 44

47

⬍ .0001

95

4

34

83

98

87

99

.0061 97

⬍ .0001 ⬍ .0001

.0116

⬍ .0001

24 8 4

88 16 8

Pts with BCR-ABL > 10% at 3 mo, n Progression to AP/BC, % On study Between 3 and 6 mo

5 83 84

aPts with evaluable polymerase chain reaction samples at 3 mo.

7056


Arsenic trioxide: Pharmacokinetics in acute promyelocytic leukemia (APL) patients. Presenting Author: Cristina Maria Ghiuzeli, Hofstra North ShoreLIJ School of Medicine, Lake Success, NY

Pharmacokinetics (PK) of ibrutinib in patients with chronic lymphocytic leukemia (CLL). Presenting Author: Juthamas Sukbuntherng, Pharmacyclics, Sunnyvale, CA

Background: Arsenic (As) has significantly increased survival for APL patients. As and its metabolites’ effects on cell proliferation, apoptosis, and methylation, especially long term, remain largely unknown. It is imperative to study the pharmacokinetics of As at therapeutic doses in order to limit untoward effects resulting from treatment. Arsenic trioxide (ATO), available as arsenous acid (iAsIII), is readily metabolized through sequential methyl group additions and electron reduction steps: iAsIII V ¡MAs ¡MAsIII ¡DMAsV ¡DMAsIII ¡TMAsVO ¡TMAsIII. iAsIII, MAsIII and DMAsIII are more biologically active and more toxic than pentavalent forms. The key enzyme involved is arsenic methyltransferase, and polymorphisms contribute to metabolic differences between individuals. Methods: Cancer patients not treated with ATO (controls) had one collection of blood and urine samples, while APL patients receiving therapeutic doses of ATO had collections immediately prior to and at 1, 2, 4, 6, and 24 hours, days 4, 8, 15, and 4 weeks after ATO-free interval. Total iAs (iAsIII⫹iAsV), MAs (MAsIII⫹MAsV) and DMAs (DMAsIII⫹DMAsV) were measured in plasma using hydride generation cryotrapping atomic absorption spectrometry, a sensitive automated method of arsine detection. The same As species were measured in urine and in exfoliated bladder cells isolated from urine. Results: We report data on ten control patients and six treated patients (ATO 0.15 mg/kg/day). Initial average As concentrations in treated patients (0.051 ng/ml) were similar at baseline to the controls (0.046 ng/ml). We observed that iAs is quickly metabolized from a peak average plasma concentration of 32 ng As/ml to a trough of 10 ng As/ml within six hours from infusion, remaining unchanged for at least 24 hours. MAs and DMAs concentrations begin to increase at six hours, and continue to rise by day 4 to an average concentration of 8.5 and 10.4 ng As/ml respectively, followed by decline to baseline 4 weeks after final ATO infusion. Conclusions: Treatment with ATO leads to the formation of MAs and DMAs whose long term toxicity in APL patients is poorly understood. Studies involving analysis of As metabolites are needed to assess possible long term toxicities on non-targeted organs.

Background: Ibrutinib is a first-in-class selective small molecular inhibitor of Bruton’s tyrosine kinase (BTK) under development for the treatment of B-cell malignancies. Because of covalent binding to cys-481 of BTK, ibrutinib has a sustained pharmacodynamic (PD) effect. The aim of this study was to determine the PK of ibrutinib in patients (pts) with CLL. Methods: A Phase 1b/2 study (PCYC-1102-CA) of an oral dosing of single agent ibrutinib was conducted in pts with treatment-naïve (TN) or relapsed/ refractory (R/R) CLL. Pts were enrolled into one of the following groups: R/R pts at 420 mg/day (n⫽27), TN pts at 420 mg/day (n⫽26), R/R pts at 840 mg/day (n⫽34), R/R high-risk pts at 420 mg/day (n⫽24), TN pts at 840 mg/day (n⫽5), and R/R pts at 420 mg/day for food-effect evaluation (n⫽16). One cycle was 28 days. Blood samples for PK assessment were obtained during the first cycle. PK parameters were calculated using non-compartmental analyses. Results: A total of 132 pts (98 males and 34 females) with CLL were treated across the 6 groups. Median ages for Groups 1 through 6 were 64, 71, 64, 68, 71, and 62 years, respectively. Ibrutinib exhibited rapid absorption (median Tmax of 2 h) and a mean elimination plasma half-life of approximately 6-9 hours. The AUCtau increased approximately proportional to doses from 420 to 840 mg/day. No accumulation of ibrutinib was apparent on Day 8. Ibrutinib exposure in males and females was similar. At 420 mg/day, pts ⱖ 65 years old had AUC values that were ~30% higher than those of pts ⬍ 65 years. In R/R pts, there were no substantive differences in systemic exposure to ibrutinib between the del 17p positive and del 17p negative pts. An increase in ibrutinib exposure (⬍2-fold) was observed when administration with high-fat breakfast was compared to administration following an overnight fast. In all cases, %CV of AUC ranged from 50 to 100%. Conclusions: Ibrutinib demonstrated rapid absorption and elimination and was well tolerated at doses of 420 and 840 mg/day. Lack of significant exposure differences with respect to age, gender, or 17p del status indicates that dose adjustment in these populations is not required. Because of a sustained PD effect ibrutinib can be dosed once daily despite a relatively rapid clearance. Clinical trial information: NCT01105247.




Open label evaluation of ECG in patients with chronic lymphocytic leukemia (CLL) receiving ibrutinib monotherapy. Presenting Author: David Loury, Pharmacyclics, Sunnyvale, CA Background: Ibrutinib is a first-in-class selective small molecule inhibitor of Bruton’s tyrosine kinase (BTK) under development for the treatment of B-cell malignancies. The aim of this study was to characterize the possible effect of ibrutinib on ECG intervals in patients with CLL. Methods: A Phase Ib/II study (PCYC-1102-CA) of oral dosing of ibrutinib was conducted in patients with treatment-naïve (TN) or relapsed/refractory (R/R) CLL. Patients were enrolled into 6 groups treated with ibrutinib at 420 mg/day or 840 mg/day (n⫽132). One cycle was 28 days. ECG data were obtained along with the blood samples during Cycle 1. Additional ECG measurement was performed on Day 28 of Cycles 3, 6, 12, 18, and 24 and at the end of study. An interim ECG analysis was performed using the data from R/R patients at 420 mg/day (n⫽18), TN patients at 420 mg/day (n⫽20), and R/R patients at 840 mg/day (n⫽29). For ECG analysis, the pre-dose values on Cycle 1 Day 1 were used as the baseline for each post-dose time-point for all ECG parameters. The QT and RR values for each beat were used for both Fridericia’s correction (QTcF) and Bazett’s correction (QTcB). The relationship between plasma concentrations of ibrutinib and ⌬QTcF (changefrom-baseline QTcF) was investigated by a linear mixed-effects modeling approach. Results: Median ages for R/R 420 mg, TN 420 mg, and R/R 840 mg dose groups were 59, 71, and 62 years, respectively. There was no clinically significant change in heart rate (HR) relative to baseline observed in either dose groups or between R/R and TN populations. There was no evidence of PR interval prolongation above 240 msec. There were no treatment-related effects on QRS duration in any of the Treatment Groups. A total of 467 ⌬QTcF measurements were included in the analysis. The population mean of baseline QTcF values was 402.0 msec with a SD of 15.2 msec. A concentration-dependent effect of ibrutinib on QTcF was not identified. Conclusions: Interim analyses of the data indicated that there was no evidence of clinically significant ECG findings or QTc prolongation with continuous daily dosing of ibrutinib at either the 420 mg or 840 mg dose in patients with TN or R/R CLL. Clinical trial information: NCT01105247.

7059


Hematopoietic cell transplantation for refractory acute myeloid leukemia. Presenting Author: Annie P. Im, University of Pittsburgh Cancer Institute, Pittsburgh, PA Background: Hematopoietic cell transplantation (HCT) can be curative for patients with AML refractory to chemotherapy or re-induction after relapse. However, the role of HCT in this setting remains unclear. Our aim was to evaluate outcomes of HCT in these patients, and determine factors that may be predictive of complete remission (CR)/complete remission with incomplete count recovery (CRi) and overall survival (OS). Methods: Patients with relapsed AML who did not respond to re-induction or with primary induction failure (PIF) who received allogeneic HCT at University of Pittsburgh Cancer Institute 2000-2012 were identified. CR/CRi rates were calculated at day 30 and 100, and 3-year OS was determined using Kaplan Meier method. Cox proportional hazards regression was used to examine associations between factors of interest, and OS and CR/CRi. These included gender, age, relapse or PIF, 1° or 2° AML, cytogenetic risk, duration of CR1 (patients in relapse), performance status, number of induction cycles, circulating blasts, percentage of bone marrow (BM) blasts prior to HCT, matched unrelated or sibling donor, donor-recipient CMV status, and acute GVHD. Results: The study cohort consisted of 71 patients (median age 44 years, range 19-64) who underwent allogeneic HCT for refractory AML (relapse n⫽35, PIF n⫽36). At day 30, CR was 31% and CRi was 49%, for total 80% response rate. At day 100, 51% remained in CR/CRi. CR/CRi was associated with younger age (HR 1.26, p⬍0.001) and lower percentage BM blasts (HR 1.03, p⫽0.026). Three-year OS was 12.3% (5.6-21.8), and median OS was 0.57 years (0.35-0.75). Lower OS was associated with matched unrelated versus sibling donor (HR 1.74, 1.02-2.96) and older age (p⬍0.06). Of the 60 patients who were deceased, 38.6% died from progressive leukemia. Conclusions: Despite high CR/CRi rates after HCT for refractory AML, 3-year OS was low. Age and percentage BM blasts were significantly associated with CR/CRi. Only sibling donor was significantly associated with OS, though there was a trend for age. Though patients with refractory AML represent a high-risk group to undergo HCT, the high response rate through day 100 with subsequent disease-related mortality suggests a role for maintenance after HCT in this population.

7058

439s


Phase I study of midostaurin and azacitidine in relapsed and elderly AML. Presenting Author: Brenda W. Cooper, University Hospital of Cleveland, Case Medical Center, Cleveland, OH Background: The Fms-like tyrosine kinase 3 (FLT3) receptor is expressed in 80% of AML and activating mutations are associated with an adverse prognosis. Midostaurin (mdn), an orally available agent, has been shown to inhibit FLT3 receptor signaling and induces cell cycle arrest and apoptosis of leukemic cells expressing both mutant and wild type FLT3 receptors. Preliminary data has shown modest single agent activity as well as safety and tolerablility of mdn in combination with standard induction chemotherapy. Methods: We conducted a phase I study of azacitidine (75 mg/m2 iv X 7days) with escalating doses of oral mdn (25 mg bid, 50 mg bid, and 75 mg bid) days 8-21 of a 28 day cycle in untreated elderly and relapsed AML. The protocol was IRB approved at participating institutions and all patients gave written informed consent. Dose limiting toxicities (DLTs) were defined as ⬎ grade 3 non-heme toxicity during cycle 1 excluding grade 3 hepatotoxicity ⬍ 7 days, grade 3/4 stomatitis or diarrhea that resolved by day 28, infections, and electrolyte abnormalities of any grade. Pharmacokinetics (pK) were obtained on day 8,15, and 21 before mdn dosing. Results: 17 pts (11 females and 6 males) ages 57-83 ( median 73) were enrolled of whom 5 patients had prior intensive treatment for AML. All pts were FLT3 negative; 5 had normal cytogenetics and 12 had high risk cytogenetics. ECOG PS: 0 (4pts), 1 (11pts), 2 (2pts). No DLT were observed during escalation or in the expansion cohort of 75 mg bid. Responses were evaluable in 14/17 pts and included 2 CR, 1 PR, and 2 HI (clearing of peripheral blasts, platelet tx independence). Median survival from enrollment was 3.5 months (range 1-12 months). 4 pts remain on treatment (2- 9⫹ cycles). 3 pts died within 60 days (2 PD, 1 treatmentrelated). Non-infectious, non hematologic SAE’s are listed on the table below. Plasma concentrations of mdn accumulated in the first week of treatment and declined thereafter despite continued dosing. Conclusions: The combination of azacitidine and midostaurin in safe and tolerable in elderly AML and should be further studied in FLT3 positive leukemia. Clinical trial information: NCT01093573. Toxicity

Cycle1

Hyponatremia Alb Nausea/vomiting Bowel perf Pain Pneumonia Hepatotoxicity # pts

7060

2 1

1 1 17

Cycle 2

Cycle 3

Cycle 4

1 1 1 1 1 1 13

1 1 1 1 5

4


Chemokine receptors as novel targets of the oncogene Notch1 in acute lymphoblastic leukemia. Presenting Author: Leonardo Mirandola, Texas Tech University Health Sciences Center and the Southwest Cancer Treatment and Research Center, Lubbock, TX Background: Malignant cells from different cancers express different profiles of chemokine receptors (CKR). Their presence may influence site-specific spread of tumor cells, by enabling them to respond to chemokine gradient, and may increase cell sensibility to chemokine mediated proliferative and anti-apoptotic stimuli. Notch ability to positively regulate CKR has been reported: stimulation of Pax5-/- pre-B cells with the Notch ligand Delta-1 results in induction of transcripts for CCR4, CCR8 and CXCR 6; the Delta-1-dependent regulation of Langerhans cell development includes induction of CCR6 expression resulting in the activation of chemotactic response to MIP-1a; Notch controls CCR7 signaling a regulator of CNS infiltration in T-acute lymphoblastic leukemia (T-ALL). Methods: This work aims to explore the correlation between the activation of the Notch oncogenic pathway in T-ALL and multiple myeloma (MM) cells and the aberrant expression CKR. Human T-ALL cell lines were treated with the Notch activation inhibitor, DAPT, or with a potent inhibitor of the Notch target, C-MYC, and evaluated the expression and functions of CCR9, CCR5, and CXCR4. Results: Treatment of human T-ALL and MM cell lines with pharmacologic inhibitors of Notch receptor activation produced a significant reduction of CCR9, CCR5 and CXCR4 expression, at both mRNA and protein levels. Results were confirmed by chemotaxis and survival assays. We identified the product of C-MYC gene as a possible mediator of Notch effect in regulating CKR networks in T-ALL and MM. Conclusions: These results suggest that Notch receptors play a previously unknown role in cancer progression and metastasis, by maintaining the expression levels of CKR. In conclusion, the identification of the potential axis Notch/CKR could have a prognostic value and provide the rationale for a tailored approach, since both Notch and CKR are targeted by emerging drugs.


440s 7061


Outcome of pregnancy in women on imatinib for CML. Presenting Author: Sadashivudu Gundeti, Nizam’s Institute of Medical Sciences, Hyderabad, India Background: The use of imatinib (IM) now offers most patients with CML lengthy remissions and the hope of normal life expectancy. Majority of our CML patients are in the reproductive age group, and these improved survivals have resulted in issues relating to fertility and procreation. There is limited literature on the outcomes of pregnancy in women who continued IM during conception and through antenatal period. Methods: All women with CML who wished to conceive were counselled about the risks of pregnancy while on IM. They were given the choice of termination or stopping IM until delivery or continuing on IM with attendant risk to mother and baby. The records of all patients with CML treated with IM at our institute were retrospectively analysed over a period of 10 years. A total of 28 pregnancies in 25 women were documented. Only those women who were exposed to imatinib during conception and first trimester were included for this analysis. We report the outcome of 24 pregnancies in 22 women who had continued on IM in antenatal period. Results: Of the total of 24 pregnancies, 23 occurred in chronic phase and 1 in Blast phase. 21 of these conceptions occurred at IM dose of 400mg/ day, 1 at 600mg/ day and 2 at 800mg/ day. The median age at conception was 24.5 years (19-38). Mean time on IM at conception was 24.25 months (3-81). 19 patients (86.4%) were in CHR at conception and 11 of 22 patients (50%) attained complete cytogenetic response. The mean exposure to IM during pregnancy was 18.08 weeks (6-39 weeks).After explaining the pros and cons of continuation of pregnancy 6 women had stopped IM and 7 patients opted for termination of pregnancy. Conclusions: IM at higher dose appears to increase the risk of fetal loss. IM at standard dose of 400 mg does not appear to increase the incidence of congenital malformations or worsen foetal outcome. Outcome of pregnancy (N ⴝ 24). Full term gestation with normal babies Preterm deliveries

8

Congenital anomalies Intrauterine deaths MTP Spontaneous abortions Ongoing Lost to follow-up

7063

3 (2 babies died within 12 hours of birth – both exposed to IM dose 800) (1 live baby with cerebral palsy – IM dose 400) 1 (Male, born at 24 weeks, death ⬍24 hrs, Imperforate anus – IM dose 400) 1 (at 7 months – IM dose 600) 7 1 (IM dose 400) at 10 weeks 2 1 (IM dose 400)


Safety and durability of ponatinib in patients with Philadelphia chromosomepositive (Phⴙ) leukemia: Long-term follow-up of an ongoing phase I study. Presenting Author: Michael J. Mauro, Oregon Health & Science University Knight Cancer Institute, Portland, OR Background: Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) that is active against native and mutated forms of BCR-ABL. The safety and anti-leukemic activity of ponatinib in patients (pts) with chronic myeloid leukemia (CML) or Ph⫹ acute lymphoblastic leukemia (ALL) were evaluated in a phase I clinical trial. Methods: Pts (N⫽81) with resistant/refractory hematologic malignancies were enrolled in this ongoing, open-label, dose escalation, phase I study. Ponatinib was dosed once daily (2– 60 mg). 65 pts had Ph⫹ leukemia and are included in the present analysis (data as of 9 Nov 2012). Median follow-up was 25 (0.5– 44) mos. Results: The median age of pts was 55 yrs; median time since diagnosis was 6.5 yrs. Pts were heavily pretreated (94% had received ⱖ2 prior TKIs, 62% ⱖ3). 65% had baseline BCR-ABL mutations. 46% (67% chronic phase [CP] CML) of pts remained on study. Progression and adverse events (AEs) were the most common reasons for discontinuation (17% each). The most common treatment-related AEs were rash (42%), thrombocytopenia (34%), arthralgia (20%), and increased lipase (20%). Significant anti-leukemic activity was observed (Table). Responses (major cytogenetic response [MCyR] for CP-CML or major hematologic response [MaHR] for accelerated phase [AP] CML, blast phase [BP] CML, or Ph⫹ ALL) were observed against the following mutations detected in ⬎1 pt at baseline: 14/19 T315I, 4/7 F317L, 2/4 G250E, 2/2 M244V, 2/2 M35IT, and 1/2 F359V. Among CP-CML pts, 73% with complete cytogenetic response (CCyR) and 63% with major molecular response (MMR) are estimated to maintain response at 2 yrs (Kaplan-Meier). Of 28 CP-CML pts with CCyR, 25 remained on study (19 with continuous CCyR); of 22 pts with MMR, 21 remained on study (15 with continuous MMR). Updated data will be presented. Conclusions: Significant and durable responses were observed in heavily pretreated CP-CML pts, regardless of mutation status, and ponatinib was generally well tolerated. Clinical trial information: NCT00660920.

MaHR, % MCyR, % CCyR, % MMR, % a

CP-CML Nⴝ43

AP-CML Nⴝ9

BP-CML Nⴝ8

Phⴙ ALL Nⴝ5

NA 72 65 51a

44 22 22 11

25 38 13 NA

40 40 20 NA

7062


Genetic and cytokine profiles associated with symptomatic stage of CLL. Presenting Author: Amit Balkrishna Agarwal, University of Arizona College of Medicine, Tucson, AZ Background: Pathogenesis of symptomatic CLL involves genetic changes associated with the CLL clone and changes within the microenvironment which contribute to chemo-resistance. To further understand these processes we compared early stage CLL to symptomatic late stage CLL using gene expression profiling as well as serum cytokine profiling for a better insight of the genetic and microenvironment changes associated with the most severe forms of the disease. Methods: We obtained pretreatment blood samples from CLL patients (10 low stage and 14 high stage) at the time of diagnosis. Patients were classified as low stage (Rai stage 0/I/II) and high stage (Rai stage III/IV). Gene expression profiles were obtained on a subset of patients using the HG-U133A 2.0 Affymetrix platform and analyzed for differential gene expression profiles. Serum from a subset of patients was used to perform cytokine profiling using the Raybiotech Cytokine Array platform (AAH-CYT-G1000) that allows for simultaneous measurement of ⬎100 different cytokines. Results: Comparison of low versus high stage CLL revealed a set of 21 differentially expressed genes. 15 genes were up regulated in the high stage versus low stage, while 6 genes were down regulated. GO Molecular function analysis revealed that 9 of the 21 genes are involved in transcription factor activity. Other genes up regulated in the high stage group include CSNK1- shown to be involved in Myc derived oncogenesis and SETD8- a histone lysine methyltransferase previously implicated in several cancers. Serum cytokine profiles showed 6 cytokines to be significantly different in high stage patients. Two chemokines SDF-1/CXCL12 and uPAR known to be involved in stem cell mobilization and homing are increased in the serum of high stage patients. IGFBP-2, BMP-4 and MCP-4 were lower among high stage patients. Conclusions: Our study revealed a novel group of transcription factors are associated with higher stage CLL. Cytokine profiling showed increased levels of SDF-1/ CXCL12, a chemokine that plays a key role in mobilization and homing of hematopoietic stem and CLL cells in high stage patients. Our study identifies putative therapeutic targets including CSNK1, SDF-1 and SETD8 for patients with high stage CLL.

7064


Effect of obesity on overall survival in patients diagnosed with chronic myelomonocytic leukemia (CMML). Presenting Author: Dima Alfakara, Mayo Clinic, Rochester, MN Background: Obesity is a growing medical challenge that has strong association with many comorbid diseases. Body mass index (BMI) is used as one indicator for obesity. A few papers have linked hematological cancers with a worse prognosis if obesity was present. Aim: to study the influence of obesity clinical outcome in patients (pts) with CMML. Methods: A retrospective chart review of pts with CMML at Mayo Clinic Rochester between 1994 –2011 was done. BMI was calculated at diagnosis or first time visit. Overweight was defined as BMI ⱖ25, while obesity as BMI ⬎30. IRB approval was obtained. Comparison between medians was done using Wilcoxon test, while survival estimates were calculated using Kaplan-Meier estimates via JMP software v.9. Results: We found227 pts with a median follow-up of 311 days, 68% of which weremales. Median age was 71 years, hemoglobin 11 gm/dL, white blood cells (WBC) 12x 109/L, and platelets 90x 109/L. Obese pts had a median age of 68 (p⫽0.0058), hemoglobin 11 gm/dL (p⫽0.0018), WBC 13.5 x 109/L, platelets 115x109/L (p⫽0.012), PB blasts 0, bone marrow (BM) blasts 3.5% compared to non-obese pts (73, 10, 11, 78, 0, 3%, respectively). Diploid cytogenetics were similar in both groups (68% vs 64%, respectively, p⫽0.54). Leukemic transformation into acute myeloid leukemia (LT) was found in 13% vs 10% (p⫽0.83). Overall response (OR) was 24% and 23%, respectively (p⫽0.2), when limited to hypomethylating agents OR was 33% vs 27%, respectively (p⫽0.62). Median OS was found to be similar (571 day vs 569 days, respectively, p⫽0.56). When compared, overweight pts had similar outcome to non-overweight. Median LT was 11% vs 15% respectively, OR was 21% vs 28% respectively (p⫽0.5), and OS was 571 days vs 549 days respectively (p⫽0.21). On a multivariate analysis age, hemoglobin, platelets, BM blasts%, gender, and obesity (p⫽0.048) were of a significant value for OS. Conclusions: When compared, both obesity and overweight did not affect demographic characteristics, overall response, or transformation into AML. When comparing median overall survival, obesity was not a significant factor, possibly due to short follow-up. However, on multivariate analysis obesity did have a negative impact on overall survival.

14 (33%) CP-CML pts achieved MR4; 8 (19%) achieved MR4.5.




7066

441s


Treatment response monitoring in chronic phase CML (CP-CML) patients receiving tyrosine kinase inhibitor (TKI) therapy in US Oncology network. Presenting Author: Kathryn S. Kolibaba, Compass Oncology, Vancouver, WA

Post hoc analysis of sustained efficacy/tolerability of >12 cycles of omacetaxine mepesuccinate in chronic myeloid leukemia (CML). Presenting Author: Delphine Rea, Service des Maladies du Sang, Hôpital SaintLouis, Paris, France

Background: To identify pts with TKI resistance in a timely manner, the National Comprehensive Cancer Network (NCCN) guidelines recommend monitoring pts at specific time points. We evaluated the relationship between NCCN guidelines and current treatment response monitoring patterns and outcomes of CP-CML pts in community practice. Methods: A retrospective longitudinal cohort study was conducted on newly diagnosed CP-CML pts initiating TKI therapy from Jan 1, 2008 to Dec 31, 2010. Data was extracted from the MSH/USON iKnowMed electronic health record database and chart reviews through Jul 31, 2012. Pts were stratified by presence of any cytogenetic monitoring by 12 mos or any molecular monitoring by 18 mos. Results: Of the 410 pts identified, 91% received imatinib and 9% received dasatinib/nilotinib. Median follow-up was 28 mos. Cytogenetic and molecular monitoring did not occur in 69% and 27% of pts, respectively. BCR-ABL mutation testing occurred in 10% of pts who were monitored for response. Pts ⱖ65 yrs old (vs ⬍65 yrs, p⬍0.01), with public insurance (vs private insurance, p⬍0.001), or with Karnofsky Score ⱕ80 (vs ⬎80, p⬍0.05) were less likely to have cytogenetic monitoring. Similar differences for age (p⬍0.05) and insurance (p⬍0.001) were seen for molecular monitoring. For pts with available monitoring results, 36% had complete cytogenetic response by 12 mos, and 59% had major molecular response by 18 mos. 4-yr overall survival (OS) rates were higher in pts with cytogenetic (98% vs. 89%, P⫽0.0003) or molecular (95% vs. 82%, Pⱕ0.0001) monitoring vs. those with no monitoring. Conclusions: In these CP-CML pts, 69% did not receive any cytogenetic monitoring by 12 mos and 27% did not receive any molecular monitoring by 18 mos. Obstacles related to monitoring may include age, payer status, and performance status. Pts that were monitored for cytogenetic and molecular responses had significantly higher OS rates at 4 yrs. Increasing the proportion of pts that are monitored according to NCCN guidelines in the community setting could improve patient outcomes.

Background: Subcutaneous omacetaxine mepesuccinate (OMA), a first-inclass cephalotaxine, inhibits protein synthesis independent of Bcr-Abl signaling. It showed clinical activity in 2 phase II, open-label CML trials, 1 in patients with a T315I Bcr-Abl mutation failing imatinib, and 1 in patients failing ⱖ2 tyrosine kinase inhibitors (TKIs). Methods: This post hoc analysis pooled patients with chronic phase (CP) or accelerated phase (AP) from the 2 trials. 28-day cycles of OMA 1.25 mg/m2BID were given ⱕ14 days for induction, ⱕ7 days as maintenance with dose delay/change as needed. Primary endpoints were major cytogenetic response (MCyR) for CP and complete hematologic response (CHR) for AP. Adverse events (AEs) were assessed. Results: Of 108 CP and 51 AP patients from the 2 trials, 31 (29%) CP and 7 (14%) AP patients received ⱖ12 cycles (Table). At baseline in the ⱖ12-cycle groups, most CP (median age 59 y) and AP patients (median age 67 y) had received hydroxyurea (17/31, 4/7) and ⱖ2 TKIs (22/31, 5/7), were not in CHR (22/31, 5/7), and were T315I positive (23/31, 3/7). As of March 31, 2012, 9 CP and 2 AP patients continued OMA treatment. Overall, mean days dosed per cycle were 6.1 for CP, 9.7 for AP; 5.3 and 8.9 at cycle 12. Grade 3/4 AEs occurred in 35/38 patients in this post hoc analysis, most in early cycles; 15/31 CP, 2/7 AP had grade ⱖ3 AEs first occurring at ⱖ12 cycles. Across all cycles, most common grade ⱖ3 AEs were thrombocytopenia (24/31 CP, 5/7 AP), anemia (16/31, 7/7), and neutropenia (17/31, 3/7).Nine patients receiving ⱖ12 cycles (5/31, 4/7) discontinued, most commonly due to disease progression (n⫽2). Conclusions: In this post hoc analysis of heavily pretreated CML-CP and CML-AP patients who had failed prior TKI therapy, efficacy was often durable for those who received OMA for ⱖ12 cycles. Most grade 3/4 AEs were hematologic and declined with time. Support: Teva BPP R and D, Inc. Clinical trial information: NCT00375219, NCT00462943.

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Do quality of life and physical function at diagnosis predict short-term outcomes during intensive chemotherapy in acute myeloid leukemia patients? Presenting Author: Narhari Timilshina, University Health Network, Toronto, ON, Canada Background: Intensive chemotherapy (IC) used to treat acute myeloid leukemia (AML) is associated with multiple short-term toxicities including mortality, particularly in older adults. Emerging data suggest that baseline quality of life (QOL) assessment and/or objective physical function tests may predict outcomes in oncology, although there are no data in AML patients. We investigated the association between baseline QOL and physical function with short-term treatment outcomes in adult and elderly AML patients. Methods: We conducted a prospective, longitudinal study of adult (age 18⫹) AML patients undergoing IC. Prior to starting IC, patients completed the EORTC QLQ-C30 and FACT-Fatigue in addition to physical function tests (grip strength, timed chair stands, and 2-minute walk test). Outcomes included 60-day mortality, intensive care unit (ICU) admission, and achievement of complete remission (CR). Univariate and multivariable logistic regression were performed to evaluate each outcome. Results: Of the 243 patients (median age 57.5 y), 56.7% were male and median Charlson comorbidity score was 0. 60-day mortality, ICU admission, and CR occurred in 9 (3.4%), 15 (6.2%), and 171 (70.4%), respectively. In univariate regressions, neither QOL nor physical function tests were predictive of 60-day mortality (all P⬎0.05), whereas cytogenetic risk group (P⫽0.04), ICU admission (P⫽⬍0.001), and remission status at 30 days (P⫽0.006) were. Fatigue was a significant predictor of ICU admission (p⫽0.02) whereas QOL and baseline physical function were not significant predictors. In univariate analyses, higher Charlson score was found to be a significant predictor of both ICU admission (P⫽0.01) and remission status at 30 days (P⫽0.002). Cytogenetic risk group was correlated with achievement of CR whereas neither QOL nor physical function were predictive (all P⬎0.05). Findings were similar when the subset of 96 elderly patients (age 60⫹) were examined. Conclusions: Baseline QOL and physical function tests in this prospective study were not associated with short-term mortality, ICU admission, or achievement of CR after the 1st cycle of chemotherapy.


Results of omacetaxine plus low-dose cytarabine (LD-araC) in older patients with acute myeloid leukemia (AML). Presenting Author: Tapan M. Kadia, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Older patients with AML have poor tolerance to intensive chemotherapy and poor prognosis. Omacetaxine is active in AML and is part of standard combination chemotherapy in China under the name of homoharringtonine. Methods: The aim of the study was to evaluate the efficacy of low intensity therapy with omacetaxine and LD-ara C in newly diagnosed older patients (⬎/⫽ 60 years) with AML or myelodysplastic syndrome (MDS). Older patients with AML not fit or who refuse intensive chemotherapy were eligible. Normal organ functions and performance status ⬍/⫽ 2 were required. Other eligibility criteria were standard. Induction therapy consisted of omacetaxine 1.25 mg/m2 subcutaneously twice daily for 3 days and ara-C 20 mg subcutaneously twice daily for 7 days. Maintenance therapy was with the same induction schedule, repeated every 4-6 weeks for up to 2 years. Dose adjustments for prolonged myelosupression or severe non-hematologic toxicities were made by reducing the number of days of omacetaxine (-1 day by level) and cytarabine (-1 to 2 days by level). Results: 30 patients have been treated, with a median age of 71 years (range 64-81); 60% were age 70 years or older. AML post MDS in 20%; chromosome 5 and 7 abnormalities were present in 23%. Overall, 9 patients achieved CR (30%), 5 had CRp (17%) and 1 had PR (3%), for an overall response rate of 50%. Induction mortality was noted in 4 (Day 5, 27, 27, and 70 from start of therapy; 13%); resistant disease in 8 (27%); too early in 4 (13%). With the median follow-up time of 10 months the median survival is 9.3 months and the estimated 1-year survival rate 42%. No serious drug related adverse effects were observed with the combination. Conclusions: Low-intensity therapy with omacetaxine ⫹ LD-ara C shows promising activity and is safe in older patients with AML not fit for intensive chemotherapy. Clinical trial information: NCT01272245.


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Result of APL treatment associated with more experience of centers and more treatment as consolidation. Presenting Author: Ardeshir Ghavamzadeh, Tehran University of Medical Sciences, Hematology-Oncology & SCT Research Center, Tehran, Iran

Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-␦,␥, in patients with relapsed/refractory CLL. Presenting Author: Manish R. Patel, Florida Cancer Specialists/Sarah Cannon Research Institute, Sarasota, FL

Background: The first line therapy strategy remains controversial in acute promyelocytic leukemia (APL) patients. Arsenic trioxide (AS2O3) approved in relapsed or resistance patients and recently studies reveals benefits of AS2O3in first line therapy. Regardless of these, important challenges are early mortality during remission induction and post treatment relapse. Methods: Between 2000 and 2012, patients suffered APL whose was new case and confirmed by t(15;17) translocation with RT-PCR, enrolled in study. Until 2007, patients received 28 days AS2O3(0.15 mg/kg iv) as induction and after 28 days rest, treatment continued for 2 courses of consolidation therapy with the same dose and after 2007, two additional consolidation courses, one and two year after start treatment, was added for prevent post treatment relapse. At beginning of 2nd and 3th consolidation, consider CSF cytology and RT-PCR for detection of APL cells and weekly CNS prophylaxis by MTX and cytarabine, IT chemotherapy start if needed. Patients received no other treatment. Results: Totally 271 patients enrolled in study. Ninety six patients received 3 dose and 175 patients received 5 dose of AS2O3. Fifty four (20%) patients died during remission induction before achieve remission. In recent years, early mortality rate reduced below 10% compared with more than 24% in the early years. With median follow-up of 30 months, 170 (78.4%) patients among 217 patients (whose survived after successful induction therapy) were alive (mortality rate: 21.6%) and 2.5-year overall survival and leukemia free survival was 85% and 73% respectively. The cumulative incidence of relapse in group which received three courses of AS2O3 and group which received five courses of AS2O3was 41.5% and 12.6%, respectively (95%CI: 2.5-9.6, P-value⫽0.0001). Conclusions: Currently according recent studies, AS2O3 has been considered as first line therapy in APL patients but either early mortality or post treatment relapse remain challengeable factors which affect treatment result. Expedite the referral of patients and improvement of emergencies care can reduce early mortality. The next step might be in order to achieve best treatment strategy for reduce post treatment relapse.

Background: Phosphoinositide-3-kinases (PI3Ks) are pivotal in cell signaling and regulate a variety of cellular functions relevant to oncogenesis. IPI-145, a potent oral inhibitor of the PI3KE␦ and PI3K-␥ isoforms, is in clinical development for patients (pts) with hematologic malignancies. Early results in pts with relapsed/refractory chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL) from an ongoing Phase I study are reported here. Methods: This dose-escalation study evaluates the safety, maximum tolerated dose (MTD), clinical activity, and pharmacokinetics (PK) of IPI-145. Expansion cohorts (EC) ⬍ MTD are allowed. IPI-145 is given orally twice daily (BID) in 28-day cycles. Tumor response is based on modified IWCLL guidelines criteria. Results: 55 pts have been dosed with IPI-145. PK, available through 50 mg BID, are linear with continuous 24 hr inhibition of pAKT (Ser473) in primary pt CLL cells after a single dose of 25 mg. In the 16 pts with CLL (5 pts in dose escalation ⬍ 25 mg BID and 11 pts in a 25 mg BID EC), the median [range] number of cycles was 2.7 [1–14] and 81% remain on study. Treatment-related adverse events (TRAEs) occurred in 10 (63%) pts with CLL, a similar incidence as seen in the total study population (56%). The most common ⬎ Grade 3 TRAE in pts with CLL was neutropenia (25%). No ⬎ Grade 3 ALT elevations occurred in pts with CLL. Among evaluable pts with CLL (n⫽11), 82% (n⫽9) had a PR or nodal response after 2 cycles of IPI-145, with a best response to date of 6 PR, 4 SD (all nodal responses), and 1 PD. Conclusions: IPI-145 appeared well tolerated and has shown clinical activity at the doses examined in pts with relapsed/refractory advanced CLL. The single agent MTD has not been determined and dose escalation continues. Updated safety and efficacy data from pts with CLL enrolled in dose escalation and ECs evaluating 25 mg BID and a higher dose (⬍MTD) of IPIE145 will be presented. Clinical trial information: NCT01476657.

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Quality of life (QOL) and physical function in one-year adult and elderly survivors of acute myeloid leukemia (AML). Presenting Author: Shabbir M.H. Alibhai, University Health Network, Toronto, ON, Canada Background: The treatment of AML with intensive chemotherapy (IC) is associated with significant short-term toxicities. We previously showed similar impairments in QOL and physical function among younger (age 18-59) and older (age 60⫹) patients with AML at diagnosis, with similar recovery over 3 cycles of IC. We now comprehensively describe QOL and physical function recovery over 1 year from diagnosis. Methods: Younger and older AML patients undergoing IC without stem cell transplant were enrolled in a prospective, longitudinal study. Assessments were done at baseline (pre-IC) and at 7 time points over the next year. At each visit, patients completed the EORTC QLQ-C30 and the FACT-Fatigue to measure QOL and fatigue, respectively, in addition to 3 physical function tests (grip strength, 2-minute walk test (2MWT), and timed chair stands). Analyses involved multivariable linear regression analyses stratified by age group. Results: 243 patients were recruited (147 younger and 96 older, 56% male). Attrition was greater in older adults due to death or disease progression/relapse. Among patients remaining in remission after IC, global QOL and fatigue improved significantly over time (p⬍0.001 for both); trends were similar between older and younger patients. All 5 QOL domains improved or remained stable over time; the greatest improvements were seen in social function and role function and were similar in both age groups. Grip strength increased slightly over time (p⫽0.04) whereas both timed chair stands (p⬍0.001) and the 2MWT (p⬍0.001) had moderate to large improvements, with trends toward greater improvement in younger patients (p⫽0.07 and 0.09, respectively). Results were similar when missing data were imputed. Conclusions: Survivors of AML after successful conventional chemotherapy achieve significant improvements in QOL, fatigue, and physical function over time. The course of recovery is remarkably similar in younger and older AML patients, although significant attrition in older adults is a noteworthy limitation. These data suggest that appropriately selected older patients do well following IC for AML.


Comparison of two major intergroup induction intensive regimens in Hispanic adolescent and young adults (AYA) with acute lymphocytic leukemia (ALL): The importance of a complete molecular response. Presenting Author: Carlos E. Vigil, Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru Background: Novel intensive chemotherapy regimens impacted in the prognosis of adolescent and young adult pts with ALL. The application of pediatric inspired therapies demonstrated complete response reported to be ⬎ 80%, and long-term survival rates range from 30% to 45%. In the past, ALL treatments had been designed on the presence of risk factors as elevated WBC, time to complete remission or immunophenotype. Recently, MRD monitoring had risen as a risk predictor. Hypothesis: Complete response(CR) associated with a CMR has impact in disease-free survival. Methods: Between March⬎ 2010 and November 2012, 101 adolescent and young adult pts were diagnosed and treated for (Ph)–negative ALL with the C10403 intergroup protocol (N⫽47) and the 2008 Spanish PETHEMA regimen (N⫽54). The residual disease status was assessed after induction by multiparametric flow cytometry (MRD ⬍0.1%). Results: The median age of the pts was 17.56 years (range, 14-24); with 69 pts (68%) ⱕ 18 year-old. 27 (26.7%) pts were WBC ⱖ 50x109/L, 63 pts (62%) B immunophenotype, cytogenetics was unknown in 69 pts. After the induction, the CR was achieved in 81% vs 79.6% pts ( Int C10403 vs Pethema, respectively ). The induction mortality rate was 0% vs 7%. Slow responders to induction chemotherapy were 23.81% and 28.8% respectively (p⫽0.591). A CMR (CR⫹MRD ⱕ0.1%) was seen on 70.21% vs 63.27%. The kaplan-meier 2-year disease free-survival rate calculated for CMR patients on C10403 was 35% vs 17% for the Pethema, which was statistically significant (p⬍ 0.04). A multivariate analysis of pts characteristics in CMR could not identified risk factors for disease prognosis. Conclusions: Two different regimens C10403 vs Pethema, could not demonstrate a statistic difference in morphological CR. Lately,the addition of minimal residual disease ⱕ0.1% (MRD) in the analysis, demonstrated a plausible monitoring variable of response. We suggest that a CMR (CR ⫹MRD at induction) could be a new standard variable to assess responses regardless of previous risk categories. Further validation may be mandatory.




Omacetaxine mepesuccinate in chronic phase chronic myeloid leukemia (CML-CP): A post hoc analysis of myelosuppression. Presenting Author: Luke Paul Akard, Indiana Blood and Marrow Transplantation, Indianapolis, IN Background: Omacetaxine mepesuccinate (OMA) was active in 2 CML trials of patients with T315I Bcr-Abl mutations or failing ⱖ2 tyrosine kinase inhibitors. Methods: Hematologic events/recovery were pooled from the 2 trials. OMA 1.25 mg/m2BID was given in 28-day cycles: ⱕ14 days induction, ⱕ7 days maintenance with dose delay/change as needed. Results: Of 108 patients, median exposure was 7.4 mos, with a median 3 cycle delays and 9 days dosing per patient. Of 91 patients receiving ⱖ2 cycles, 79 (87%) had ⱖ1 delay (366 delays in 729 cycles), most due to grade ⱖ3 thrombocytopenia. Median delay was longest early—peaking at 25 days in cycle 3. Predefined hematologic nadirs (see Table) were reached mostly in initial cycles and less after dose adjustments; 80 patients received blood products, 10 antibiotics. Most common lab grade 3/4 hematologic toxicities were thrombocytopenia (85%), neutropenia (81%), and anemia (62%). Grade 3/4 adverse events included 12 infections (6 treatment related, including 1 pneumonia, 1 sepsis) and 7 hemorrhages (1 related conjunctival, 1 postprocedural, 2 cerebral, 3 gastrointestinal [1 related]); 38 events were fatal (related: 1 pancytopenia, 2 sepsis, 2 unknown). There were 11 hematologic hospitalizations. Conclusions: In heavily pretreated CML-CP, myelosuppression was most common after initial OMA cycles, improved with dose adjustments, and rarely led to severe outcomes. Support: Teva BPP R&D, Inc. Clinical trial information: NCT00375219, NCT00462943. Cycles

Platelet sample, n pts Mean (SD) d to nadir Nadir 600 U/L (%) Cytogenetics – t(9,22) and t(4,11) (%) t(8,14) (%) Others (%) Histology Subtype Pre-B (%) Burkitt (%) T (%) CR rates (%) Resistant disease (%) Toxic death (%) Recurrence rate (%) Time to CR (days) Median OS (m)

HDAM arm

HyperCVAD arm

Entire cohort

62 38 43.5 58.1 8100 38.7 75.8 48.4 21.1 0 78.9 86.7 0 13.35 85.2 6.6 8.2 44.4 29 21.4

49 41 40.8 55.1 7310 49 81.6 55.1 11.1 8.9 80 59.2 14.3 26.5 84.1 13.6 2.3 39.5 (NS) (p⫽ 0.67) 27 (NS) 26.8 (NS)(p⫽0.72)

111 39 42.3 56.7 8050 43.2 78.4 51.4 16.5 4.1 79.4 74.3 6.4 19.3 84.8 9.5 5.7 42.4 29 22.7


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Results of a phase I trial of the proteasome inhibitor carfilzomib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). Presenting Author: Jennifer Ann Woyach, The Ohio State University, Columbus, OH Background: CLL is an incurable malignancy, and survival for patients (pts) with relapsed disease is limited. Carfilzomib (CFZ) has shown efficacy in multiple myeloma, and our group has shown significant in vitro activity in primary CLL cells. Therefore, we have undertaken a phase I trial of this agent in CLL. Methods: This is a single institution phase I trial of CFZ in pts with relapsed or refractory CLL. Primary endpoints were to determine maximal tolerated dose (MTD) and describe toxicity. Pts with CLL relapsed after at least one therapy were enrolled using a 3x3 design. CFZ was administered on the standard myeloma schedule. The first two doses were administered at 20 mg/m2 with remainder given at doses starting at 27 mg/m2 for dose level 1 with escalation to 56 mg/m2. Results: 17 pts received at least 1 dose of CFZ. 12 pts completed at least 1 cycle of therapy, with the remaining 5 experiencing PD during cycle 1. The MTD was not reached, with 3 pts accrued to each dose level to the maximal dose tested without dose limiting toxicity. Most adverse events (AE) were grade (G) 1 or 2. G3/4 AE were quickly reversible and included G3 neutropenia (4 pts), G4 neutropenia (2), G3 febrile neutropenia (1), and G3 thrombocytopenia (3). G1/2 toxicities observed in ⱖ 20% of pts included anemia (10), thrombocytopenia (7), and hypocalcemia (8). Median number of cycles was 3, with 9 pts achieving stable disease after 2 cycles. Of 3 pts enrolled at maximal dose level, 2 remain on therapy after 5 and 7 months, with 1 achieving a clinical partial response. Of 5 evaluable pts, at least 50% proteasome inhibition was seen in all at 1 hour, with minimal recovery at 24 hours. PK was best characterized by a two-compartment model. Maximum plasma concentrations across all dose levels ranged from 0.81 to 8.1 uM. Across the evaluated dose range, area under the curve increased in an apparent dose-proportional manner. Conclusions: Despite relatively limited efficacy in this study, CFZ has acceptable toxicity in CLL, with no MTD identified up to 56 mg/m2. This suggests that CFZ may be better studied in CLL using a different schedule or in combination with other active agents. Clinical trial information: NCT01212380.

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The role of salvage induction chemotherapy after azacitidine (AZA) treatment failure. Presenting Author: Karen W. L. Yee, Princess Margaret Cancer Center, Toronto, ON, Canada Background: Hypomethylating agents (HMA) such as AZA, are considered standard of care for patients (pts) with IPSS Int-2 or High-risk MDS. These agents are not curative. Many centers have used HMAs as a bridge to alloSCT in pts with MDS in an attempt to reduce tumor burden and prolong time to progression to AML. However, pts are at risk of AZA treatment failure, which may delay or prevent subsequent alloSCT. Recent data have demonstrated poor responses to intensive chemotherapy after AZA failure [ORR of 0% (0 of 4 pts) to 14% (3 of 22 pts) (J Clin Oncol 2011; Br J Haematol 2012)]. Methods: This retrospective analysis evaluates the outcomes of 18 pts with MDS, CMML and AML, who failed AZA therapy, and subsequently received induction chemotherapy at the Princess Margaret between July 2009 and December 2012. Results: Median age was 57.7 y (range, 19 - 75 y); only 1 pt was ⬎ 70 y. 56% were male. Of the 18 pts, 83% were treated for MDS, 6% CMML-2, and 11% AML. IPSS was Int-2/High-risk in 16 pts and Int-1 risk in 2 pts. 83% of pts had been treated with AZA as first-line therapy. Two pts had received growth factors & 1 pt hydroxyurea prior to AZA. Median number of AZA cycles administered was 5.5 (range, 1 - 18) with 72% of pts receiving ⬍ 6 cycles. Eleven (61%) pts had primary AZA failure, 5 (28%) secondary AZA failure, and 2 (11%) were taken off AZA to receive induction chemotherapy as an HLA-identical donor was found. At the time of induction chemotherapy, 15 pts had s/tAML, 2 RAEB-2 and 1 CMML-2. Cytogenetic risk was intermediate in 4 and poor in 11 pts, respectively. Karyotype analysis was not done or inconclusive in 3 pts. ORR was 44% and 37.5% in all pts and in AZA failures only, respectively. CR rate was 22% and 25%, CRi 27% and 12.5%, and MLFS 6% and 0% in all pts and in AZA failures only, respectively. Four pts died during induction. Four of 8 responders received an alloSCT, with the remaining 4 pts relapsing (3 while awaiting an alloSCT). Median F/U of all pts was 12.6 mos, with a median OS of 8.3 mos. Conclusions: Contrary to prior reports, salvage induction chemotherapy can yield responses in a significant number of pts who have failed AZA therapy. However, response duration and OS remain poor for AZA treatment failures. There is an unmet need for novel therapeutic agents in this group of patients.

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Plasma trough imatinib levels and molecular response in patients of chronic myeloid leukemia (CML): A single institution study from India. Presenting Author: Hemant Malhotra, Birla Cancer Center, SMS Medical College Hospital, Jaipur, India

Phase I study of NRC-an-019, a tyrosine kinase inhibitor, in imatinibresistant chronic myeloid leukemia (CML) in an Indian tertiary care hospital. Presenting Author: Raghunadharao Digumarti, Nizam’s Institute of Medical Sciences, Hyderabad, India

Background: One of the reasons proposed for suboptimal responses in Chronic Myeloid Leukemia (CML) patients receiving standard-dose Imatinib has been low blood levels of the drug. Our study aimed to determine the correlation between mean trough Imatinib plasma levels and molecular response in CML chronic phase patients at our centre. We also attempted to compare imatinib plasma levels in patients receiving Gleevec (Novartis) versus patients who were on the generic version of the drug. Methods: One hundred and thirty one (131) CML Chronic phase patients were included in this study. All patients had received 400 mg of imatinib for more than 2 year. Plasma Imatinib trough levels were estimated by high-performance liquid chromatography (HPLC). In order to estimate a threshold for plasma imatinib level that correlates with a favorable response, a receiver operating characteristic (ROC) curve was constructed. Patients were divided into two groups: those with Major Molecular Response (MMR) [bcr/abl : abl ratio ⬍1% as assessed by RQ-PCR] or better (Responders) and those without MMR (bcr/abl : abl ratio ⫽/⬎ 1% as assessed by RQ-PCR) [Non Responders]. Imatinib plasma levels were also compared in patients who were on Gleevec versus those who were on the generic version of the drug. Results: The mean trough imatinib plasma level in the responders was significantly higher (2.10⫾1.18␮g/ml) than in the non responders (1.31⫾0.72␮g/ml) with p value of 0.001. The area under ROC curve was 0.733, with best sensitivity (51.85%) and specificity (89.42%) at a plasma threshold of 0.988 ␮g/ml. There was no significant difference between the mean trough plasma imatinib levels of the patients who were on Gleevec as compared to those who were on generic Imatinib (p value ⬎ 0.05). Conclusions: Plasma Imatinib trough levels were statistically similar in the Gleevec and generic Imatinib groups. These levels showed a statistically significant correlation with molecular response. Trough plasma imatinib levels may be a marker for suboptimal response to Imatinib and may identify patients in whom increase of drug dose or change to second generation tyrosine kinase inhibitors may be indicated.

Background: NRC-AN-019 is an orally administered tyrosine kinase inhibitor (TKI) of the Bcr-Abl protein-tyrosine kinase. The drug was given to patients as a ready-to-use liquid formulation. Methods: The primary objectives of the Phase-I study were to estimate the Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD) of NRC-AN-019 and also to establish the safe dose for Phase II clinical trial. The secondary objectives were to study the pharmacokinetic properties and antileukemic activity of NRC-AN-019. Philadelphia positive CML patients in all phases, in the age group of 18-65 years were eligible. They had to be resistant or intolerant to Imatinib, with ECOG ⱕ 2. Dosing was initiated at 50 mg/day and dose escalation was done in increments of 50 mg per each additional cohort. The maximum dose administered was 450 mg/day. The protocol-specific study duration was 30 days; patients continued to receive the study drug subsequently based on Investigator’s decision. Results: A total of 30 patients were enrolled (3 at 50 mg, 4 at 100 mg, 3 at 150 mg, 3 at 200 mg, 4 at 250 mg, 4 at 300 mg, 3 at 350 mg, 3 at 400 mg, and 3 at 450 mg). DLT was not observed and MTD was not reached. The recommended Phase II-A dose is 300 mg/day, with a scope for escalation up to 450 mg/day. The maximum plasma concentration of NRC-AN-019 was 9,342 ng/mL and AUC was 1,262,191 ng.hr/mL. Common adverse events were skin rash, nausea, and vomiting. Hematological response was observed in 11 patients, cytogenetic response in 7 patients and molecular response in 5 patients. The maximum duration a patient has been on NRC-AN-019 is 863 days. Conclusions: Based on the Phase-I data, NRC-AN-019 showed considerable safety and response; it could be a potential treatment option for imatinib-resistant CML. Clinical trial information: CTRI/2009/091/ 000204.




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Clinical features and outcome of T-cell acute lymphoblastic leukemia in patients older than 9 years: A single center experience of 110 patients from AIIMS, New Delhi, India. Presenting Author: Sunu lazar Cyriac, All India Institute of Medical Sciences, New Delhi, India

Clinical features and outcome of B-cell acute lymphoblastic leukemia in patients older than 9 years: A single center experience of 241 cases from AIIMS, New Delhi, India. Presenting Author: Atul Sharma, All India Institute of Medical Sciences, New Delhi, India

Background: It is known that T cell acute lymphoblastic leukemias (ALL) have poorer outcomes than their B cell counterparts. Data on T-ALL in the age group of ⬎9 years from India is minimal. Methods: This is a single institutional analysis of patients of above 9 years who were treated from January 2000 to December 2010. All patients who completed at least 4 weeks of induction therapy were analysed for various outcomes. Results: T-ALL formed 30% of all ALL in this age group. Of the 110 newly registered patients of T-ALL, the median age was 17 years (Range 10-50 years) with an M:F ratio of 5.9:1. Of this 62%, 30% and 18% patients belonged to 10-18, 19-30 and ⬎ 31 years age group respectively. Eighteen (19%) and 2 (2%) and 33 (30%) had CSF, testicular and other extramedullary sites involvement respectively. Twenty eight per cent had a total leucocyte count (TLC) of above 100x109/L. Patients available for survival analysis were 104(94.5%). Complete remission (CR)rate was 68.2% and induction mortality was 14.4%. At a median follow up of 56.4 months 5 year leukemia free survival was 52.3% (median not attained). Twenty seven (38%) patients relapsed (median relapse time of 15.2 months, range 0.7 to 47.3 months), 55% during maintenance phase. The 5 year overall survival (OS) was 46.9% (median OS of 35.4 months). The 5 year OS of 10-18, 19-30 and ⬎ 31 years age groups were 42.8%, 71% and 16.6% respectively (p value not significant). Not attaining CR in 1st induction, spontaneous tumor lysis syndrome and peripheral blood blast count of ⬎ 80% were significant poor prognostic factors for survival. Conclusions: This is one of the largest study of T-ALL outcomes in patients above 9 years from a single center from India. Attainment of CR in 1st induction was the most important risk factor for survival. 5 year OS was 47%.

Background: Data on B cell Acute Lymphoblastic leukemia (ALL) in the poor prognostic age group of ⬎ 9 years from India is minimal. Methods: This is an analysis of patients of above 9 years that were diagnosed and treated from January 2000 to December 2010 at a single institute . All patients who completed at least 4 weeks of induction therapy were analysed for various outcomes. Results: Of the 241 newly registered patients, the median age was 19 years (Range 10-78 years) with an M:F ratio of 1.9:1. Out of this 47%, 25% & 28% patients belonged to 10-18, 19-30 & ⬎ 31 years age group respectively. Twenty seven (11.6%) and 5(2%) had CSF and testicular involvement respectively. Thirty nine per cent had a total leucocyte count (TLC) of above 30x109/L. Philadelphia chromosome (Ph) positivity was seen in 27% and was equally distributed among the different age groups. Patients available for outcome analysis were 213(88.4%). Complete remission rate (CRR) was 66.6% and induction mortality was 26.3%.At a median follow up of 65.8 months 5 year leukemia free survival was 30.5%. Seventy eight (55%) patients relapsed (median relapse time of 13.5 months, range 1.7 to 53.4 months) , 55% during maintenance phase. The 5 year overall survival (OS) was 30.3% with a median OS of 15.8 months. The OS was similar in 10-18 and 19-30 age groups (5 year OS 35% vs. 27.5%, p⫽0.641) but it was significantly lower in ⬎31 years (5year OS 21%, p⫽0.008). Apart from this, extramedullary disease, not attaining a CR in 1st induction, albumin at presentation below 3.5gm% and TLC of ⬎100x109/L were significant poor prognostic markers for survival. Conclusions: This is a large study of B-ALL outcomes in patients above 9 years from a single center in India. Patients above 30 years had a worse prognosis while the prognosis of 10-18 and 19-30 years age group were similar. Induction mortality was higher mainly because of advanced disease and poor performance status at presentation.

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7084


Study of different mutations in chronic myeloid leukemia in India and their co-relation with drug resistance. Presenting Author: Priti Mitra, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata, India Background: Emergence of ABL point mutations is the most frequent cause for imatinib resistance in CML. Aim of our study is to investigate two potential resistance mechanisms i.e.,mutations of BCR-ABL tyrosine kinase domain (TKD) and Additional Chromosomal Abnormalities during TKI treatment in CML. Methods: Karyotyping and BCR-ABL TKD mutation screening are performed in 100 imatinib resistant CML patients who were on imatinib at the time of loss of hematologic response, cytogenetic or molecular response. Imatinib–Resistance Mutation Analysis (Qualitative) were detected by Nested RTPCR and Sanger’s Sequencing. In 100 cases, 34 received escalated imatinib, 34 nilotinib and another 32 dasatinib. Results: In 100 BCR-ABL positive imatinib, nilotinib and dasatinib resistant cases, 11 different BCR-ABL TKD mutations were detected. Analysis revealed no mutations-43 cases, M351T-12 cases, G250E-10 cases, F317L-8 cases, M244V-5 cases, E255K-4 cases, V379I-4 cases, F359V-3 cases, H396R-3 cases, Y253F-3 cases, E355G-3 cases, T315I-2 cases. 11 novel mutations (F317L, G250E, M244V, Y253F, E255K, M351T, F359V, H396R, V379I, E355G, T315I) conferring imatinib resistance, 10 nilotinib–resistant mutations (M244V, F359V, T315I, E355G, G250E) and 8 dasatinib-resistant mutations (H396R, F317L, H396R, T315I, M351T) were seen in our patient population. T315I was found more frequently in cases on dasatinib than on imatinib therapy. Conclusions: T315I which confers resistance to all TKIs was detected only in 2/100 patients who demonstrated loss of response in our population. As compared with other western studies, incidence of T315I mutation was very low in our study. In addition analysis of mutation patterns at baseline may help in stratifying patients for treatment. For cases with TKI resistance, mutation and ACA screening may play role in identifying patients with poorer prognosis. In our practice if nilotinib–resistant mutation was detected, dasatinib was preferred and for dasatinib-resistant mutation, nilotinib was preferred. We are planning for using bosutinib, panotinib and omacetaxine (SC route) in third line therapy in imatinib resistant different mutation positive chronic myeloid leukemia.


Hypomethylating agents as first-line therapy in acute myeloid leukemia (AML). Presenting Author: Samuel D Bailey, University of Kentucky, Lexington, KY Background: Hypomethylating agents are used in older AML patients (pts) who are not considered candidates for standard induction therapy. However, data regarding their efficacy remains unclear. Methods: We retrospectively evaluated a cohort of 24 consecutive AML pts who were placed on hypomethylation therapy at diagnosis between October 2010 and June 2012 at Markey Cancer Center. Results: Baseline characteristics of the patients are described in table 1. Response rate (CR⫹PR) was 45.8%. Median number of infections were 1 (8 pts), 2 (5 pts), 3 (4 pts).Median hospital admissions required were 1 (10 pts), 2 (4 pts), 3 (5 pts), 4 or greater (2 pts). Average length of hospital stay was 10.3 days (0-37 days). Median units of packed red cell and platelet transfusions were 10 and 11 units (Range⫽0-64 and 0-78) respectively. After a median follow up of 145.5 days, 13 pts had died. Cause of death was AML (6 pts), infection and end organ failure (7pts).Median overall survival (OS) was 9.7 months (95%CI: 3.2-16.5 months). On multivariate analysis, blast count less than 30% was borderline significantly associated with better OS (P⫽0.05). However after addition of average hospital stay in the model only age (HR⫽1.3, CI⫽1.061.67), gender (HR⫽11.5, CI⫽1.2, 110.5), and average hospital stay were significantly associated with OS (HR⫽1.2, CI ⫽ 1.04- 1.32). Conclusions: In this cohort of pts the median OS was 9.7 months. Older pts and those with longer average hospital stay had a higher mortality. Better selection of pts in a larger cohort who are likely to gain more benefit from these agents may impact outcomes. Baseline characteristics. Age (years) Blast % WBC at presentation (k/ul) Hemoglobin at presentation (g/dl) Platelets at presentation (k/ul) Creatinine (mg/dl) Male Comorbidity Index 0/1 Blast presentation, < 30% Therapy Decitabine Decitabine ⴙ azacitidine Azacitidine Cytogeneticsa Complex Intermediate Other

Median

(Min, Max)

69 39% 3.7 9.6 54.5 1.06

(44, 82) (20%, 85%) (1.3, 387) (6.0, 12.7) (11, 336) (0.51, 4.71)

N 13 15 10

% 54.2% 62.5% 41.7%

17 2 5

70.8% 8.3% 20.8%

12 6 6

50.0% 25.0% 25.0%

a Complex⫽Deletion 7q, Complex; Intermediate⫽ del(9)(q13q22), Normal; Other⫽ Trisomy 10, Trisomy 8, Unknown.


446s 7085


7086


mTOR inhibition in MDR acute myeloid leukemia. Presenting Author: Aditi Karmakar, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata, India

Variation in health-related quality of life (HRQOL) by line of therapy, age, and gender among patients with chronic lymphocytic leukemia. Presenting Author: Christopher Flowers, Emory University, Atlanta, GA

Background: Signaling through the PI3K/PTEN/AKT/mTOR pathway is aberrantly activated in several human cancers, including Acute Myeloid Leukemia (AML) patients where it contributes to leukemic cell proliferation, survival and drug resistance. In leukemia patients treated with drugs such as anthracyclines, vinca alkaloids, chemo-resistance one of the major problems contributing to therapeutic failure, where all this drugs are modulated in their intracellular retention by a 170 kDa Phosphoglycoprotein, an mdr-1 gene product. The role of mTOR in various processes such as proliferation, growth, has been comprehensively described in many reviews, following its inhibition by rapamycin. Thus inhibition of mtor signaling in AML blasts could account for enhancing their sensitivity to cytotoxic agents. This study is to embrace the effect of Rapamycin, an allosteric mTOR inhibitor on MDR AML patients. Methods: We selected samples of 25 MDR AML patients isolated from bone marrow or peripheral blood and cultured in vitro. The effects of Rapamycin on fresh AML samples were analyzed by treating the cells with intermediate drug concentrations (100 nM) for 24 h, 48 h, 72 h, 96 h respectively followed by cytotoxicity assay (MTT assay). The effects of the drug on proliferation of cells were analyzed also by cell counting. Results: A marked reduction in cell viability at 96 h was detected in 25 samples treated with rapamycin. Out of the 25 analyzed samples, 16 were sensitive to the drug where it was observed that the leukemic cell count came down to almost 2% whereas 9 samples displayed various degree of resistance to the drug. Overall, these findings demonstrated that rapamycin has a cytotoxic activity against primary cells from AML patients with up-regulated mTOR signaling. Conclusions: We have evaluated the in vitro effects of Rapamycin on AML patient samples where reduced cell viability primary cells from AML patients were observed. However, further studies of the additional effects of rapamycin will be of the supreme importance, as they could help in designing more efficient curative protocols, for the treatment of acute leukemia patients.

Background: The HRQOL of patients (pts) with chronic lymphocytic leukemia (CLL) has not been adequately delineated across patient, disease and treatment characteristics. We evaluated HRQOL of CLL pts undergoing treatment in the United States (US) by age, gender and line of therapy. Methods: Data were collected in Connect CLL, a prospective observational US registry. Physicians provided data on demographics, clinical characteristics and line of therapy at enrollment. HRQOL was self-reported by pts at enrollment using the Functional Assessment of Cancer Therapy-Leukemia, an instrument that yields a leukemia-specific total HRQOL score (FACTLeu) and a cancer-specific total HRQOL score (FACT-G). Mean total scores were analyzed by line of therapy, age and gender. Statistical significance was ascertained by ANOVA using SAS 9.2. Multivariate analyses were conducted to assess the relative association of line of therapy, age and gender with HRQOL. Results: Among 1,252 pts enrolled from 161 geographically diverse centers (90% community, 8% academic, 2% veterans/military), pts were predominantly male (63%), white (89%) with mean age 69 yrs. Pts were categorized by line of therapy at enrollment: First 61%, Second 18%, Third 11%, Higher 9%; and by age group: ⬍65 33%, 65-74 35%, 75⫹ 32%. Univariate analyses suggested that the total FACT-Leu score was significantly better in men than women (P⫽0.004); in pts aged 65-74 vs younger or older pts (P⫽0.033); and in pts initiating first-line treatment vs pts receiving subsequent treatments (P⫽0.0002). Similar results were found with the FACT-G score except that gender differences were not statistically significant. Multivariate analysis confirmed that line of therapy (P⫽0.007), gender (P⬍0.0001), and age group (P⫽0.039) were each associated with significant differences in the FACT-Leu total score. Conclusions: Results from the Connect CLL Registry indicate that HRQOL is better among pts initiating first-line therapy compared to pts initiating subsequent treatments, and that this remains true when age and gender are considered. Future analyses should determine how HRQOL may change over time relative to treatment and treatment response.

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Apoptosis induction mediated through PI3-kinase/AKT/mTOR pathway using anti-ROR1 monoclonal antibody in chronic lymphocytic leukemia cells. Presenting Author: Amir Hossein Danesh Manesh, Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden Background: The PI3K/AKT/mTOR is a central pathway activated in many types of cancer. Mammalian target of rapamycin (mTOR) is a serine/ threonine protein kinase regulating cell growth, proliferation and survival. In CLL cells PI3K pathway is constitutively activated leading to AKT activation with subsequent phosphorylation of other downstream signaling molecules. ROR1 is a type I transmembrane RTK, overexpressed and constitutively phosphorylated in CLL. A unique anti-ROR1 mAb directed against CRD region of ROR1 was capable of inducing direct apoptosis as well as dephosphorylating the ROR1 molecule. Here, we investigated the apoptotic effect of the anti-ROR1 mAb and effects on the PI3K/AKT/mTOR pathway using primary CLL cells. Methods: Apoptosis was detected by the MTT assay and Annexin V/PI methods in a 24 h assay. Antibody untreated and treated cell lysates were prepared and subjected to Western blot analysis for identification of the signaling molecules involved in apoptosis induced by the ROR1 mAb. We analysed total and phosphorylated levels of the following signaling proteins: AKT, p-AKT, PI3K, p-PI3K, mTOR, p-mTOR, ERK, p-ERK, PKC and p-PKC. Phosphoproteins were measured before incubation with the mAb and after 20 min-24 h. Results: ROR1 detection on surface of the CLL cells was 80-85% and apoptotic frequency 45-50%. Western blot analysis showed decreased levels of p-AKT, p85 isoform of p-PI3K and p-mTOR in treated compared to untreated samples. No changes in the phosphorylation levels of ERK and PKC proteins were seen. Conclusions: Incubation of CLL cells with the anti-ROR1 mAb induced apoptosis of CLL cells. Apoptosis was preceded by dephosphorylation of PI3K, AKT and mTOR proteins indicating deactivation of these proteins by the ROR1 mAb. In untreated CLL cells no effect was noted. Furthermore no dephosphorylation of PKC or ERK was seen. We suggest that activation of mTOR might occur via the PI3K/AKT pathway and may be a survival signal in CLL cells associated with the aberrant expression of ROR1. Further studies are warranted to understand better the signaling pathways associated with ROR1 and the downstream signaling effects of ROR1 targeting drugs.


Predictive factors associated with achievement of major cytogenetic response (MCyR) to omacetaxine mepesuccinate among patients with chronic phase chronic myeloid leukemia (CML-CP). Presenting Author: Meir Wetzler, Roswell Park Cancer Institute, Buffalo, NY Background: Omacetaxine mepesuccinate (OMA), a first-in-class cephalotaxine, is a protein synthesis inhibitor not dependent on Bcr-Abl signaling. OMA has shown clinical activity in CML patients resistant/intolerant to tyrosine kinase inhibitors (TKIs). This subanalysis of 2 phase 2 studies examines predictors of MCyR to OMA in patients failing ⱖ2 TKIs. Methods: OMA 1.25 mg/m2BID was given in 28-day cycles: ⱕ14 days for induction, ⱕ7 days for maintenance. MCyR was defined as ⱕ35% Ph⫹ metaphases in bone marrow. A full logistic regression model with 11 baseline parameters was examined by Hosmer and Lemeshow Goodness-of-Fit test. Results: Of 81 patients (median age 59 y; range 26-83), 16 (20%) achieved MCyR. Mean (SD) baseline body surface area (BSA) was 1.90 kg/m2(0.240). Median time since last TKI to start of study was 1.3 mo (range 0.2-28.0) and median time from diagnosis was 75.4 mo (range 7.9-234.3). The final model had 8 baseline predictors (goodness of fit of p⫽0.1473; Table). (Sex, 2 vs 3 TKIs, or status of any mutation were not in the final model.) Logistic regression analysis showed a significant association between MCyR and no hydroxyurea (HU) use at baseline (p⫽0.0118). Numerically higher MCyR rates occurred in patients with baseline CHR and BSA ⱖ1.94 kg/m2. Conclusions: This small sample suggests that omacetaxine may be an important option for a range of patients, regardless of Bcr-Abl T315I mutation status. Prior HU may indicate more proliferative disease. Support: Teva BPP R&D, Inc. Clinical trial information: NCT00375219, NCT00462943. Baseline

MCyR (%)

Ratio

95% CI

P value

Age 65 y Complete hematologic response ⴙ – T315I mutation Absent/unknown Present

14/56 (25) 2/25 (8) 9/24 (38) 7/57 (12)

5.165

0.785-33.963

0.0875

4.243

0.975-18.457

0.0540

12/58 (21) 4/23 (17)

1.841

0.311-10.897

0.5012

BSA >1.94 kg/m2 1 mo prior TKI 65 y < 65 y Rai III-IV 0-II B2M > 4 mg/L 50% 65 PS 1 Current smoker (vs. former/never) Male sex Elevated LDH >ⴝ 2 prior regimens (vs. only 1) Weight loss > 5% Prior radiation S0802 (vs. S0435 or S0327)

HR

OS

95% CI

P value

HR

95% CI

P value

1.11 1.07 1.33 0.90

0.83 0.8 0.99 0.67

1.49 1.43 1.77 1.22

0.49 0.63 0.06 0.51

1.25 1.06 1.43 1.05

0.93 0.78 1.05 0.77

1.69 1.43 1.94 1.43

0.14 0.72 0.02 0.77

1.14 1.83 0.87

0.87 1.37 0.51

1.51 2.43 1.47

0.35 ⬍.0001 0.59

1.36 2.04 0.79

1.01 1.52 0.44

1.83 2.76 1.4

0.04 ⬍.0001 0.42

1.09 1.22 1.82

0.8 0.87 1.29

1.48 1.70 2.55

0.59 0.26 0.001

1.53 0.89 1.28

1.11 0.64 0.90

2.12 1.25 1.81

0.01 0.51 0.17


Lung Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers 7512


Comprehensive genomic analysis of small cell lung cancer in Asian patients. Presenting Author: Shigeki Umemura, National Cancer Center Hospital East, Kashiwa, Japan Background: Small cell lung cancer (SCLC) is an aggressive disease with poor prognosis. There is an urgent need for detecting well-defined therapeutic targets, however, little is known about the molecular events causing SCLC. This report describes findings from the integrated genomic analyses of 47 human SCLC samples in Asian population. Methods: We performed whole exome sequencing and copy number analysis on surgically resected tumor and matched normal samples from previously untreated Japanese patients with SCLC. Frequency of driver gene alterations were compared with previous two reports intended for non-Asian population (Peifer et al. Nature Gen 2012 and Rudin et al. Nature Gen 2012). Results: The demographics of 47 patients were as follows: median age 67 years (range: 42-86); female 8 (17%); history of smoking 47 (100%) and pathological stage I/II/III/IV⫽26/12/8/1. The average of protein-altering mutations was 193 (range: 51-633, standard deviation: 129). Genomic alterations including copy number amplifications and deletions in at least one of three frequently occurred driver genes, TP53, RB1, and MYC family, were detected in 93.6% of tumors. Mutation frequencies were 76.6%, 42.6%, and 12.8% for TP53, RB1, and MYC family respectively, which were equivalent to the previous reports. Recently reported candidate new driver genes were also recurrently confirmed in the present study: PTEN 4.3%, CREBBP 4.3%, EP300 4.3%, SLIT2 4.3%, MLL 4.3%, CCNE1 8.5% and SOX2 2.1%. Many of them were potentially targetable with currently available drugs. Conclusions: The genomic landscape of SCLC was not significantly different between Asian and non-Asian population. We perform additional targeted re-sequencing on biopsy samples obtained from metastatic SCLC to further assess the relevance of our results.

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The European Thoracic Oncology Platform Lungscape project: Clinical outcome data as a basis for molecular correlations in resected non-small cell lung cancer. Presenting Author: Solange Peters, Department of Medical Oncology, Centre Hospitalier Universitaire de Vaud, Lausanne, Switzerland Background: Lungscape allowed building the largest virtual biobank of radically resected NSCLC with comprehensive annotated clinical data, with the aims of expediting knowledge on biomarkers and facilitating translation of research to the clinic. Methods: 2,403 stage I-III radically resected NSCLC cases from 15 sites with mandatory comprehensive clinical annotations including at least 2 years of follow-up have been collected retrospectively. A systematic data review of every single case was performed. Relapse-free survival (RFS), time to relapse (TTR) and overall survival (OS) have been analyzed overall and by subgroups. Results: Median age of the cohort is 66 years, with 35% women, and respectively 14%, 32% and 49% never, current and former smokers. Histological types included 52% adenocarcinoma, 40% squamous cell carcinoma, and 4.5% large cell carcinoma and some rarer/mixed subtypes. As shown in the Table, median RFS, TTR and OS differ significantly by stage (p⬍0.001). Stage remained a significant predictor for outcome in the multivariate Cox models in the presence of other potential prognostic factors. Conclusions: This is the first report on the full Lungscape series based on 7th TNM classification on OS, RFS and TTR across clinical and pathological subgroups. This complete clinical dataset, in particular the information on TTR will be invaluable to investigate the impact of molecular characteristics on outcome, allowing refining TNM staging using biomarkers. Ultimately Lungscape will provide a platform for marker-driven trials of novel therapeutics. RFS p2cm vs. 4 mm

Nodules > 8mm

100 (37.5) 0 (2.0) 0.90 [0.84, 0.93]

100 (8.3) 0 (1.0) 0.87 [0.78, 0.92]

Low Mid High

5-year incidence LCSM CM ACM

ACM

0.29 0.34 0.37

80% 91% 95%

0.07 0.14 0.21

0.36 0.48 0.58

Power LCSM 80% 86% 87%

Adjustment N % 0 140 250

19% 35%


474s 7564

Lung Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers General Poster Session (Board #23B), Sat, 8:00 AM-11:45 AM

Dose-escalation study of chemoradiotherapy with use of involved-field conformal radiotherapy and accelerated hyperfractionation for stage III non-small cell lung cancer. Presenting Author: Naruo Yoshimura, Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, Osaka, Japan Background: To determine a recommended dose (RD) of chemoradiotherapy with use of involved-field conformal radiotherapy and accelerated hyperfractionation (AHF) for stage III non-small cell lung cancer (NSCLC). Methods: Eligible patients had unresectable stage III NSCLC, age of less than 75 years, PS: 0 or 1, V20 of 35% or less. PET was used for staging. Cisplatin (80mg/m2) was administered on day 1 and vinorelbine (20mg/m2) was administered on days 1 and 8 for two cycle. Twice-daily radiation therapy (1.5 Gy per fraction) without elective nodal irradiation started on day 1. Total doses were 60Gy in 40 fractions and 66Gy in 44 fractions at levels 1 and 2 respectively. After concurrent chemoradiotherapy, consolidation chemotherapy regimen was cisplatin (80mg/m2) on day 1 and vinorelbine (20mg/m2) on days 1 and 8 every 4 week for three cycles. The dose-limiting toxicity (DLT) was defined as grade ⱖ 3 esophagitis, grade 3 neutropenic fever, grade ⱖ 3 other non-hematologic toxicities and interruption of irradiation for more than 2 weeks. DLT was monitored for 90 days. Results: A total of 12 patients were enrolled (6 patients in Level 1, 6 patients in Levels 2). DLTs were noted in 2 patients at Level 1, which were grade 3 esophagitis and grade 3 febrile neutropenia. Radiation dose was escalated up to 66 Gy in 44 fractions (Level 2), and there was no DLT. In principle, Sixty-six Gy in 44 fractions (Level 2) should be the RD. Major toxicities were leucopenia, neutropenia, and anemia. The response rate, the median progression free survival time, and the median overall survival time was 83.3%, 10.4 months, and 36.3 months for all patients, respectively. Conclusions: The RD was 66 Gy in 44 fractions (Level 2). The toxicity of this chemoradiothrapy regimen was manageable and efficacy is promising. The efficacy and safety of this regimen should be confirmed in a phase II study. Clinical trial information: UMIN000003769.

7566


Automated tumor size assessment: Consistency of computer measurements with an expert panel. Presenting Author: Matthew S. Brown, Center for Computer Vision and Imaging Biomarkers, University of California, Los Angeles, CA Background: Manual tumor measurements for use in diagnosis and longitudinal assessment suffer from intra- and inter-observer variability. In practice they are also limited to 1-dimensional diameter measurements because manual contouring of 3D tumor boundaries is impractical. In this work we evaluated a fully automated tumor assessment system in the setting of lung nodules on CT by comparing its tumor size and density measurements against independent measurements made by an expert panel of radiologists. Methods: A new computer-aided detection (CAD) system has been developed that performs fully automated lung nodule detection and measurement. In order to identify the nodule boundary in 3D the system performs automated intensity thresholding, a Euclidean Distance Transformation, and segmentation based on watersheds. The system computes nodule diameter, volume, and mean density in Hounsfield Units (HU). The automated measurements were evaluated against data from the publically available Lung Imaging Database Consortium (LIDC), where each CT scan was reviewed and annotated (with volumetric tumor contours) by an expert panel of four radiologists. Nodule were included from consecutive subjects in the database that were ⱖ 4 mm. The CT slice thickness ranged from 0.6 – 3.0 mm. For each nodule measure, the intra-class correlation coefficient (ICC) was computed among the four radiologists and then re-computed with CAD as a fifth observer. Results: 51 lung nodules from 44 subjects were analyzed. The ICCs were computed as shown in the table using a log transformation for volume and diameter. All nodule measures have similar ICCs and overlapping confidence intervals (CI). Conclusions: A new fully automated CAD system has been developed that provides CT lung nodule measurements that are consistent with an expert panel of radiologists. The automated computer system enables practical 3D tumor assessment and reduces measurement variability, which has implications for longitudinal studies.

Volume Longest diameter Mean HU density

4 Radiologists ICC [95%CI]

4 Radiologists ⴙ CAD ICC [95%CI]

0.97 [0.96, 0.98] 0.92 [0.89, 0.96] 0.73 [0.63, 0.83]

0.96 [0.94, 0.98] 0.91 [0.87, 0.95] 0.72 [0.62, 0.81]

7565


Impact of environmental tobacco smoke (ETS) on ALK rearrangements in never smokers (NS) with non-small cell lung cancer (NSCLC): Analyses on a prospective multinational ETS registry. Presenting Author: Akihito Kubo, Aichi Medical University School of Medicine, Nagakute, Japan Background: EGFR and ALK are important driver mutations in NS. While we reported the significant association of increased ETS with EGFR mutations in Japanese cohort (Kawaguchi, Clin Cancer Res, 2011), ETS association with ALK has not been reported. Methods: ETS exposure on NS with NSCLC was evaluated using the standardized questionnaire including exposure period, place, and duration. Cumulative dose of ETS (CETS) was defined as a sum of the number of the exposure years in childhood and in adulthood, and was treated as a continuous variable or quintile. EGFR mutations and ALK rearrangements were tested by PCR-based detection and fluorescence in situ hybridization, respectively. Multivariate analyses were done using the generalized linear mixed model (GLIMMIX procedure, SAS v9.3). Results: From March 2008 to December 2012, 498 NS with NSCLC were registered with the following patient characteristics: ethnicity (nationality) of Asian/ Caucasian/ others, 425 (Japanese 250, Korean 102, Chinese 46, others 2)/ 48/ 25; male/female, 114/384; age ⬍65/⬎⫽65, 286/212. EGFR status was wild type 43.6%, exon 19 deletion 25.3%, L858R 21.5% and other mutations 9.6%. ALK status was wild type 52.0%, rearranged 10.6% and unknown 37.3%. Average CETS (years) of NS with EGFR (⫹), ALK (⫹) and wild type tumors were 45.4, 26.9 and 37.7, respectively. In multivariate generalized linear mixed model, incidence of activating EGFR mutations, not ALK rearrangements, was significantly associated with the increment of CETS in female, not in male gender. Odds ratios (OR) for EGFR mutations in female (n⫽384) were 1.084 (95% CI, 1.003-1.171; p⫽0.0422) for each increment of 10 years in CETS while OR in male (n⫽114) were not significant (OR 0.890; 95% CI, 0.725-1.093; p⫽0.2627). OR for ALK rearrangements in female (n⫽238) and those in male gender (n⫽74) were 0.930 (0.791-1.094; p⫽0.3814) and 0.854 (0.620-1.178; p⫽0.3319). Conclusions: Increased ETS exposure was closely associated with EGFR mutations in NS with female gender and NSCLC in the expanded multinational cohort. However, the association of ETS and ALK rearrangements in NS with NSCLC was not significant.

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Prognostic role of MET expression in early stage NSCLC. Presenting Author: Tom John, Ludwig Institute for Cancer Research/Austin Health, Melbourne, Australia Background: The MET receptor tyrosine kinase and its ligand are associated with the malignant phenotype. In non-small cell lung cancer (NSCLC) MET expression increases with disease stage and is involved in de novo and acquired resistance to tyrosine kinase inhibitors. Despite this, in early stage NSCLC small data series have failed to demonstrate MET expression to be prognostic. We investigated a large cohort of patients who underwent curative surgical resection at our institution to determine whether MET receptor or gene amplification was prognostic. Methods: Tissue Microarrays (TMAs) were constructed using 1mm cores of FFPE primary NSCLC tissues in triplicate. TMAs were stained with the SP44 clone (Novus Biologicals) and a H-score calculated based on % cells stained and intensity; (%cellsx1)⫹(%cellsx2)⫹(%cellsx3) with a minimum of 0 and maximum of 300. The mean of triplicate values was calculated. MET gene amplification was detected using Ventana’s MET DNP probe with ultraView SISH DNP silver detection, performed on Ventana’s XT autostainer. DNA was isolated and subjected to mutational profiling using Sequenom’s LungCarta panel. Results: Data for 508 patients, 352 (69%) male, were available for analysis including 329 pathological node negative (pN0), 67 pN1, 104 pN2 and 8 patients with resected primaries and solitary brain metastases (M1). Most patients were smokers with only 33 (6%) non-smokers. The median MET H-score was 100 and consistent across N0, N1 and N2 patients, although was higher in M1 patients. Median H-scores were significantly higher in adenocarcinoma compared to squamous cell carcinoma (140 vs 91.5, p⬍0.0001). Increased MET expression (H-score⬎100) was seen in 227 (45%) patients and associated with significantly improved overall survival (HR 1.28 95% CI 1.04-1.59; p⫽0.023). In univariate analyses improved survival occurred in all stages and histologies. DNA and multivariate analyses are pending. MET gene copy number amplification was detected in 11 cases. Conclusions: In contradistinction to advanced NSCLC, increased MET receptor expression is associated with improved survival in a large cohort of early stage lung cancer. Further correlation with mutation status and gene rearrangements will be reported.




Genomic rearrangements in lung adenocarcinoma: Lineage relationships between the in situ and invasive components. Presenting Author: Stephen J Murphy, Mayo Clinic, Rochester, MN Background: The molecular events in the initiation and progression of invasive lung adenocarcinoma remain poorly characterized. These tumors are thought to develop through an adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), invasive adenocarcinoma (AD) sequence. The goal of our study was to assess lineage relationships between in situ and invasive components within adenocarcinomas with prominent lepidic growth patterns. Methods: Frozen tissue from fourteen lung adenocarcinomas with mixtures of AD together with an adjacent in situ component (AIS), varying in ratio between 40 to 80%, were selected from our Lung Specimen Registry. Laser capture microdissection (LCM) of each component was performed separately for each tumor. Genomic DNA was isolated using a direct in situ whole genome amplification (WGA) methodology, and Next Generation Sequencing performed using an Illumina Mate Pair (MP) library protocol. MP sequence reads were mapped to the human genome and primers spanning the fusion junctions were used in validation PCRs. Results: Genomic break points identical and unique to a specific patient were identified between the AIS and AD components in 13 (of 14) cases. The total number of events per case ranged from 4-215, and the number of identical events shared between the AIS and AD components ranged from 30 to 90%. Recurrent genomic breakpoints between cases were also observed, with the 2 most common involving 8q24.3 in 5 cases and FAM19A2 on chromosome 12 in 4 cases. PCR validation of selected genomic alterations confirmed the genomic break points identified from sequencing in both the AIS and AD in all cases. Interestingly, we also observed a limited number of genomic alterations present in a zonal distribution of surrounding normal lung around the tumor mass. Conclusions: Our study demonstrates unique chromosomal alterations present in both the AIS and AD components of individual lung tumors with features of lepidic growth. These data provide evidence for lineage relationship and clonal relatedness between the two components, and provide genomic evidence for a model of stepwise progression from AIS to invasive AD in this subset of lung adenocarcinomas.

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Clinical characteristics of patients with multiple primary lung cancers: Moving beyond the Martini and Melamed criteria. Presenting Author: Marjorie Glass Zauderer, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Deciding to operate for lung cancer in patients with a prior lung cancer resection is influenced by the extent of disease at 1st resection and the certainty that the new lesion is a 2nd primary lung cancer. While the Martini and Melamed (M&M) criteria (J Thorac Cardiovasc Surg 1975) guide the decision whether a new lesion represents a 2nd lung cancer, improvements, incorporating detailed clinical and molecular analyses, are needed. Methods: From a prospective database, we identified 130 patients who underwent two curative resections from 1995 to 2009 for non-small cell lung cancers. We examined associations between clinical factors and patterns of recurrence/DFS/OS following 2nd surgery. Results: Patient characteristics: median age 66; 42% men; and 8% never smokers. See Table for stage, histology, and completeness of resection. DFS and OS were not associated with smoking status, surgical procedure, and histology. Stage at 1st resection was not associated with patterns of recurrence (none vs local vs distant, p⫽0.77), DFS (p⫽0.61), or OS (p⫽0.37). Earlier stage at 2nd resection was associated with improved DFS (p⬍0.001) and OS (p⬍0.001), as well as a trend toward less distant recurrence (p⫽0.06). As many surgeries predated routine genotyping, very few patients (5%) had genotyping from both resections. 38% of 2nd resection stage IA lung cancers recurred distantly. 20% had a third lung cancer and 47% had at least one other malignancy. Conclusions: Outcomes after 2nd primary lung cancers are unaffected by the stage of the 1st lung cancer. Pursuit of curative interventions should not be influenced by the stage of the 1st cancer. We need more detailed molecular analysis to help correctly identify new primaries. We also need additional features to help discriminate among those at most risk for another lung cancer vs local recurrence vs distant recurrence. Stage IA IB IIA IIB IIIA Histology Adenocarcinoma Squamous Large cell Non-small cell NOS Complete resection R0 R1/R2

1st resection N (%)>

2nd resection N (%)

74 (57) 31 (24) 14 (11) 4 (3) 5 (4)

90 (69) 16 (12) 7 (5) 7 (5) 10 (8)

98 (75) 24 (18) 4 (3) 4 (3)

100 (77) 23 (18) 5 (4) 2 (2)

119 (92) 11 (8)

121 (93) 9 (7)

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Dual intervention with a lymph node (LN) specimen collection kit and enhanced specimen dissection to improve staging of resectable non-small cell lung cancer (NSCLC). Presenting Author: Srishti Sareen, Boston Baskin Cancer Foundation, Memphis, TN Background: LN metastasis impairs survival of resectable NSCLC, but routine pathologic nodal staging is suboptimal. We tested the impact of a dual intervention (a surgical specimen collection kit with specific, pre-labeled LN collection cups, to improve intraoperative hilar/mediastinal LN dissection; and a fastidious gross dissection of the resected lung specimen for perihilar/ intrapulmonary LNs) on the rate of detection of LN metastasis. Methods: We matched dual intervention cases with controls performed with standard surgical specimen collection and pathology examination protocols. Controls were hierarchically matched for extent of resection, laterality, surgeon, pathologist and T-stage. All statistical comparisons were made with Exact Conditional Logistic Regression, to account for the matched case-control design. Results: Patient demographic, tumor histology, and size characteristics were similar between the groups. The impact of the dual interventions is shown in the Table. Conclusions: The dual interventions significantly increased retrieval of N1 and N2 LNs, the rate of detection of LN metastasis, and nodal up-staging. There were strong trends towards higher aggregate stage and increased adjuvant therapy eligibility. The interventions may improve stage-adjusted survival by improving stage accuracy, and improve aggregate survival by increasing the appropriate use of post-operative adjuvant therapy. A prospective randomized trial to test survival impact of the dual interventions is at an advanced planning phase. # LN examined (mean, SD) N1 N2 Total Patients meeting LN # criteria, % >10 lymph nodes >17 lymph nodes # LN positive (mean, SD) N1 N2 Total Nodal stage, % of patients pN0 pN1 pN2 Any positive LN Aggregate stage, % of patients I II III Eligibility for adjuvant therapy Chemotherapy Radiation therapy

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Cases, Nⴝ100

Controls, Nⴝ100

P

11 (7.9) 7 (4.1) 18 (8.9)

3 (2.9) 2 (2.6) 6 (4.1)

⬍.0001 ⬍.0001 ⬍.0001

79 41

13 2

⬍.0001 ⬍.0001

1.1 (2.6) 0.3 (0.8) 1.4 (3.0)

0.3 (0.9) 0.1 (0.4) 0.5 (1.1)

⬍.001 .069 ⬍.001

65 20 15 35

79 12 9 21

.0486 .02

54 24 22

66 20 14

0.0629

51 15

40 9

.07 .24


Outcomes of early stage lung cancer treatments in older patients: A SEER database analysis. Presenting Author: Alissa S. Marr, University of Nebraska Medical Center, Omaha, NE Background: Although the majority of lung cancer patients are over the age of 65, there are limited data on outcomes of treatment options for early stage lung cancer in older patients. Methods: Treatment and outcome data of stage I and II non-small cell lung cancer (NSCLC) patients were obtained from the Surveillance, Epidemiology and End Results (SEER) database. Treatment modalities included no treatment, surgery, radiation, and a combination of surgery and radiation. Patients were divided based on age groups into ⬍65, 65-75, and ⬎75 years old. Multivariate logistic regression was used to compare the likelihood of survival in the three age groups while controlling for gender and race. Results: A total of 10,763 patients diagnosed with stage I and II NSCLC between 1988 and 2007 within the SEER database were analyzed. The age distribution was as follows: ⬍65 (n⫽3558), 65-75 years (n⫽ 4454), ⬎75 years (n⫽2751). Patients ⬍65 years of age were more likely than those ⬎75 years of age to be treated with surgery (72.5% vs. 53.5%, respectively; p ⫽ ⬍0.0001). Patients ⬎75 years of age were more often treated with radiation alone (23%) or no treatment (18.2%) as compared to those patients ⬍65 (9% and 4.9%, respectively; p ⫽ ⬍0.0001). Patients ⬍65 years of age with stage I lung cancer had a statistically significant improved lung cancer-specific 5-year survival with surgery alone as compared to those 65-75 years and ⬎75 years. Lung cancer specific mortality at 5 years was 19%, 26% and 30%, respectively; p⫽ ⬍0.0001. Similar results were seen in stage II patients. When stage I patients received radiation therapy, lung cancer-specific deaths at 5 years were not different between the three groups (66% vs. 63% vs. 66%, respectively; p⫽0.1263). The 5-year lung cancer- related mortality was lower in younger patients who received no treatment (51% in ⬍65, 56% in 65-75, and 57% in ⬎75 years old; p⫽0.006). Conclusions: Older patients treated surgically for stages I and II NSCLC have a lower lung cancer-specific survival when compared to younger patients. In contrast, there is no difference in lung cancer-specific survival for patients treated with radiation therapy. Hence, careful selection of older patients for surgical therapy of early stage NSCLC is warranted.


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Lung Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers General Poster Session (Board #24B), Sat, 8:00 AM-11:45 AM

Identification of actionable mutations in surgically resected tumor specimens from Japanese patients with non-small cell lung cancer by ultra-deep targeted sequencing. Presenting Author: Yasuhiro Koh, Division of Drug Discovery and Development, Shizuoka Cancer Center Research Institute, Nagaizumi-chou, Shizuoka, Japan Background: Detection of tumor genetic alterations is critically needed for lung cancer clinic as well as for the development of molecular targeted therapeutics. Here we report the results of a broad spectrum of genetic alterations identified in Japanese non-small cell lung cancer (NSCLC) patients by ultra-deep targeted sequencing. Methods: Highly multiplexed amplicon sequencing was performed using genomic DNA extracted from snap-frozen tumor specimens. TruSeq amplicon cancer panel was used for the detection of somatic mutations in 48 cancer related genes followed by ultra-deep sequencing (Illumina) at an average coverage of approximately 2800x. ALK, ROS1 and RET traslocations and EGFR, MET, PIK3CA, FGFR1 and FGFR2 amplifications were also detected by multiplex RT-PCR and quantitative PCR, respectively. Results: The demographics of 204 consecutive patients enrolled in this prospective study at Shizuoka Cancer Center between July 2011 and November 2012: median age 69 years (range: 38-92); male 66%; never smoker 25.5%; histology: adenocarcinoma 68.6%, squamous cell carcinoma (SQ) 27.0%, others 4.4%; tumor stage: I 53.9%, II 28.4%, III 12.7%, IV 4.9%. TP53 mutation was most frequently detected (44.4%) in all patients, particularly in SQ (67.9%). Mutations in genes such as MLH1 (4.9%), STK11 (6.3%), CTNNB1 (5.6%), SMAD4 (1.4%), VHL1 (1.4%), PTPN11 (0.7%) and GNAS (0.7%) were detected besides major mutations in genes such as EGFR (43.0%), KRAS (17.6%) and PIK3CA (14.1%) in adenocarcinoma. PIK3CA (21.4%), MLH1 (5.4%), APC (3.6%), STK11 (3.6%), FGFR2 (1.8%) and VHL (1.8%) mutations were identified in SQ and notably, 48.2% of SQ patients harbored simultaneous gene mutations, suggesting the genetic complexity of this histology. FGFR1 amplification was found in 8.9 % of SQ, suggesting lower frequency in Asian population than in Caucasian population. Conclusions: We managed to detect a wide range of genetic alterations and identified additional actionable mutations besides popular driver mutations. This approach may facilitate elucidation of detailed molecular characteristics of NSCLC, thereby implementing personalized cancer medicine.

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Patient-reported symptom burdens in NSCLC patients undergoing proton, 3DCRT, or IMRT. Presenting Author: Xin Shelley Wang, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Concurrent chemoradiation (CXRT) for stage III non-small-cell lung cancer (NSCLC) patients is associated with the development of systemic self-reported symptom burden as well as radiation esophagitis (RE). This longitudinal study aims to provide a profile of the symptom burden among 3 radiation techniques concurrently used with chemotherapy: 3-dimensional conformal radiation therapy (3DCRT), intensitymodulated radiation therapy (IMRT) and proton beam therapy (PBT). Methods: NSCLC patients (N⫽164) treated at MD Anderson Cancer Center rated symptoms via the M. D. Anderson Symptom Inventory (MDASI) weekly from pre-therapy up to 20 weeks post-therapy. Descriptive analysis identified major symptom burden, and mixed effect modeling examined change over time in symptom outcomes among the 3 types of CXRT. Results: Average total radiation dose was higher (p⫽.0003) for PBT (N⫽30, 71.6 Gy) and IMRT (N⫽67, 66.3 Gy) than for 3DCRT (N⫽24, 62.1 Gy). Over time, all patients reported a cluster of symptoms that increased as the dose accumulated, including fatigue, drowsiness, pain, difficulty swallowing, poor appetite and sore throat; symptoms generally peaked at week 7-9 and returned to pre-therapy levels at week 13. The IMRT group had significant less-severe sore throat (p⫽.03), while there were no significant differences in symptom severity among the 3 types of CXRT for the other major symptoms before, during and after CXRT. However, there was a trend of more patients reporting moderate to severe sickness symptoms as a component score (fatigue, pain, sore throat, poor appetite and drowsiness) in the 3DCRT group than in the IMRT or PBT groups at end of CXRT (50% vs. 44%, 31%) and at 13 weeks (53% vs. 23%, 25%). Also, there was a trend of more patients under 3DCRT than IMRT or PBT had moderate to severe sore throat (RE symptom) by end of CXRT (60% vs. 44%, 46%) and no different by 13 weeks (27% vs. 25%, 31%). Conclusions: Although clinical studies have reported the toxicities of CXRT, this is the first longitudinal study that compared symptom profiles for NSCLC patients receiving PBT, IMRT and 3DCRT. There is an impression of more severe treatment-related symptoms for 3DCRT (although in lower radiation dose) than IMRT or PBT.

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Lung adenocarcinoma microRNA-31 expression levels to predict lymph node metastasis and patient survival. Presenting Author: Tim Lautenschlaeger, Department of Radiation Medicine, The Ohio State University, Columbus, OH Background: In this study we performed genome-wide microRNA-seqencing (miRNA-seq) in lung adenocacinoma (ADC) patient samples and used bioinformatic analyses to identify novel and annotated microRNAs that are differentially expressed between patients with and patients without lymph node metastasis, as well as examining their potential prognostic value. Methods: Sixty four frozen tissue specimens from lung ADC patients collected between 2003 and 2012 were obtained through the OSUCCC Tissue Procurement Shared Resource, approved by internal review board (IRB). Total RNA samples were processed and loaded on the Applied Biosystems SOLiD 4 sequencing system for data acquisition. 249 patients from the TCGA lung ADC cohort were used for results validation. Human lung ADC cell lines H23 and H1573 were used for in vitro functional assays. Results: We identified several microRNAs that were associated with the presence of lymph node metastasis in primary lung adenocarcinoma tissues using genome-wide miRNA-seq. We confirmed miR-31 to be up-regulated in lung ADC tissues from patients with lymph node metastasis in a separate patient cohort (p⫽0.009, t-test), and to be expressed higher in ADC tissues than in matched normal adjacent lung tissues (p⬍0.0001, paired t-test). MiR-31 was then validated as a marker for lymphnode metastasis in an external validation cohort of 233 lung ADC cases of the TCGA that did not have distant metastasis (p⫽0.031, t-test). In vitro functional assays showed that miR-31 upregulation increases cell migration, invasion, and proliferation. In addition, overexpression of mir-31 increased the expression of markers of epithelial-mesenchymal transition (EMT) and associated with activated ERK1/2 signaling. MiR-31 was a significant predictor of survival in a multivariate Cox regression model even when controlling for tumor stage. In silico analysis showed that low expression of miR-31 was associated with excellent survival for T2N0 patients. Conclusions: In summary, we applied microRNA-seq to study microRNomes in lung ADC tissue samples for the first time and identified a microRNA that could predict the presence of lymph node metastasis and survival outcomes in lung ADC patients.

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A favorable population among clinical stage IIIA-N2 non-small cell lung cancer: The importance of the location of the primary tumor and involved nodes. Presenting Author: Takeshi Matsunaga, Juntendo University School of Medicine, Tokyo, Japan Background: The number of station of involved N2 nodes has been considered to be one of the most important prognostic factors for lung cancer. However most reports detailed with not clinical nodal status, but pathological nodal status. We investigated the relationship between prognosis and the location of the primary tumor and involved nodes. Methods: A retrospective study was conducted on 1257 patients with primary lung cancer, which was resected between 1996 and 2009. Among them, 79 patients (6.3%) had cN2, c-stage IIIA, pN2 and NSCLC. Mediastinal lymph node with a diameter of 10mm or more in the short axis was diagnosed as metastasis. We defined cN2␣ as only involvement of upper mediastinal lymph node (UMLN) in main tumor located on upper lobe or as that of lower mediastinal lymph node (LMLN) in main tumor located on lower lobe. And we did cN2␤ as involvement of LMLN in main tumor located on upper lobe with or without metastatic UMLN or as that of UMLN in main tumor located on lower lobe with or without metastatic LMLN. We analyzed preoperative clinical factors and investigated overall and disease-free survival. Results: The overall 5-year survival rate was 30.2% and median follow-up was 52.8 months. The disease-free 5-year survival rate was 22.2%. The differences in survival between cN2␣ and cN2␤ were statistically significant (29.5% vs. 0%, p-value⫽0.0007), whereas no significant differences was found between cN2 single station and multiple station (23.3% vs. 19.4%, p-value⫽0.1220). Multivariate analysis with cox’s hazard model disclosed that cN2␣ was independent good disease-free prognostic factor(HR: 0.426, 95%CI: 0.193-0.941). The sensitivity, specificity and positive predictive value for pN2 single station based on cN2 single station were 71.4%, 49.1% and 34.9% (p⫽0.1269). Conclusions: Clinical mediastinal lymph node status based on the location of the primary tumor and involved nodes was an important preoperative prognostic factor. Thus this factor should be taken into consideration for planning and evaluating clinical trials. Another fruit of the study was that clinical single nodal N2 was not always pathological single N2 disease.




Reproducible molecular characterization of non-small cell lung cancer from paraffin. Presenting Author: Matthew Wilkerson, The University of North Caroline at Chapel Hill, Chapel Hill, NC Background: Recommendations exist to aid the clinically relevant non-small cell lung cancer (NSCLC) classification of squamous (SQ) versus adenocarcinoma (AD), including immunohistochemistry (IHC) for TTF1 and p63. We hypothesize that PCR of RNA gene panels may improve the diagnostic accuracy over IHC. Methods: A multi-institutional cohort of NSCLC patients was abstracted for use of IHC in clinical practice. RNA was isolated from routine paraffin sections and a 54-gene Histology by gene Expression Predictor (HEP) was implemented to distinguish SQ, AD, and other NSCLC variants. IHC for TTF1 and p63 was obtained on a subset of patients in a standardized manner. To compare the reproducibility of PCR diagnostics to morphologic diagnosis, a subset of samples was processed as matched pairs from the same tumor, in blinded manner. Results: 493 clinical samples were analyzed from 419 patients. Pathologists obtained any IHC in 22% of the cases, with TTF1 or p63 in ⬍10% of cases. In the subset of cases where standardized TTF1 and p63 was obtained, the stains were un-evaluable or incompletely obtained in 30% for reasons including technical failure, limited sample, and ambiguous staining (i.e positive for both p63 and TTF1); on this same subset, the HEP technical failure rate was 7%. In cases where staining was successful, both IHC and the HEP agreed with the clinical diagnosis at high rates (93 and 91% respectively). In IHC un-evaluable cases, slides were reviewed by up to 7 additional pathologists. In general such cases failed to produce a consensus diagnosis, suggesting that IHC failure indicates a difficult to diagnose case (kappa statistic ⬍0.5). As another concordance assessment method, we evaluated a second diagnostic property, reproducibility, by taking paired samples from the same case for blinded review. Strikingly, morphologic review in a blinded manner by pathologist generated low agreement with overall agreement of 65% compared to the HEP agreement of 92%. Conclusions: PCR based diagnostics such as the HEP may improve NSCLC diagnostic performance

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Has the paradigm changed away from lobectomy for stage I non-small cell lung cancer (NSCLC)? Anatomic segmentectomy: Surgery’s answer to image-guided ablation/radiation therapy for the small peripheral lung lesion. Presenting Author: Matthew J. Schuchert, Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA Background: Lobectomy has been the “gold standard” for stage I NSCLC management. Image guided ablation/radiation therapy approaches are now being touted as alternatives to surgery despite concerns regarding diagnosis, pathologic staging, local control, and delayed toxicities. We evaluated the diagnostic utility and oncologic efficacy of lung sparing, anatomic segmentectomy for indeterminate pulmonary nodules and clinical stage I NSCLC. Methods: Retrospective review of 1,005 anatomic segmentectomies from 2002-2012 for indeterminate pulmonary nodules and clinical stage I NSCLC. Outcome variables included perioperative data, morbidity and mortality. Survival was assessed with the Kaplan-Maier method. Results: Mean age was 66.7 years. Median lesion size was 1.9 cm. VATS was employed in 62.8% of cases. Median operative time and blood loss was 112 minutes and 80 ml, respectively. Median hospital stay was 5 days. Major complications occurred in 12.7%. Thirty-day mortality was 1.0%. Of these, NSCLC was identified in 71.6%, metastases in 8.7%, and other benign conditions in 19.7%. Among patients with clinical stage I NSCLC, clinical: pathological upstaging was seen in 34.5%. Local recurrence rate was 5.2% and five-year freedom from any recurrence was 69%, equivalent to lobectomy in our experience. Conclusions: Anatomic segmentectomy is a valuable primary surgical approach today. In this era of competing image-guided ablation modalities, anatomic segmentectomy provides safety, diagnostic accuracy and adherence to oncologic surgical principles including completeness of resection with adequate surgical margins, systematic nodal staging improving pathologic accuracy, and tissue for pharmacogenomic assessment to guide individualized adjuvant therapy.

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Multi-institutional study of reirradiation with proton beam radiotherapy for non-small cell lung cancer. Presenting Author: Abigail T. Berman, Department of Radiation Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA

Total lesion glycolysis (TLG) at baseline FDG-PET/CT compared with maximum standard uptake value (SUVmax) to predict survival in non-small cell lung cancer (NSCLC). Presenting Author: Ling Li, Deparment of Radiation Oncology, University of Michigan, Ann Arbor, MI

Background: The management of recurrent non-small cell lung cancer (NSCLC) in the setting of prior radiation (RT) is complex. Proton radiotherapy (PRT) is ideally suited to minimize toxicity by sparing dose to previously-irradiated organs. Herein we report the safety and feasibility of PRT for NSCLC reirradiation. Methods: Patients (pts) with recurrent NSCLC in or near their prior RT field were identified in three proton centers. An interval of 3 months was required between original RT course and PRT start. Pts were classified as low volume (LV, clinical target volume [CTV] ⱕ250 cc) or high volume (HV, CTV ⬎250 cc). PRT was deemed infeasible if pts were unable to tolerate 15% of fractions or complete all treatments in ⬍10 days of estimated end date and without a break ⱖ5 days. Results: Between 10/2010-11/2012, 24 pts were reirradiated, with 12 on a prospective trial of PRT for reirradiation. Median age was 69 (51-89). Histologies included squamous cell carcinoma (50%), adenocarcinoma (39%), and other (13%). Stage at initial diagnosis was I (8.3%), II (20.8%), III (50%), IV (12.5%), and unknown (8.3%). All pts were ECOG PS 0-2. Median prior dose was 62.4 Gy (30.6-80); 1 pt had 2 prior RT courses. The majority of pts (63%) were LV (median CTV 75.3, 11.9-236) and 38% were HV (359, 297.8-695.7). Concurrent systemic therapy (platinum-based or erlotinib) was given in 63%. Median PRT dose was 66.6 Gy (36-74). Average mean lung dose was 7.6 and 10.8 Gy and lung volume receiving 5 and 20 Gy was 16 and 24% and 26 and 33% in LV and HV pts, respectively. Follow up was ⬎60 days in 17 pts. Overall, 46% of pts were hospitalized. PRT was infeasible in 3/9 HV and 1/15 LV pts. In HV pts, there were 2 grade 5 toxicities (hemoptysis and neutropenic fever). There was 1 in-field and 4 other thoracic recurrences, and 5 and 4 deaths in LV and HV pts, respectively. Conclusions: Preliminary results show promising early outcomes and acceptable toxicity in LV pts; due to the toxicity seen in HV pts, additional exclusion criteria were added for NSCLC pts in the ongoing trial. NSCLC reirradiation should continue to be studied in prospective trials to identify pts that may derive clinical benefit. Mature follow up is needed prior to standardizing NSCLC reirradiation with PRT.

Background: SUVmaxat baseline FDG-PET has been reported as a significant prognostic factor while recent studies suggest that metabolic tumor volume (MTV) may be more important factor in patients with NSCLC. We hypothesized that TLG is a better prognostic factor than either SUVmax or MTV alone for overall survival (OS) and progression free survival (PFS) in NSCLC because it integrates both volumetric and biologic activity. Methods: The study population included a prospectively recruited cohort of stage I-III NSCLC patients treated with chemoradiation. FDG PET/CT scans were performed within 2 weeks from treatment start. The SUV in the tumor was normalized to that of the background level in the middle of ascending aorta to minimize the confounding effect from inter-scan variation in SUV measurement. MTV was delineated by auto-threshold at 1.5 times background level in the aorta followed by knowledge based manual editing. Mean and maximum SUV normalized to the background level were computed. TLG was calculated as the product of lesion SUVmean and MTV. Results: A total of 96 patients with minimum follow-up of 1 year were eligible. The median follow-up among survivors was 30 months. Univariate analysis demonstrated that MTV and TLG were significant factors for both OS and PFS (all P⬍0.05). There was a significant correlation between SUVmean and PFS (P⫽0.013), but there was no significant association between SUVmean and OS. SUVmax was not a significant factor for either OS or PFS (all P⬎0.05). Under multivariate Cox regression analysis, MTV (HR⫽ 2.62, P⫽ 0.003) and NSUVmean (HR⫽0.351, P⫽0.003) were significantly associated with PFS; but only TLG was significantly associated with OS (HR⫽2.14, P⫽0.006)adjusted by of TNM stage and other clinical factors. Conclusions: These results support our hypothesis that metabolic tumor volume and biologic average glucose metabolic activity of this volume are more important prognostic factors for overall prognosis than SUVmax in NSCLC patients treated with chemoradiation. Should this be validated by independent studies, future clinical trial should take this into consideration for individualized care.


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Serum miRNA signature to identify a patient’s resistance to high-dose radiation therapy for unresectable non-small cell lung cancer. Presenting Author: Nan Bi, Department of Radiation Oncology, University of Michigan, Ann Arbor, MI

Genomic characterization and high-throughput therapeutic screening of malignant mesothelioma to reveal novel tumor dependencies. Presenting Author: Constantine Alifrangis, University of Cambridge, Cambridge, United Kingdom

Background: There is a growing literature on unique profiles of serum micro RNAs (miRNAs) expression to predict clinical outcome of metastatic and early stage non-small cell lung cancer (NSCLC). However, the predictive role of circulating miRNAs in unresectable NSCLC treated with definitive radiation therapy (RT) is unknown. Methods: 134 patients with inoperable/ unresectable NSCLC treated with definitive RT (18-month minimum follow-up) were eligible. Serum samples were collected prospectively before treatment. 100 patients had enough serum and reliable miRNA profile quality, which were randomly divided into training and validation sets (50 patients each). MiRNA profiling was performed using real-time PCR-based array, containing a panel of 84 miRNAs detectable in human bodily fluids. Spiked-in cel-miR-39 was used for normalization. Stepwise regression Cox model building was used to build a miRNA signature on the training set, which was then assessed on the validation set both alone and with clinical factors. Results: The median age was 67 years; 76% were stages III and 79% received chemoradiation; the median physical dose was 70.0 Gy. A serum hsa-miR-885/hsa-miR-7 signature was identified as significant predictors for overall survival (OS) in the training set, which was validated by the validation set (p⫽0.02). After adjustment for GTV Volume and KPS, the only two significant clinical factors in univariate analysis, this signature remained significant (p⫽0.04). In the high-dose RT group (⬎70 Gy, n⫽45), individuals with low-risk had a significantly longer OS than patients with high-risk (70.7 vs. 18.8 months, p⫽0.007); while in the low-dose RT group (ⱕ70 Gy, n⫽55), no significant association was observed (OS, 22.0 vs. 13.3 months, p⫽0.43). Conclusions: Circulating hsa-miR-885/hsa-miR-7 signature may be used as a putative non-invasive biomarker for predicting survival and radiation resistance in unresectable NSCLC, which may potentially help to select patients who will not benefit from high-dose radiation. Independent validation studies are needed to confirm our findings. Clinical trial information: NCT01190527.

Background: Clinical trials of targeted therapeutics in mesothelioma have demonstrated limited efficacy. It has been suggested that combinations of targeted agents may be more effective in this disease, but given the unknown status of tractable oncogenic mutations it has been difficult to ascertain which key signalling nodes drive these tumours that may lend themselves to therapeutic intervention. We therefore aimed to characterise a representative panel of mesothelioma cell lines at the genomic level, and then determine critical “nodes” utilising a high throughput screen of targeted agents. Methods: 19 mesothelioma cell lines and 6 mesothelioma primary tumour early passage lines underwent Illumina whole exome sequencing and copy number analysis. In parallel a high throughput screen was performed utilising a panel of targeted therapeutics enabling each mesothelioma to be screened across 48 compounds. Efficacy was confirmed in 3D spheroid culture. Results: Exome sequencing of the mesothelioma panel revealed mutations in tumour suppressor genes previously described in mesothelioma including NF2, as well as previously unreported mutations in this disease affecting histone modifying genes MLL2 and SETD2. Notably an absence of mutated “driver” oncogenes was observed. High throughput screening demonstrated limited activity for most small molecule inhibitors as single agents. However, despite an absence of mutations in PIK3CAor related genes, PI3K/mTORC inhibition had the broadest single agent efficacy. Conclusions: We demonstrate that mutations in cell lines are similar to those found in patient-derived tumours implying fidelity at the genomic level. Mesotheliomas harbour multiple mutations in tumour suppressors, but lack commonly tractable oncogenic mutations which may explain poor efficacy seen in clinical trials to date. We further demonstrate that PI3K may represent a critical node therapeutically that may be useful in combinatorial approaches.

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Multiplexed genetic analysis of malignant pleural mesothelioma and the relationship to clinical outcome. Presenting Author: Takehito Shukuya, Division of Thoracic Oncology, Shizuoka Cancer Center, Nagaizumi-chou, Shizuoka, Japan Background: Genotype-based stratification is essential to improve cancer treatment. We have developed a multiplexed tumor genotyping panel for detecting gene alterations relevant to molecular targeted therapies. We applied this genotyping panel to malignant pleural mesothelioma (MPM) and evaluate the relationship between clinical outcome and gene alterations. Methods: Surgical specimens and tumor biopsies from 40 patients with MPM were collected from 2003 to 2012. Pathological diagnoses were confirmed by immunohistochemistry in addition to HE stain. 37 patients were genotyped with multiplexed tumor genotyping panel developed to assess 9 gene mutations (EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN and HER2) and 5 genes amplifications (EGFR, MET, PIK3CA, FGFR1 and FGFR2) using pyrosequencing plus capillary electrophoresis, and qRT-PCR, respectively. Other 3 patients were analyzed by ultra-deep targeted sequencing with next generation sequencer. 5 fusion genes (EML4-ALK, CD74-ROS1, SLC34A2-ROS1, KIF5B-RET and CCDC6-RET) were tested in 2 patients with fresh frozen specimens. Results: Gene alterations were detected in 6 patients (Table shown below). These patients harboring gene alterations showed poorer survival than the patients in whom gene alterations were not detected (median survival time (MST): 583 vs 164 days, log-lank: p⫽0.009). Moreover, the patients with PIK3CA amplification/mutation showed poorer survival than the patients without PIK3CA amplification/mutation (MST: 583 vs 103 days, log-lank: p⫽0.031). Conclusions: Gene alterations which could be a target for molecular targeted therapy were detected in MPM. Especially, PIK3CA pathway is a potential target. Gender

Age

Histology

PS

Asbestos exposure

Stage

Type of genetic abnormality

Initial therapy

Response to CTx

PFS

OS

M M M F M M

60 73 63 26 68 63

Sarcomatoid Epithelioid Epithelioid Sarcomatoid Sarcomatoid NOS

1 0 0 2 0 1

Definite Definite Suspected Not definite Definite Suspected

IV III I IV IV IV

PIK3CA amplification PIK3CA amplification PIK3CA K111R KRAS G12D EGFR exon 19 deletion APC A1485T, TP53 R342Q

CDDP⫹PEM Operation Operation CBDCA⫹PEM CDDP⫹PEM CDDP⫹PEM

PD PD SD PD

67 38 162⫹ 40 247 30

144 62 193⫹ 50 393⫹ 184


A feasibility study of induction pemetrexed plus cisplatin followed by extrapleural pneumonectomy (EPP) and postoperative hemithoracic radiation (H-RT) for malignant pleural mesothelioma (MPM): First all-Japan trial. Presenting Author: Fumihiro Tanaka, Deaprtmant of Surgery, University of Occupational and Environmental Health, Kitakyusyu, Japan Background: The first all Japan multi-institutional trial was conducted to evaluate the feasibility of tri-modality therapy for MPM with support by the Special Coordination Funds for Promoting Science and Technology from the Japanese Ministry of Education, Culture, Sports, Science and Technology, and the first analyses data including macroscopic complete resection (MCR) rate by EPP as well as treatment-related mortality were presented at the ESMO meeting 2011 after completion of planned patient enrollment, and all survival data collection has been completed in January 2013. Methods: Major eligibility criteria: a histologically confirmed diagnosis of MPM, including all subtypes clinical T0 –3, N0 –2, M0 disease considered to be completely resectable; no prior treatment for the disease; age between 20 and 75 years; ECOG performance status of 0 or 1; a predicted postoperative forced expiratory volume in 1 s of ⬎1000 ml; and written informed consent. Treatment methods: Induction chemotherapy of pemetrexed 500 mg/m2 plus cisplatin 60 mg/m2 for 3 cycles, followed by EPP and postoperative H-RT (54 Gy). Primary endpoints: MCR rate by EPP and treatment-related mortality for tri-modality therapy. Results: A total of 17 institutions in Japan with certified specialists in oncology, surgery and radiation therapy participated in this trial. The study was initiated in May 2008 and patient enrollment was completed in November 2010 with 42 eligible patients. Median age 64.5 (range 43–74), M: F ⫽ 39:3, Clinical stage I:II:III ⫽ 14:13:15, Histological type epithelial: sarcomatous; biphasic; others ⫽ 28: 1: 9: 4. The trial met the primary endpoints with MCR rate of 71% and treatment-related mortality of 9.5%. All survival data to calculate disease-free survival and overall survival at 2 years after EPP have been collected, and results will be presented at the meeting. Conclusions: Results of the present trial will be the foundation of treatment strategy for resectable MPM. Clinical trial information: 000001154.




Independent validation of progression-free survival rate at 9 and 18 weeks (PFSR-18, PFSR-9) as predictor for overall survival (OS) in patients with malignant pleural mesothelioma (MPM): EORTC 08052 study. Presenting Author: Baktiar Hasan, European Organisation for Research and Treatment of Cancer Headquarters, Brussels, Belgium Background: The increasing incidence and the plateau of current treatment outcomes in MPM necessitates development of new therapeutic approaches. Reliable and meaningful response assessment is difficult in phase II trials thus a primary endpoint based on progression free survival (PFS) rate at certain time point has been proposed (Greillier et al, 2011). EORTC 08052 was a phase II study in MPM where independent validation of PFSR-18 weeks was foreseen. We extend this to PFSR-9. Methods: Association of PFS and response with OS was assessed at two distinct time points; 9 and 18 weeks after registration. Landmarks method was used, PFS status (CR/PR/SD vs. PD) and response status (CR/PR vs. PD/SD) were determined at those time points. Cox regression and logrank test were performed and the corresponding c-indexes were calculated. Results: Of 82 registered patients, 28.4% achieved CR/PR and 77.8% had disease control (CR/PR/SD) as their best overall response. PFSR-18 and PFSR-9 were both strongly correlated with OS. Patients with no progression at 18 weeks had median OS of 16.9 months compared to 11.9 months in those who progressed at 18 weeks. Hazard ratio [HR] (95 confidence interval [CI]) was 0.46 (0.32-0.67), logrank test was 0.007 and C-index ⫽ 0.60. Adjusting for 3 important baseline prognosis factors, histology, performance status and disease stage resulted in PFS-18 as the only significant factor. When 9 weeks landmark was chosen, patients with no progression had median OS of 16.9 months vs. 6.8 months in those who progressed with HR (CI), logrank test and C-index 0.35(0.25-0.49), ⬍ 0.0001 and 0.66 respectively. When adjusted by 3 important baseline prognosis factors PFS-9 remained the only significant factor. The results also confirmed that response at 18 weeks and 9 weeks was correlated with OS. Conclusions: PFSR-18 was strongly correlated and discriminated patients with better OS from the poorer prognosis patients. An earlier endpoint, PFSR-9 was also strongly correlated to OS and had a better discriminating capacity. Previous results on correlation between PFSR-9 and PFSR-18 and OS were independently validated.

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Platelet counts (PLT) at baseline and on treatment as predictor for progression free survival (PFS) in patients with advanced malignant pleural mesothelioma (MPM): EORTC 08052 study. Presenting Author: Rabab Mohamed Gaafar, National Cancer Institute, Cairo University, Cairo, Egypt Background: PLT values at baseline are considered as a negative prognostic factor in several different tumor types (lung, colorectal, renal and endometrial cancer) in both early and advanced disease settings. This is an exploratory analysis of PLT (baseline and changes during treatment) and their value in predicting PFS and overall survival (OS) in patients with stage IV MPM treated with cisplatin/bortezomib in the context of a single-arm phase II trial (EORTC 08052). Methods: Patients participating in the clinical trial were chemo-naïve with histological proven MPM and PS 0/1 (cisplatin 75 mg/m2 d1 and bortezomib 1.3 mg/m2 on d1, 4, 8, 11 q3wks). PLT analysis was pre-planned in the protocol and was recorded at baseline and at each cycle. Nadir of change in PLT was recorded at 8 and 18 weeks according to predefined cut off points (median PLT value). The association of the PLT with PFS and OS was analyzed. Results: 82 patients from EORTC-08052 study were analyzed with 1394 records of PLT. The cut off point for baseline was median PLT 374x103/mm3. We confirmed that patients with baseline PLT less than median had longer PFS compared to patients with counts higher than median (median PFS: 5.7 vs. 3.7 months [mo]; HR: 0.55; 95% CI: 0.34-0.88; p: 0.012). There was also a trend towards higher OS for patients with baseline PLT values less than median (median OS: 14.8 vs.10.6 mo; HR: 0.62; 95% CI: 0.38-1.02; p: 0.059). The median decrease of PLT values at 8 wks of treatment was 243 x103/mm3. Patients with decrease lower than median had higher PFS (median PFS: 7.5 vs. 5.7 mo; HR: 2.2; 95% CI: 1.3-3.8; p: 0.003) and a trend towards higher OS (median OS: 14.9 vs. 10.6 mo; HR: 1.6; 95% CI 1-2.7; p: 0.06). Changes at 18 weeks had no prognostic value. Conclusions: Besides low baseline PLT values we observed that a decrease in PLT at 8 weeks (but not 18 weeks) during treatment could predict PFS and to less extent OS. Validation of this observation is planned.

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A novel microRNA-based treatment approach for malignant pleural mesothelioma. Presenting Author: Glen Reid, Asbestos Diseases Research Institute, Sydney, Australia

A clinical-based risk score for decision making for surgery after induction chemotherapy in malignant pleural mesothelioma patients. Presenting Author: Isabelle Opitz, University Hospital Zurich, Zurich, Switzerland

Background: Malignant pleural mesothelioma (MPM) is recalcitrant to treatment and new approaches are needed. The microRNA miR-16 has been implicated as a tumor suppressor in a range of cancer types, and restoration of miR-16 expression has been shown to inhibit tumor cell proliferation. The miR-16 status in MPM is largely unknown. Methods: MicroRNA expression was analysed by TaqMan-based RT-qPCR in 10 MPM cell lines and 60 tumour specimens consisting of archival blocks from patients undergoing surgery. MicroRNA expression was restored in vitro using mimics corresponding to the sequence of the mature microRNA, and effects on proliferation and target genes were assessed with standard methods. Human xenograft-bearing mice were treated with miR-16 mimics packaged in minicells targeted with EGFR-specific antibodies. Results: Expression of miR-16 was consistently down-regulated in MPM cell lines and MPM tumor specimens as were the co-expressed miR-15a and miR-15b. A decrease of 2- to 5-fold in miR-16 expression was found when MPM cell lines were compared with the normal mesothelial cell line MeT-5A. When tumor specimens were compared with normal pleura, the down-regulation of miR-16 was in the order of 10-fold. Using synthetic miR-16 mimics to restore miR-16 expression in MPM cell lines led to timeand dose-dependent growth inhibition in a panel of MPM cell lines but did not affect growth of MeT-5A. Growth inhibition correlated with cell cycle arrest and concordant down-regulation of miR-16 target genes including Bcl-2 and CCND1. In a series of experiments with nude mice bearing MPM (MSTO-H211) xenografts, intravenous administration of miR-16 mimics packaged in minicells led to consistent and dose-dependent inhibition of tumor growth. Conclusions: Restoring miR-16 expression represents a novel approach to treatment for MPM. Preparations are being made to test miR-16 packaged in minicells as a new treatment approach for patients with recurrent MPM and NSCLC.

Background: Scoring tools predicting the potential benefit from surgery after induction chemotherapy in mesothelioma patients may influence decision making. Our score is based on 4 clinical variables available before surgery. Methods: 128 patients were uniformly treated with cisplatin based induction chemotherapy followed by extrapleural pneumonectomy between 1999 and 2011. Based on clinical experience and survival influencing factors resulting from uni-and multivariate analysis, we designed a risk score. All 4 variables building up the score were available for 59 patients: pre chemotherapy volumetry above 500 ml, non-epithelioid histotype in the diagnostic biopsy, pre chemotherapy CRP value above 30 mg/l and progressive disease after chemotherapy according to modified RECIST criteria. The 5 resulting groups were analyzed for overall survival (OAS) and progression free survival (PFS) using Kaplan-Meier and Cox regression model. Results: The score strongly stratified patients into high and low risk groups for shorter OAS (Table) (p⬍0.0005). As to PFS, patients with Score 0 also had significantly longer median PFS (16 months; 95% CI: 12; 20) in comparison to patients with score 3 or higher (6 months; 95% CI: -; -) (p⬍0.0005). In Cox regression analysis the risk factor for shorter OAS and PFS increased correspondingly to our score. Conclusions: Our new score based on 4 clinical variables available before surgery identifies patients’ subgroups who may benefit from surgery after induction chemotherapy, which will be further assessed prospectively. Score 0 Score 1 Score 2 Score 3 Score 4 Overall

Total number

Median OAS

95% CI

18 25 12 3 1 59

34 months 17 months 12 months 4 months 4 months 18 months

18; 50 9; 25 8; 16 3; 6 . 9; 26


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Lung Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers General Poster Session (Board #28A), Sat, 8:00 AM-11:45 AM

Interim outcome analysis of a prospective phase I trial of surgical resection with intracavitary hyperthermic cisplatin and gemcitabine for patients with resectable malignant pleural mesothelioma. Presenting Author: William G. Richards, Brigham and Women’s Hospital, Boston, MA Background: We completed a phase I trial of cisplatin and dose-escalated gemcitabine in a hyperthermic intra-operative lavage (IOHC) following extrapleural pneumonectomy (EPP arm) or extended pleurectomy (PD arm). Primary and secondary endpoints including gemcitabine MTD (1000 mg/m2 with 175 mg/m2 cisplatin) and pharmacokinetics, toxicity and mortality were reported (IMIG congress, 9/11-14/2012, abstract IIB.4 [1]). To define phase II indications, we explored patient outcome in comparison to published phase II results of a similar trial using cisplatin IOHC alone following EPP (J Thorac Cardiovasc Surg 2009, 138:405 [2]). Methods: The protocol was registered and IRB approved. Informed consent was obtained. Overall survival was calculated from the date of surgery to the date of death or censored at the date of most recent contact. Patients who were treated on the EPP arm at 500 to 1000 mg/m2 gemcitabine dose levels were included, grouped by epithelial (E) or non-epithelial (NE) histological subtype. Median, 1-year and 2-year survival was estimated using Kaplan-Meier methods. Results: 141 patients were registered. Median age was 65 (43-85) and 22 (21%) were women. Histology was epithelial (63), biphasic (32), and sarcomatoid (8). Two patients died perioperatively (2%). 59 patients were treated on the EPP arm of which the 27 (13 censored) treated at 500 to 1000 mg/m2 gemcitabine were studied. Qualitative comparison with a prior phase II trial of cisplatin IOHC (ref [2]) suggests incremental survival benefit to adding gemcitabine for patients with epithelial but not non-epithelial tumor histology (Table). Conclusions: Patients with epithelial histology tumors who require EPP for macroscopic complete resection appear likely to benefit from the addition of gemcitabine and should be included in a phase II investigation of this combination. Patients with non-epithelial biopsy who require EPP should be considered for other treatment strategies. Clinical trial information: NCT00571298. Procedure

Cis mg/m2

Gem mg/m2

Histology

N

Median (months)

1-year (%)

2-year (%)

EPP EPP[ref 2] EPP

175 225 175

500-1000 None 500-1000

E E NE

16 53 11

25.5 17 6.8

94 ~65 27

70 ~35 0

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Genetic analysis of the separate morphologic components in combined small cell lung cancer. Presenting Author: Hongyang Lu, Zhejiang Cancer Hospital, Hangzhou, China Background: Combined small cell lung cancer (CSCLC) is currently considered a subset of SCLC and have been reported to account for less than 1-3.2% of all SCLCs. Accurate understanding of CSCLCs is of great importance because treatment strategies are significantly different for NSCLC and SCLC. To address molecular features of different components in CSCLC we analyzed mutation status in CSCLC tumor samples in EGFR signal pathway. Methods: Seven CSCLC samples were included in direct sequencing for mutation analysis of EGFR, KRAS, PIK3CA, BRAF, and PTEN. Results: Mutations were detected in 4 of 7 (57.1%) CSCLC patients. EGFR Exon 18 mutations were identified in two patients among whom the mutation was identified in both adenocarcinoma component and SCLC combined adenocarcinoma component of one patient. The similar situation also happened in another one with PTEN C511T mutations both conventional SCLC component and SCLC combined adenocarcinoma component. Both KRAS and PIK3CA were detected in one SCLC combined adenocarcinoma patient and no mutation in BRAF was identified. Conclusions: Our result is consistent with previous work that the individual components of CSCLC are closely related, despite their distinct morphologic appearances.

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Prophylactic cranial irradiation in patients > 70 years old with limited stage small cell lung cancer: A Surveillance, Epidemiology, and End Results analysis. Presenting Author: Bree Ruppert Eaton, Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA Background: Prophylactic cranial irradiation (PCI) improves survival in patients with limited stage small cell lung cancer (SCLC) who have a complete response to chemotherapy and radiation (RT). Yet in clinical practice, concerns exist regarding PCI-related toxicity and the extent of benefit in elderly patients. This exploratory analysis evaluates the effect of PCI on survival among patients ⱖ 70 years old. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified 4,003 patients ⱖ70 years old with localized or regional SCLC diagnosed between 1988 and 1997. Patients with no brain RT information (n⫽974) were excluded. Patients with overall survival (OS) ⬍6 months (n⫽1103) were also excluded to eliminate patients with an aggressive disease course and minimize selection bias. Survival rates for patients who received brain RT versus no brain RT were estimated by the Kaplan Meier method and compared with the Log-rank test. A Cox proportional hazards model was further fitted to estimate the effect of brain RT on OS after adjusting for age, race, gender, and stage. Results: Of the 1926 patients included, the median age was 75 years (range, 70-94). The majority of patients were white (68%) and male (52%). According to SEER Historic Stage A, 68% of patients had regional stage and 32% had localized stage. One-hundred and thirty-eight patients (7.2%) received brain RT. Patients treated with brain RT were younger at diagnosis (p⬍0.01) and more likely to have regional stage disease (p⫽0.02). Five-year OS was 11.6% (95% CI: 6.9-17.6) among patients who received brain RT versus 8.6% (95% CI: 7.32-9.91) among patients who did not (p⫽0.03). Younger age, female gender, white race, and localized stage were also significant factors associated with improved OS. On multi-variable analysis, receipt of brain RT remained an independent predictor of OS (HR 0.825, 95% CI: 0.69-0.98, p⫽0.03). Conclusions: The receipt of brain radiotherapy is associated with improved overall survival in patients ⱖ70 years old with localized or regional stage SCLC, suggesting the benefit of PCI is maintained in the elderly population.

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Phase I/IIa study of the novel combination of bendamustine (B) with irinotecan (I) followed by etoposide (E) and carboplatin (C) in untreated patients (Pts) with extensive-stage small cell lung cancer (ESSCLC). Presenting Author: Daniel Joseph Allendorf, University of Alabama at Birmingham, Birmingham, AL Background: Standard therapy for ESSCLC consisting of E and a platin drug (Plat) yields a median time to progression (TTP) of 4 months (m) and overall survival (OS) of 9 m. DNA damage from B is repaired by excision repair, akin to Plat. The activity of I, a topoisomerase (Top)-1 inhibitor, leads to increases in Top-2, the target of E. The sequence B⫹I ¡ E⫹C was hypothesized to increase TTP by exploiting mitotic catastrophe. Methods: This is an open label trial enrolling pts with ESSCLC and evaluable disease. The phase I primary endpoint was to determine the maximum tolerated dose (MTD) of B⫹I; the phase IIa primary endpoint was TTP after B⫹I¡E⫹C. Secondary endpoints were objective response rate (ORR) and OS. In the phase I (N⫽15), cohorts received I (150 mg/m2, d 1) with B at 80, 100, or 120 mg/m2/day (d 1,2) every 3 weeks for 3 cycles. Phase IIa Pts were treated at the recommended dose of B⫹I for 3 cycles followed by E (100 mg/m2, d 1-3) ⫹ C (AUC 6, d 1) for 3 cycles. Restaging was performed after 3 cycles of each regimen. The phase IIa was powered to detect a 30% increase in TTP from 4 to 5.2 m with a of 0.1. The Kaplan-Meier method was used to calculate TTP and OS. Toxicities were evaluated using the NCI CTCAE. Results: The MTD of B was not reached. The recommended phase IIa dose of B was 100 mg/m2; dose-escalation was allowed in subsequent cycles of therapy. Dose limiting toxicities were diarrhea, nausea, and vomiting. One treatment-related death from metabolic encephalopathy occurred in the phase IIa. The commonest grade 3/4 hematologic toxicity was neutropenia. Fatigue, nausea, vomiting, and diarrhea were common non-hematologic toxicities. Conclusions: B⫹I is an active regimen in ESSCLC and the treatment sequence B⫹I¡E⫹C seems to improve the TTP and OS in ESSCLC compared to historic values for E⫹C. Toxicities were increased compared to historic values for E⫹C, but were manageable. Correlative studies with pre-treatment assessment of tumor ERCC-1, Top-1, and Top-2 as predictors of response are ongoing. Clinical trial information: NCT00856830. Efficacy parameters (Nⴝ29). Median TTP Median OS ORR Median tumor reduction after EⴙC

6.0 m (95% CI 5.0-7.0)

10.0 m (95% CI 8.3-11.7) 75% B⫹I

65%

73%




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Circulating tumor cells as a prognostic factor in patients with small cell lung cancer. Presenting Author: Satoshi Igawa, Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Japan

Small cell lung cancer (SCLC) among patients who are never smokers. Presenting Author: Anna M. Varghese, Memorial Sloan-Kettering Cancer Center, New York, NY

Background: Research on the detection of circulating tumor cells (CTCs) in peripheral blood is currently an important field of research. The aim of this study was to evaluate a new method of detecting CTCs in the peripheral blood of small cell lung cancer (SCLC) patients by using the telomerasespecific replication-selective adenovirus OBP-401. Methods: We prospectively enrolled 30 consecutive newly diagnosed SCLC patients who were being started on chemotherapy or chemoradiotherapy as the subjects of this study. We collected peripheral blood specimens from the SCLC patients and detected viable CTCs in them after incubation with a telomerase-specific, replication-selective, oncolytic adenoviral agent carrying the green fluorescent protein (GFP) gene. We also investigated whether the CTC count per 7.5 ml of peripheral venous blood was associated with the outcome of SCLC. Results: CTCs were detected in 96% of the patients (29 of the 30 patients). The group of 22 patients with a CTC count of ⬍ 2 before treatment (baseline) had a significantly longer median survival time than the group of 8 patients with a CTC count of ⱖ 2 before treatment (14.8 months and 3.9 months, respectively, P ⫽ 0.001). The results of a multivariate analysis showed that the baseline CTC count was an independent prognostic factor for survival (hazard ratio ⫽ 5.11, P ⫽ 0.038). Conclusions: CTCs in the peripheral blood of SCLC patients can be detected by the OBP-401assay, and based on the results of this study the CTC count before treatment appears to be a strong prognostic factor.

Background: Although most patients (pts) with SCLC are current or former smokers, SCLC has been reported in pts who are never smokers, most recently in pts with EGFR-mutant lung cancers who develop acquired resistance (AR) to EGFR tyrosine kinase inhibitors (TKIs). We describe clinical, pathologic, and molecular characteristics of never-smoking pts with SCLC at diagnosis and in the AR setting. Methods: We identified cases through systematic review of pts seen at MSKCC from 2005 – 2012. Smoking history was obtained prospectively. SCLC diagnosis was confirmed by expert pathology review. We collected age, sex, stage, treatment, and survival data. EGFR, KRAS, PIK3CA, and ALK testing and next generation sequencing of 279 cancer genes was performed on available samples. Results: 2.2% (23/1040, 95% CI 1.5 to 3.3%) of pts with SCLC seen at MSKCC were never smokers: 61% women, median 64 years, 74% extensive stage, and 22% with brain metastases at diagnosis. 83% (19/23) had de novo SCLC, whereas only 17% had SCLC as AR to EGFR TKI after treatment for EGFR-mutant lung cancers, all of whom had persistent EGFR mutation confirmed at resistance. Median survival from SCLC diagnosis is 23 months (95%CI: 11-26) for all pts and 23 months (95% CI: 8 –27) for the 19 pts with de novo SCLC. Pathologic review demonstrated 19 cases of pure SCLC and 4 mixed histology cases with SCLC and other histologies. Treatment history was available for 15/19 pts with de novo SCLC: 53% etoposide-platinum sensitive. ALK rearrangement and KRAS mutations were identified in 0/5 and 0/10, respectively. One pt with de novo mixed SCLC and adenocarcinoma had an EGFR mutation and another pt with de novo pure SCLC had EGFR and PIK3CA mutations. Mutations were identified in p53 and Rb1 with amplification in TERT in 1 sample to date tested with next generation sequencing. Conclusions: 2% of pts with SCLC are never smokers. While transformation to SCLC can occur in the setting of AR to EGFR TKI, de novo SCLC occurs in the majority of our never smokers with this disease. EGFR mutations uniformly exist in SCLC in the AR setting. EGFR mutations were rare, and we found no KRAS mutations or ALK rearrangements. Comprehensive, multiplexed genotyping can aid in providing optimal care and facilitate research in this unique population.

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Predictive value of BRCA1, ERCC1, ATP7B, PKM2, TOPO-I, TOPO-iia, TOPO-iib, and c-MYC genes in patients with small cell lung cancer (SCLC) who received first-line therapy with cisplatin and etoposide. Presenting Author: Chara Papadaki, Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Greece Background: to evaluate the predictive value of genes correlated with cisplatin-etoposide (EP) metabolism or mode of function in patients with SCLC. Methods: Tumor samples from 184 patients, with SCLC were analyzed for ERCCI, BRCA1, ATP7B, TOPOI, TOPOIIA, TOPOIIB PKM2 and C-MYC mRNA expression by quantitative real-time PCR, from microdissected cells derived from patients’ primary tumors. All patients were treated with EP (plus radiotherapy for patients with limited disease-LS) in the department of Medical Oncology of the University Hospital of Heraklion. Results: The median age of the patients was 63 years (min-max: 33-78). One hundred-twenty (65%) patients presented with extended stage (ES), LDH was above the UNL in 75 (41%), while ECOG performance status was 0-1 in 131 (71%) of them. Shorter progression free survival (PFS) was observed in patients with LS-SCLC whose tumors expressed high ERCC1 (p⫽0.028), PKM2 (p⫽0.046), TOPO-I (p⫽0.008), TOPO-IIA (p⫽0.002) and TOPO-IIB (p⬍0.001) expression. High expression of ERCC1 (p⫽0.014), PKM2 (p⫽0.026), TOPO-IIA (p⫽0.021) and TOPOIIB (p⫽0.019) was correlated with shortened median overall survival (OS) in LS-SCLC patients. In patients with ES-SCLC, only high TOPO-IIB expression was associated with decreased OS (p⫽0.035). The favorable genotype (low expression of ERCC1, PKM2, TOPO-IIA and TOPO-IIB) was correlated with significantly improved PFS in both LS-SCLC (p⬍0.001) and ES-SCLC (p⫽0.007) patients as well as with improved OS in the LS-SCLC (p⫽0.007) and ES-SCLC (p⫽0.011) group. Unfavorable genotype was independent predictor of poor PFS (HR: 3.18; p⫽0.002) and OS (HR: 4.35; p⫽0.001) in LS-SCLC as well as for both PFS (HR: 3.14; p⫽0.021) and OS (HR: 3.32; p⫽0.019) in ES-SCLC. Conclusions: Single gene’s expression analysis as well as the integrated analysis of ERCC1, PKM2, TOPO-IIA and TOPO-IIB may predict treatment outcome in patients with SCLC. The results of our study, if validated prospectively, may help in selecting patients for personalized therapeutic strategies.


A multicenter phase III randomized double-blind placebo controlled trial of pravastatin added to first-line standard chemotherapy in patients with small cell lung cancer (SCLC). Presenting Author: Michael Seckl, Charing Cross Hospital Trophoblastic Disease Centre, London, United Kingdom Background: Most SCLC patients initially respond to chemotherapy but then relapse and die so new therapies are urgently required. Pre-clinical data shows statins induce growth arrest and apoptosis in SCLC and several other tumour cell types and are additive with chemotherapy. This may in part be due to impaired Ras superfamily function as statins deplete mevalonate, reducing geranylgeranylation and farnesylation of these proteins. We therefore undertook this large pragmatic phase III trial in order to determine if overall survival (OS) was affected by the addition of pravastatin in SCLC. Methods: Patients with limited (LD) or extensive (ED) stage SCLC were randomised to pravastatin 40mg OD or placebo for up to 2 years and given standard chemotherapy according to local practice recommended as either cisplatin 60mg/m2 iv or carboplatin AUC 5 or 6 and etoposide 120 mg/m2iv d1 to 3 or 100 mg BD po d2 & 3; max 6 cycles plus radiotherapy as usually given. Patients were excluded if they had used statins within 12 months prior to randomisation. Stratification was: LD vs ED and ECOG 0,1 vs 2,3. Endpoints were: primary - OS; secondary - progression free survival (PFS), local PFS (local control), response rates (RR) and toxicity. Results: Between 2007 and 2012, 846 patients were randomised, 422 (49.9.%) received pravastatin and 424 (50.1%) placebo in 93 participating sites in the UK. The median age was 64 years (range 54-69); ECOG performance status: 0: 23%; 1: 54%; 2: 17% and 3: 6%; weight 72.6 kg; LD, 357 (42.2%); ED, 479 (56.6%); 211 (24.9%) had ipsilateral effusion and 201 (23.8%) had ipsilateral SCF lymph nodes; Relative Dose intensity of cisplatin/carboplatin and etoposide was 91.6% (range 80.8 to 99.7), and 94.7% (range 85.7 to 100); 83.4% vs 86.3% completed ⬎ 4 cycles of chemotherapy on the pravastatin and placebo arms respectively. Most patients completed 6 cycles of chemotherapy: 263 (62.3%) vs 265 (62.5%) in the pravastatin vs. placebo groups. Updated results showing OS, PFS, local PFS and toxicity will be presented. Conclusions: This trial will report on whether pravastatin 40 mg OD added to standard therapy alters the outcome for SCLC patients. Clinical trial information: ISRCTN56306957.


482s 7596

Lung Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers General Poster Session (Board #29F), Sat, 8:00 AM-11:45 AM

Can hippocampus be spared in patients with small cell lung carcinoma (SCLC) during cranial radiation therapy (CRT)? Presenting Author: Vijayananda Kundapur, Department of Radiation Oncology, Saskatoon Cancer Center, Saskatchewan Cancer Agency, University of Saskatchewan, Saskatoon, SK, Canada Background: Although CRT is a standard therapy for prevention and treatment of brain metastases (BM) in patients with SCLC, neurocognitive impairment (NI) following therapeutic whole brain radiation treatment (WBRT) or prophylactic cranial irradiation (PCI) is a major problem and can cause impairment in quality of life. A RTOG study is assessing various outcomes by avoiding the hippocampus (AH) during WBRT in different malignancies. The estimated risk of hippocampal avoidance region metastases (HM) in patients with SCLC before & after WBRT/PCI is not known. AH during CRT may delay the onset of NI in such patients. Our study aims to determine risk of HM in patients with SCLC and to assess clinical factors correlate with it. Methods: A patients cohort of SCLC diagnosed and treated at the Saskatoon Cancer Center between 2005 and 2012 were followed. All MRI and/or CT scans were independently reviewed by a neuroradiologist. HM was defined as BM within 5 mm of hippocampus. Binary Logistic regression analysis was done to assess correlation between various clinical variables and HM using SPSS. Results: 162 patients with SCLC were identified, 60 (37%) have developed BM. The preliminary data of 39/60 patients is presented here. All 39 patients received CRT and 17 patients received upfront chemotherapy. Their median age was 63 yrs (range: 41-82) & M:F was 22:17. 30 (77%) had extensive stage SCLC and 30 (77%) had de novo BM before CRT. A total 198 (range: 1-33) BM were identified among these patients with a mean BM of 6.6 per patient. 4 (13.3%) of 30 patients had HM involvement with mean BM of 1.3 per patient. Median follow up was 13.5 months (range: 1-69). Post-CRT 13 (33%) of 39 patients (4 PCI, 9 WBRT) developed central nervous system (CNS) progression. None of 13 patients with CNS failure following CRT developed HM. Overall 4 (10.2%) of 39 patients developed HM. No clinical factors significantly correlated with HM. Conclusions: The preliminary result revealed that overall incidence of HM before and after WBRT/PCI is low. AH in such patients may consider during CRT to avoid NI. The study is ongoing and final analysis will be presented.

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Oral (O) versus intravenous (IV) etoposide and platinum in the treatment of extensive-stage small cell lung cancer (SCLC). Presenting Author: Scott Alan Dorroh, University of Arkansas for Medical Sciences, Little Rock, AR Background: Platinum and etoposide chemotherapy is the treatment for patients with SCLC. O etoposide is substituted for IV by many clinicians at twice the dose for bioavailability but the outcome of these subjects has not been studied. To compare the efficacy of O vs. IV etoposide in extensive stage SCLC, a retrospective analysis of subjects treated in the VISN 16 network of 10VA hospitals was undertaken. Methods: Subjects with SCLC diagnosed between 10/1/1996 and 9/30/2010 were identified from the VISN-16 tumor registry. Study was limited to extensive disease by excluding those treated with radiation therapy. Chemotherapy details were obtained from the pharmacy data in the VISN 16 database. Overall survival (OS) was computed as the time in months from the first etoposide issue date to the date of death or last contact. Kaplan-Meier methods were used to compute median OS, and etoposide groups were compared via log-rank test. Results: 300 subjects were eligible for analysis, with median age 67 yrs (range 45-84). 295 deaths were observed during 2,419 total months of follow-up. The median OS of all subjects was 6.3 months (interquartile range (IQR) 2.0-11 months). In addition to platinum, 153 subjects received only O etoposide, 147 received some form of IV etoposide. The median duration (IQR) of therapy for all subjects was 29 (1-110) days; 23 days for those who received any IV etoposide and 43 days for those who received only oral etoposide. The median OS was 7.6 months for those who received only O etoposide vs. 5.4 months for any IV etoposide (P⬍0.0001). In the latter group, those receiving purely IV etoposide had only 1.5 months’ median OS vs. 8.8 months for those receiving both O and IV etoposide (P⬍0.0001). Conclusions: Survival of subjects with SCLC treated with O etoposide is comparable to those who received a combination of O and IV therapy. Poor OS for those with only IV therapy may be due to selection bias of poor-performance subjects. Etopside (n)

Median OS mos. (range)

Oral 153 Any IV 147

7.6 (2.7-13) 5.0 (1.5-9.6)

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P ⬍0.0001

Etopside (n)

Median no. of days on etoposide

Median OS mos. (range)

Oral only (153) Oral⫹ IV (82) IV only (65)

43 108 3

7.6 (2.7-13) 8.8 (0.5-11) 1.5(0.5-1.1)

P ⬍0.0001


Advanced pulmonary carcinoid (APC): 20-year experience at Johns Hopkins (JH). Presenting Author: Patrick M. Forde, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD

Molecular profiling of small cell lung cancers in Japanese patients. Presenting Author: Kazushige Wakuda, Division of Thoracic Oncology, Shizuoka Cancer Center, Nagaizumi-cho, Shizuoka, Japan

Background: APC is a rare thoracic malignancy with limited prognostic data and a perceived lack of treatment options other than surgical resection. This is the largest series of APC patients (pts) ever reported and contains data on locally advanced and metastatic disease. Here we compare clinical outcomes and treatment responses for typical carcinoid (TC) and atypical carcinoid (AC). Methods: This retrospective cohort includes pts referred to JH from 1992 to 2012. Pts were identified using pathology and medical record databases. Information extracted included, pathology, demographics, stage, prior curative resection, time to relapse, chemotherapy/targeted agents and response rate (RR), date of death/last follow-up. Primary outcome was overall survival (OS), defined as time from diagnosis of advanced disease to death from any cause. Secondary endpoint was recurrence-free survival (RFS), defined as time from curative resection to tumor recurrence. OS and RFS were estimated by using the Kaplan-Meier method and log-rank test comparing TC and AC. Results: 49 APC pts (30 female/19 male; 32 AC/17 TC) were identified. 25 pts had relapsed after previous curative resection. Median RFS (n⫽25), was significantly longer for TC vs. AC (119 months (m) vs. 66 m, p⫽0.008). Median OS was 85m and significantly longer for TC vs. AC (122m vs. 48m, p⫽0.009). 39 (80%) pts received systemic therapy for APC. RR to first-line chemotherapy was 22% (5/23) with all 5 (3 AC, 2 TC) responses occurring in pts receiving cisplatin/etoposide. First-line somatostatin therapy was given to 11 pts with 1 partial response (PR) (9%) and 10 pts with stable disease (5 AC, 5 TC) for a median 15m. 5 pts received first-line targeted agents including sunitinib and gefitinib however no responses were seen. 50% (2/4 pts) RR occurred to second-line temozolomide/capecitabine An ongoing PR ⬎ 6m to everolimus occurred in a heavily pretreated AC pt. Conclusions: Both AC and TC may recur many years after resection. This study demonstrates significantly poorer survival for AC in advanced disease. Thoracic oncologists perceive APC as resistant to systemic therapy however here we report that both AC and TC may respond to cisplatin/etoposide, temozolomide/ capecitabine and mTOR targeted therapy.

Background: Molecular abnormalities discovered in the last decade have led to a paradigm shift in the diagnosis and treatment of lung adenocarcinoma. But there have been few reports about molecular profiling of small cell lung cancers (SCLC). We conducted the Shizuoka Lung Cancer Mutation Study to analyze driver mutations in patients with thoracic SCLC malignancies. Methods: We collected molecular profiling data of SCLC from the biobanking system in conjunction with the clinic, including the pathology lab, where 23 mutations in 9 genes (EGFR, KRAS, BRAF, PIK3CA, NRAS, MEK1, AKT1, PTEN and HER2), EGFR, MET, PIK3CA, FGFR1 and FGFR2 amplifications, and EML4-ALK translocations were assessed using pyrosequensing plus capillary electrophoresis, qRT-PCR, and RT-PCR, respectively. To evaluate mutation status for SCLC patients, we collected patient characteristics data from medical records. Results: Between July 2011 and July 2012, fifty small cell lung cancer patients were assessed in our biobanking system. Patient characteristics were as follows: median age (range) 70 (43 - 82) years; male 82%; smoker 96%; limited disease/ extended disease 56/44%; small cell carcinoma/combined small cell carcinoma with adenocarcinoma 94/6%; surgically resected snap-frozen samples 8, formalin-fixed paraffin-embedded samples 40 and pleural effusion 7. We detected driver mutations in 8 cases (16%). Mutations found: EGFR 1 (2%), KRAS 1 (2%), PIK3CA 2 (4%), AKT1 1 (2%), MET amplification 1 (2%), PIK3CA amplification 6 (12%). EGFR and KRAS mutation were found in combined small cell carcinoma with adenocarcinoma. No significant differences in age, sex, disease extent at diagnosis or smoking status were found between patients with mutations and those without mutations. But serum neuron-specific enolase (NSE) levels were significantly higher in patients without mutations (p⫽0.03). Conclusions: In our analysis, driver mutations were found in 16% of SCLC patients and PIK3CA amplification seemed to be relatively frequent in SCLC. Our results suggest that PIK3CA might become a target of treatment for SCLC patients.




Prospective molecular evaluation of small cell lung cancer (SCLC) utilizing the comprehensive mutation analysis program at Memorial Sloan-Kettering Cancer Center (MSKCC). Presenting Author: Maria Catherine Pietanza, Memorial Sloan-Kettering Cancer Center, New York, NY

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Development of a SOMAmer (slow off-rate modified aptamer)-based assay to detect NSCLC. Presenting Author: Noh Jin Park, Quest Diagnostics, San Juan Capistrano, CA

Background: Oncogenic events in adenocarcinoma and squamous cell cancers of the lung are well described. In contrast, the repertoire of possible molecular targets in SCLC is still unclear. Recent studies using next generation sequencing on rare resected SCLC specimens have provided insights into the molecular heterogeneity of this disease. Comprehensive, prospective molecular profiling of patients with SCLC using the small biopsy specimens available in clinical practice has not been performed. Methods: Utilizing an IRB-approved protocol to prospectively test SCLC tumors (Small Cell Lung Cancer Mutation Analysis Program, “SC-MAP”), these biopsies are evaluated by: FISH for FGFR1 and MET amplification; immunohistochemistry for MGMT and PTEN loss; point mutation genotyping with Sequenom for PIK3CA (and others); and nextgeneration sequencing with our MSK-IMPACT assay (Integrated Mutation Profiling of Actionable Cancer Targets). MSK-IMPACT uses exon capture followed by massively parallel sequencing to profile all protein-coding exons and select introns of 279 cancer-associated genes, enabling the identification of mutations, indels, and copy number alterations of these genes. We tested the feasibility of this approach in a series of patients with SCLC. We performed next generation sequencing with MSK-IMPACT, with findings confirmed by FISH. Results: We identified 11 patients with SCLC with FFPE samples available from both matched normal tissue and small tumor biopsies, including 3 core biopsies and 8 fine needle aspirations. 9/11 patients had adequate tissue for MSK-IMPACT, which revealed recurrent mutations in Rb1 (N⫽7) and p53 (N⫽7), FGFR1 amplification (N⫽2), and MET amplification (N⫽1), using as little as 15 nanograms of DNA. FGFR1 and MET amplification were confirmed by FISH testing. We have initiated this prospective SC-MAP program for our patients with SCLC. Conclusions: Comprehensive molecular evaluation of SCLC is feasible on clinically available, small samples. Such analyses will allow us to characterize the molecular diversity of this disease and identify patients who will be candidates for targeted therapies.

Background: Support for low-dose helical computed tomography (CT) screening for lung cancer in a high risk population has emerged from the National Lung Screening Trial (NLST). However, the low specificity of CT raises concerns regarding the cost and potential morbidity associated with resection of benign nodules. Non-invasive lung cancer biomarkers may serve as a useful complement to imaging, providing a simple means to further clarify the diagnosis of suspicious pulmonary nodules. SOMAmerbased chip technology was previously used to identify a panel of serological biomarkers capable of accurately classifying NSCLC. Here we assess the analytical and clinical performance of an automated assay that uses SOMAmer reagents and qPCR to simultaneously quantify a subset of these markers (n⫽12). Methods: Biomarker levels were measured in sera from 43 subjects with stage I-III NSCLC and 63 long-term smoker controls. qPCR results were analyzed by relative (⌬⌬CT) quantitation, which uses calibrator serum and a set of normalizers. Linear mixed-effects models were fit to identify key sources of analytical variability (variance components), including plate-to-plate, within-sample, and between sample effects. Clinical performance for distinguishing NSCLC from control sera was established by a random forest predictive model. Results: Median within-sample %CV for the 12 markers was 6.7%. Variance components analyses suggest that, on average, 5.7% of the variance for a given biomarker was due to withinsample effects, 5.2% to plate-to-plate effects, and 86.2% to betweensample effects. A 10-marker random forest model exhibited an AUC [95% CI] of 0.915 [0.905, 0.924], classifying NSCLC from control sera with 79% sensitivity and 90% specificity. Conclusions: We have developed a highly reproducible automated assay designed for the clinical laboratory. Combining SOMAmer-based protein capture and qPCR-based quantification, the assay monitors the levels of 12 potential lung cancer markers. An algorithm-based model incorporating 10 of these markers showed good accuracy for distinguishing NSCLC from control sera. Further studies are warranted to evaluate the performance of the test in classifying pulmonary nodules.

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Thymic carcinoma: A cohort study of prognostic factors after surgical resection from the European Society of Thoracic Surgeons database. Presenting Author: Enrico Ruffini, Thoracic Surgery, University of Torino, Torino, Italy

Thymic epithelial tumors at University Federico II of Naples: A 30-year experience. Presenting Author: Carlo Buonerba, Department of Clinical Oncology and Endocrinology and Rare Tumors Reference Center Campania Region, University Federico II, Naples, Italy

Background: Thymic carcinomas are rare tumors which have recently been separated from thymomas due to their different histologic/clinical characteristics. Most of the current literature is composed of small series spanned over extended time periods Methods: The European Society of Thoracic Surgeons (ESTS) developed a retrospective database collecting data on patients with thymic tumors submitted to surgery (1990-2011). Out of 2,265 incident cases, there were 229 thymic carcinomas. Clinicalpathologic characteristics were analyzed including age, gender, stage (Masaoka), histologic subtypes (squamous cell/others), type of resection (complete/incomplete), tumor size, induction and adjuvant therapy (chemotherapy-ChT/radiotherapy-RT), recurrence. Primary outcome was overall survival (OS); secondary outcomes were disease-free survival (DFS) and the cumulative incidence of recurrence. Survival analysis was performed using univariate and multivariate (Cox-shared frailty) competing-risk models. Missing data were analysed using multiple-imputation techniques Results: A multidisciplinary approach (surgery, ChT and RT) was used in most patients. Induction therapy was employed in 78 patients (ChT, 53; ChT/RT 23; RT, 2). Adjuvant therapy was employed in 150 patients (ChT, 19; ChT/RT, 72; RT, 59). Complete resection (R0) was achieved in 71% of the patients. Five and 10-year OS were 60% and 35%. Five and 10-year DFS were 62% and 43%. Cumulative incidence of recurrence was 0.25, 0.32 and 0.40 at 3, 5, and 10 years. Independent OS predictors (multivariate analysis) were young age (p⫽0.006), stage I/II (vs. III/IV, p⫽0.02), R0 resection (p⬍0.001), adjuvant therapy (ChT, RT or both) (p⫽0.02). Independent predictor of recurrence (univariate analysis) was tumor size (p⫽0.05). Conclusions: In thymic carcinomas submitted to surgical resection, increased age,Masaoka stages III-IV and incomplete resection had a significant impact in worsening survival. Larger tumors had an increased risk of recurrence. The administration of adjuvant ChT or RT was associated with improved overall survival. A multidisciplinary approach to these rare tumors remains essential.

Background: According to the 2004 WHO classification, thymic epithelial tumors (TETs) comprise different histologies, including thymomas, thymic carcinoma, typical and atypical carcinoids. Histology classification of TETs has a dramatic impact on the prognosis and therapeutic strategy. We here review all TETs treated at our Institution over the past 30 years. Methods: Eligible patients had a pathologically confirmed TET and had at least one access at our Institution. Relevant demographic and clinical data were retrieved. An exploratory analysis was conducted using a step-wise model in patients with completely resected tumors to seek for factors predictive of recurrence after radical surgery. Results: One hundred and three patients with TETs were included in this retrospective analysis. Forty-three were female, sixty were male. Median age was 43 years (range 32-58). Forty-three patients had myasthenia gravis. Four had a thymic neuroendrocrine tumor, 19 had a thymic carcinoma, while the remaining had a thymoma. Forty-seven patients were alive at the time of analysis. Median overall survival was 5.85 years (range, 2.58-9.9). In the whole sample population, seventy-six patients had a completely resected tumor with clear pathological margins. In this sub-group of 76 patients (median age: 46, 35-55; 30 females, 46 males), 12 had a thymic carcinoma and 30 patients recurred after radical surgery. At multivariate analysis, which included age, sex, adjuvant chemotherapy, adjuvant radiotherapy, maximum tumor diameter, presence of myasthenia gravis and stage, the only factor significantly predictive of recurrence was tumor histology (odds ratio: 3,8182, 95% CI: 1,03 to 14,1; p ⫽ 0.04). Conclusions: We showed that patients with thymic carcinomas are at increased risk of recurrence after radical surgery independently on adjuvant chemotherapy/radiotherapy treatment. Additional therapeutic options are required in the adjuvant setting of completely resected thymic carcinomas.


484s 7604

Lung Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers General Poster Session (Board #30F), Sat, 8:00 AM-11:45 AM

Antitumor activity in advanced cancer patients with thymic malignancies enrolled in early clinical drug development program (phase I trials) at Institut Gustave Roussy. Presenting Author: Myriam Kossai, Institut Gustave Roussy, Villejuif, France

7605


A gene signature to determine metastatic behavior in thymic carcinoma. Presenting Author: Yesim Gokmen-Polar, Indiana University School of Medicine, Indianapolis, IN

Background: Thymic epithelial neoplasms (TENs) represent a rare entity with poor prognosis and limited systemic treatment options, particularly in advanced stages and/or in thymic carcinomas (TC). The aim of this study was to assess the clinical benefit, the efficacy and toxicities of agents for patients (pts) with a refractory TEN enrolled in Phase I trials. Methods: We reviewed retrospectively pts with advanced pretreated TEN enrolled in Phase I trials at the Institut Gustave Roussy (SITEP) between 1994 and 2012. Toxicities were reported and scored according to NCI CTCAE version 3.0. Efficacy was assessed using RECIST version 1.1. Results: Twenty-two treated pts were enrolled (14 with TC, 8 with thymomas). The median number of prior systemic therapies was 2 (1-8). The median age was 50 years (range 23-72), and 4 females were treated. Treatment received were mTOR inhibitor (mTORi) in 4 of pts, antiangiogenic agents (AA) in 11 pts, and other targeted therapies in 7 pts. The median follow-up time was 22.1 months (range, 1.25-77.79 months). Autoimmune associated disease (AID) was reported in 6 pts. 18% had grade III/IV toxicity, 54% grade I/II toxicity and no toxic death was reported. AID exacerbated in one patient. One patient experienced a complete response (CR) and 3 a partial response (PR); 16 pts had stable disease (median 6.6 months) and 2 had a progressive disease. Objective response rate (ORR) was 42%, 25.0% for thymoma and 21.4% for TC. The median overall survival was 54.5 months (95% CI 25-75.50 months), 54.5 for thymoma and 62 for TC. The median progression free survival (PFS) was 6.6 months (95% CI 1.35-11.59 months), 5.2 for thymoma and 6.9 for TC. Median PFS was 11.6 months for mTORi, 6.9 for AA, and 6.6 for other targeted therapies. Conclusions: Phase I trials appear as a sound therapeutic option in TENs pts progressing after standard treatments. Use of AA and mTORi seem to yield a good clinical response. Novel targeted therapies might be tested setting in a biology-oriented approach rather than a stochastical one. We are currently offering a molecular profiling in our patients (MOSCATO trial NCT01566019) for a better selection of appropriate Phase I trial.

Background: Thymomas and thymic carcinomas (TC) are rare epithelial tumors derived from the thymic gland in the anterior mediastinum. Although all histological types of thymomas, albeit with different frequencies, can give rise to metastases, TC have a more aggressive behavior and metastasize earlier and more frequently than thymomas. We previously developed a prognostic gene signature able to accurately determine metastatic behavior of thymomas (Gökmen-Polar et al. ASCO 2012). The signature is currently used in clinical practice to identify patients at high or low risk for metastatic disease. In the current study, we sought to evaluate the utility of this signature for determining risk from TC tumors. Methods: FFPE tissue sections were macrodissected from 35 primary TC. RNA was isolated and RT-PCR was performed to assess the expression of 23 genes (19 test and four reference genes). Predictive modeling was performed using Radial Basis Machine (RBM) software from JMP Genomics (SAS), and survival analysis was done using the Kaplan-Meier method. Results: Samples from the TC cohort ranged from stage II through IVB, with a median age of 54 years. 26 samples had evidence of metastatic progression, while nine samples did not. Prediction of metastasis, based upon comparison to the previously developed thymoma training set and using a 19-gene signature, yielded an ROC ⫽ 0.66. Independent analysis of the TC cohort with the thymoma 19-gene signature resulted in a predictive model with an ROC ⫽ 0.97 (overall accuracy ⫽ 87%, sensitivity ⫽ 73% and specificity⫽100%). Further modeling and gene set reduction revealed a separate ten-gene signature able to segregate metastatic from nonmetastatic cases with 100% accuracy. All the cases classified as high risk (n⫽ 26) developed metastasis within 5 years while none of the cases categorized as low-risk (n⫽ 9) had any events at 5 years of follow-up. Conclusions: A ten-gene signature was established that appears to predict metastatic behavior of TC with a high degree of accuracy; however, validation in an independent cohort is necessary. Our data suggests that the biologic determinants of the clinical course of TC maybe distinct from thymoma and could be used to improve patient management.

TPS7606

TPS7607


A multicenter phase II randomized study of customized neoadjuvant therapy versus standard chemotherapy (CT) in non-small cell lung cancer (NSCLC) patients with resectable stage IIIA(N2) disease (CONTEST trial). Presenting Author: Francesco Grossi, Lung Cancer Unit, National Institute for Cancer Research, Genova, Italy Background: Stage IIIA NSCLC constitutes 30% of all NSCLC patients (pts). The most powerful prognostic factor that has been identified in this stage is clearance of mediastinal lymph nodes and pathologic complete response (pCR). A pCR is obtained in 5-15% of pts with a significant survival prolongation. The identification of molecular biomarkers, such as excision repair cross-complementation 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), and thymidylate synthase (TS), may predict response to CT. Similarly, EGFR mutations may predict response to EGFR inhibitors. Methods: CONTEST, a multicenter (19 Italian centers), randomized (2:1) 2-arm phase II study, recruits pts with resectable stage IIIA (N2) NSCLC. Pts will be randomized to receive before resection either standard CT with Cisplatin (CDDP) 75 mg/m2 ⫹ Docetaxel (Doc) 75 mg/m2 on day (d) 1 q 21 d for 3 cycles (cys) or customized therapy using predetermined values for ERCC1, RRM1, TS, and EGFR mutations. The choices of customized arms are as follows: -EGFR⫹: Gefitinib 250 mg/d for 8 weeks. -EGFR-/non-squamous (NS)/TS-/ERCC1-: CDDP 75 mg/m2 ⫹ Pemetrexed 500 mg/m2 d 1 q 21 d for 3 cys. -EGFR-/squamous (S) or NS TS⫹/ERCC1-/ RRM1⫹: CDDP 75 mg/m2 ⫹ Doc 75 mg/m2 d 1 q 21 d for 3 cys. -EGFR-/S or NS TS⫹/ERCC1-/RRM1-: CDDP 75 mg/m2 d 1⫹ Gemcitabine (Gem) 1250 mg/m2 d 1,8 q 21 d for 3 cys. -EGFR-/S or NS TS⫹/ERCC1⫹/ RRM1⫹: Doc 75 mg/m2 d 1 ⫹ Vinorelbine 20 mg/m2 d 1,8 q 21 d for 3 cys. -EGFR-/S or NS TS⫹/ERCC1⫹/RRM1-: Doc 40 mg/m2 y 1, 8 ⫹ Gem 1200 mg/m2 d 1,8 q 21 d for 3 cys. The primary end point will be obtained by comparing the pCR in all randomized pts based on treatment arm. Because pCR is a surrogate endpoint and given the expected proportion of pCR’s in the control group pc⫽ 5%, the minimal clinically worthwhile effect of this customized treatment is an increase in this proportion to 20%. To detect such an effect at the 0.05 (1-sided) significance level with 80% power, a total of 168 pts will be enrolled. This study is open for accrual; further details can be found on ClinicalTrials.gov (NCT01784549). Funded by Italian Ministry of Health – RF 2009-1530324. Clinical trial information: NCT01784549.


CRS-207 vaccine plus chemotherapy as front-line treatment for subjects with malignant pleural mesothelioma (MPM). Presenting Author: Raffit Hassan, National Cancer Institute, Bethesda, MD Background: CRS-207 is a live-attenuated Listeria monocytogenes (Lm) vaccine expressing the tumor-associated antigen mesothelin which is overexpressed in MPM. CRS-207 was well tolerated and induced Lm- and mesothelin-specific T cell immunity in a phase 1 study in adults with mesothelin-expressing cancers (Le et al., Clin. Cancer Res. 2012). Preclinical and clinical studies suggest that vaccines and chemotherapies work synergistically and augment anti-tumor effectiveness of subsequent chemotherapies. Methods: This phase 1B study is evaluating the safety and induction of mesothelin-specific immune responses by CRS-207 plus chemotherapy with pemetrexed (P) and cisplatin (C) in adults with newly diagnosed, unresectable MPM. Two doses of 1⫻109colony forming units (CFU) CRSE207 are administered intravenously two weeks apart followed two weeks later by up to six cycles of P (500 mg/m2) and C (75 mg/m2) given every 3 weeks. Two booster vaccinations of CRS-207 are administered three weeks apart 4 weeks after completing PC. Secondary and exploratory endpoints will assess objective tumor response, time to progression, overall survival and immune correlates. This is one of the first trials to assess the synergy between vaccines and chemotherapy in newly diagnosed patients with MPM. Sponsor: Aduro BioTech, Inc. ClinicalTrials.gov ID: NCT01675765. Clinical trial information: NCT01675765.


Lung Cancer—Non-Small Cell Local-Regional/Small Cell/Other Thoracic Cancers TPS7608


TPS7609

485s


CA184-156: Randomized, multicenter, double-blind, phase III trial comparing the efficacy of ipilimumab (Ipi) plus etoposide/platinum (EP) versus placebo plus EP in patients (Pts) with newly diagnosed extensive-stage disease small cell lung cancer (ED-SCLC). Presenting Author: Joachim Von Pawel, Asklepios Hospital Munich-Gauting, Munich, Germany

Cabazitaxel (Cbz) versus topotecan in patients (pts) with small cell lung cancer (SCLC) that has progressed during or after first-line treatment with platinum-based chemotherapy: A randomized phase II study. Presenting Author: Tracey L. Evans, Perelman Center for Advanced Medicine, Philadelphia, PA

Background: Phase III studies have not reported improvement for ED-SCLC beyond EP. Moreover, chemotherapeutic response in SCLC is short-lived, with a median survival of 8 –12 months and 5-year survival rates ranging from 1%–2%. Ipi, a fully human monoclonal antibody which binds CTLA-4, augments antitumor immune responses and may potentially improve the clinical benefit of EP. A randomized phase II study of Ipi ⫹ paclitaxel/ carboplatin (PC) in pts with ED-SCLC showed significant improvement in progression-free survival (PFS) [measured by immune-related response criteria (irRC)] over PC in pts receiving phased Ipi ⫹ PC; irRC were derived from WHO criteria to better capture response patterns observed with Ipi. Addition of Ipi trended toward prolonged overall survival (OS) and did not exacerbate PC toxicity; immune-related adverse events were managed using protocol-specific guidelines. This global (~227 sites among 34 countries), multicenter phase III study in pts with ED-SCLC (ClinicalTrials.gov identifier NCT01450761) will determine if adding Ipi to EP increases OS vs EP alone. Methods: Pts with first-line ED-SCLC and ECOG 0-1 will be eligible; pts with a history of autoimmune disease will be ineligible. Pts will be randomized (1:1 to either Arm A or Arm B) to 2 cycles of EP (etoposide [100 mg/m2, IV on Days 1-3 Q3W] and cisplatin [75 mg/m2, IV] or carboplatin [AUC⫽5, IV] once Q3W), followed by 4 cycles of blinded study drug (Ipi 10 mg/kg, IV in Arm A or placebo in Arm B, Q3W) with 2 concurrent cycles (during cycles 3-4) of EP and Ipi (6 cycles of total therapy). Eligible pts will receive Ipi maintenance therapy Q12W until disease progression or unacceptable toxicity; pts with a complete response will also be eligible for prophylactic cranial irradiation at investigator’s discretion. The primary endpoint is OS; secondary endpoints include OS among pts who receive blinded therapy, immune-related and mWHO PFS, best overall response rate, and duration of response. The trial will also characterize safety, and is estimated to enroll 1100 pts. Clinical trial information: NCT01450761.

Background: Approximately 12–15% of pts with lung cancer have SCLC. Although first-line platinum-based chemotherapy regimens may be effective, pts often experience rapid relapse and develop systemic metastases. Median survival after SCLC relapse varies from 13 to 35 weeks. As such, there is a substantial unmet need for more effective second-line treatments. Clinical studies suggest that taxanes are effective in relapsed SCLC, and Cbz, a next-generation taxane, has shown efficacy in the second-line treatment of taxane-resistant tumors (de Bono JS, et al. Lancet 2010;376: 1147–54; Pivot X, et al. Ann Oncol 2008;19:1547–52). Assessment of Cbz treatment for SCLC is therefore warranted. Methods: This is a multinational, open-label Phase II study (NCT01500720) in pts with confirmed, measurable, locally advanced or metastatic SCLC whose disease has progressed during/after first-line platinum-based chemotherapy. Pts aged ⱖ 18 years with ECOG performance status ⱕ 1 are eligible, but those with ⬎ 1 prior chemotherapy regimen or prior topotecan or taxane use are excluded. Pts are randomized 1:1 to receive IV Cbz 25 mg/m2 (Day 1 Q3W) or IV topotecan 1.5 mg/m2 (Days 1–5 Q3W). Pts are divided into chemo-sensitive and chemo-refractory subgroups, while stratification is based on the presence of brain metastases (yes vs no) and by lactate dehydrogenase plasma concentration (ⱕ or ⬎ upper limit). Pts will be treated until disease progression, unacceptable toxicity or withdrawal of consent. The primary objective is assessment of progression-free survival (PFS). Secondary objectives include assessment of other efficacy endpoints (proportion of pts free of disease progression at 12 weeks, tumor response and overall survival), safety and health-related quality of life. A centralized imaging review process is being used to independently review tumor measurements. Planned enrollment is 172 pts (to provide 80% power for PFS analysis). The first pt was enrolled in March 2012. By December 2012, 91 pts had been randomized in 38 sites. Clinical trial information: NCT01500720.

TPS7610


Randomized phase II study of IV topotecan versus CRLX101 in the second-line treatment of recurrent extensive-stage small cell lung cancer (ES-SCLC). Presenting Author: Thomas A. Hensing, NorthShore University HealthSystem, Evanston, IL Background: SCLC remains an area of high unmet medical need with an aggressive clinical course and ⬍ 10% 5-year overall survival. In the U.S., topotecan (Hycamtin, GlaxoSmithKline) is the reference standard for treatment of chemotherapy (C)-sensitive (S) relapsed disease but its use remains compromised by toxicity. There currently exists no standard therapy for patients (pts) with C-resistant (R) disease (relapse occurring ⬍ 60 days from last C). CRLX101 is a novel cyclodextrin-containing polymer conjugate of camptothecin (CPT) that self-assembles into nanoparticles and delivers sustained levels of active CPT into cancer cells while substantially reducing systemic exposure. In vitro and in vivo data suggest superior activity of CRLX101 compared to approved agents in multiple animal tumor models including SCLC. A monotherapy recommended phase 2 dose of 15 mg/m2 IV every 2 weeks has now been administered to over 150 cancer pts across five ongoing phase 2 clinical trials. Methods: This ongoing, randomized phase 2 clinical trial compares the effect on progression free survival (PFS) of 2nd-line treatment with IV CRLX101 (15 mg/m2 on days 1 and 15 every 28 days) to IV topotecan (1.5 mg/m2 on days 1-5 every 21 days) in pts with CS relapsed ES-SCLC. In parallel, the effect of 2nd-line CRLX101 on 3-mo. PFS rate of pts with CR relapsed ES-SCLC will be evaluated. Secondary objectives in both cohorts include evaluation of objective response rates (by RECIST v1.1), overall survival, and safety. In the randomized cohort, 112 pts (56/arm) will be enrolled in order to achieve 90% power to detect an improvement in median PFS from 3 to 5 mos. (HR⫽0.60). An interim analysis will be performed after 1/2 of expected PFS events have occurred. Pts with CR disease will all receive CRLX101 and the trial will employ a 2-stage design: 14 pts will be enrolled in stage 1 and the study will be terminated if ⱕ 3 pts remain progression free at 3 mos. Otherwise, an additional 30 pts will be enrolled and if ³ 15/44 (34%) pts remain progression free at 3 mos., the drug will be considered worthy of further investigation. The first patient on this clinical trial was enrolled on January 30, 2013. Clinical trial information: NCT# is pending.


486s 8000

Lung Cancer—Non-Small Cell Metastatic Oral Abstract Session, Mon, 3:00 PM-6:00 PM

Biomarkers (BM) France: Results of routine EGFR, HER2, KRAS, BRAF, PI3KCA mutations detection and EML4-ALK gene fusion assessment on the first 10,000 non-small cell lung cancer (NSCLC) patients (pts). Presenting Author: Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Hôpital Nord, Marseille, France Background: Personalized medicine is now a reality for advanced NSCLC pts on the basis of routine screening for EGFR mutation and ALK gene fusion assessment. The French NCI (INCa) also decided to additionally fund the routine assessment of 4 additional BM (HER2, KRAS, BRAF, PI3KCA). Methods: Starting on April 2012, these BM analyses were prospectively collected into a database head by the IFCT (www.ifct.fr) with 15-20,000 analyses awaited after one year. The physicians prescribing each of these BM analyses were then connected to this database and were asked to regularly complete epidemiological, clinical and therapeutic data for each corresponding patient. Results: 10,000 BM analyses were collected and entered into the BM France database at the time of this first analysis (January 2013). On the basis of available data, the patients were mainly male (63.8%), (ex)smokers (83.3%) and stage IV pts (64%). The tumors were mainly adenocarcinomas (76.1%). The samples for BM analysis were collected under bronchoscopy, surgery or transthoracic biopsy in 27.4, 28.1 and 24.2%, respectively. The 10,000 molecular profiles were characterized by 9.4% EGFR (including 0.8% EGFR resistant), 0.9% HER2, 26.9% KRAS, 1.6% BRAF, and 2.6% PI3KCA mutated and 4.0% EML4-ALK fusion genes. Double mutations were seen in 0.9% of the tumors. On January 2013, data on treatment were available for 18.6% of patients among whom 56.9% of patients received a treatment according to their molecular profile (labeled drugs or bio-guided trials). Updated data will be presented during the meeting. Conclusions: Biomarkers France is the largest ever conducted biomolecular study on advanced NSCLC patients and provides solid data on the value of a nationwide BM screening policy for NSCLC patients.

LBA8002


8001


Molecular analysis-directed, international, phase III trial in patients with advanced non-small-cell lung cancer. Presenting Author: Gerold Bepler, Karmanos Cancer Institute, Wayne State University, Detroit, MI Background: ERCC1 (E1) and RRM1 (R1) are predictive markers for platinum agents and gemcitabine (G) respectively. In a phase II trial that utilized E1 and R1 mRNA expression levels for therapeutic decisionmaking, a response rate of 44%, PFS of 6.6 m, and OS of 13.3 m was achieved. Methods: Pts with advanced, chemo-naive NSCLC, PS 0-1, measurable disease, and a FFPE histological or cell block tumor specimen were eligible. E1 and R1 were analyzed by AQUA and categorized as high or low. Pts were randomized 2:1 to arm A, which received G and carboplatin (Cb) for R1/E1 low, docetaxel (D) and Cb for R1 high and E1 low, G and D for R1 low and E1 high, and D and vinorelbine (V) for R1/E1 high, or arm B, which received GC. Pts received up to 6 cycles. Efficacy was assessed every 6-8 weeks until 1 year from treatment initiation. The primary goal was to improve the 6-m PFS from 38% in arm B (median PFS 4.3 m) to 50% in arm A (median PFS 6.0 m). Secondary goals were improvements in OS (8.0 to 12.0 m) and RR (25% to 50%). Results: Of 275 eligible pts, 183 randomized to arm A. 56 were assigned to GCb, 26 to DCb, 37 to GD, and 64 to DV, which was not significantly different (p⫽.2) from the expected assignment (30%, 20%, 20%, 30%). In arm B, all 92 pts received GCb. Protein analysis was successful in 91% of pts. The median time from consent to completed gene analysis was 11 days. A tumor rebiopsy for the specific purpose of gene analysis was required in 17% of pts. The 6-m PFS rate and median PFS were 52.0% and 6.1 m in arm A and 56.5% and 6.9 m in arm B (p ⫽ 0.18). PFS was not significantly different among the treatment groups in arm A (p ⫽ 0.1). A significant survival advantage was found for pts with low E1 and low R1 in arm B compared to the same group in arm A (p ⫽ 0.02) although both received GCb therapy. OS and RR were not significantly different between both groups. A comparison between protein and mRNA levels for both genes revealed no significant correlation. Conclusions: This demonstrates that gene expression analysis for therapeutic decision making is feasible in newly diagnosed advanced-stage NSCLC pts. A tumor rebiopsy is safe, required in 17%, and acceptable to 89% pts. The survival results are false negative based on the internal control included in the trial. Clinical trial information: NCT00499109.

LBA8003


Interim analysis of The Spanish Lung Cancer Group (SLCG) BRCA1-RAP80 Expression Customization (BREC) randomized phase III trial of customized therapy in advanced non-small-cell lung cancer (NSCLC) patients (p) (NCT00617656/GECP-BREC) Presenting Author: Teresa Moran, Institut Catala dÓncologia, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain

Randomized, open-label, phase III study of pemetrexed plus carboplatin followed by maintenance pemetrexed (Arm A) versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab (Arm B) in patients with advanced nonsquamous (NS) non-small cell lung cancer (NSCLC). Presenting Author: Ralph Zinner, The University of Texas MD Anderson Cancer Center, Houston, TX




Lung Cancer—Non-Small Cell Metastatic 8004


A phase III study of pemetrexed (Pem) plus carboplatin (Cb) plus bevacizumab (Bev) followed by maintenance pem plus bev versus paclitaxel (Pac) plus cb plus bev followed by maintenance bev in stage IIIb or IV nonsquamous non-small cell lung cancer (NS-NSCLC): Overall and age group results. Presenting Author: Mark A. Socinski, University of Pittsburgh, Pittsburgh, PA Background: This study compared Pem⫹Cb⫹Bev followed by Pem⫹Bev maintenance (Pem arm) to Pac⫹Cb⫹Bev followed by Bev maintenance (Pac arm). The primary endpoint of improved overall survival (OS) for the Pem arm was not met. Methods: Advanced NS-NSCLC pts, ECOG PS 0/1, were randomized to 4 cycles of induction Pem⫹Cb⫹Bev with folic acid⫹vitamin B12 or Pac⫹Cb⫹Bev (Pem 500 mg/m2or Pac 200 mg/m2; Cb AUC 6; Bev 15 mg/kg) every 3 weeks. Eligible pts received maintenance Pem⫹Bev or Bev. OS, progression-free survival (PFS), overall response (ORR), and toxicity were evaluated. A hazard ratio (HR) of 0.80 required 676 OS events/900 pts with 2-sided type-I error .05 and at least 80% power for superiority of Pem over Pac arm. Exploratory Cox models estimated treatment HRs with 95% confidence intervals (CIs) for each age subgroup analyzed: ⱕ or ⬎65, 70 (prespecified) and ⱕ or ⬎75 yrs (not prespecified). Results: 939 pts (median age, 64.7) were randomized. Median (m) OS for ITT pem and pac arms was 12.6 vs 13.4 mos (HR 1.00, p⫽0.949); mPFS was 6.0 vs 5.6 mos (HR 0.83, p⫽0.012) Subgroup efficacy is shown in the Table; ⱕ or ⬎65 data were similar to ITT. Pem pts had significantly more drug-related grade 3/4 thrombocytopenia, anemia (except ⬎75 yrs) and fatigue (except ⬎70 and ⬎75 yrs). Pac pts had significantly more grade 3/4 neutropenia (except ⬎70 and ⬎75 yrs), sensory neuropathy (except ⬎75 yrs) and grade 1/2 alopecia. Results parallel overall safety data. Conclusions: OS was not significantly different in any of the age subgroups. PFS was significantly longer in Pem arm overall and for pts ⱕ70, but was similar for pts ⬎70, ⬎75 yrs. Toxicity profiles differed; subgroup safety data paralleled overall data. Clinical trial information: NCT00762034.

Efficacy endpoint OS (mos) HR (95% CI)

70 Pac nⴝ129 27.6%

>75 Pem nⴝ52 11.0%

>75 Pac nⴝ55 11.8%

14.3

12.7 0.90 (0.67-1.21) 0.484 5.7 0.98 (0.73-1.31) 0.872 27.1

11.5

11.8 0.98 (0.63-1.51) 0.923 5.4 0.82 (0.52-1.30) 0.393 19.2

8.9

5.6

35.2

5.6

27.1

LBA8005


Randomized proteomic stratified phase III study of second-line erlotinib (E) versus chemotherapy (CT) in patients with inoperable non-small cell lung cancer (PROSE). Presenting Author: Chiara Lazzari, Department of Oncology, Istituto Scientifico Ospedale San Raffaele, Milan, Italy


4.5

23.6


Randomized phase III trial of erlotinib (E) versus docetaxel (D) as secondor third-line therapy in patients with advanced non-small cell lung cancer (NSCLC) who have wild-type or mutant epidermal growth factor receptor (EGFR): Docetaxel and Erlotinib Lung Cancer Trial (DELTA). Presenting Author: Yoshio Okano, National Hospital Organization Kochi Hospital, Kochi, Japan Background: E and D are standard cares for previously treated patients with advanced NSCLC. Although E shows significant clinical benefits over best supportive care in the EGFR wild type tumors, it remains unknown whether E or D is more active against the disease. Methods: This is an open-label, multi-center phase III study, sponsored by the Japanese National Hospital Organization. Patients were randomized to E (150 mg, daily), or D (60 mg/m2, q3w) by the minimization method according to gender, performance status, histology, and institution. The primary endpoint was progression free survival (PFS), and secondary endpoints included overall survival (OS), response rate, safety, and analyses on EGFR wild type tumors. Eligible patients were those with pathologically proven NSCLC with stage IIIB or IV (AJCC version 6) previously treated with one or two chemotherapy regimens including at least one platinum agent, evaluable or measurable disease, and ECOG PS 0-2. Target sample size was calculated to be 280 based on the assumption that E was superior to D in PFS (3.5 months [m] v 2.5 m, ␣ ⫽0.05 [two sided], ␤ ⫽0.80). Results: From August 2009 to July 2012, 301 patients were accrued from 41 institutions. In the ITT population, 150 and 151 patients were randomly assigned to E and D, respectively, including respective 109 (73%, E) and 89 (59%, D) with EGFR wild type tumors. Median PFS and OS for E v D were 2.0 m (95% CI: 1.3-2.8) v 3.2 m (2.8-4.0, log-rank p⫽0.092; HR⫽1.22, 95% CI: 0.97-1.55), and 14.8 m (9.0-19.4) v 12.2 m (9.0-15.5, p⫽0.527; HR⫽0.91, 95% CI: 0.68-1.22), respectively. In the EGFR wild type tumors, PFS and OS for E v D were 1.3 m v 2.9 m (p⫽0.013; HR ⫽1.44, 95% CI: 1.08-1.92), and 9.0 m v 9.2 m (p⫽0.914; HR ⫽0.98, 95% CI: 0.69-1.39), respectively. Main grade 3/4 toxicities were rash (13.3% [E] v 0.7% [D]) and leukopenia (5.4% [E] v 62.9% [D]). Conclusions: E failed to show better PFS over D. While PFS was significantly longer in D than E in EGFR wild type tumors, the difference did not translate into OS in this pragmatic trial. Clinical trial information: 000002314.

CRA8007


A randomized study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel versus docetaxel alone for second-line therapy of lung adenocarcinoma (GALAXY-1). Presenting Author: Suresh S. Ramalingam, The Winship Cancer Institute of Emory University, Atlanta, GA



488s 8008

Lung Cancer—Non-Small Cell Metastatic Oral Abstract Session, Mon, 3:00 PM-6:00 PM

8009

Clinical Science Symposium, Mon, 9:45 AM-11:15 AM

Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). Presenting Author: David R. Spigel, Sarah Cannon Research Institute, Nashville, TN

Interim results of phase II study BRF113928 of dabrafenib in BRAF V600E mutation–positive non-small cell lung cancer (NSCLC) patients. Presenting Author: David Planchard, Department of Medical Oncology, Institut Gustave Roussy, Villejuif, France

Background: Human lung cancer expresses high levels of PD-L1, which may inhibit anti-cancer immune responses. MPDL3280A, a human monoclonal Ab containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Methods: Pts with squamous or nonsquamous NSCLC received MPDL3280A IV q3w at doses between 1-20 mg/kg in a Ph I expansion study. Pts were treated for up to 1 y. Objective response rate (ORR) was assessed by RECIST v1.1. Reported ORR includes u/cCR and u/cPR. Results: As of Jan 10, 2013, 53 NSCLC pts were evaluable for safety and treated at doses of ⱕ1 (n⫽2), 10 (n⫽10), 15 (n⫽19) and 20 mg/kg (n⫽22). Pts had a median age of 61 y (range 24-83 y), 98% were PS 0-1, 89% had prior surgery and 55% had prior radiotherapy. 98% of pts received prior systemic therapy. Pts received treatment for a median duration of 106 days (range 1-324) of MPDL3280A. The incidence of all G3/4 AEs, regardless of attribution, was 34%, including pericardial effusion (6%), dehydration (4%), dyspnea (4%) and fatigue (4%). No G3-5 pneumonitis or diarrhea was reported. 37 NSCLC pts enrolled prior to Jul 1, 2012, were evaluable for efficacy. RECIST responses were observed at dose levels between 1 and 20 mg/kg, with all responses ongoing or improving. An ORR of 24% (9/37) was observed in pts with squamous and nonsquamous histologies, including several with rapid tumor shrinkage. Additional pts had delayed responses after apparent radiographic progression (not included in the ORR). The 24-week PFS was 48%. Analysis of biomarker data from archival tumor samples demonstrated a correlation between PD-L1 status and efficacy. Pts who were PD-L1 tumor status–positive showed an ORR of 100% (4/4) and a PD rate of 0% (0/4), while pts who were PD-L1 tumor status–negative showed an ORR of 15% (4/26) and a PD rate of 58% (15/26). Updated data will be presented. Conclusions: Treatment with MPDL3280A was well tolerated, with no pneumonitis-related deaths. Rapid and durable responses were observed. PD-L1 tumor status correlated with response to MPDL3280A. Clinical trial information: NCT01375842.

Background: Activating BRAF V600E mutations in NSCLC are present in ⬍ 2% of tumors, primarily adenocarcinoma. The BRAF inhibitor dabrafenib has demonstrated clinical activity in BRAF V600 mutation–positive melanoma. Here we report interim efficacy and safety data obtained in 17 BRAF V600E–mutant NSCLC patients enrolled in dabrafenib phase II study BRF113928. Methods: Single-arm, 2-stage, phase II study in stage IV BRAF V600E mutation–positive NSCLC pts who failed at least 1 line of chemotherapy. Dabrafenib dosed at 150 mg orally twice daily. The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST 1.1 criteria. Results: The median age of the 17 pts was 69 years (range, 51-77 years). Most pts (12/17) were male, all were white with adenocarcinoma, and 13 were former smokers. All pts had failed at least 1 line of prior anticancer therapy, and 5 subjects had failed ⱖ 2. At the time of reporting, 11 pts remain on therapy, and 6 have stopped therapy (5 with PD and 1 due to an AE). Thirteen pts were evaluable for efficacy. The best response for these pts included 7 PRs (5 confirmed PRs), 1 SD, and 4 PD; 1 pt discontinued due to an SAE (hypersensitivity reaction) prior to response assessment (ORR, 54%). The median duration of treatment for all 17 pts is approximately 9 weeks (range, 1-69 weeks). Among the 5 pts with confirmed PRs, duration of response was 29 and 49 weeks for the 2 pts who progressed, while the remaining 3 pts were responding for 6⫹ to 24⫹ weeks. The safety of dabrafenib in NSCLC pts appears to be generally consistent with what has been previously observed. The most common AEs were decreased appetite, fatigue, asthenia, dyspnea, and nausea, mostly grade 1 or 2. Five pts (29%) had a grade 3 AE, and 1 pt (6%) had a grade 4 SAE (hemorrhage). Conclusions: Dabrafenib shows early antitumor activity in BRAF V600E mutation–positive pretreated NSCLC pts, with an ORR of 54% and with the longest duration of response of 49 weeks thus far. Dabrafenib is generally well tolerated, and the study has met the minimum response rate (ⱖ 3 of first 20 pts) to continue into the second stage. This study represents the first clinical evidence of BRAF as a therapeutic target in NSCLC. Clinical trial information: NCT01336634.

8010

LBA8011


Clinical activity of the ALK inhibitor LDK378 in advanced, ALK-positive NSCLC. Presenting Author: Alice Tsang Shaw, Massachusetts General Hospital Cancer Center, Boston, MA Background: Lung cancers harboring anaplastic lymphoma kinase (ALK) gene rearrangements are sensitive to the tyrosine kinase inhibitor (TKI) crizotinib (CRZ), but invariably develop resistance. LDK378 is a novel, more potent ALK TKI than CRZ, with significant antitumor activity in preclinical models. Methods: In this multicenter phase I study, 131 patients (pts) with advanced malignancies harboring a genetic alteration in ALK, including 123 with ALK-rearranged (ALK⫹) NSCLC (as determined by FISH), were enrolled. LDK378 was administered orally at doses of 50 –750 mg once daily. All pts were assessed for PK, response to therapy, and adverse events (AEs). In ⬎20 pts with CRZ-resistant disease, tumor biopsy was performed before LDK378 treatment to identify CRZ resistance mutations. Results: As of November 8, 2012, 131 pts had been enrolled (38% male, median age 53 years), including 59 pts in the dose escalation phase, during which the MTD of 750 mg once daily was established, and 72 pts in an expanded cohort at the MTD. Among 88 evaluable NSCLC pts who received LDK378 at 400 –750 mg daily, the overall response rate (ORR) was 70%, with 40 confirmed and 22 unconfirmed responses. In the subset of 64 CRZ-resistant pts, the ORR was 73%, with 31 confirmed and 16 unconfirmed responses. As of November 8, 2012 50% of pts with unconfirmed responses were ongoing. Responses were observed in pts with different CRZ resistance mutations as well as in pts without detectable mutation. Responses were also seen in pts with untreated CNS metastases. Among NSCLC pts with confirmed response, median duration of response (DOR) was 7.4 months (95% CI, 6.7 – NR), and 78% had a DOR of ⱖ6 months. In all 123 NSCLC pts, median PFS was 8.6 months (95% CI, 4.3 – 19.3). The most common AEs were nausea (72%), diarrhea (69%), vomiting (50%), and fatigue (31%). The most common Grade 3/4 AEs were ALT elevation (12%), diarrhea (7%), and AST elevation (6%). Conclusions: LDK378 induces durable responses in the majority of pts with advanced, ALK⫹ NSCLC, including CRZ-resistant pts with and without CRZ resistance mutations. These results suggest that more potent ALK inhibition by LDK378 represents a highly efficacious treatment strategy for ALK⫹ pts, particularly those who relapse on CRZ. Clinical trial information: NCT01283516.


Nintedanib (BIBF 1120) plus docetaxel in NSCLC patients progressing after one prior chemotherapy regimen: Results of Lume-Lung 1, a randomized, double-blind, phase III trial. Presenting Author: Martin Reck, Department of Thoracic Oncology, Grosshansdorf Hospital, Grosshansdorf, Germany





8013

489s


Exploratory analyses of efficacy and safety of pemetrexed (Pem) plus bevacizumab (Bev) and bev alone as maintenance therapy (MT) in patients (Pts) with stage IIIb or IV nonsquamous non-small cell lung cancer (NS-NSCLC). Presenting Author: Jyoti D. Patel, Feinberg School of Medicine, Northwestern University, Chicago, IL

65 plus: A randomized phase III trial of pemetrexed and bevacizumab versus pemetrexed, bevacizumab, and carboplatin as first-line treatment for elderly patients with advanced nonsquamous, non-small cell lung cancer (NSCLC). Presenting Author: Wolfgang Schuette, Hospital MarthaMaria Halle-Doelau, Halle, Germany

Background: In a phase III superiority study, Pem⫹carboplatin (Cb)⫹Bev followed by Pem⫹Bev improved PFS compared with paclitaxel (Pac)⫹Cb⫹Bev followed by Bev in NS-NSCLC pts. Superior OS (primary endpoint) was not met. These analyses assessed the efficacy and safety in pts who received MT. Methods: Prespecified exploratory analyses were performed in the maintenance population (MP) and timed from the start of induction. Pts ⱖ18 years with stage IIIB/IV NS-NSCLC (ECOG status 0 –1) from the multicenter, randomized, open-label, phase III superiority study were included in the MP if they received at least one dose of MT. For MT, pts received intravenous Pem 500 mg/m2⫹Bev 15 mg/kg (n⫽292) or Bev 15 mg/kg (n⫽298). OS, PFS, and safety were evaluated. Comparison is made to the intent-to-treat (ITT; Pem⫽472, Pac⫽467) or safety population (SP; Pem⫽442, Pac⫽443; received at least one dose of one drug). Results: Baseline pt and disease characteristics for the ITT and MP were similar between arms. In the ITT/MP population, the median number of cycles was 7/10 (range, 1-41/4 – 41) in the Pem arm and 6/9 (range, 1-39/5–39) in the Pac arm. In the ITT/MP, OS was 12.6/17.7 months (mos; Pem) and 13.4/15.7 mos (Pac). Survival rates (%) at 12 and 24 mos with Pem (ITT/MP) were 52.7/71.7 and 24.4/34.5; Pac, 54.1/66.5 and 21.2/26.5%. In pts not receiving MT, OS was 4.7 mos (Pem) and 6.1 mos (Pac). PFS (mos) in the ITT/MT was 6.0/8.6 (Pem) and 5.6/6.9 (Pac). In pts not receiving MT, PFS was 2.3 mos and 2.5 mos with Pem and Pac, respectively. From induction, both SP/MP had significantly more grade 3/4 thrombocytopenia, anemia, and fatigue with Pem and neutropenia and sensory neuropathy with Pac (pⱕ0.001). During MT only, the difference in grade 3/4 neutropenia rates between arms was no longer significant. Conclusions: Improved efficacy outcomes were consistent with previous Pem maintenance and Bev studies and no new toxicities were observed. Clinical trial information: NCT00762034.

Background: Pemetrexed (P) and bevacizumab (B) are efficacious drugs for treatment of non-squamous NSCLC. In this trial the benefit of combining PB with carboplatin (C) was investigated in elderly patients (pts) ⱖ 65 years with NSCLC. Methods: In this German multicenter (27 centers), open-label phase III trial pts with stage IIIb/IV non-squamous NSCLC were recruited. Pts were randomized 1:1 to P (500 mg/m2) ⫹ B (7.5 mg/kg) or P⫹B⫹C (AUC5) d1 q3 wks for 4 to 6 cycles followed by maintenance therapy with B or P⫹B. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), 1-year survival rate, overall response rate (ORR) as well as tolerability (AEs/SAEs). Results: 271 pts were enrolled from Sep 2009 to Jan 2012, the ITT population consists of 251 evaluable pts, less than 10 pts are still receiving maintenance therapy. Baseline characteristics were balanced between both treatment groups (PB 118 pts, PBC 133 pts). Median age was 71 years in PB and 72 in PBC. Median PFS time was 4.8 mo in PB and 6.8 mo in PBC. Treatment comparison for ECOG performance status (PS) 0-1 subgroup (PB 112 pts, PBC 126 pts): p⫽0.0426 (Wilcoxon test), hazard ratio (HR) ⫽ 1.31 (95% CI 0.99-1.73). ORR was 31.4% in PB vs. 44.4% in PBC (p⫽0.0343). Median OS time was 11.6 mo in PB vs. 15.2 mo in PBC. Treatment comparison ECOG PS 0-1: p⫽0.2050, HR ⫽ 1.20 (95% CI 0.85-1.70). 1-year survival rates were 48.2% and 58.8%, respectively. Compared to this the median OS time in the small group of pts with ECOG PS 2 was 11.5 mo in PB vs. 3.8 mo in PBC. AE grade 3/4 and SAE profiles were comparable in both treatment arms, 76 pts (64.4%) with AEs grade 3/4 in PB and 87 pts (65.4%) in PBC, 58 pts (49.2%) with SAEs in PB and 64 pts (48.1%) in PBC. 46 pts (39.0%) in PB vs. 69 pts (51.9%) in PBC received maintenance therapy. Conclusions: Combination of PBC demonstrates with a median OS of 15.2 mo a strong efficacy with acceptable toxicity profile for elderly patients. Addition of carboplatin is recommended for eligible patients. However, in patients with ECOG PS 2 the administration of carboplatin must be carefully reviewed. Clinical trial information: NCT00976456.

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Effect of maintenance bevacizumab (Bev) plus pemetrexed (Pem) after first-line cisplatin/Pem/Bev in advanced nonsquamous non-small cell lung cancer (nsNSCLC) on overall survival (OS) of patients (pts) on the AVAPERL (MO22089) phase III randomized trial. Presenting Author: Achim Rittmeyer, Lungenfachklinik Immenhausen, Immenhausen, Germany Background: Maintenance monotherapy has been associated with improved survival for NSCLC pts. AVAPERL was designed to evaluate the safety and efficacy of bevacizumab with or without pemetrexed as continuation maintenance treatment and demonstrated improved progression-free survival (PFS) (Barlesi, JCO in press). Methods: Pts with advanced nsNSCLC received first-line Bev (7.5 mg/kg), cisplatin (75 mg/m2), and Pem (500 mg/m2) every 3 weeks (q3w) for 4 cycles. Those non progressing were randomized to maintenance Bev (7.5 mg/kg) ⫹/-Pem (500 mg/m2) q3w until progressive disease or unacceptable toxicity. The primary end point (PFS) was met. An independent update analysis has been conducted to assess OS. Results: A total of 376 pts receive induction treatment; 125 and 128 were randomized to the Bev-alone and Bev⫹Pem arms, respectively. Induction therapy resulted in confirmed disease control in 71.9% of pts. After a median follow-up of 14.8 months, PFS for the Bev⫹Pem arm was significantly improved both from induction (10.2 v 6.6 m, HR 0.58 [0.45-0.76], p⬍.0001) and randomization (7.4 v 3.7 m, HR 0.57 [0.44-0.75], p⬍.0001). With 58% of events, OS for the Bev⫹Pem arm was also improved both from induction (19.8 v 15.9 m, HR 0.88 [0.64-1.22], p⫽.32) and randomization (17.1 v 13.2 m, HR 0.87 [0.63-1.21], p⫽.29). The PFS and OS improvements were comparable across age, PS, smoking status, and response to induction (SD vPR/CR) subgroups. No new safety signal was observed during this updated analysis. Conclusions: Continuation maintenance with Bev⫹Pem in an unselected population of nsNSCLC pts who had achieved disease control after induction was associated with an increase by almost 4 months in OS benefit over standard Bev alone. Clinical trial information: NCT00961415.


Different-dose docetaxel plus cisplatin as first-line chemotherapy and then maintenance therapy with single-agent docetaxel for advanced non-small cell lung cancer (TFINE study, C-TONG 0904). Presenting Author: Li Zhang, Sun Yat-sen University Cancer Center, Guangzhou, China Background: Docetaxel (75 mg/m2) has been reported as first-line and maintenance treatment for Western population with advanced NSCLC. Different doses of docetaxel (60 mg/m2) are currently delivered in Asian population. Pharmacogenomics alterations in taxanes disposition in different ethnic groups may explain this difference. TFINE study was to evaluate the efficacy, safety, and tolerability of docetaxel in the maintenance setting, and to identify the preferable dose of docetaxel in Asian population. Methods: Previously untreated patients, aged between 18 and 75 years, histologically or cytologically confirmed advanced NSCLC with PS of 0-1 were included. Patients were initially randomized (R1, 1:1) to receive cisplatin (75 mg/m2) plus docetaxel of 75 mg/m2 or 60 mg/m2 for 4 cycles. Patients with disease control after the initial treatment were subsequently randomized (R2, 1:2) to best supportive care (BSC) or maintenance docetaxel of 60 mg/m2 for up to 6 cycles. Genomic DNA was prospectively collected from all enrolled patients. The primary endpoint was PFS since R2, and the secondary endpoints included ORR, overall survival, and toxicity. This study is registered with ClinicalTrials.gov (NCT01038661). Results: This randomized study was undertaken in 15 centers in China. A total of 378 patients were enrolled to R1 and 184 patients (48.7%) were enrolled to R2 (61 vs. 123). Maintenance docetaxel plus BSC significantly prolonged PFS compared with BSC (5.4 months [95% CI 2.8, 7.0] vs. 2.8 months [1.8, 3.1]; P⫽0.002). The difference of ORR during initial chemotherapy was not significant, with 32.4% in the 60 mg-group and 33.7% in 75 mg-group (P⫽0.80).The data concerning the overall survival and toxicity, together with the information of pharmacogenomics alterations, will be presented in the meeting subsequently. Conclusions: Maintenance therapy with docetaxel is well tolerated and offers improved PFS in patients with advanced NSCLC.The dose of 60 mg/m2 of docetaxel demonstrated similar efficacy and better tolerability than that of 75 mg/m2 and should be preferred in Asian population. Clinical trial information: NCT01038661.


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Lung Cancer—Non-Small Cell Metastatic Poster Discussion Session (Board #5), Sun, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

LUX-Lung 6: A randomized, open-label, phase III study of afatinib (A) versus gemcitabine/cisplatin (GC) as first-line treatment for Asian patients (pts) with EGFR mutation-positive (EGFR Mⴙ) advanced adenocarcinoma of the lung. Presenting Author: Yi Long Wu, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China Background: A is an oral, irreversible, ErbB Family Blocker, blocking signaling from EGFR (ErbB1), HER2 (ErbB2) and ErbB4. A was superior to first-line pemetrexed/cisplatin in a global phase III trial (LUX-Lung 3) in EGFR M⫹ NSCLC. This study compared the safety and efficacy of first-line A with GC in EGFR M⫹ Asian pts. Methods: The trial was conducted in Asian countries. Following central testing for EGFR mutations (TheraScreen EGFR RGQ PCR kit), 364 pts (stage IIIB/IV, PS 0 –1, chemo-naïve) were randomized 2:1 (A: 242; GC: 122) to daily A 40 mg or IV GC (1,000 mg/m2 D1, 8 ⫹ 75 mg/m2q21 days up to 6 cycles). Primary endpoint was PFS by central independent review. Results: Baseline characteristics were balanced in both arms: Female (64.0 vs 68.0%), non-smoker (74.8 vs 81.1%), exon 19 deletion (51.2 vs 50.8%), L858R (38.0 vs 37.7%) in A and GC arms, respectively. PFS was significantly prolonged with A compared with GC by independent review (median PFS 11.0 vs 5.6 months, HR⫽0.28, p⬍0.0001); this finding was consistent across all subgroups. Results from the investigator review were similar: HR⫽0.26, p⬍0.0001, median 13.7 (A) vs 5.6 months (GC). Objective response (66.9% vs 23.0%, p⬍0.0001) and disease control (92.6% vs 76.2%, p⬍0.0001) rates (ORR/DCR) were significantly higher with A. OS, based on 43% of events shows HR⫽0.95, p⫽0.7593. Drug-related AEs of ⱖG3 were reported in 36.0% (A) and 60.2% (GC) of pts, the most common of which were rash/acne (14.6%), diarrhea (5.4%) and stomatitis/mucositis (5.4%) with A and neutropenia (17.7%), vomiting (15.9%) and leukopenia (13.3%) with GC. Related AEs led to discontinuation in 5.9% (A) and 39.8% (GC) of pts. Patient reported-outcomes (PROs) showed significantly better control of cancer-related dyspnea, cough and pain with A. Conclusions: In EGFR M⫹ Asian pts, A significantly prolonged PFS with significant improvements in ORR, DCR, PROs. AEs in both arms were as expected, with a more favorable safety profile with A. LUX-Lung 6 is the largest prospective trial in EGFR M⫹ lung cancer, providing further evidence of superiority of A over standard chemotherapy in this setting. Clinical trial information: NCT01121393. 8018


Response to erlotinib and prognosis for patients with de novo epidermal growth factor receptor (EGFR) T790M mutations. Presenting Author: Gregory J. Riely, Memorial Sloan-Kettering Cancer Center, New York, NY Background: A secondary mutation in exon 20 of EGFR, T790M, is the most common cause of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in patients with EGFR mutant lung cancers. De novo EGFR T790M mutations in TKI-naïve patients are rare when assessed by standard genotyping methods. The response to EGFR TKIs in patients with de novo EGFR T790M mutations is unknown. Methods: Patients with EGFRmutations were identified through routine testing, using PCR-based fragment length analysis, mass spectrometry-based genotyping (Sequenom), and Sanger sequencing. Clinical characteristics, progression free survival (PFS) from start of EGFR TKI and overall survival (OS) were obtained from the medical record. Results: From 2008-2012, we observed EGFR T790M in 21 tumors from 20 patients who had not previously been treated with an EGFR TKI representing ⬍2% of all tumors with identified EGFR mutations. Two patients are included in reports from the Lung Cancer Mutation Consortium. The median age at lung cancer diagnosis was 57 (range 35-90). 55% presented with stage IV disease. 60% were women. 65% were never-smokers. In all cases, T790M occurred concurrently with another EGFR mutation, L858R (76%, 16/21) or exon 19 deletion (24%, 5/21). Compared to a contemporary cohort of 593 patients with EGFR mutations, in these patients with de novo EGFR T790M, L858R was more frequent than exon 19 deletion (p⫽0.003). Thirteen patients received erlotinib monotherapy as treatment for metastatic disease. Their response rate (CR⫹PR) was 9% (1/11, 95% Confidence Interval: 0-40%). SD was observed in 36% (4/11). The median progression-free survival was 3 months and the median overall survival was 16 months. Conclusions: De novo EGFR T790M mutations are rare and occur most commonly with EGFR L858R. Overall survival for patients with de novo EGFR T790 mutations is shorter than what is seen in patients with EGFR exon 19 deletions or L858R, and appears more similar to EGFR wild-type patients. Response rate to EGFR TKI in these patients is low. EGFR TKI therapy for patients with de novo EGFR T790M appears to have limited objective benefit and should be considered only after standard cytotoxic chemotherapy.

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Explicit and implicit attitudes toward lung cancer (LC) relative to breast cancer (BC). Presenting Author: Joan H. Schiller, The University of Texas Southwestern Medical Center, Dallas, TX Background: Emerging research suggests that LC may be associated with greater levels of stigma, shame and hopelessness compared to other cancers. This study measured explicit, conscious attitudes (EAs) and used the Implicit Association Test (IAT) to assess implicit, unconscious attitudes (IAs) of LC relative to BC. Methods: To assess EAs, participants (Ps), [people with cancer (n⫽243), caregivers (n⫽677), healthcare providers (HCPs, n⫽142), and the general public (n⫽864)] were asked to rate their agreement, on a six-point scale, with statements about how people with LC and BC “do feel” (descriptive attitudes) or “ought to feel” (normative attitudes) about their disease. IAs were measured with three IATs that used LC or BC images with words representing good/bad; hope/despair; or suitable/shameful. An IAT D score indicated the strength of bias against LC relative to BC: ⬎0.65 ⫽ strong bias; 0.35-0.65 ⫽ moderate bias; 0.15-0.35 ⫽ slight bias; -0.15 -⫹0.15 ⫽ no bias, and ⬍ -0.15 indicated bias against BC. Results: EAs and IAs were substantially more negative towards LC. Most Ps provided more negative ratings for LC than BC for both descriptive (70%vs.8%) and normative statements (56% vs. 3%). Ps had strong negative IAs towards LC compared to BC (bad: 74% vs. 10%; despair: 75% vs. 9%; shame: 67% vs. 17%). These trends were consistent across caregivers, patients, HCPs, and the public. EAs and IAs were uncorrelated. Conclusions: Ps had greater explicit and implicit negative bias against LC compared to BC. Caregivers Explicit Negative descriptive 75%, 7%, 18% Negative normative 59%, 3%, 38% Bad Despair Shame

Patients

HCPs

General public

81%, 7%, 12% 64%, 2%, 34%

88%, 5%, 7% 65%, 3%, 32%

74%, 8%, 18% 56%, 3%, 41%

D⫽0.43 73%, 12%, 15% D⫽0.43 73%, 10%, 17%

D⫽0.33 72%, 13%, 15% D⫽0.54 76%, 5%, 19%

D⫽0.33 63%, 17%, 20.0% D⫽0.44 77%, 13%, 10%

D⫽0.44 74%, 9%, 17% D⫽0.47 77%, 8%, 15%

D⫽0.32 65%, 18%, 17%

D⫽0.52 82%, 9%, 9%

D⫽0.41 72%, 11%, 17%

D⫽0.35 66%, 17%, 17%

Percentage order: LC bias%, BC bias%, No bias%. D⫽mean IAT score. All comparisons significant with ps⬍0.001.

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A multicenter effort to identify driver mutations and employ targeted therapy in patients with lung adenocarcinomas: The Lung Cancer Mutation Consortium (LCMC). Presenting Author: Bruce E. Johnson, Dana-Farber Cancer Institute, Boston, MA Background: The detection of driver mutations in the EGFR and ALK genes and targeted therapy has transformed treatment of lung cancer. The LCMC was established in 2009 to assay lung adenocarcinomas for driver genomic alterations in 10 genes and to study and treat patients by their molecular subtypes. Methods: The 14-member LCMC enrolled patients with metastatic adenocarcinoma of the lung and tested their tumors in CLIA laboratories for KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, MEK1, and NRAS mutations using multiplexed assays, and for ALK rearrangements and MET amplifications using fluorescence in situ hybridization (FISH). Results: 1,102 eligible patients were enrolled; 1,007 underwent testing for at least one genomic alteration with 733 undergoing testing for all 10 genes. 600 patients were women (60%) with a median age of 63; 341 were never smokers (34%) and 589 former smokers (58%). A driver alteration was detected in 622 (62%) of the 1,007 with any genotyping, and in 465 (63%) of the 733 fully genotyped cases. Among the tumors with full genotyping, drivers were found as follows: KRAS 182 (25%), sensitizing EGFR 107 (15%), ALK rearrangements 56 (8%), other EGFR 43 (6%), two genes 29 (4%), BRAF 16 (2%), HER2 15 (2%), PIK3CA 6 (1%), MET amplification 5 (1%), NRAS 5 (1%), MEK1 1 (⬍1%), and AKT1 0 (0%). Results were used to select targeted therapy or targeted trials in 279 patients with a driver alteration (28% of 1,007 total). Among 938 patients with clinical follow-up and treatment information, 264 with a driver alteration treated with a targeted agent had a median survival of 3.5 years; 313 with a driver who did not receive targeted therapy had a median survival of 2.4 years; while 361 without an identified driver had a median survival of 2.1 years (p⬍0.0001). Conclusions: An actionable driver alteration was detected in 62% of tumors from patients with lung adenocarcinomas, leading to use of a targeted therapy in 28%. The patients with an identified driver treated with a targeted agent lived longer than those patients who did not receive targeted therapy. Multiplexed genomic testing can aid physicians in matching patients with targeted treatments and appropriate clinical trials.




Clinical next generation sequencing (NGS) to reveal high frequency of alterations to guide targeted therapy in lung cancer patients. Presenting Author: Siraj M. Ali, Foundation Medicine, Inc., Cambridge, MA Background: Cancer genomic profiling via NGS in a clinical setting can reveal additional actionable genomic alterations (GA) in patients with lung cancer (LC) previously tested only by hotspot analysis and leading to unanticipated avenues of targeted treatment. Methods: We performed an NGS-based diagnostic test (FoundationOne) to characterize all classes of GA across 3,320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on 386 LC FFPE specimens in a CLIA-certified lab (Foundation Medicine). Specimens included fine needle aspirates, core needle biopsies, and malignant effusions. 95% of cases were NSCLC (367/386). Actionable GAs are defined as those linked to targeted anti-cancer therapies approved or being evaluated in clinical trials. NGS confirmed known hotspot results for EGFR, KRAS and EML4: ALK in 100% of cases. Results: Genomic profiles were generated from 364/386 (94%) of lung cancer cases, identifying 1205 GA, averaging 3.31 alterations per tumor (range 0 to 10). 85% of tumors (310) harbored at least one actionable GA, with a mean of 1.79 GA per tumor (range 0 to 6). In 68% of tumors (248), at least one GA was detected that would be missed by current ‘hotspot assays’. ERBB2 harbored base substitutions or indels in 1.3% of cases. BRAF and C-Kit were altered at frequencies of 2% and 1% respectively. The mTOR/PI3K pathway is likely to be activated via alterations in tumor suppressors STK11 (11%), NF1 (6%) and PTEN (4%), as well as by alterations of PIK3CA (10%) and in AKT1/2/3 (4%), suggesting possible benefit from mTOR/PI3K inhibitors. The Hedgehog pathway (PTCH1/SMO/SUFU) was altered in 2% of cases. ALK and RET were rearranged in 4% and 2% of cases, respectively, with several cases initially diagnosed negative by FISH testing. Conclusions: Profiling the tumor genomes of 364 LC patients led to the identification of a series of GA not detectable by hotspot testing that could significantly inform targeted treatment decisions. Moreover, actionable GA appeared in unexpected tumor type, i.e. an EGFR mutation in a SCLC, reinforcing the likely utility of clinical cancer genomic profiling for the personalized treatment of LC patients.

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Detection of EGFR-activating mutations from plasma DNA as a potent predictor of survival outcomes in FASTACT 2: A randomized phase III study on intercalated combination of erlotinib (E) and chemotherapy (C). Presenting Author: Tony Mok, The Chinese University of Hong Kong, Hong Kong, China Background: Biomarker analysis of tumor from FASTACT 2 confirmed predictive power of EGFR mut on the benefit of intercalated combination of E and C as 1st line in advanced NSCLC (T. Mok, ESMO 2012). However, only limited tumor were available. Recent development allowed us to detect EGFR mut in cell-free DNA from plasma (pEGFRmut). In this study, we studied the concordance between pEGFRmut and EGFR mut in tumor (tEGFRmut), and the role of pEGFRmut as predictor of PFS and OS. Methods: Retrospective EGFR mut testing of FFPET and plasma from FASTACT 2 were performed with two allele-specific PCR assays, cobas EGFR_FFPET test and cobas EGFR_blood test (in development). Both tests are designed to detect EGFR activating mut (exon 19 deletions, L858R, G719X). One FFPET section was used for tissue test and 2-ml plasma was used for blood test. Results: Among 268 tumors from 451 enrolled pts, 90% (241/268) were analyzable. 40% (96/241) harbored at least one activating EGFR mut. All 427 plasmas from 451 enrolled pts were analyzable. 32% (136/427) were positive for EGFR activating mut. The concordance of two tests from 224 matched tissue and plasma samples was summarized below. Using tissue as comparator, the sensitivity of plasma test was 76% (68/89) and the specificity of plasma test was 96% (130/135) respectively. Positive and negative predictive values for EGFR activating mut were 93% (68/73) and 86% (130/151) respectively. Median PFS of patients with pEGFRmut treated with intercalated combination versus chemotherapy alone was 13.8 vs. 6.1 m (HR⫽0.21 p⬍0.0001), and for pEGFR wild-type, 6.7 vs. 6.0 m (HR⫽0.80, p⫽0.06). Median OS of patients with pEGFRmut treated with intercalated combination versus chemotherapy alone was 32.4 vs. 19.0 m (HR⫽0.51, p⫽0.0035), and for pEGFR wild-type, 16.1 vs 13.3 m (HR⫽0.89, p⫽0.39). Conclusions: cobas EGFR_blood test can be used to reliably detect EGFR mutations in plasma. pEGFRmut is a potent predictor of survival outcomes in FASTACT 2. Clinical trial information: NCT00883779/ MO22201/CTONG0902. Nⴝ224 EGFR mut* (T) Wild-type† (T)

EGFR mut*(P)

Wild-type† (P)

68 5

21 130

P: plasma; T: tissue; *activating mut positive; †activating mut negative.

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Patterns of metastasis and survival in patients with PI3K pathway-driven stage IV squamous cell lung cancers (SQCLC). Presenting Author: Paul K. Paik, Memorial Sloan-Kettering Cancer Center, New York, NY

NTRK1 gene fusions as a novel oncogene target in lung cancer. Presenting Author: Robert Charles Doebele, University of Colorado Cancer Center, Aurora, CO

Background: The majority of actionable drivers in SQCLCs occur in the PI3K (30%) and FGFR1 (20%) pathways. The biologic behaviors and natural histories of these oncogenic subtypes are not well characterized. Methods: As of October 2011, all patients with SQCLCs at MSK have undergone prospective, multiplex testing of their FFPE tumors for FGFR1 amplification (FISH), PIK3CA mutations (Sequenom), PTEN loss (IHC), and PTEN mutations (exon sequencing), among others. Patient characteristics, outcomes, and metastatic sites were identified. Survival probabilities were estimated using the Kaplan-Meier method. Group comparisons were performed with log-rank tests and Cox proportional hazards methods. Results: 68 stage IV SQCLC patients were analyzed. 39 had tissue sufficient for next-gen sequencing. Genotypes were: FGFR1 amplified (16%); PTEN loss (24%), PIK3CA mutant (7%), PTEN mutant (13%). Events were non-overlapping save for 2 cases with PTENnonsense mutations and PTEN loss. The sole significant clinical difference (KPS, age, sex, lines of tx) was sex (women in PI3K group 52% vs. in others 23%, p⫽0.02). Metastatic patterns vs. other are shown in the Table. Median OS for PI3K vs. other: 10mo (95%CI:6.5-14.3) vs. 14mo (95%CI:9.6-36.7), p⫽0.02. Median OS for FGFR1 vs. others: 19mo (95%CI:9-NR) vs. 10mo (95%CI:6.514.3), p⫽0.3. Multivariate analysis for OS: PI3K vs. other, HR death⫽2.3 (95%CI:1.1-4.8, p⫽0.03); Age ⱖ65, HR⫽1.3 (95%CI:0.6-2.9, p⫽0.6); KPSⱖ70, HR⫽0.5 (95%CI:0.2-1.7, p⫽0.3); Male sex, HR⫽0.7 (95%CI: 0.3-1.4, p⫽0.3). Conclusions: Patients with stage IV PI3K-aberrant SQCLCs have poorer survival compared to other patients with SQCLCs. Brain metastases occurred exclusively in patients with PI3K-aberrant tumors. These data suggest that PI3K pathway activation confers a distinct biology, and that targeting this in SQCLC patients with brain metastases may be an effective therapeutic strategy.

Background: The identification and therapeutic targeting of oncogenic drivers in lung adenocarcinoma has led to significant clinical improvements for patients with EGFR mutations or ALK fusions. However, many lung cancer patients do not yet have an identified oncogenic driver and the discovery of new actionable oncogenic drivers is thus an active area of investigation. Methods: Tumor samples from 36 ‘pan-negative’ (EGFR, KRAS, ALK, and ROS1) lung adenocarcinoma patients were analyzed using a next generation sequencing (NGS) test performed in a CLIA-certified lab (Foundation Medicine, Cambridge, MA). Fluorescence in situ hybridization (FISH) screening using a novel NTRK1 break-apart assay was performed on an additional 61 pan-negative samples. Cells expressing the novel NTRK1 fusions were assayed for transformation and pharmacologic inhibition. Results: Two tumor samples were identified with gene fusions containing the kinase domain of TrkA, encoded by NTRK1, including one each with an MPRIP-NTRK1 (M21;N14) and CD74-NTRK1 (C8;N12) fusion. RT-PCR confirmed mRNA expression and identity of the fusion partner and FISH analysis detected split 5’/3’ signals corresponding to the NTRK1 gene. A third sample was identified by FISH analysis. Cloning and expression of MPRIP- and CD74-NTRK1 into NIH3T3 and Ba/F3 cells show constitutive activation of the TrkA kinase domain and transformation. Treatment of cells expressing NTRK1 fusions with several candidate pan-Trk inhibitors (ARRY-772, -523, and -470) as well as CEP-701 and crizotinib demonstrate decreased phosphorylation of the fusion oncoprotein and inhibition of cell proliferation. Treatment of the index patient harboring the MPRIPNTRK1fusion with crizotinib led to minor transient tumor shrinkage. Conclusions: We identified a novel class of oncogenes, NTRK1 fusions, in lung adenocarcinomas that can be detected by NGS or FISH. Additional studies to determine the frequency and characteristics of NTRK1 fusions in lung cancer are ongoing. Our findings suggest prospective clinical trials of Trk inhibitors in NTRK1 fusion positive patients may be warranted. Support: CO Bioscience Discovery and Evaluation Grant and CO Clinical and Translational Sciences Institute Grant.

Site Brain Pleura Liver Bone Lung Adrenal Pericardium

PI3K

P

FGFR1

P

Other

Total

6 (24%) 4 (16%) 4 (16%) 6 (24%) 12 (48%) 2 (8%) 1 (4%)

0.002 0.4 0.4 0.8 0.8 1 1

0 (0%) 3 (27%) 1 (9%) 2 (18%) 7 (64%) 1 (9%) 1 (9%)

0.6 0.7 1 0.7 0.2 1 0.3

0 (0%) 9 (28%) 2 (6%) 10 (31%) 11 (34%) 4 (13%) 0

6 (9%) 16 (25%) 7 (10%) 18 (26%) 30 (44%) 7 (10%) 2 (3%)


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RET rearrangements detected by FISH in “pan-negative” lung adenocarcinoma. Presenting Author: Marileila Varella-Garcia, University of Colorado School of Medicine, Aurora, CO Background: RET rearrangements have recently been reported in NSCLC and there is pre-clinical evidence that RET tyrosine kinase inhibitors (TKIs) block activated RET kinase. Efficient and accurate detection of RET rearrangements are crucial for the success of RET TKIs in clinical trials. RET rearrangements have been detected by specialized sequencing techniques with limited applicability to clinical practice. Methods: A 3-target FISH probe set was developed to detect KIF5B-RET fusions and identify patterns suggestive of RET rearrangements with non-KIF5B partners. 51 lung adenocarcinomas negative for EGFR, KRAS, ALK and ROS1 (36 were also negative for 7 other molecular markers) were investigated. Clinical and demographic characteristics were collected. Results: Eight patients (15%) had rearrangements in the RET gene: 5 with KIF5B-RET fusions, 2 with patterns consistent with the CCDC6-RET fusion, and 1 with extra copies of single 3’RET (loss of 5’RET). Atypical FISH patterns were detected both in RET ⫹ and negative specimens suggesting high genomic instability in the KIF5B – RET region. RT-PCR assay determined the exon/fusion variant in 4 cases including 2 patients with K15:R12, 1 with K16:R12 and 1 with C1:R12. Median age at diagnosis was 58.5 in the mutation negative and 63 in the RET⫹ patients. Both cohorts were predominantly male (66% and 56%, respectively), with a majority of never smokers (59 and 89%, respectively), and stage IV disease at diagnosis (72 and 89%, respectively). Two heavily pretreated RET⫹ patients had stable disease at their initial restaging scans following treatment with the RET inhibitor vandetanib (radiographic assessment per RECIST 1.1); two others had early radiographic progression with sunitinib. Conclusions: The FISH probe proved efficient to detect RET rearrangements in lung adenocarcinomas, involving KIF5B and non-KIF5B partners. Frequency of RET rearrangements in this enriched lung adenocarcinoma cohort was considerably higher than reported in unselected cohorts. Further molecular analyses are being performed to increase understanding of the natural history of this new molecular subtype of NSCLC. Support: B J Addario Foundation, NCI P50CA058187, NCI CCSG P30CA046934.

8026


Two parallel randomized phase II studies of selumetinib (S) and erlotinib (E) in advanced non-small cell lung cancer selected by KRAS mutations. Presenting Author: Corey Allan Carter, Walter Reed National Military Medical Center, Bethesda, MD Background: KRAS mutations are present in 20% of NSCLC and are associated with primary resistance to erlotinib (E). KRAS mutations result in constitutive activation of the Ras/Raf/MEK/ERK pathway. Selumetinib (S) (AZD6244, ARRY-142886) is a selective and uncompetitive inhibitor of MEK kinase. Preclinical studies demonstrated increased activity in NSCLC cell lines using S⫹E regardless of KRAS status. Methods: Advanced NSCLC patients with progressive disease after platinum based chemotherapy ⫹/- one other treatment were stratified by KRAS status, which was centrally assessed using macrodissection and pyrosequencing for all mutations involving codons 12, 13, and 61. Patients were randomized to receive either the standard of care E or a combination of S⫹E in KRAS wild type (wt) and S alone or S⫹E in patients with KRAS mutations. Single agent E and S were administered orally at 150 mg daily and 75 mg twice daily respectively. Combination dosing were S 150 mg every morning and E 100 mg every evening. The primary endpoint for the KRAS wt group was PFS and for the KRAS mutant group objective response rate. Results: From March 2010 to January 2013, 79 patients screened; 78 enrolled: KRAS mutant, 39; KRAS wt, 40; M/F (39:39); median age: 64 years (33-84); median WHO PS 1(0-2); 66 former and 13 never smokers; 67 adenocarcinoma, 9 squamous cell. Three patients died of complications prior to first evaluation (1 coronary disease, 1 pulmonary fibrosis, and 1 disease progression) of which none were related to S. Dose reductions occurred in 5% E, 40% S, and 56% E⫹S. Most grade 3/4 AEs occurred in combination therapy; diarrhea (23%), fatigue (23%) lymphopenia (13%), myositis (10%), dyspnea (10%), rash (7%). Discontinuation due to AEs was 8% all occurring in S⫹E cohorts. Conclusions: This study failed to show improvement of combination therapy over single agent in KRAS wt and mutant patients. Toxicity was increased in the combination arms. Interestingly, the KRAS mutant cohort had longer PFS than KRAS wt patients, although not statistically significant (p⫽0.11). Clinical trial information: NCT01229150. KRAS WT E n* RR Median PFS(m)

E⫹S 19 0 2.3

S 18 6% (n⫽1) (p⫽1.00) 2.1 (p⫽0.69)

KRAS MUT S⫹E 9 0 3.9

30 7% (n⫽2) (p⫽1.00) 4.5 (p⫽0.95)

8025


Comparison of the characteristics and clinical course of 677 patients with metastatic lung cancers with mutations in KRAS codons 12 and 13. Presenting Author: Helena Alexandra Yu, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Patients (pts) with KRAS mutant lung cancers have a shorter survival compared to pts with KRAS/EGFR wild type tumors (Johnson et al, Cancer 2012). Whether outcomes for patients with KRAS mutant metastatic lung cancers differ by smoking status or specific amino acid substitution is unknown. In order to understand the impact of KRAS mutation subtype in the metastatic setting, we analyzed a large cohort of patients with KRAS mutant metastatic lung cancer. Methods: We identified all pts with KRAS mutant metastatic or recurrent lung cancers from Feb 2005 to Aug 2011. KRAS mutation type, clinical characteristics, and outcomes from diagnosis were obtained from the medical record. A multivariate cox proportion hazard model was used to identify factors associated with overall survival. Results: KRAS mutations were identified in 677 pts (53 at codon 13, 624 at codon 12). Median age: 66 (range 31-89), women: 62%, never smokers: 7%. Pts with transition mutations (n⫽157) were more likely to be never-smokers (p⬍0.0001). There was no difference in outcome for pts with KRAS transition versus transversion mutations (p⫽1) or when comparing current/former smokers to never smokers (p⫽0.33). There was no difference in overall survival (OS) when comparing specific amino acid substitutions (G12C⫽366, G12V⫽141, G12D⫽114, G12A⫽68, G13C⫽27, G13D⫽23, G12S⫽19, G12F⫽11)(p⫽0.20). Pts with KRAS codon 13 mutant tumors had inferior OS compared to pts with codon 12 mutant tumors, median 13 months (mo) (95% CI 13-17 mo) and 16 mo (95% CI 9-16 mo), respectively (p⫽0.009). There was no difference in frequency of receiving platinum-based chemotherapy or chemotherapy of any kind between pts with codon 12 and 13 mutant tumors. In a multivariate Cox model which included age, gender and smoking status, KRAS codon 13 mutation was associated with worse overall survival than KRAS codon 12 mutation (HR 1.52 95% CI 1.112.08 p⫽0.008). Conclusions: Among pts with KRAS mutant metastatic lung cancers, smoking history, and specific amino acid substitution do not affect outcome. Patients with KRAS codon 13 mutant metastatic lung cancer have shorter survival compared to pts with KRAS codon 12 mutant lung cancer.

8027


Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with pemetrexed for KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): A phase I/Ib trial. Presenting Author: Karen Kelly, Division of Hematology and Oncology, UC Davis Comprehensive Cancer Center, Sacramento, CA Background: Lung cancer patients with mutated KRAS tumors present a treatment challenge. Trametinib ⫹ pemetrexed (pem) enhanced growth inhibition and apoptosis compared with either agent alone in lung cancer cell lines with WT or mutated RAS/RAF. Methods: This 2-part, multiarm, phase I/Ib, open-label study evaluated the safety and efficacy of trametinib plus chemotherapy (NCT01192165). Part 1 determined the recommended phase II dose (RP2D) for trametinib ⫹ pem in patients (pts) with advanced solid tumors. In part 2, NSCLC pts were stratified as KRAS WT or mutation unknown (WT) or KRAS-mutant (KRAS) and were treated with trametinib ⫹ pem at the RP2D. Primary study objectives were safety and tolerability; secondary objectives were efficacy and pharmacokinetics (PK). Exploratory mutational profiling was done using circulating-free DNA from plasma and available archival tumor tissue. Results: As of January 2013, 42 NSCLC pts (22 WT [82% had ⱖ 2 prior therapies], 20 KRAS [55% had ⱖ 2 prior therapies]) have been treated at the trametinib ⫹ pem RP2D (1.5 mg ⫹ 500 mg/m2). Nausea, fatigue, and peripheral edema were the 3 most frequent toxicities. 26% of pts reported grade 3-4 hematologic toxicity. Dose reduction occurred in 15 pts (33%), most often for diarrhea, decreased ejection fraction, and fatigue (all 7%). Preliminary PK suggests no drug-drug interaction. In KRAS pts, the best investigator-assessed response (confirmed ⫹ unconfirmed) was 3 partial response (PR; RR ⫽ 15%) and 10 stable disease (SD; 50%); additionally, 3 pts had ⬎ 20% tumor shrinkage. The disease control rate (DCR) was 65%. Final response and progression-free survival (PFS) data will be reported upon maturity. In WT pts, 3 PR (RR ⫽ 14%) and 13 SD (59%) were observed (73% DCR); preliminary median PFS was 5.8 months (95% CI, 2.8-6.7 months). Biomarker analyses, including assessment of KRAS mutation subtype vs efficacy, are ongoing. Conclusions: MEK inhibition with trametinib ⫹ pem demonstrates tolerability and clinical activity in both KRAS-mutant and WT NSCLC, exceeding expectations for each drug alone and warranting further study. Clinical trial information: NCT01192165.

* 75 patients evaluable.




Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with docetaxel in KRAS-mutant and wild-type (WT) advanced non-small cell lung cancer (NSCLC): A phase I/Ib trial. Presenting Author: David R. Gandara, Division of Hematology and Oncology, UC Davis Comprehensive Cancer Center, Sacramento, CA Background: KRAS-mutant NSCLC, usually reflecting tobacco-related carcinogenesis, represents an unmet medical need in lung cancer therapy. Trametinib plus docetaxel (doc) enhances growth inhibition and apoptosis of NSCLC cell lines in vitro with and without RAS/RAF mutations when compared with either agent alone. Methods: This 2-part, multiarm, phase I/Ib, open-label study evaluated the safety and efficacy of trametinib plus chemotherapy (NCT01192165). Part 1 determined the recommended phase II dose (RP2D) for trametinib⫹doc in patients (pts) with advanced solid tumors. In part 2, NSCLC pts were stratified as KRAS WT or mutation unknown (WT) or KRAS-mutant (KRAS) and were treated with trametinib ⫹ doc at the RP2D. Primary study objectives were safety and tolerability; secondary objectives were efficacy and pharmacokinetics (PK). Exploratory mutational profiling was done using circulating-free DNA from plasma and available archival tumor tissue. Results: As of January 2013, 46 NSCLC pts (24 WT [67% had ⱖ 2 prior therapies] and 22 KRAS [41% had ⱖ 2 prior therapies]) have been treated at the trametinib ⫹ doc RP2D (2.0 mg ⫹ 75 2 mg/m ⫹ growth factors). Diarrhea, fatigue, asthenia, and nausea were the 4 most frequent toxicities. Dose reduction occurred in 10 pts (22%), mostly for diarrhea, fatigue, mucositis, neutropenia, and skin fissures (all 4%). Preliminary PK suggests no drug-drug interaction. In KRAS pts, the best investigator-assessed response (confirmed ⫹ unconfirmed) was 3 partial response (PR; RR ⫽ 17%) and 8 stable disease (SD; 44%); additionally, 4 pts had ⬎ 20% tumor shrinkage. The current disease control rate (DCR) is 61%; 4 pts have not had postbaseline scans. In WT pts, 5 PR (RR⫽21%) and 11 SD (46%) were observed (67% DCR). Final response and progression-free survival data will be reported upon maturity. Biomarker analyses, including assessment of KRAS mutation subtype vs efficacy, are ongoing. Conclusions: MEK inhibition with trametinib ⫹ doc (⫹ growth factors) demonstrates tolerability and clinical activity in both KRAS-mutant and WT NSCLC, exceeding expectations for each drug alone and warranting further study. Clinical trial information: NCT01192165.

8030


Survival and long-term follow-up of the phase I trial of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in patients (pts) with previously treated advanced non-small cell lung cancer (NSCLC). Presenting Author: Julie R. Brahmer, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD Background: The immune checkpoint receptor programmed death-1 (PD-1) negatively regulates T-cell activation. Nivolumab, a PD-1 receptor blocking antibody, was evaluated in a phase 1 study in pts with various tumors including NSCLC (Topalian et al, NEJM 2012;366:2443). Methods: Pts with ⱖ1 prior chemotherapy regimen received nivolumab (1-10 mg/kg IV Q2W) for ⱕ12 cycles (4 doses/8W cycle) or until discontinuation criteria were met. We report initial overall survival (OS) and updated safety and response data for NSCLC pts. Results: 127 pts evaluable for safety received nivolumab at 1, 3, or 10 mg/kg as of July 2012. Common drug-related AEs were decreased appetite (9%), anemia (8%), diarrhea, nausea, and pruritus (7% each). The most common G3/4 AEs were fatigue, pneumonitis, and elevated AST (2% each). Two drug-related deaths from pneumonitis occurred early in the trial and led to increased monitoring without further deaths from pneumonitis. Median OS (mOS) across all dose cohorts was 9.2 mo and 9.6 mo for squamous (sq) and non-sq NSCLC, respectively. mOS was not reached at the 3 mg/kg dose (phase 3 dose) for either histology. Sustained OS was observed, with 44%/ 41% and 44%/ 17% of pts (sq/non-sq) alive at 1 and 2 years, respectively (Table). Prolonged ORs occurred in both histologies (Table). Conclusions: In this long-term follow-up of a phase I trial, nivolumab had an acceptable safety profile and showed an encouraging sustained OS benefit across histologies in previously treated advanced NSCLC. Follow-up through a Feb 2013 data cut (ⱖ1 yr follow-up for all pts) will be provided at presentation. Clinical trial information: NCT00730639. Dose, mg/kg All NSCLC pts All Non-sq 1 3 10 All Sq 1 3 10 OS ratea,% (95% CI), pt at risk, n 1 Yr 2 Yr

ORR n/N (%)

mOS Mo (95% CI)

20/122 (16) 11/73 (15) 1/18 (⬍6) 5/18 (28) 5/37 (14) 9/48 (19) 0/13 (0) 4/15 (27) 5/20 (25)

9.6 (7.4-13.7) 9.6 (5.3-13.7) 9.2 (5.3-NR) NR (5.2-NR) 7.2 (4.6-10.1) 9.2 (7.6- NR) 8.3 (3.2-NR) NR (6.7-NR) 10.5 (8.6-NR)

Sq 44 (27-61), 8 44 (27-61), 3

Non-Sq 41 (28-53), 16 17 (0-42), 1

aAcross doses. OS estimates after 1 Yr reflect heavy censoring and shorter follow-up for pts enrolling in the later portion of the study. NR ⫽ not reached.

8029

493s


MEK114653: A randomized, multicenter, phase II study to assess efficacy and safety of trametinib (T) compared with docetaxel (D) in KRAS-mutant advanced non–small cell lung cancer (NSCLC). Presenting Author: George R. Blumenschein, Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX Background: KRAS mutations are detected in 25% of NSCLC, and there are no approved targeted therapies for this subset of NSCLC. D, an approved second-line treatment for NSCLC, has a response rate of ⬍ 10%. T is a reversible, highly selective allosteric inhibitor of MEK1/2 activation and kinase activity. This phase II trial (NCT01362296) evaluated the efficacy of T vs D in pts with advanced KRAS-mutant NSCLC who had received prior platinum-based chemotherapy. Methods: Pts were randomized 2:1 to T (2 mg QD) or D (75 mg/m2 IV every 3 weeks) and stratified by type of mutational status and gender. Crossover to the other arm after progressive disease was allowed. Primary endpoint was PFS in pts with KRAS-mutant NSCLC (modified ITT; mITT). Secondary endpoints were OS, ORR, duration of response, and safety. PFS and OS were compared using a stratified log-rank test. The trial was stopped early for futility at a planned interim analysis; 92 PFS events were reported at the time of study termination. Results: Between September 2011 and July 2012, 134 pts were randomized to T (89) or D (45); 129 pts had KRAS-mutant NSCLC. Mean age was 61.4 y and 53% were male. In the mITT, 61/86 pts (71%) on T and 31/43 (72%) on D had a PFS event. HR for PFS was 1.14 (95% CI, 0.75-1.75; P ⫽ .5197) with a median PFS of 11.7 vs 11.4 wk for T vs D. ORR was 12% for T (10/86) and for D (5/43). With 27 (31%) deaths on T and 15 (35%) on D, HR for OS was 0.97 (95% CI, 0.52-1.83; P⫽ .934). Five fatal SAEs were reported during treatment with T but none with D; 1 unspecified death was considered related to T. Frequent AEs reported with T were rash (59%), diarrhea (47%), nausea (34%), hypertension (34%), and dyspnea (33%). Grade 3/4 AEs with T were hypertension (16%/0), dyspnea (7%/3%), rash (6%/3%), diarrhea (6%/0), and asthenia (6%/0). Rate of treatment related SAEs was 15% with T and 12% with D. Conclusions: T did not improve PFS in pts with KRAS-mutation–positive NSCLC compared with D. However, an ORR of 12% for T in KRAS-mutant NSCLC suggests that an effort to better identify responsive mutations is warranted. The safety profile did not favor T, but is, in general, consistent with the overall T safety profile. Clinical trial information: NCT01362296. 8031


First-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies: Updated results. Presenting Author: D. Ross Camidge, University of Colorado Cancer Center, Aurora, CO Background: AP26113 is a novel tyrosine kinase inhibitor (TKI) that potently inhibits mutant activated forms of anaplastic lymphoma kinase (ALK⫹) and epidermal growth factor receptor (EGFRm), and TKI-resistant forms including L1196M (ALK) and T790M (EGFR). AP26113 does not inhibit native EGFR. Methods: The dose finding phase (3⫹3 design) of this phase I/II open-label, multicenter study is ongoing in pts with advanced malignancies (except leukemia) refractory to available therapies or for whom no standard treatment exists. Initial dosing is orally once daily. Results: As of 14 Jan 2013, 44 pts were enrolled: 30 mg n⫽3, 60 mg n⫽3, 90 mg n⫽8, 120 mg n⫽8, 180 mg n⫽11, 240 mg n⫽9, 300 mg n⫽2; 64% female, median age 60 yrs; diagnoses: non-small cell lung cancer (NSCLC, n⫽37), other (n⫽7). 26 pts discontinued: 18 disease progression, 6 adverse event (AE), 2 deaths (sudden death, hypoxia; both possibly related). Most common AEs: nausea (45%), fatigue (39%), diarrhea (27%); most common grade 3/4 treatment-related AE: diarrhea (5%). 2 dose limiting toxicities observed: grade 3 ALT increase, 240 mg; grade 4 dyspnea, 300 mg. Doses ⬍300 mg are being explored further. 21 pts had ALK⫹ history (18 NSCLC, 3 other). Among 18 evaluable ALK⫹ pts, 10 responded. 15 ALK⫹ pts had 0 (n⫽3) or 1 (n⫽12) prior ALK TKI (crizotinib); of these, 2/3 and 8/12 pts (67%) responded, including 2 complete responses. The longest response is 40 wks (ongoing). 4 of 5 ALK⫹ pts with untreated or progressing CNS lesions at baseline and with follow-up scans had evidence of radiographic improvement in CNS, including 1 pt resistant to crizotinib and LDK378 (overall response ⫽ stable disease). 16 pts had EGFRm history (15 NSCLC, 1 SCLC); 14 pts had ⱖ1 prior EGFR TKI. Of 12 EGFRm pts with a follow-up scan, 1 pt (prior erlotinib) responded at 120 mg (duration 21 wks, ongoing), 6 pts had stable disease (2 ongoing, duration 7-31 wks). Conclusions: AP26113 has promising anti-tumor activity in ALK⫹ pts, with initial evidence of activity in EGFRm pts, and is generally well tolerated. Phase II will begin after the recommended phase II dose is determined, with 4 cohorts: crizotinib-naïve NSCLC; crizotinib-resistant NSCLC; EGFR TKI-resistant NSCLC; other tumors. NCT01449461. Clinical trial information: NCT01449461.


494s 8032


Efficacy and safety of crizotinib in patients with advanced ROS1rearranged non-small cell lung cancer (NSCLC). Presenting Author: SaiHong Ignatius Ou, Chao Family Comprehensive Cancer Center, Orange, CA Background: ROS1 receptor tyrosine kinase rearrangements define a subset of NSCLC sensitive to the small-molecule tyrosine kinase inhibitor crizotinib, approved multinationally for the treatment of advanced ALK-positive NSCLC. Updated efficacy and safety data are presented for crizotinib in patients with advanced ROS1-rearranged NSCLC. Methods: ROS1 status was determined by break-apart FISH assays, and patients were enrolled into an expansion cohort of an ongoing phase 1 crizotinib study (NCT00585195). Patients received crizotinib 250 mg BID. Responses were assessed using RECIST v1.0. The disease control rate (DCR; % stable disease [SD] ⫹ partial response [PR] ⫹ complete response [CR]) was evaluated at weeks 8 and 16. Results: At the data cut-off, 33 patients with ROS1-positive NSCLC had enrolled, and 31 had received crizotinib, with 25 evaluable for response. Median age was 51 years (range 31–72), 79% of patients were never-smokers and 97% had adenocarcinoma histology. The median number of prior treatments for advanced disease was 1 (range 0 –7). The objective response rate (ORR) was 56% (95% CI: 24.4 – 65.1), with 2 CRs, 12 PRs and 8 SDs. 8-week and 16-week DCRs were 76% and 60%, respectively. Median PFS has not been reached, with ~60% of patients still in follow-up for PFS; 6-month PFS probability was 71% (95% CI: 45.6 – 86.0). Median treatment duration was 24 weeks (range 2.3– 112), and 24 patients were on treatment at the data cut-off; 5 patients died (all disease-related). 91% of patients had treatment-related adverse events (AEs): most commonly visual impairment (82%), nausea (36%) and diarrhea (33%). Most AEs were grade 1 in severity. Peripheral edema and elevated transaminases were also reported, similar to the previous experience of crizotinib. There were no treatment-related serious AEs or treatmentrelated permanent discontinuations. Accrual of patients with ROS1positive NSCLC is ongoing. Conclusions: As observed in ALK-positive NSCLC, crizotinib had dramatic antitumor activity with a high ORR (56%) in patients with ROS1-positive NSCLC and a generally tolerable and manageable AE profile. These findings indicate that crizotinib is an effective therapy for advanced ROS1-positive NSCLC. Clinical trial information: NCT00585195.

8034


Lume-lung 2: A multicenter, randomized, double-blind, phase III study of nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with advanced nonsquamous non-small cell lung cancer (NSCLC) after failure of first-line chemotherapy. Presenting Author: Nasser H. Hanna, Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis, IN Background: Nintedanib (N) is an oral inhibitor of VEGFR, FGFR, and PDGFR. This global phase 3 study investigated the safety and efficacy of N ⫹ pemetrexed (PEM) vs placebo (P) ⫹ PEM in patients (pts) with advanced, non-squamous NSCLC previously treated with chemotherapy. Methods: Pts were randomized 1:1 to N 200 mg po bid ⫹ PEM 500 mg/m2 iv q21d (n⫽353, Arm A) or P ⫹ PEM (n⫽360, Arm B). Continuation until PD or unacceptable toxicity with N, P, PEM, or a combination was permitted. 1° endpoint was centrally reviewed PFS. The null hypothesis was tested on the ITT population after 394 events had occurred (two sided ␣⫽5%). 2° endpoints included OS, investigator-assessed PFS, response rate (RR), safety, and QoL. Results: Baseline pt characteristics were balanced between Arm A vs B (median age 59 y, female 45– 42%, ECOG PS 1 62-61%, adenocarcinoma 95–93%, prior bevacizumab 8%). Based on a planned DMC futility analysis of investigator-assessed PFS, enrolment was halted after randomizing 713/1300 planned pts (no safety issues identified). Ongoing pts were unblinded and follow-up continued per protocol. Subsequent ITT analysis of the 1° endpoint (centrally reviewed PFS) favored Arm A vs B (median 4.4 vs 3.6 mo, HR 0.83 [95% CI: 0.7– 0.99], p⫽0.04). Disease control was also significantly improved in N-treated pts (61 vs 53%, odds ratio 1.37, p⫽0.039). No difference in OS (HR 1.03) or RR (9%) was found. Exploratory analyses identified time since start of 1st-line therapy as a predictive marker of improved outcome with N ⫹ PEM (ASCO 2013). There was no increase in SAEs or G5 AEs with N ⫹ PEM. Addition of N to PEM resulted in a higher incidence of ⱖG3 elevated ALT (23 vs 7%), elevated AST (12 vs 2%), and diarrhea (3 vs 1%), but no difference in ⱖG3 hypertension, bleeding, thrombosis, mucositis, or neuropathy. Conclusions: The 1° endpoint was met even though the study was stopped prematurely. Treatment with N ⫹ PEM significantly improved centrally reviewed PFS vs P ⫹ PEM in pts with advanced non-squamous NSCLC previously treated with chemotherapy, and had a manageable safety profile. Clinical trial information: NCT00806819.

8033


A phase I/II study with a highly selective ALK inhibitor CH5424802 in ALK-positive non-small cell lung cancer (NSCLC) patients: Updated safety and efficacy results from AF-001JP. Presenting Author: Kazuhiko Nakagawa, Kinki University Faculty of Medicine, Higashi-Osaka City, Japan Background: Anaplastic lymphoma kinase (ALK) is a constitutively activated tyrosine kinase in a subset of NSCLC with ALK fusion gene derived from chromosomal rearrangement. Previously, CH5424802, a highly selective, second-generation ALK inhibitor, has demonstrated clinically meaningful antitumor activity and a favorable toxicity profile (ESMO 2012). Here we report the updated results of this study. Methods: Patients (Pts) with ALK-positive NSCLC and no prior ALK inhibitor therapy were treated with CH5424802 at 300 mg bid until progressive disease or intolerable toxicity to investigate the efficacy and safety. Results: As of the cut-off date of Dec. 14, 2012, 58 pts have been treated with CH5424802: median age 49.5 years, M/F 25/33, ECOG PS 0/1 26/32, never-smoker 60.3%, ⱖ2 prior chemotherapy regimens 62%. Among the 46 pts in phase II part of this study, the overall response rate was 93.5% (95% CI: 82.1%, 98.6%) with 2 CRs and 41 PRs. Tumor shrinkage by 30% (PR) was achieved quickly with 65% occurring within 3 weeks of treatment and 87% within 6 weeks. With a median follow-up period of 12.6 months, 47/58 pts (40/46 pts in phase II part) were still on study treatment, and the median treatment duration has passed 10.3 months. The major treatment-related AEs were dysgeusia (21/58, 36%), rash, AST increased, blood bilirubin increased (19/58, 33% each), constipation and blood creatinine increased (17/58, 29% each), mostly grade 1-2. The major treatment-related grade 3 AEs were neutrophil count decreased (4/58, 7%). No grade 4 or fatal AEs were observed. Treatment-related visual disorders, vomiting and nausea were rare and mild. Conclusions: In patients with ALK-positive NSCLC but naïve to any ALK inhibitor therapy, treatment with CH5424802 demonstrated generally mild toxicity and lead to high response rate of 93.5% and durable treatment beyond 10 months, expecting that treatment duration can be longer than that of crizotinib. CH5424802 is therefore a promising new ALK inhibitor for NSCLC. Clinical trial information: JapicCTI-101264.

8035


Randomized phase II trial of NGR-hTNF in combination with standard chemotherapy in previously untreated non-small cell lung cancer (NSCLC). Presenting Author: Vanesa Gregorc, Department of Oncology, Istituto Scientifico Ospedale San Raffaele, Milan, Italy Background: NGR-hTNF, a selective antivascular agent, induces at low dose an initial vascular normalization that greatly enhances the intratumoral chemotherapy uptake, with synergistic effects that were noted especially in combination with cisplatin and gemcitabine. Methods: Chemo-naive patients (pts) with advanced NSCLC were stratified by histology (nonsquamous or squamous) and PS (0 or 1) and randomly assigned to receive cisplatin 80 mg/m2/d1 plus either pemetrexed 500 mg/m2/d1 (nonsquamous) or gemcitabine 1,250 mg/m2/d1⫹8 (squamous) every 3 weeks (q3w) for 6 cycles, with (arm A) or without (arm B) NGR-hTNF given at 0.8 ␮g/m2/d1/q3w until progression. Progression-free survival (PFS) was primary aim (1-␤⫽80%, 1-sided ␣⫽10%, n⫽102). Secondary aims comprised adverse events (AEs), response rate (RR), and overall survival (OS). Results: Baseline characteristics in arm A (n⫽62) vs B (n⫽59) were: median age: 62 vs 63 years; men: 37 vs 39; PS 1: 23 vs 23; squamous: 18 v 17; smokers: 41 vs 43. For the nonsquamous stratum, 299 cycles were given in arm A (mean 7.0; range 1-20) and 192 in arm B (4.8; 1-6), while for the squamous stratum, 113 in arm A (6.7; 1-31) and 52 in arm B (3.5; 1-6). Rates of grade 3/4 AEs were similar (arm A vs B): neutropenia 13% vs 18%, anaemia 7% vs 4% and fatigue 7% vs 11%. No grade 3/4 AEs related to NGR-hTNF or bleeding/pulmonary hemorrhage events were reported in the squamous subset. With median follow-up time of 24.2 months, median PFS (5.8 vs 5.6 months; HR⫽0.92), RR (25% vs 21%) and 1-year OS (53% vs 53%) were similar between the two treatment arms. However, by predefined analysis in the squamous stratum, median PFS was 5.6 months for arm A and 4.3 months for arm B (hazard ratio, HR⫽0.75) and median OS was 14.2 months for arm A and 9.7 months for arm B (HR⫽0.49; p⫽0.07). In pts with squamous histology, RR was 38% for arm A and 27% for arm B (odds ratio⫽1.6), while the median changes in tumor size on treatment from baseline to 2nd, 4th and 6th cycle for arm A vs B were -32% vs -20%, -41% vs -19%, and -42% vs -14%, respectively. Conclusions: Clinical tolerability and benefit were noted in squamous NSCLC with NGR-hTNF plus cisplatin and gemcitabine, which deserve further investigation. Clinical trial information: NCT00994097.




A phase II study of HSP90 inhibitor AUY922 and erlotinib (E) for patients (pts) with EGFR-mutant lung cancer and acquired resistance (AR) to EGFR tyrosine kinase inhibitors (EGFR TKIs). Presenting Author: Melissa Lynne Johnson, Feinberg School of Medicine, Northwestern University, The Robert H. Lurie Comprehensive Cancer Center, Chicago, IL Background: AUY922 is a synthetic HSP90 inhibitor that degrades client onco-proteins including EGFR. Preclinical studies demonstrate HSP90 inhibitors are effective agents against models of AR in EGFR-mutant lung cancer cell lines and xenografts harboring the “gatekeeper” mutation EGFR T790M. Pts with EGFR mutations who develop AR often continue E with 2nd-line therapies to avoid “disease flare” associated with discontinuing TKI. This phase II study combines AUY922 and E for the treatment of pts with EGFR-mutant lung cancer and RECIST-progression on 1st-line EGFR TKIs. Methods: Eligible pts had EGFR mutations and developed AR (Jackman, JCO 2010) after treatment with EGFR TKIs. Pts underwent tumor biopsies after developing AR and prior to study entry. Pts received AUY922 70 mg/m2 IV weekly and E 150 mg oral daily in 28-day cycles. Response assessment occurred at 4 weeks (wks), 8 wks, and every 8 wks thereafter. The primary objective was overall response rate (ORR, CR⫹PR) at 8 wks. A Simon mini-max design determined sample size (stage I: 16 pts (ⱖ2 responses needed to proceed to stage II), stage II: 9 pts; ␣⫽10%, ␤⫽10%, p0⫽10%, p1⫽30%). Tumor tissue from re-biopsy at study entry was analyzed for EGFR T790M. Results: Sixteen pts have been treated (10 women, median age 58 [range 47-76]). The median time on EGFR-TKI prior to the development of AR was 12 mo (range 2-42 mo). Seven pts had EGFR T790M confirmed by tumor re-biopsy. ORR was 2/16 (13%, 95% CI 2-37%). Both pts with PR had EGFR T790M. Four other pts had stable disease for at least 8 wks, two remain on study after more than 12 wks. Adverse events reported in ⱖ20% of pts were diarrhea, fatigue, myalgias, nausea, and transient flashing lights or night blindness. One pt each experienced grade 3 diarrhea and cardiac abnormalities. Conclusions: AUY922 and E is a well-tolerated regimen for pts with EGFR-mutant lung cancer and AR to EGFR TKIs. Two pts remain on study and 9 additional pts will be accrued in stage II; final response rate and survival outcomes will be reported. Supported by Novartis, Inc. Clinical trial information: NCT01259089.

8038


A randomized phase II trial comparing continuation maintenance therapy with pemetrexed and switch maintenance therapy with docetaxel after first-line therapy with carboplatin and pemetrexed in patients with advanced nonsquamous non-small cell lung cancer. Presenting Author: Masato Karayama, Department of Clinical Oncology, Hamamatsu University School of Medicine, Hamamatsu, Japan Background: Emerging evidence suggests that maintenance chemotherapy could prolong survival in patients with advanced non-small-cell lung cancer (NSCLC), whereas the optimal treatment strategy remains controversial. Methods: We conducted a randomized phase II study to compare the efficacy and safety of continuation maintenance with pemetrexed (500 mg/m2) and switch maintenance with docetaxel (60 mg/m2) in patients with non-squamous NSCLC who achieved disease control after first-line chemotherapy with four cycles of carboplatin (AUC 6) and pemetrexed (500 mg/m2). Results: Eighty-five patients participated in the study, and 26 and 25 patients were randomized to the pemetrexed and the docetaxel maintenance therapies, respectively. The docetaxel group showed a trend toward longer progression-free survival (median 8.2 months, 95% CI; 3.9-12.2 months) compared with the pemetrexed group (median 4.1 months, 95% CI; 3.0-6.1 months), but not significantly (log-rank p⫽0.084). Grade 3/4 hematologic toxicity was significantly more frequent in the docetaxel group (80%) than the pemetrexed group (20%, p⬍0.0001). Conclusions: Continuation maintenance with pemetrexed after induction therapy with carboplatin and pemetrexed may be an efficacious treatment with less toxicity. In contrast, switch maintenance with docetaxel frequently causes severe hematologic toxicity but may be more efficacious. Further studies are warranted to evaluate the risks and benefits of maintenance therapies. Clinical trial information: 000004075.

8037

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Combination chemotherapy with irinotecan and cisplatin (IP) for advanced large-cell neuroendocrine carcinoma (LCNEC) of the lung: A multicenter phase II study. Presenting Author: Seiji Niho, Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan Background: LCNEC and small cell lung cancer (SCLC) are recognized as high-grade neuroendocrine carcinoma of the lung. A differential diagnosis between LCNEC and SCLC using a tiny biopsy specimen is frequently difficult. Consequently, prospective clinical trials examining chemotherapy for advanced LCNEC have seldom been reported. We conducted a phase II study of combination chemotherapy with IP in patients (pts) with advanced LCNEC. Methods: The eligibility criteria included a chemotherapy-naïve status, a histological diagnosis of advanced LCNEC, an age of 20-75 years, and an ECOG PS of 0-1. Pts received I (60 mg/m2, days 1, 8, and 15) and P (60 mg/m2, day 1) every 4 weeks for up to 4 cycles. The primary endpoint was the response rate (RR). The sample size was determined to be 44, with a one-sided alpha of 0.1, a beta of 0.2, and expected and threshold values for the primary endpoint of 50% and 30%. Results: 44 pts from 11 institutes were enrolled between Jan 2005 and Nov 2011. The median age was 62.5 years; 21 pts had a PS of 0, and 35 pts were male. 5 pts had stage IIIB, 28 had stage IV, and 11 had recurrences after surgical resection. The RR was 54.5% (95% CI, 38.8-69.6). Grade 3 or 4 neutropenia was observed in 24 pts, but only 3 pts experienced febrile neutropenia. Other toxicities were mild and manageable. The median progression-free survival (PFS) was 5.9 months (95%CI, 5.5-6.3), and the median survival time (MST) was 15.1 months (95%CI, 11.2-19.0). Pathological specimens for a pre-planned central review were available for 41 pts. 30 pts were diagnosed as having LCNEC, whereas 10 pts were diagnosed as having SCLC, and 1 patient was diagnosed as having non-SCLC with a neuroendocrine morphology. Subgroup analyses were shown in the Table. Conclusions: Combination chemotherapy with IP was active in pts with advanced LCNEC, but the RR and the overall survival period in pts with LCNEC seemed to be inferior to those in pts with SCLC. Clinical trial information: UMIN000004796. Central pathological review (nⴝ40) LCNEC (nⴝ30) SCLC (nⴝ10)

P

RR (%) (95%CI) 46.7 (28.3-65.7) 80 (44.4-97.5) 0.0823 Median PFS (months) (95%CI) 5.8 (3.8-7.8) 6.2 (5.2-7.2) 0.382 MST (months) (95%CI) 12.6 (9.3-16.0) 17.3 (11.2-23.3) 0.047

8039


An analysis of the prevalence of HER2 and KRAS mutations, and ALK rearrangements and clinical outcomes in Cancer and Leukemia Group B [CALGB (Alliance)] trial 30406 in advanced non-small cell lung cancer (NSCLC). Presenting Author: Tom Stinchcombe, The University of North Carolina at Chapel Hill, Chapel Hill, NC Background: CALGB (Alliance) 30406 was a randomized phase II trial that investigated erlotinib alone or in combination with carboplatin and paclitaxel in patients (pts) with a never or light smoking history with advanced NSCLC. Tissue collection was mandatory. Methods: Between August 2005 and April 2009 188 pts were enrolled. Tumor specimens were assessed using ALK immunohistiochemistry (IHC; clone D5F3; Cell Signaling); KRAS and HER2 mutations were tested. Results: The rate of mutations was: KRAS 10% (17/164), HER2 2% (3/164), and ALK ⫹ 7% (8/114). Given the small numbers of KRAS, HER2 and ALK positives, the analysis combines data from both arms. Pts with ALK ⫹ compared to ALK- NSCLC had an inferior ORR and PFS (Table). No statistically significant differences in ORR, PFS, OS between pts with KRAS or HER2 mutant and wild-type NSCLC were observed. In multivariate analysis pts with ALK⫹ compared to ALK- tumors experienced a statistically significant worse PFS (HR⫽2.67, p⫽0.0114) but not OS (HR⫽1.48, p⫽0.3217). One pt was identified as having an EGFR exon 21 mutation and ALK ⫹; the pt experienced a best response of progressive disease, a PFS of 2.9 months, and OS of 17.4 months. Conclusions: (1) Pts with ALK⫹ compared to ALK- NSCLC have a lower ORR, worse PFS, but not OS with erlotinib alone or with carboplatin and paclitaxel. (2) The prevalence ALK⫹, KRAS and HER2 mutations observed was 7%, 10% and 2%, respectively. Clinical trial information: 00126581.

ALK (nⴝ114) Positive (nⴝ8) Negative (nⴝ106) 2-sided p value* KRAS (nⴝ164) MUT (nⴝ17) WT (nⴝ147) 2-sided p value* HER2 (nⴝ164) MUT (nⴝ3) WT (nⴝ161) 2-sided p value*

ORR (%) (95% CI)

PFS (months) (95% CI)

OS (months) (95% CI)

0 (0 – 36.9) 38.7 (29.4 – 48.7) 0.0491

2.2 (0.6 – 6.6) 6.3 (5.0 – 8.0) 0.0039

12.9 (0.9 – 26.1) 20.7 (15.0 – 27.8) 0.1948

29.4 (10.3 – 56.0) 42.2 (34.1 – 50.6) 0.4359

4.0 (2.8 – 12.4) 6.7 (5.3 – 8.0) 0.1318

18.0 (7.7 – 39.9) 23.8 (18.7 – 27.9) 0.4615

0 (0 – 70.8) 41.6 (33.9 – 49.6) 0.2706

4.2 (1.2 – 9.7) 6.6 (5.0 – 7.4) 0.2732

17.5 (2.9 – 27.8) 23.7 (18.4 – 27.8) 0.1911

* P values of testing ORR difference between positive vs. negative/MUT vs. WT are from Fisher’s exact tests, while those for PFS and OS are from log-rank tests.


496s 8040

Lung Cancer—Non-Small Cell Metastatic General Poster Session (Board #32D), Sat, 8:00 AM-11:45 AM

Clinical trial risk reduction in non-small cell lung cancer though the use of biomarkers and receptor-targeted therapies. Presenting Author: Adam Falconi, Department of Pharmacy, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada Background: We analyzed the risk of clinical trial failure duringnon-small cell lung cancer (NSCLC) drug development between 1998 and 2012. Methods: NSCLC drug development was investigated using trial disclosures from publically available resources. Compounds were excluded from the analysis if they began phase I clinical testing before 1998 and if they did not use treatment relevant endpoints. Analysis was conducted in regards to treatment indication, compound classification and mechanism of action. Costs of clinical drug development for advanced NSCLC were calculated using industry data and assumptions, a 9% yearly discount rate and assuming a clinical trial length of 2.5 years for phase I trials, 4 years for phase II trials, 5 years for phase III trials and an average of 5 phase I trials, 7 phase II trials, and 4 phase III trials per approved drug. All funding costs are in US dollars (USD). Results: 2,407 clinical trials met search criteria. 676 trials and 199 unique compounds met our inclusion criteria. The likelihood, or cumulative clinical trial success rate, that a new drug would pass all phases of clinical testing and be approved was found to be 11%, which is less than the expected industry aggregate rates (16.5%). The success of phase III trials was found to be the biggest obstacle for drug approval with a success rate of only 28%. Biomarker-guided targeted therapies (with a success rate of 62%) and receptor targeted therapies (with a success rate of 31%) were found to have the highest likelihood of success in clinical trials. The risk-adjusted cost for NSCLC clinical drug development was calculated to be 1.89 billion US dollars. Use of biomarkers decreased drug development cost by 26% to 1.4 billion US dollars. Potential savings may be even higher if fewer clinical trials are required for successful development. Conclusions: Physicians that enroll patients in NSCLC trials should prioritize their participation in clinical trial programs that involve either a biomarker or receptor targeted therapy, which appear to carry the best chances for a successful treatment response. Given the high adjusted cost of clinical testing alone in NSCLC, efforts to mitigate the risk of trial failure need to explore these factors more fully.

8042


A phase II trial comparing pemetrexed with gefitinib as the second-line treatment of nonsquamous NSCLC patients with wild-type EGFR (CTONG0806). Presenting Author: Jinji Yang, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China Background: Pemetrexed or gefitinib is one of the standard second-line treatments for advanced non-squamousNSCLC in East Asia. The CTONG 0806 a multi-center, randomized, controlled, open-label phase II trial was designed to explore the efficacy of pemetrexed versus gefitinib as the second-line treatment in advanced NSCLC patients without EGFR mutation. Methods: The patients with locally advanced or metastatic, nonsquamous NSCLC previously treated with platinum-based chemotherapy and no EGFR mutation in exons 18-21 were enrolled. Patients were 1:1 randomized to receive either gefitinib 250 mg per oral every day (G arm) or pemetrexed 500 mg/m2 iv day 1 with vitamin B12 and folic acid supplement every 21 days (P arm) until disease progression, unacceptable toxicity, or discontinuation of treatment due to other reason. The primary endpoint was progression-free survival (PFS). The secondary endpoints were 4-month and 6-month progression-free survival rate, overall survival (OS), objective response rate (ORR), quality of life using the FACT-L questionnaire and safety, EGFR and K-ras mutation status were evaluated and correlated with outcomes. Results: From Feb. 2009 to Aug. 2012, 157 evaluable patients were randomized (81 cases in G arm and 76 in P arm). Baseline age, gender, and ECOG performance status were balanced between arms. The primary endpoint of PFS was met with 1.6 months for G arm versus 4.8 months for P arm, the HR is 0.51 (95% CI 0.36~0.73, P⬍0.001). Overall response rates were 14.7 % and 13.3 % (P⫽0.814) and DCR were 32.0% and 61.3% (P⬍0.001) for G arm and P arm, respectively. OS data were not yet mature. More skin rash and diarrhoea were seen in G arm, but more fatigue and ALT increased in P arm. CTCAE grade 3 or 4 of AEs was 12.3% in G arm and 32.9% in P arm (p⫽0.002). The further analyses of efficacy evaluated by IRR and biomarkers analysis will be presented on the ground. Conclusions: CTONG0806 is the first trial to show significant improvements in PFS and DCR with pemetrexed compared with gefitinib in second-line setting for advanced NSCLC with EGFR wild type. Patients with EGFR wild type did not benefit from EGFR TKI gefitinb in second-line setting. Clinical trial information: NCT00891579.

8041


Effect of primary tumor size in patients with metastatic non-small cell lung cancer (NSCLC). Presenting Author: Bing Xia, Yale School of Medicine, New Haven, CT Background: Primary tumor size is a known prognostic factor for patients with early stage NSCLC treated with either surgery or radiation therapy. Although tumor volume has been associated with outcomes in patients with metastatic disease, it is labor intensive and rarely reported outside of a clinical trial. Since the primary tumor size is more commonly described, we evaluated its prognostic impact in patients with metastatic disease. Methods: The SEER was searched for patients with stage M1b NSCLC, with known tumor (T), lymph node (N) status, and diagnosed between 2004 and 2008. Patients with T0 and malignant pleural effusion were excluded. Tumor size is reported as the largest diameter and was subdivided into S1 (0.1-3 cm), S2 (3.1-5 cm), S3 (5.1-7 cm) and S4 (7.1-20 cm), roughly corresponding to T1, T2a, T2b and T3. Overall survival (OS) was estimated by the Kaplan-Meier method, while the hazard ratios (HR) were estimated and compared by Cox proportional hazard models. Results: Tumor size was available in 21879 (84.4%) out of 25919 patients with complete TNM staging. The frequencies of S1, S2, S3 and S4 were 33.4%, 33.8%, 17.1% and 13.7% respectively. 1-year OS rates for S1 to S4 were 34%, 27.9%, 24.0% and 19.0% respectively. Primary tumor size was an independent predictor for OS after adjustment for age, gender, race, histology, T and N status (p ⬍ 0.0001). The decreased OS from each subsequent category of tumor size was statistically significant in both univariate and multivariable analyses (Table). Conclusions: Primary tumor size is readily available and represents a significant prognostic factor for survival in patients with stage M1b NSCLC, independently of T and N status. Univariate analysis Hazard ratio (95% CI), p value Comparisons S1 vs S2 S2 vs S3 S3 vs S4 S1 vs S4

8043

0.84 (0.81-0.87), p ⬍ 0.0001 0.89 (0.85-0.93) p ⬍ 0.0001 0.85 (0.81-0.90), p ⬍ 0.0001 0.65 (0.62-0.67), p ⬍ 0.0001

Multivariable analysis Hazard ratio (95% CI), p value 0.89 (0.85-0.93), p ⬍ 0.0001 0.90 (0.87-0.94), p ⬍ 0.0001 0.87 (0.83-0.92), p ⬍ 0.0001 0.70 (0.67-0.74), p ⬍ 0.0001


Prospective randomised phase II trial of oral vinorelbine (NVBo) and cisplatin (P) or pemetrexed (Pem) and P in first-line metastatic or locally advanced non-small cell lung cancer (M or LA NSCLC) with nonsquamous (Non SCC) histological type. NAVoTRIAL01: Final results. Presenting Author: Jaafar Bennouna, Institut de Cancerologie de l’Ouest, Nantes, France Background: NVBo⫹P is considered as a standard treatment in M or LA NSCLC. The recent approval of Pem⫹P as front line chemotherapy (CT) for non SCC demonstrates that today, histology could become a “new guidance” to treat patients (pts). The importance of histological types was highlighted in a phase III trial (Scagliotti. JCO 2008). Moreover, the higher chemosensitivity of non SCC is recognised and reported with other chemotherapies (Ardizzoni. JNCI 2007). In GLOB 3 study, NVBo⫹P also showed better survival in adenocarcinoma (11.7m) than in SCC (8.9m) (Tan. Ann Oncol. 2009). This trial was set up to assess the efficacy of NVBo⫹P (Arm A) and Pem⫹P (Arm B) for pts with Non SCC histological type, evaluated in terms of Disease Control Rate (DCR) (SD⫹PR⫹CR). Methods: Pts were randomised to receive q3w NVBo 80 mg/m² D1D8 (60 at Cycle 1) ⫹ P 80 mg/m² D1 (Arm A) or Pem 500 mg/m² ⫹ P 75 mg/m² D1 (Arm B). After 4 cycles of combination, pts with DCR received single agent NVBo (Arm A) or PEM (Arm B) as maintenance until progression or toxicity. Pts were randomised on a 2/1 basis and stratified according to stage (IIIB IV - relapse), non SCC confirmed by histology or cytology, gender, smoking status and centre. Results: From 11/09 to 02/11, 153 pts were randomised to Arm A (102 pts) or Arm B (51 pts). DCR after combination and maintenance was 75.0% (95% CI, 65.3 to 83.1) in Arm A and 76.5% (95% CI, 62.5 to 87.2) in Arm B. Median PFS was 4.2 (95% CI, 3.6 to 4.7) and 4.3 months (95% CI, 3.8 to 5.6) in Arm A and Arm B, respectively. Median OS was 10.2 months (95% CI, 7.8 to 11.9) and 10.8 months (95% CI, 7.0 to16.4) in Arm A and Arm B, respectively. During the combination period grade 3/4 neutropenia was 44.0% in Arm A and 18.3% in Arm B but febrile neutropenia was 2% in both arms; grade 3/4 thrombopenia was 0% and 6% in Arm A and Arm B, respectively. Conclusions: Even if the current results should be confirmed in a phase III study, the choice of a platinum-based doublet with oral vinorelbine as front-line chemotherapy could be a useful alternative in non SCC. Clinical trial information: 2009-012001-19.




Serum and tumor biomarkers to predict outcome in the eLung trial, a multicenter, randomized phase IIb study of standard platinum doublets (PD) plus cetuximab (CET) as first-line treatment of advanced non-small cell lung cancer (NSCLC). Presenting Author: Paul J. E. Miller, ACORN Research, Memphis, TN Background: The eLung trial randomized chemotherapy naïve advanced NSCLC patients (pts) to 1 of 3 PD and concurrent CET followed by CET maintenance until progression, stratified by non-squamous (NSQ) and squamous (SQ) histology. Primary outcome results were reported (ESMO, Schwartzberg 2012). Pre-treatment tumor tissue and serum samples were prospectively collected. Methods: Tumor samples were analyzed for H-score (graded 0-300), calculated by the intensity and number of cells expressing EGFR by IHC; a score of ⬎200 was considered high (Pirker 2011). Mutation analysis of EGFR and KRAS was performed by PCR. The VeriStrat multivariate serum protein test was performed on available serum samples assigning good and poor classifications (Taguchi 2007). Results: Of 601 pts enrolled on the trial, 378 consented to blood/tissue or both. The available tissue (N⫽210) and serum subsets (N⫽203) had similar demographics and survival outcome to the full trial set. Results for biomarkers/ cohorts in the Table demonstrate that VeriStrat was highly significant for OS in all pts and NSQ, while H-score and EGFR mutations were significant only in NSQ. In adjusted Cox analysis VeriStrat was an independent predictor for OS, HR⫽.665, p⫽.026; H-score was not. Conclusions: VeriStrat classification significantly correlated with survival outcome in all pts treated with PD and CET and the NSQ subset; tissue biomarkers correlated in NSQ only. Further evaluation of these markers is warranted. Biomarker All patients H-score high H-score low VeriStrat good VeriStrat poor NSQ subgroup H-score high H-score low VeriStrat good VeriStrat poor K-RAS mutated K-RAS WT EGFR mutated EGFR WT SQ subgroup H-score high H-score low VeriStrat good VeriStrat poor

8046

N

OS, median, months

OS, 95% CI, months

Log-rank p

40 170 142 61

10.0 9.4 10.9 6.4

5.3-16.2 7.5-10.7 9.5-12.9 4.0-9.0

.334

17 108 99 28 42 88 12 117

30.6 9.6 11.4 6.4 11.1 10.5 30.6 10.4

6.2-35.1 6.4-11.7 9.0-14.9 3.6-12.1 6.4-20.0 7.0-13.2 12.8-undef. 6.3-11.7

23 62 43 53

5.6 8.3 10.0 6.4

3.6-9.1 6.0-10.7 7.1-12.9 3.6-9.0

⬍.0001 .033 .001 .998 .010 .322 .059


8045

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Retrospective evaluation of RET biomarker status and outcome to vandetanib in four phase III randomized NSCLC trials. Presenting Author: Adam Platt, AstraZeneca, Macclesfield, United Kingdom Background: The prevalence of the tumorigenic KIF5B:RET fusion gene in NSCLC tumors has been estimated at 0.2– 6% (Jiu et al 2012; Lipson et al 2012). We retrospectively analyzed tumor samples from 4 Phase III NSCLC trials of vandetanib, a TKI that selectively targets RET, VEGFR and EGFR signaling, to determine the prevalence of RET fusions and other RET biomarkers, and any potential association with outcome to vandetanib (V). Methods: The studies evaluated were ZODIAC (NCT00312377; docetaxel ⫾ V 100mg), ZEAL (NCT00418886; pemetrexed ⫾ V 100mg), ZEPHYR (NCT00404924; V 300mg vs placebo) and ZEST (NCT00364351; V 300mg vs erlotinib). RET biomarkers evaluated included RET fusions (including KIF5B:RET) and RET gene copy number (assessed by a 4-probe FISH assay), as well as RET protein expression (by IHC). Results: Of 4089 patients randomized across the 4 studies, 1291 and 1234 had tumor samples available for FISH and IHC analysis, respectively, with evaluable data obtained for 944 and 1102. RET fusions (in ⬎10% of tumor cells) were detected in 7 of 944 samples (vandetanib, n⫽3; comparator, n⫽4), at a prevalence of 0.7% (95% CI, 0.3–1.5%). None of the 3 vandetanibtreated RET fusion-positive patients had an objective RECIST response, although there was radiologic evidence of tumor shrinkage in 2. Overall, 2.8% (n⫽26) of samples had RET amplification (innumerable RET clusters, or ⱖ7 copies in ⬎10% tumor cells), 8.1% (n⫽76) had lower RET gene copy number gain (4 – 6 copies in ⱖ40% tumor cells) and 8.3% (n⫽92) were RET expression positive (signal intensity ⫹⫹ or ⫹⫹⫹ in ⬎10% of tumor cells). There was no difference in ORR between vandetanib and comparator for the RET amplification-positive subset (both 8.3% [1/12]), the RET copy number gain subset (9.8% [4/41] vs 9.1% [3/33], respectively) or the RET protein expression-positive subset (15.2% [7/46] and 13.6% [6/44], respectively). Conclusions: The prevalence of RET fusions was estimated at 0.7%. There were too few vandetanib-treated patients with RET fusions to make any firm conclusion regarding association with efficacy. Evidence from the other RET biomarkers tested suggested that these do not infer a differential advantage in patients treated with vandetanib. Clinical trial information: NCT00312377; NCT00418886; NCT00404924.

8047


Association between baseline tumor dimensions and survival in advanced non-small cell lung cancer (NSCLC). Presenting Author: Daniel H. Ahn, The University of Texas Southwestern Medical Center, Dallas, TX

Occurrence of HER2 amplification in EGFR-mutant lung adenocarcinoma with acquired resistence to EGFR-TKIs. Presenting Author: Giuseppe Altavilla, Medical Oncology University of Messina, Messina, Italy

Background: It is not known to what extent radiographic tumor burden is associated with survival in patients with advanced NSCLC. The purpose of this study is to assess whether baseline tumor dimensions are associated with patient survival in advanced NSCLC. Methods: Data were derived from the Eastern Cooperative Oncology Group (ECOG) 4599 trial of carboplatinpaclitaxel (CP) ⫾ bevacizumab (B) for advanced nonsquamous NSCLC. Associations between the Response Evaluation Criteria in Solid Tumors (RECIST) baseline sum longest diameter (BSLD) and progression-free survival (PFS) and overall survival (OS) were evaluated using univariate and multivariable Cox regression models. Results: 759 of 850 patients (89%) enrolled in E4599 had measurable disease and were included in the analysis. 76% of patients were age ⬍ 70 years, 46% were female, and 86% were white. Median number of target lesions was 2; median BSLD was 7.5 cm. In univariate Cox models, BSLD predicted OS (HR 1.41; P⬍0.001) and had a trend toward association with PFS (HR 1.14; P⫽0.08). OS was 12.6 months (mos) for BSLD ⬍ 7.5 cm, compared to 9.5 mos for BSLD ⱖ 7.5 cm. This association persisted across both treatment groups (CP: median OS 11.5 vs 8.5 mos; CP⫹B: median OS 14.1 vs 10.7 mos), when BSLD was categorized according to quartile (median OS: 13.3, 11.5, 11.6, and 8.3 mos; P⬍0.001), and in a multivariable model controlling for prognostic factors and the presence and site of extrathoracic disease (OS HR 1.24; P⫽0.01). Conclusions: Radiographic disease burden, as determined by RECIST BSLD, is associated with survival in the E4599 trial. If validated in other populations, this parameter merits consideration in the stratification of patients for clinical trials and may provide important prognostic information for patients and clinicians.

Background: Patients with EGFR-mutant lung adenocarcinoma develop progression of disease on TKIs therapy after a median of 12 months;this acquired resistance is mainly due to a secondary mutation in EGFR (T790 M) in about 50% of patients, amplification of MET in 15%, PIK3CA mutations in 5%, an unknown mechanism in almost 30% and a SCLC transformation in some pts. Recently, Takezawa and colleagues pointed out that HER2 amplification is a mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers without EGFR T790M mutation. To aid in identification and treatment of these patients we examined a cohort of patients whose cancers were assessed with tumor biopsies at multiple times before and after their treatment with TKIs. Methods: 41 lung adenocarcinomas pts. (20 male, 21 female, median age 55 years) with EGFR mutations at 19 or 21 exons received TKIs as first line of treatment. 31 pts. (75%) showed a clinical response and relapsed after a mTTP of 12 months. At the time of relapse a new biopsy was performed, histologic samples were reviewed to re-confirm the diagnosis, EGFR, MET and HER-2 amplification were identified by FISH, while EGFR mutations have been tested by DNA sequencing. Results: At the time that drug resistence was acquired all 31 pts. retained their original activating EGFR mutations, 16 pts. developed EGFR T790M resistance mutation with pronunced EGFR amplification in 5, 4 pts. developed MET amplification, 3 pts. were found to have a diagnosis of small cell lung cancer. HER2 amplification was observed in four pts. (13%), with dramatic progression and a median OS of 5 months after treatment with CDDP ⫹ pemetrexed. Notably all 4 cases were EGFR T790M negative. Conclusions: Among pts. with acquired resistence to EGFR TKIs the presence of HER2 amplification defines a clinical subset with a more adverse prognosis and rapid progression. Interestingly, recent data suggest that afatinib combined with cetuximab could have promising activity in pts. with acquired resistance due to HER2 amplification.


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Exploratory analysis of angiotensin converting enzyme (ACE) and aldosterone (Ald) serum levels as prognostic and predictive biomarkers on the NCIC CTG BR24 trial. Presenting Author: Jair Bar, Sheba Medical Center, Tel HaShomer, Israel

Predictors of survival for younger patients (pts) less than 50 years of age with non-small cell lung cancer (NSCLC): A California Cancer Registry (CCR) analysis. Presenting Author: Matthew Stephen Lara, Davis Senior HS and UC Davis Comprehensive Cancer Center, Davis, CA

Background: Benefit from angiogenesis inhibitors (AI) has been linked to high blood pressure. One of the main determinants of blood pressure is the renin-angiotensin axis. We undertook an exploratory, retrospective analysis of ACE and Ald serum levels on specimens banked during the conduct of the BR24 study. The aim was to evaluate these markers for their prognostic significance and their predictive value regarding Cediranib (Ced) treatment. Methods: The NCIC CTG BR24 study randomized advanced nonsmall cell lung cancer patients (pts) to carboplatin and paclitaxel (CP) ⫹/Ced. ACE and Ald serum levels were retrospectively tested on baseline samples using commercial ELISA kits. A graphic method, differentiating treatment effect by the range of marker, was used to determine cutoff points (JCO 2010, 28: 5247). Exploratory analyses were performed to correlate biomarkers levels with pts characteristics and overall survival (OS). Association between categorical variables was assessed by Chisquare test or Fisher’s exact test; time to event correlation with biomarkers was tested using a Cox regression model. Potential confounding factors including medications were integrated into the statistical model. Results: Biomarker data was available in 226 of 296 randomized pts. The tested pts vs. all the randomized pts were more likely to have a lower performance status (PS, p⫽0.03), a normal LDH (p⫽0.05) and to be ever-smokers (p⫽0.015). The determined cutoffs were ACE: 115ng/ml and Ald: 250 pg/ml. High ACE was associated with a better PS (p⫽0.03). High ACE levels were prognostic for longer OS (adjusted HR 0.52 [95%C.I. 0.290.92], p⫽0.025). High ACE pts had no OS benefit (HR 1.27 [95% C.I. 0.78 –2.08], p⫽0.34), while low ACE predicted OS benefit from the addition of Ced to CP (HR 0.64 [95%CI 0.42-0.97], p⫽0.03). Interaction p value⫽0.03; this remained significant after adjustment in multivariate analyses. Ald levels were neither prognostic nor predictive. Conclusions: This exploratory analysis suggests high ACE serum levels maybe prognostic for better OS, while low ACE may predict benefit from Ced when added to CP.

Background: Lung cancer is often seen in older pts, with a median age at diagnosis of 70 years (yrs). Epidemiology and outcomes are reportedly different among younger NSCLC pts (⬍ 50 yrs). We hypothesized that these pts have longer cause-specific survival (CSS) and that baseline clinical features prognostic for CSS would be identified. Methods: NSCLC pts in the CCR diagnosed between 1/98 through 12/09 were included. The primary outcome was CSS. Hazard ratios (HR) for CSS were calculated using Cox Proportional Hazards (PH) models for all ages & for pts ⬍50 years, adjusted for baseline variables. Results: We identified 132,671 lung cancer pts: 114,451 (86.3%) had NSCLC. 6,389 (5.6%) were ⬍ 50 yrs (median, 46 yrs). Demographics: White (3,557, 56%); Histology: AdenoCA (AC) (3,406, 53%), Squamous (781, 12%), BAC (291, 4.6%); Stage IV (3,655, 57%). Fewer pts ⬍ 50 yrs were diagnosed in later yrs: from 37% in ‘98-’01 to 29% in ‘06-‘09. Results of Cox PH models for all ages and ⬍ 50 years are shown. Conclusions: The relative proportion of pts ⬍ 50 yrs has declined by 22% over the past decade. Age ⬍ 50 years was an independent predictor of improved CSS (HR 0.83, p⬍0.001). In younger pts, AC histology was not prognostic for CSS (versus squamous) despite known differences in clinical and biologic behavior between subtypes.Importantly, clinical variables strongly prognostic for CSS were identified in pts ⬍ 50 yrs. All pts Selected clinical variables* Female Age < 50 Rural Stage II III IV Primary treatment Surgery ChemoRT Year of diagnosis 2002-05 2006-09 Socioeconomic status (SES) Mid (3) High (4,5) Histology AC NOS BAC Large cell

Pts < 50 yrs of age

HR

P value

HR

P value

0.86 0.83 0.99

⬍0.001 ⬍0.001 0.375

0.84

⬍0.001

1.09

0.166

1.75 2.24 3.51

⬍0.001 ⬍0.001 ⬍0.001

1.94 2.49 4.37

⬍0.001 ⬍0.001 ⬍0.001

0.22 0.53

⬍0.001 ⬍0.001

0.23 0.53

⬍0.001 ⬍0.001

0.91 0.82

⬍0.001 ⬍0.001

0.89 0.73

⬍0.001 ⬍0.001

0.96 0.90

⬍0.001 ⬍0.001

0.95 0.83

0.173 ⬍0.001

0.93 1.03 0.66 1.1

⬍0.001 0.0049 ⬍0.001 ⬍0.001

0.99 1.04 0.86 1.09

0.788 0.497 0.112 0.312

N/A

* Referent groups: Male, Age ⬎/⫽ 50, Urban, Stage I, No treatment, 1998-2001, Lowest SES (1,2), and Squamous.

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Success and failure rates of tumor genotyping techniques in routine pathologic samples with non-small cell lung cancer. Presenting Author: Paul A VanderLaan, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA Background: Identification of somatic molecular alterrations in NSCLC has become evidence-based practice. The success and failure rate of using commercially-available tumor genotyping techniques in routine day-to-day NSCLC pathology samples is not well described. We sought to evaluate the success and failure rate of EGFR mutation, KRAS mutation and ALK FISH. Methods: Clinicopathologic data, tumor genotype success and failure rates were retrospectively compiled and analyzed from 381 patient-tumor samples sent for routine tumor genotype in clinical practice. Results: Mean age was 65, 61.2% women, 75.9% white, 27.8% never-smokers, 73.8% had advanced NSCLC and 86.1% adenocarcinoma histology. Tumor tissue was obtained from surgical biopsies in 48.8%, core biopsies in 17.9% and as cell blocks from aspirates/fluid in 33.3%. Anatomic sites for tissue collection included lung (49.3%), lymph nodes (22.3%), pleura (11.8%), bone (6.0%), brain (6.0%), among others. In the 207 tumors in which the three tests were ordered concurrently, the success rate for EGFR was 92.3%, for KRAS 91.8% and for ALK FISH 89.9%. The highest failure rates were observed when the tissue was obtained from core biopsies (30.8%, 20.5% and 30.8% for EGFR, KRAS and ALK tests, respectively) and bone specimens (23.1%, 15.4% and 23.1% for EGFR, KRAS and ALK tests, respectively). In specimens obtained from bone, the failure rate was significantly higher in non-surgical than surgical specimens (40% vs 0%, p⫽0.024 for EGFR) and decalcified than non-decalcified samples (60% vs 5.5%, p⫽0.021 for EGFR). Conclusions: The success rate of multiple tumor genomic analyses techniques for EGFR, KRAS and ALK gene abnormalities using routine lung cancer tissue samples was ~90%. The highest failure rates occurred in tumors obtained from core biopsies and in bone samples from core biopsies with decalcification; specimens that may need to be scrutinized before submission to molecular studies. Tumor genotype techniques are feasible in most other samples obtained with current tumor acquisition methods, and therefore expansion of routine tumor genotype into the care of patients with NSCLC may not require special tissue acquisition or manipulation.

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A randomized open-label phase II study evaluating antitumor activity of the survivin antisense oligonucleotide LY2181308 (LY) in combination with docetaxel (DO) for second-line treatment of patients with non-small cell lung cancer (NSCLC) using change in tumor size (CTS). Presenting Author: Denis Charles Talbot, Department of Oncology, Oxford University Hospitals Trust, Churchill Hospital, Oxford, United Kingdom Background: Resistance to chemotherapy in progressive NSCLC is associated with overexpression of antiapoptotic proteins including survivin. Down-regulation of survivin can sensitize NSCLC to DO in vitro and in xenograft studies. On the basis of preclinical/phase I results we examined antitumor activity of DO⫹LY compared with DO alone. Methods: Key eligibility criteria: ECOG PS 0-1, stage IIIB/IV NSCLC all histologies, progression after first-line platinum regimen. Patients randomized (N⫽180) 2:1 to receive DO⫹LY (LY 750 mg IV loading ⫻3, Q1W maintenance) or DO alone (75 mg/m2 D1Q3W) until progression/toxicities. Antitumor activity was compared using CTS from baseline to end of cycle (C) 2 in each arm. This analysis, which uses tumor measurements as a continuous variable rather than a categorical endpoint based on RECIST, increases statistical efficiency and enables early assessment of clinical benefit. Secondary objectives included assessment of toxicity, PK, PFS and OS. Results: 114 patients received study drug and were included in the analyses. Baseline patient demographics were similar. No statistically significant difference in mean CTS ratio at C2 or in PFS was observed between the 2 arms: CTS was 1.07 with LY⫹DO (SD, 0.28) and 1.04 with DO (SD, 0.28); median PFS was 2.83 mo (95% CI, 1.84 –3.65) with LY⫹DO and 3.35 mo (95% CI, 2.69 – 4.57) with DO (log-rank p⫽0.191). However, Cox regression revealed CTS to be a statistically significant factor for PFS: decreased CTS was associated with increased PFS (HR 0.45; 95% CI, 0.30 – 0.68, p⫽0.0001). Median OS was 7.9 mo (90% CI, 6.6 –9.7) with LY⫹DO and 8.8 mo (90% CI, 5.7–13.8) with DO (log-rank p⫽0.481). There were no differences in toxicities or other secondary parameters. Incidence of grade III/IV toxicities was similar in both arms and was consistent with the known profile of LY⫹DO as was the PK profile. Conclusions: Addition of LY to DO did not improve the antitumor activity of DO. CTS appears to be a useful endpoint in phase II studies and should be considered further as an endpoint for early decision-making. Clinical trial information: NCT01107444.




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Molecular marker assessments for epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC) and histoscore (H-score) in the phase III SELECT trial. Presenting Author: Edward S. Kim, Levine Cancer Institute, Carolinas Healthcare System, Charlotte, NC

Nimotuzumab plus chemotherapy versus chemotherapy alone in advanced non-small cell lung cancer: A phase II, open-label, multicenter, randomized study. Presenting Author: Kumar Prabhash, Tata Memorial Hospital, Mumbai, India

Background: SELECT was a phase III study that investigated whether the addition of cetuximab (C) to pemetrexed (P) improved outcome in previously treated patients (pts) with recurrent or progressive non-small cell lung cancer (NSCLC). Clinical results have been reported previously and demonstrated that adding C to P did not improve progression-free survival (PFS) or overall survival (OS). H-score has been reported to be a potential predictor of outcome for C therapy. Prespecified biomarker analyses, including EGFR IHC and H-score, are reported here. Methods: EGFRexpression in tumor tissue was not required for eligibility; however, tissue was collected and analyzed for EGFR expression by IHC using standard methods. In addition, H-score evaluation was performed by trained central pathologists and correlated with clinical outcome using a predefined cutoff for “low” and “high” of ⬍200 and ⱖ200, respectively. Results: A total of 449 (IHC) and 406 (H-score) pt specimens were evaluable. Demographics for pts with tissue available for EGFR analysis were similar to the overall population. For IHC⫹ pts (n⫽396), median PFS for C⫹P was 3.02 months (95% CI, 2.76 –3.45) compared with 2.99 months (95% CI, 2.63– 4.14) for P (HR, 1.02 [95% CI, 0.83–1.24]; p⫽.86). For pts with low H-score (N⫽99 [C⫹P] and N⫽111 [P]), median PFS was 2.7 months (95% CI, 1.8 –3.2) with C⫹P and 3.1 months (95% CI, 2.6 – 4.1) with P (HR, 1.11 [95% CI, 0.84 –1.46]; P⫽.48); median OS was 6.7 months (95% CI, 5.3– 8.6) with C⫹P and 6.6 months (95% CI, 4.7–9.2) with P (HR, 0.96 [95% CI, 0.72–1.27]; P⫽.76). Among pts with high H-scores (N⫽101 [C⫹P] and N⫽ 95 [P]), median PFS was 3.2 months (95% CI, 2.7– 4.6) with C⫹P and 3.7 months (95% CI, 1.7– 4.5) with P (HR, 1.02 [95% CI, 0.77–1.37]; P⫽.86); median OS was 7.7 months (95% CI, 6.5–10.9) with C⫹P and 8.0 months (95% CI, 7.0 –9.1) with P (HR, 1.17 [95% CI, 0.86 –1.57]; P⫽.32). Conclusions: EGFR H-score was not predictive of benefit for the addition of C to P in this population of pts with NSCLC. There was also no treatment effect in the IHC⫹ group. Clinical trial information: NCT00095199.

Background: To evaluate the safety and efficacy of nimotuzumab in combination with chemotherapy (docetaxel and carboplatin) versus chemotherapy alone in stage IIIB/IV non-small cell lung cancer (NSCLC) patients. Methods: This multicenter, open-label, phase II study, randomized 110 patients to receive nimotuzumab plus chemotherapy (nimotuzumab group) or chemotherapy alone (control group), and comprised concomitant, maintenance, and follow-up phases. Nimotuzumab (200 mg) was administered once weekly for 13 weeks during the first 2 phases with 4 cycles of chemotherapy; docetaxel (75 mg/m2) and carboplatin (area under the curve [AUC] ⫽ 5 mg/ml*min), every 3 weeks for a maximum of 4 cycles during the concomitant phase. The primary endpoint was objective response rate (ORR; sum of complete response [CR] and partial response [PR]). Secondary endpoints, overall survival (OS), and progression-free survival (PFS) were estimated using Kaplan-Meier method. Efficacy was evaluated on the intent-to-treat (ITT) and efficacy-evaluable (EE) sets. Safety was assessed from adverse events (AEs) and serious adverse events (SAEs) data. Results: ORR was significantly higher in the nimotuzumab group than in the control group in the ITT (54% vs. 34.5%; P⫽0.04) population. CR and PR were achieved in 3.6% and 50% patients, respectively, in the nimotuzumab group, and in 4% and 30.9% patients, respectively, in the control group. No significant differences in median PFS and OS were observed. Safety profiles were comparable between the 2 groups. Conclusions: Nimotuzumab plus chemotherapy significantly improved ORR as compared to chemotherapy alone; the combination was safe and well tolerated in stage IIIB/IV NSCLC patients.

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A comparison of bronchofiberscopic (BFS) washing cytology (BWC) and formalin-fixed paraffin-embedded tissue (PPFE) in the analysis of EGFR mutations in advanced non-small cell lung cancer (NSCLC). Presenting Author: Naoya Hida, Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen’s Hospital, Yokohama, Kanagawa, Japan Background: In the treatment of advanced NSCLC, EGFR mutation status is one of the most predictive factors for the efficacy of EGFR tyrosine kinase inhibitors, and the evaluation of EGFR mutation status using the PPFE has been widely used for this analysis throughout the world. However, whether BWC can be used as an alternative for PPFE in the analysis of EGFR mutations is unknown. The largest study evaluating these 2 methods included only around 20 samples. Therefore, in the current study, we compared the freeze stock solution of BWC with PPFE for the determination of EGFR mutation status in a large sample set. Methods: In diagnostic BFS examinations, after curetting or brushing and biopsy to target lesions, subsequent bronchial washing by saline was performed. Thereafter, the saline fluid in which the forceps were washed and the bronchial washing fluid were mixed in a sterilized tube and were immediately frozen in a -20°C freezer. EGFR mutation testing for both BWC and PPFE was performed using high-sensitivity PCR (BML, PCR-Invader). Results: A total of 440 BFS examinations were performed from Aug 2010 to Nov 2011 in our hospital. The BWCs of 268 suspected cases of lung cancer were successfully obtained. Of these, 51 cases that were pathologically confirmed as adenocarcinoma based on both BWC and PPFE were analyzed in this study. EGFR mutations were identified in 25 cases, while the remaining 26 cases had wild-type EGFR. In 49 of 51 cases, the results of EGFR mutation status were the same for BWC and PPFE, and the concordance rate was 96%. In one case, an exon-18 mutation was detected only by BWC. In another case an exon-21 mutation was detected only by PPFE. In 24 of 25 cases of EGFR mutation, the mutation site was the same in both samples. The kappa coefficient was 0.92. Conclusions: This is the largest genetic study to date demonstrating a head-to-head comparison of BWC and PPFE for the evaluation of EGFR mutations. Both methods showed high reliability and concordance using high-sensitivity PCR. BWC is considered a simple, rapid method and represents an effective alternative for PPFE in EGFR mutation testing.


BIM deletion polymorphism to predict systemic treatment outcome in advanced non-small cell lung cancer. Presenting Author: Jih-hsiang Lee, Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) and chemotherapies are treatments for EGFR mutant non-small cell lung cancer (NSCLC) patients. We explored the predictive factors for progression-free survival (PFS) and overall survival (OS) on first-line EGFR-TKIs and second-line chemotherapies in NSCLC patients. Methods: One hundred and six chemonaïve NSCLC patients who received first line gefitinib in a phase II study were prospectively followed until death. Clinical and molecular biomakers were correlated with PFS and OS. Results: The OS and PFS of first-line gefitinib treatment were 19.4 (95% CI 15.6-23.3) months and 7.4 (95% CI 6.7-8.1) months, respectively. Sixty-nine patients (65%) received subsequent second-line chemotherapy. Median PFS and OS of second-line chemotherapy were 5.7 (95% CI 4.8-6.6) and 15.1 (95% CI 10.5-20.2) months. Bcl-2-like protein 11 (also named as BIM) deletion polymorphism was found in 17 out of 101 (16.8%) patients tested. The median PFS from first-line gefitinib in patients carrying normal BIM and deletion polymorphism were 8.1 months and 3.6 months, respectively (p⬍0.001), and the median OS were 22.1 months and 14.1 months, respectively (p⫽0.041); in 44 patients with common EGFR mutations (del 19 or L858R), the PFS for patients carrying normal BIM and deletion polymorphism were 9.6 months and 7.4 months, respectively (p⫽0.034). A multivariate analysis suggested that BIM deletion polymorphism and EGFR mutational status were independent predictors for gefitinib PFS (hazard ratio 2.83, p⫽0.001, and 0.63, p⫽0.03, respectively). Conclusions: BIM deletion polymorphism predicts shorter PFS in EGFR mutation NSCLC patients treated with first line gefitinib.


500s 8056


8057


Safety and efficacy of nintedanib (BIBF 1120) plus pemetrexed in Japanese patients with advanced or recurrent non-small cell lung cancer (NSCLC): A phase I study. Presenting Author: Haruko Daga, Department of Clinical Oncology, Osaka City General Hospital, Osaka, Japan

Phase II study of metronomic chemotherapy (MC) with bevacizumab (B) in patients (Pts) with advanced (Adv) nonsquamous non-small cell lung cancer (NS-NSCLC). Presenting Author: Carrie Lee Marquette, University of Alabama at Birmingham, Birmingham, AL

Background: Nintedanib (N) is a potent, orally bio-available triple angiokinase inhibitor that targets VEGFRs, PDGFRs and FGFRs, as well as RET and Flt3. The open-label phase I part of this phase I/II study was designed to determine the maximum tolerated dose (MTD) of N when combined with standard-dose pemetrexed (PEM), and to investigate safety and efficacy in Japanese patients (pts) with advanced/recurrent NSCLC. Methods: Eligible pts had histologically/cytologically confirmed stage IIIB/IV or recurrent NSCLC (any histology) after failure of first-line chemotherapy. Pts received PEM 500 mg/m2 iv on day 1 followed by N twice daily (bid) po on days 2–21 every 21 days using a standard 3⫹3 design. N was started at 100 mg bid and escalated to 200 mg bid in 50 mg bid intervals. Pts received ⱖ4 cycles of combination therapy with an option of continuing with single-agent N until disease progression or undue adverse events (AEs). Primary endpoints were MTD, defined as the highest dose at which incidence of dose-limiting toxicities (DLTs) was ⬍33.3%, and safety. DLTs were defined as grade 3 non-hematologic or grade 4 hematologic AEs. Secondary endpoints included objective tumor response and pharmacokinetics (PKs). Results: 18 pts (14 male) were treated: 3 at N 100 mg bid, 6 at N 150 mg bid, and 9 at N 200 mg bid. DLTs were observed in 0/3, 1/6, and 2/9 pts in each cohort, respectively; 2 of these pts had liver enzyme elevations. The MTD for N (plus PEM) was 200 mg bid. The most common drug-related AEs were increased GGT, increased AST, decreased appetite, and diarrhea. Grade 3 AEs included neutropenia (22.2%), increased AST, increased ALT, and lymphopenia (each 11.1%); no pts experienced grade 4/5 AEs. Two pts (11.1%) achieved a partial response and 12 (66.7%) had stable disease. At the MTD, N exposure after PEM administration was similar to that seen with N monotherapy in a previous Japanese study. Co-administration of N did not affect the PKs of PEM. Conclusions: The combination of N and standard-dose PEM had a manageable safety profile and showed promising signs of efficacy in previously treated Japanese pts with advanced/recurrent NSCLC. As in Caucasian pts, the MTD of N was 200 mg bid. Clinical trial information: NCT00979576.

Background: Targeting vascular endothelial growth factor (VEGF) has shown modest improvement in pts with adv NS-NSCLC. The incorporation into MC regimens of antiangiogenic agents has been shown to further enhance efficacy in preclinical models. The goal of this pilot study was to achieve a 30% improvement in the 6.4 months (M) progression-free survival (PFS) observed in ECOG 4599. Methods: Untreated pts with stage 4 NS-NSCLC, PS 0-1 and measurable disease were treated with a 4-week (W) cycle of paclitaxel (80mg/m2 D1, 8, 15), gemcitabine (G) (200-300mg/m2 D1, 8, 15) and B (10mg/m2 D1, 15) for 6 cycles. Pts without progressive disease or significant toxicity (Tx) received maintenance B every 2 w. Primary endpoint:PFS. Secondary endpoints: ORR, OS, Tx and biomarker (BM) correlation. Blood samples for angiogenic (VEGF, sVEGFR2, BFGF, PLGF, PDGF␣, Ang-2, IL-8, E-Selectin, ICAM-1, TGF␤-1, SDF-1␣, endocan) and antiangiogenic (Thrombospondin-1, Ang-1) bm were collected at different intervals in 21 pts. Response assessment (RECIST) was performed every 8 w. Results: 33 evaluable pts were enrolled. Pt characteristics: median age 59 yrs (37-76), 60% female, 70% ⬎ 5% weight loss, 24% never/light smokers, 48% genetic testing (mut EGFR-4; ALK(⫹)-1), and 9% brain mets. Efficacy parameters are shown in the table. 24 pts had an OR (CR-1, PR-23) and 6 pts had stable disease. No significant differences were observed in the efficacy parameters between former smokers vs. never/light smokers. Worst hematologic and non-hematologic Tx: gr 3 neutropenia (N⫽1); gr 3/4 nausea/vomiting (N⫽1); gr 3/4 fatigue (N⫽2); ischemic colitis (N⫽1); cerebral ischemia (N⫽1); gr 3/4 pneumonitis [related to G] (N⫽2); gr 3/4 proteinuria (N⫽3), and no gr 3/4 hypertension. Conclusions: While conclusions are limited by the size of the trial, the results are consistent with the hypothesis that the addition of B to MC may result in enhanced anti-angiogenic effect and clinical benefits in adv NS-NSCLC. Analysis of prognostic or predictive bm of angiogenesis will be presented. Clinical trial information: NCT00655850.

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8059


Clinical outcome ORR Median PFS Median OS 1-yr survival 2-yr survival

73% 9M 30M 74% 55%

(95% CI 0.57-0.87) (95% CI 7-10) (95% CI 18-37)


Prospective observational cohort study of second-line chemotherapy administration after first-line platinum-based chemotherapy for patients with advanced NSCLC in Japan (SAPPHIRE study). Presenting Author: Kiyotaka Yoh, Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan

Final overall survival (OS) results of a noncomparative phase II study of bevacizumab (B) plus first-line chemotherapy or second-line erlotinib (E) in nonsquamous NSCLC (ns-NSCLC) patients with asymptomatic untreated brain metastases (BM) (BRAIN). Presenting Author: Benjamin Besse, Institut Gustave Roussy, Villejuif, France

Background: Maintenance therapy after first-line platinum-based chemotherapy (first-CT) is reported to be beneficial to patients with advanced non-small cell lung cancer (NSCLC). However, its impact on overall survival appears to be marginal or negligible, if those without maintenance receive active second-line chemotherapy (second-CT), which is initiated at disease progression. The purpose of this study is to investigate the proportion of second-CT administration after first-CT for patients with advanced NSCLC. Methods: From April 2010 to September 2011, 865 patients with advanced NSCLC who were initiated on first-CT at 30 institutions in Japan were enrolled in this prospective observational study. Baseline characteristics, regimens and responses to first-CT, whether or not they received second-CT, and if not, reasons for non-administration were recorded. This report describes from patients with at least 6 months of follow up. This study was supported by the Public Health Research Center Foundation CSPOR. Results: A total of 865 eligible patients with advanced NSCLC provided patient characteristics and details of first-CT. Of all patients, 70% had adenocarcinoma, 20% had squamous cell carcinoma, and 10% were positive for the EGFR mutation. At this data cut off, 225 patients were excluded from the analysis due to disease progression and loss of follow-up during first-CT, and 194 (22%) patients received maintenance therapy after first-CT. Among the 508 patients who were followed up for at least 6 months, 131 patients (26%) could not receive second-CT; the reasons were as follows: declined PS, 79 (60%); patient refusal, 28 (21%); death of any cause, 6 (5%); others, 18 (14%). Conclusions: Preliminary results of this large observational study in Japan suggested that around 20% of patients missed an opportunity to receive appropriate second-CT despite the follow-up of advanced NSCLC patients after first-CT. Further investigation is needed to elucidate the selection criteria of patients that may benefit the most from maintenance therapy, not second-CT at disease progression.

Background: The non-comparative BRAIN study (NCT00800202) is the first trial to evaluate efficacy/acceptable safety of B in pts with ns-NSCLC and untreated BM. We report final efficacy/safety results. Methods: Eligible pts (stage IV ns-NSCLC; PS 0 –1; untreated, asymptomatic BM ineligible for surgery/ radiosurgery) received until unacceptable toxicity/disease progression: 1st-line B ⱕ6 cycles (15mg/kg q3w) plus carboplatin (AUC 6 q3w) and paclitaxel (200mg/m2 q3w; B⫹CP; n⫽67); or 2nd-line B plus E (150mg/day; B⫹E; n⫽24). Primary endpoint is 6-month progression-free survival (PFS). Six-weekly assessments included mandatory brain MRI. The trial could be halted if there were ⬎3 (B⫹CP) or ⬎2 (B⫹E) brain hemorrhages (ICH). Results: Baseline (BL) characteristics are reported. With a median follow-up of 16.3 (B⫹CP) and 11.8 months (B⫹E), efficacy data are summarized. Adverse events (AE) were comparable with those in previous trials of B. Only 1 grade ⱖ3 bleeding AE (grade 3, extracranial site; B⫹E) and only one ICH event (grade 1, resolved; B⫹CP) occurred. Most frequent cause for B withdrawal was progression: intracranial only in 20.9% (B⫹CP) and 16% (B⫹E); extracranial only in 50.7% (B⫹CP) and 54.2 % (B⫹E). Conclusions: The finalBRAIN results demonstrate promising efficacy and acceptable safety of B with 1st-line chemotherapy or 2nd-line E in ns-NSCLC pts with asymptomatic untreated BM. Clinical trial information: NCT00800202. BⴙCP BⴙE nⴝ67 nⴝ24 BL characteristics Male, n (%) Median age, years (range) ECOG PS 0, n (%) WHO histology, Adenocarcinoma n (%) Never smokers, n (%) Clinical outcomes (95% CI) 6-month PFS,a % Median PFS, months Median OS, months ORR,b% RR,b % Intracranial BM Extracranial lesions

46 (68.7) 61.0 (40–79) 37 (55.2) 59 (88.1)

11 (45.8) 54.0 (34–70) 13 (54.2) 23 (95.8)

14 (20.9)

3 (12.5)

56.5 (43.8–67.4) 58.0 (36.0–74.8) 6.7 (5.7–7.1) 6.3 (2.5–8.4) 16.0 (12.0–21.0) 12.0 (8.9–20.2) 62.7 (50.0–74.2) 12.5 (2.7–32.4) 61.2 (48.5–72.9) 20.8 (7.1–42.2) 64.2 (51.5–75.5) 12.5 (2.7–32.4)

a Met pre-defined endpoint (lower 95% CI B⫹CP⬎30%, B⫹E⬎15%; point estimate B⫹CP⬎50%, B⫹E⬎35%). b Unconfirmed response.




LUX-Lung 6: Patient-reported outcomes (PROs) from a randomized openlabel, phase III study in first-line advanced NSCLC patients (pts) harboring epidermal growth factor receptor (EGFR) mutations. Presenting Author: Sarayut Lucien Geater, Division of Respiratory and Respiratory Critical Care Medicine, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand

8062

501s


First-line carboplatin, pemetrexed, and panitumumab in patients with advanced nonsquamous KRAS wild type (WT) non-small cell lung cancer (NSCLC). Presenting Author: Tarek Mekhail, Florida Hospital Cancer Institute, Orlando, FL

Background: Afatinib (A) is an oral, irreversible, ErbB Family Blocker, blocking signaling from EGFR (ErbB1), human epidermal growth factor receptor 2 (HER2; ErbB2) and ErbB4. In LUX-Lung 6, A was significantly better than gemcitabine/cisplatin (GC) in terms of progression free survival (PFS) and tumor response, with a more favorable safety profile. Here, we report the PRO results. Methods: 364 pts were randomized (2:1) to receive A or GC. PROs were measured using EORTC questionnaires QLQ-C30/LC13 at baseline and q3w until progression. Changes of ⱖ10 points (scale 0 –100) were considered clinically significant. Analyses of cough, dyspnea and pain were prespecified. Time to deterioration (1st 10-point worsening from baseline) was analyzed using a stratified log-rank test. Percentage improved/worsened by ⱖ10 points or stable was determined. Mean scores over time were estimated using longitudinal (mixed-effects growth curve) models. Results: Compliance on treatment with questionnaires was ⬎90%. Baseline symptom burden was low (cough: 35; dyspnea: 25; pain: 24). Compared with GC, therapy with A significantly delayed time to deterioration for cough (HR⫽0.45; p⫽0.0001), dyspnea (HR⫽0.54; p⬍0.0001) and pain (HR⫽0.70; p⫽0.03). A higher proportion of A-treated pts had ⱖ10-point improvements in cough (76% vs 55%; p⫽0.0003), dyspnea (71% vs 48%; p⬍0.0001) and pain (64% vs 47%; p⫽0.003) compared with GC, particularly among pts with baseline symptoms. Mean scores over time for cough, dyspnea and pain also significantly favored A. Consistent with their safety profiles, a significantly higher proportion of A-treated pts had worsening of diarrhea, sore mouth and dysphagia, while fatigue, nausea, and vomiting were significantly worse with GC. Overall, therapy with A significantly improved global health-related quality of life (HRQoL; p⬍0.0001), physical (p⬍0.0001), role (p⫽0.01) and social (p⬍0.001) functioning compared with GC. Conclusions: In LUX-Lung 6, prolongation of PFS with A was associated with significantly better HRQoL and significantly longer control of lung cancer-related symptoms compared with GC. Clinical trial information: NCT01121393.

Background: KRAS WT colorectal cancer (CRC) is responsive to the EGFR inhibitors panitumumab (P) and cetuximab. Phase III data suggest a small, but statistically significant overall survival (OS) advantage with cetuximab ⫹ chemotherapy in KRAS unselected NSCLC (Pirker, Lancet 2009); and phase I data suggest P alone has activity in non-CRC tumors including NSCLC (Weiner, Clin Ca Res. 2008). This single-arm phase II trial examined the safety and efficacy of P in combination with carboplatin (C) and pemetrexed (Pem) in patients (pts) with advanced non-squamous KRAS WT NSCLC. The addition of P was hypothesized to improve the median time-to-progression (TTP) from 3.6 months (mos) (historical) to 5.4 mos (1-sided ␣ .10, 80% power). Methods: Pts with previously untreated, unresectable stage IIIB/IV non squamous KRAS WT NSCLC received P 9 mg/kg, Pem 500 mg/m2, and C AUC⫽6 IV day 1 every 21 days for 6 cycles, followed by P and Pem maintenance every 21 days until progressive disease or unacceptable toxicity. Responses were evaluated every 2 cycles per RECIST 1.1. KRAS mutation testing was performed centrally (DxS kit). Tissue was also collected for EGFR FISH testing. Results: 60 pts were enrolled; median age, 65 years; 58% female, ECOG PS 0-1 (98%), and prior adjuvant chemotherapy (10%). Median number of cycles was 5 (range 1-22). At a median follow-up of 8.7 mos, the median TTP was 6.2 mos (95% CI: 3.7, 9.5), PFS 6.2 mos (95% CI 3.0, 9.0), 1 year OS 65.5% (95% CI 44.8%, 80%). 23 pts (38%) had partial responses (PR); the disease control rate (PR ⫹ proportion with stable disease) was 68%. Treatment-related toxicity (TRT) included (all grades) nausea (38%), fatigue (30%), rash (30%), and mucositis (23%). Severe (grade 3/4) TRT in ⬎ 2 pts included: thrombocytopenia (11%), neutropenia (7%), and dehydration (5%). There were no treatment-related deaths. EGFR mutation and FISH analyses will be presented. Conclusions: The addition of panitumumab to carboplatin and pemetrexed in the first-line treatment of advanced KRAS WT NSCLC was safe and well-tolerated; the median TTP of 6.2 mos met the primary endpoint. Definitive assessment of the value of panitumumab in this setting requires a randomized trial. Clinical trial information: NCT01042288.

8063

8064


Phase II study of afatinib, an irreversible ErbB family blocker, in demographically and genotypically defined non-small cell lung cancer (NSCLC) patients. Presenting Author: Jacques De Greve, Oncologisch Centrum UZ Brussel, Brussels, Belgium Background: EGFR mutation⫹ (M⫹) NSCLC pts have an improved response to EGFR TKIs vs non-M⫹ pts. Data on EGFR FISH⫹ (gene amplified) and HER2 M⫹ pts are, however, limited. Afatinib is an irreversible ErbB Family Blocker with efficacy in Ph II/III trials in EGFR M⫹ NSCLC. This exploratory, open-label trial assessed afatinib in 3 genotypically and demographically defined NSCLC groups. Methods: Never/ex-smokers with stage IIIB/IV lung adenocarcinoma with EGFR M⫹ tumors who had failed prior EGFR TKIs, HER2 M⫹ tumors independent of prior therapy, or EGFR FISH⫹ tumors who received ⱕ3 prior chemotherapies were enrolled. Afatinib 50 mg qd was administered until disease progression or intolerable adverse events. Tumor assessments (RECIST 1.0) were performed every 8 wks. Pts who progressed on afatinib but experienced clinical benefit could continue treatment with afatinib 40 mg qd ⫹ paclitaxel 80 mg/m² qw on days 1, 8 and 15 every 28-day cycle. Primary endpoint: Confirmed objective response. Results: 41 pts were treated: 63% female; median age 63 yrs; 68% never smokers; 32% ex-smokers. 33 pts received afatinib monotherapy only; 8 pts received afatinib followed by afatinib/paclitaxel combination therapy. 78% (n⫽32) of pts were EGFR M⫹, 5% (n⫽2) were EGFR FISH⫹ and 17% (n⫽7) were HER2 M⫹. For afatinib monotherapy, 1 confirmed partial response (PR) was observed (EGFR FISH⫹), stable disease (SD) was seen in 5/7 HER2 M⫹, 2/2 EGFR FISH⫹ and 17/32 EGFR M⫹ pts, and overall disease control (DC) rate was 59% (n⫽24); mean duration of DC was 26 wks.Median PFS was 16 wks (17 wks in HER2 M⫹ pts). Of 8 afatinib/paclitaxel-treated pts, 1 had a confirmed PR and 2 had SD; median PFS was 7 wks. Most frequently reported drug-related AEs in afatinib monotherapy pts were diarrhea (n⫽39; grade ⱖ3 n⫽13), rash/acne (n⫽33; grade ⱖ3 n⫽4) and stomatitis (n⫽19; grade ⱖ3 n⫽2). In the combination arm these were diarrhea (n⫽4; grade ⱖ3 n⫽1) and nausea (n⫽3; grade ⱖ3 n⫽0). Conclusions: Efficacy of afatinib in EGFR M⫹ NSCLC pts has been established in previous trials. Novel activity of afatinib in HER2 M⫹ and EGFR FISH⫹ NSCLC pts has been demonstrated here, with a manageable safety profile of afatinib in the overall population. Clinical trial information: NCT00730925.


Phase II study of gefitinib and inserted cisplatin plus docetaxel as a first-line treatment for advanced non-small cell lung cancer haboring an epidermal growth factor receptor activating mutation. Presenting Author: Shintaro Kanda, Division of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan Background: Gefitinib yields a longer progression-free survival (PFS) period than platinum– doublet chemotherapy as a first–line treatment for patients with advanced non–small– cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) activating mutation, but most patients develop resistance against gefitinib after the initial response. We hypothesized that the insertion of platinum– doublet chemotherapy during the initial response could prevent the emergence of acquired resistance and prolong survival, compared with gefitinib alone. Methods: We performed a phase ⌱⌱ study of the following first–line treatment for patients with advanced NSCLC with EGFR mutation. Gefitinib (250 mg) was administrated on days 1–56. After a two–week rest, three cycles of cisplatin (80 mg/m2) and docetaxel (60 mg/m2) were administered on days 71, 92, and 113. Gefitinib was re–started on day 134 and was continued until progression. The primary endpoint was the two–year PFS rate. The sample size was estimated at 33, and this treatment was considered worthy for further development if more than 11 of the 33 patients who started treatment had a 2–year PFS. Results: Thirty–three Japanese patients were enrolled. Twenty–five patients could re–start gefitinib, 12 achieved a PFS period of over 2 years, and 9 continued to receive the protocol treatment without experiencing progression. The 1–, 2–, and 3–year estimated PFS rates were 59.4%, 37.5%, and 33.8%, respectively, and the median PFS time was 19.2 months. The 1–, 2–, and 3–year estimated survival rates were 90.0%, 82.9%, and 62.4%, respectively, and the median survival time had not been reached at the time of analysis. Treatment–related deaths and unexpected severe toxicities were not seen. Conclusions: Our results indicated that first–line treatment consisting of gefitinib and inserted cisplatin plus docetaxel is promising for patients with advanced NSCLC with EGFR mutation. A phase ⌱⌱⌱ study of this treatment compared with gefitinib alone is warranted. Clinical trial information: 000001738.


502s 8065

Lung Cancer—Non-Small Cell Metastatic General Poster Session (Board #35E), Sat, 8:00 AM-11:45 AM

Rebiopsy in TKI-resistance: A retrospective analysis. Presenting Author: Justine Leonie Kuiper, VU University Medical Center, Amsterdam, Netherlands Background: EGFR-TKI provides a clinical benefit in patients with EGFR-mutated NSCLC with median progression-free survival (PFS) of 12 months. Several resistance mechanisms (e.g. T790M mutation) have been described, however data are sparse. We analysed EGFR-mutation spectra in NSCLC patients with acquired resistance to TKI. Methods: Biopsies from patients with EGFR-mutation or TKI-response⬎24 weeks with both pre- and post TKI biopsy available were retrospectively analysed. Information was collected from the medical record. Response to TKI-treatment was assessed according to RECIST. PFS after TKI-treatment was calculated with a Kaplan-Meier curve. Results: 63 patients were included for analysis. Pre- and post TKI biopsy results are described in the Table. 32 patients received 1 (38%), 2 (10%) or 3 (3%) lines of chemotherapy before start of TKI and 18 patients received 1 (13%), 2 (11%), 3 (3%), or 5 (2%) lines of therapy after TKI treatment. Median PFS on TKI-treatment was 12,3 months (range: 1,4 – 43,2). Objective response rate was 61,9%. 47,6% of patients developed the T790M mutation. One patient developed transformation to SCLC with the original exon 19 deletion. One patient with pre-TKI an exon 18 ⫹ exon 21 mutation was found to have a KRAS-mutation post-TKI. Conclusions: In this cohort, frequency of development of T790M mutation was consistent with earlier reports. Transformation to SCLC occurred less than described earlier. Two patients did not retain their original mutation. Surprisingly, one patient developed a KRAS mutation: a second primary tumor is not excluded in this case. Rebiopsy in TKI-resistance provides important information on dynamic tumour characteristics and has management implications in certain patients. Pre- versus post-TKI biopsy results. Post-TKI Mutation No analysis EGFR EGFR T790M ⴙ T790M ⴙ EGFR Exon 18 ⴙ SCLC ⴙ malignant No not exon19 exon21 exon 19 exon 21 exon 20 exon 20 Exon 19 KRAS cells mutation possible Total EGFR exon19 EGFR exon21 Pre-TKI EGFR mutation NOS Exon 18 ⫹ exon 20 Exon 18 ⫹ exon 21 T790M ⫹ exon 21 No mutation Mutation analysis not possible No mutationanalysis performed Total

8067

13 0 0

0 5 0

17 0 1

0 3 2

1 0 0

0 0 0

1 0 0

0 0 0

2 0 0

2 0 0

0 0 0

36 8 3

0

0

0

0

0

1

0

0

0

0

0

1

0

0

0

0

0

0

0

1

0

0

0

1

0

0

0

1

0

0

0

0

0

0

0

1

0 0

0 0

0 1

0 0

0 0

0 0

0 0

0 0

1 0

1 0

1 0

3 1

3

0

4

1

0

0

0

0

0

1

0

9

16

5

23

7

1

1

1

1

3

4

1

63


Screening for RET and ROS1 fusions in an enriched cohort of pan-negative never-smokers with advanced lung adenocarcinomas to identify patients for treatment in targeted therapy trials. Presenting Author: Alexander Edward Dela Cruz Drilon, Memorial Sloan-Kettering Cancer Center, New York, NY Background: RET and ROS1 fusions have been identified pre-clinically as drivers of tumor growth in lung adenocarcinomas. In addition, based on response to crizotinib in ROS1-positive tumors and emerging data on RET inhibition in some tumors, these fusions represent druggable targets. While each occurs in 1-2% of unselected patients, a screening paradigm based on testing never-smokers whose tumors have no known oncogenic mutations or fusions may enrich identification for ongoing clinical trials. Methods: Patients with a never-smoking history (⬍100 lifetime cigarettes) and advanced pan-negative lung adenocarcinomas (absence of mutations in EGFR, KRAS, NRAS, BRAF, HER2, PIK3CA, MEK1, and AKT, and ALK fusions) were selected for testing. Screening for RET and ROS1 fusions was performed in real-time via dual-probe FISH breakapart assays, RT-PCR, and next-generation sequencing in selected cases. We enrolled patients onto a phase II trial of cabozantinib for RET fusion-positive lung cancers (NCT01639508) and, as part of the Lung Cancer Mutation Consortium (LCMC), a phase I trial of crizotinib for ROS1-positive lung cancers (NCT00585195). Results: Thirty five (n⫽35) never-smokers with advanced pan-negative lung adenocarcinomas were identified. A RET or ROS1 fusion was found in 31% [n⫽10/32, 95% CI, 15-47%] of patients. RET and ROS1 fusions were found in 15% [n⫽5/34, 95% CI, 3% - 27%] and 15% [n⫽5/33, 95% CI, 2%-27%] of patients, respectively. 1 patient had a novel TRIM33-RET fusion. 3 of 5 patients with RET fusion-positive tumors were eligible for treatment with cabozantinib, 2 of which had partial responses to therapy. 1 of 5 patients with ROS1 fusion-positive tumors was treated on-protocol with crizotinib and achieved a partial response. Conclusions: 31% of never-smokers with pan-negative advanced lung adenocarcinomas harbor a gene fusion involving either RET or ROS1. Until multiplexed mutation and fusion testing is routinely available, targeting this population for screening represents an interim enrichment strategy for patient identification and enrollment on clinical trials where responses are already being documented.

8066


Randomized phase III trial of gemcitabine and cisplatin versus gemcitabine alone in patients with advanced non-small cell lung cancer (NSCLC) and a performance status (PS) 2: CAPPA-2 study. Presenting Author: Alessandro Morabito, National Cancer Institute, G.Pascale Foundation, Napoli, Italy Background: Platinum-based chemotherapy (CT) is the standard treatment for patients (pts) with advanced NSCLC, but the evidence of its efficacy among ECOG PS2 pts is weak, because these pts are usually excluded from clinical trials; concern exists about tolerability and feasibility of standard CT in these pts. No prospective randomized trial has tested the addition of cisplatin to single-agent CT in pts with advanced NSCLC and PS2. Methods: CAPPA-2 was a multicentre, randomized phase III study for first-line treatment of PS2 pts with advanced NSCLC. Patients, aged 18-70, were eligible if they had stage IV or IIIB with malignant pleural effusion or metastatic supraclavicular nodes (TNM VI ed.) and adequate organ function. Patients in standard arm received gemcitabine 1,200 mg/m2 dd1 and 8.Patients in experimental arm received cispaltin 60 mg/m2 d1 plus gemcitabine 1,000 mg/m2 dd1 and 8. All treatments were repeated q3w, up to 4 cycles, unless disease progression or unacceptable toxicity. Primary endpoint was overall survival (OS). To have 80% power of detecting hazard ratio (HR) 0.71, corresponding to an increase in median OS from 4.8 to 6.8 months, 285 deaths were required. Results: The study was stopped in June 2012 after the enrolment of 57 pts, due to the slow accrual and the report of positive results from a similar study. Median OS was 3.0 months with single-agent gemcitabine and 5.9 months with cisplatin ⫹ gemcitabine (HR 0.52, 95% CI 0.28-0.98, p⫽0.039). Combination CT produced longer PFS (median 1.7 vs. 3.3 months, HR 0.49, 95% CI 0.27-0.89, p⫽0.017) and higher response rate (4% vs. 18%, p⫽0.19), without substantial increase in toxicity. Conclusions: Addition of cisplatin to single-agent gemcitabine improves survival as first-line treatment of PS2 patients with advanced NSCLC. Clinical trial information: NCT00526643.

8068


Final efficacy and safety results of pemetrexed (pem) continuation maintenance (mtc) therapy in the elderly from the PARAMOUNT phase III study. Presenting Author: Cesare Gridelli, SG Moscati Hospital, Avellino, Italy Background: The PARAMOUNT phase III trial showed that mtc pem after pem-cisplatin induction was well tolerated and effective for patients (pts) with advanced nonsquamous NSCLC. Here we present the final OS and safety data from this study in elderly (ⱖ70 yrs) vs. non-elderly (⬍70 yrs) pts. Methods: In this double-blind study, 539 pts with a PS of 0/1 were randomized (2:1, stratified for stage, PS and induction response) to receive mtc pem (n⫽359, 500 mg/m2, day 1, 21 day cycle) or placebo (plc) (n⫽180). The study was powered for PFS (previously reported) and key secondary OS. Subgroup analyses were done for pts ⱖ70 yrs and ⬍70 yrs. Results: Subgroups (ⱖ70: n⫽92, 17%; ⬍70: n⫽447, 83%) had similar baseline characteristics except for PS and sex (elderly, PS 0/1: 22%/77%, M/F: 66%/34%; non-elderly, PS 0/1: 34%/65%, M/F: 56%/44%). The median ages were 73 yrs (ⱖ70) and 60 yrs (⬍70). The mean cycles received for pts ⱖ70 were 7.4 (range 1-36, dose intensity (DI) 91%) for pem and 4.5 for plc, and for pts ⬍70 were 8.0 (range 1-44, DI 94%) for pem and 5.1 for plc. The OS HRs (pem vs. plc) were 0.89 (95% CI: 0.55-1.4) for ⱖ70 yrs and 0.75 (95% CI: 0.60-0.95, p⫽0.015) for⬍70 yrs. The median OS (95% CI) (ⱖ70) was 13.7 mo (10.4-19.4) for pem and 12.1 mo (8.4-16.9) for plc; the median OS (95%CI) (⬍70) was 13.9 mo (12.5-16.1) for pem and 10.8 mo (9.5-12.9) for plc. The 1 and 2 yr OS rates (95% CI) for the elderly were 60% (45-71%) and 34% (21-47%) for pem vs. 52% (36-66%) and 28% (15-43%) for plc, respectively. For non-elderly pts, the 1 and 2 yr OS rates were 58% (52-63%) and 31% (26-37%) for pem vs. 43% (35-52%) and 19% (13-27%) for plc, respectively. The Table shows a subset of drug-related AEs. Conclusions: Continuation mtc pem had comparable survival and toxicity profiles in the ⱖ70 and ⬍70 yrs subgroups. However, Gr 3/4 anemia and neutropenia were numerically higher for pts ⱖ70 yrs. Clinical trial information: NCT00789373. CTCAEs. All mtc cycles Event (%) Fatigue Anemia Neutropenia Renal* Rash Edema

>70 yrs

60 mL/min CrCl Efficacy (mo) Median PFS Median OS Grade 3/4 AEs (%) Neutropenia Anemia Infection

< 60 mL/min

POM ⴙ LoDEX

HiDEX

HR (P)

POM ⴙ LoDEX

HiDEX

HR (P)

3.7 Not reached

1.8 9.2

0.47 (⬍.001) 0.57 (.021)

3.2 10.3

1.6 4.6

0.44 (⬍ .001) 0.51 (.008)

41 24 23

15 26 23

— — —

44 33 28

15 34 24

— — —


Lymphoma and Plasma Cell Disorders 8528


Pomalidomide plus low-dose dexamethasone (POM ⴙ LoDEX) versus high-dose dexamethasone (HiDEX) in relapsed/refractory multiple myeloma (RRMM): Impact of cytogenetics in MM-003. Presenting Author: Hartmut Goldschmidt, Universitätsklinikum Heidelberg, Heidelberg, Germany Background: RRMM patients (pts) who fail lenalidomide (LEN) and bortezomib (BORT) have poor prognosis. High-risk cytogenetics predict shorter survival. POM ⫹ LoDEX has demonstrated efficacy in pts with prior LEN and BORT and high-risk cytogenetics. MM-003 is an open-label, multicenter, phase III trial comparing POM ⫹ LoDEX vs. HiDEX in RRMM pts who failed LEN and BORT treatment (Tx) and have progressed on their last therapy. Methods: Pts must have been refractory to the last prior Tx (progressive disease [PD] during or within 60 days) and failed LEN and BORT after ⱖ 2 consecutive cycles of each (alone or in combination). Randomization was 2:1 to POM 4 mg D1–21 ⫹ DEX 40 mg (20 mg for pts aged ⬎ 75 y) weekly; or DEX 40 mg (20 mg for pts aged ⬎ 75 y) D1– 4, 9 –12, and 17–20 (28-day cycles). Tx continued until PD or unacceptable adverse events (AEs). The primary endpoint was progression-free survival (PFS). Secondary endpoints included OS and AEs. This analysis examined pts meeting modified high-risk cytogenetic criteria— del(17p13) and/or t(4p16/14q32). Results: 302 pts received POM ⫹ LoDEX, and 153 pts received HiDEX. 225 and 107 pts, respectively, were evaluable for cytogenetics. Baseline characteristics were similar. Median PFS and OS were significantly longer with POM ⫹ LoDEX vs. HiDEX, regardless of cytogenetic risk (Table). The most common grade 3/4 AEs were neutropenia, anemia, and infection (Table). Discontinuation due to AE was low: 4% vs. 6% (high risk) and 10% vs. 4% (standard risk). Conclusions: Median PFS and OS were significantly longer with POM ⫹ LoDEX vs. HiDEX in pts with cytogenetically-defined high-risk disease, consistent with results from the intent-to-treat population. Tolerability was acceptable. POM ⫹ LoDEX should be considered a new Tx option in pts failing LEN and BORT. Clinical trial information: NCT01311687. High Cytogenetic risk Efficacy (mo) Median PFS Median OS Grade 3/4 AEs (%) Neutropenia Anemia Infection

8530

Standard

POM ⴙ LoDEX (n ⴝ 77)

HiDEX (n ⴝ 35)

HR (P)

POM ⴙ LoDEX (n ⴝ 148)

HiDEX (n ⴝ 72)

HR (P)

3.1 11.1

1.2 4.5

0.39 (⬍ .001) 0.48 (.017)

4.0 Not reached

2.1 9.0

0.46 (⬍ .001) 0.60 (.050)

50 37 20

29 37 23

– – –

44 27 31

13 29 19

– – –


Phase Ib dose escalation study of oral quisinostat, a histone deacetylase inhibitor, in combination with bortezomib and dexamethasone for patients with relapsed multiple myeloma. Presenting Author: Xavier Leleu, Service des Maladies du Sang, Hôpital Claude Huriez, Lille, France Background: Aggresome formation is a mechanism of resistance to agents (e.g., bortezomib) which block proteasome activity. HDACi (e.g., quisinostat) prevents aggresome formation by deacetylation of tubulin that allows the transport of unfolded proteins to lysosomes for degradation. Methods: Patients received quisinostat (Q) at escalated doses (6, 8, 10 and 12 mg) on days 1, 3, and 5 weekly, subcutaneous VELCADE (V) at 1.3 mg/m2on days 1, 4, 8, and 11 of a 3-week cycle, and oral dexamethasone (D) at 20 mg on the day of and the day after VELCADE dosing. The primary endpoint was the maximum tolerated dose (MTD) of Q in the combination (Q⫹V⫹D). The secondary endpoints included safety, overall response rate, and pharmacodynamic biomarkers. Results: Eighteen patients (3, 3, 6, and 6 in increasing Q doses) were enrolled: 56% male; median age ⫽ 69 (range 50-82) years; multiple myeloma stage: IA ⫽ 11% and IIIA ⫽ 89%; prior lines of therapy: 1 ⫽ 100%, 2 ⫽ 55.6%, and 3 ⫽ 11.1%; prior VELCADE treatment ⫽ 50%. At the highest dose (12 mg) 2 patients had dose-limiting toxicity, 1 with QTc prolongation and 1 with atrial fibrillation. The MTD was established at the 10 mg Q for the Q⫹V⫹D regimen. The most common adverse events (ⱖ 10% of patients) were diarrhea (39%), asthenia (33%), peripheral oedema (22%), nausea (17%), thrombocytopenia (17%), alopecia (11%), constipation (11%), and vomiting (11%); most were grade 2 or lower in toxicity. To date, 13 patients have discontinued treatment, of which 5 completed 11 cycles of treatment. The overall response rate was 87.5% (14/16, 95% CI: 61.7% to 98.5%), including 1 complete response, 2 very good partial response, and 11 partial responses. Most patients (9/11) showed a decrease in number of circulating multiple myeloma cells after 1 cycle. Two of 5 patients showed an increase in acetylated histone 3 from baseline as measured in peripheral blood mononuclear cells. Conclusions: The MTD is 10 mg quisinostat in combination with VELCADE and dexamethasone. The combination is active in the treatment of relapsed multiple myeloma and has an acceptable safety profile. Clinical trial information: NCT01464112.

8529

525s


Final results from the phase Ib/II study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in patients with relapsed or progressive multiple myeloma. Presenting Author: Michael Wang, Department of Lymphoma and Myeloma, University of Texas M. D. Anderson Cancer Center, Houston, TX Background: Carfilzomib (CFZ) is approved in the US as single-agent treatment for patients with multiple myeloma (MM) who have progressed after bortezomib (BTZ) and an IMiD and are refractory to last line of treatment. We previously reported interim data from PX-171-006 (NCT00603447), a Ph 1b/2 study of CRd in relapsed or progressive MM (Wang et al. ASCO 2011). Herein we report final results. Methods: Patients (1–3 prior treatments) received CRd in 28-day (D) cycles—CFZ IV on D1, 2, 8, 9, 15, 16, lenalidomide (LEN) PO D1–21, and dexamethasone (dex) wkly. In phase 1, CFZ (15–27 mg/m2) and LEN (10 –25 mg) doses were escalated to determine the maximum tolerated dose (MTD) with a maximum planned dose (MPD) of CFZ 20 mg/m2 D1, 2 of Cycle 1 and 27 mg/m2 thereafter, LEN 25 mg/d, and dex 40 mg/wk, followed by phase 2 expansion at MTD/MPD. Endpoints included IMWG overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and safety. Results: A total of 84 patients were enrolled since June 2008. Overall, prior treatment included BTZ (77%/18% refractory) and LEN (70%/35% refractory); 20% had high-risk cytogenetics/FISH. MTD was not reached in Ph 1, supporting expansion at the MPD (n⫽52, 23% BTZ refractory and 42% LEN refractory). As of Nov 2012 (median follow-up 24.4 mo): ORR was 69% overall and 76.9% at MPD with very good partial response in 36.9% and 38.5% and stringent complete response in 3.6% and 3.8%, respectively; median DOR was 18.8 (95% CI 9.7– 41.5) and 22.1 mo (95% CI 9.5–NE) respectively; median PFS was 11.8 (95% CI 7.6 –20.7) and 15.4 mo (95% CI 7.9 –NE), respectively. Seven responders at MPD pursued other therapy and were censored for PFS.A median of 8.5 (range 1⫺46) CFZ cycles were started; 4% required CFZ dose reductions; 15% discontinued CFZ due to adverse events (AEs). Grade 3/4 AEs were generally consistent with earlier studies in advanced MM that used similar doses of single-agent CFZ; grade 3/4 peripheral neuropathy was 1%. Conclusions: CRd was well tolerated, providing robust and durable responses in this pt population where 35% were LEN refractory. This combination is being further evaluated in several ongoing phase 2/3 trials. Clinical trial information: NCT00603447. 8531


Clinical response by baseline characteristics in patients (pts) with relapsed and bortezomib (BTZ)-refractory multiple myeloma treated with panobinostat (PAN), BTZ, and dexamethasone (DEX; PANORAMA 2). Presenting Author: Melissa Alsina, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL Background: In PANORAMA 2, PAN ⫹ BTZ ⫹ DEX recaptured responses in heavily pretreated pts with BTZ-refractory MM; overall response rate (ORR), clinical benefit rate (CBR), and progression-free survival (PFS) were 34.5%, 52.7%, and 5.4 months, respectively. Here, we evaluate clinical response per baseline characteristics. Methods: Response was based on European Group of Blood and Marrow Transplantation 1998 criteria. High-risk cytogenetics was defined as del(17p), t(4;14), or t(14;16). Quality of life (QoL) was measured with Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) v4.0 scale. Results: Response rate trended higher in pts whose prior BTZ therapy was not their last line of therapy (Table). Although no trend in response rate was noted, PFS appeared longer in pts progressing within 60 days of their last BTZ-containing regimen than in those progressing on their last BTZ-containing regimen. In the 14 pts with high-risk cytogenetics, ORR was 42.9% and CBR was 71.4%. The mean FACT/GOG-Ntx subscale did not exhibit a clinically meaningful change from baseline (mean ⫾ standard deviation [SD], 114.2 ⫾ 21.1; n ⫽ 41) to cycle 9 day 1 (day 169; 104.2 ⫾ 15.4; n ⫽ 16) as determined by 50% SD threshold for minimally important difference. Other QoL parameters were similarly unchanged. Conclusions: PAN ⫹ BTZ ⫹ DEX demonstrated activity regardless of baseline demographics in heavily pretreated pts with BTZ-refractory MM. Clinical trial information: NCT01083602. Disease progression On BTZ Within 60 days of BTZ BTZ in last prior line of therapy Yes No DEX in last BTZ-containing regimen Yes No DEX in last prior line of therapy Yes No

n

ORR, % (95% CI)

CBR, % (95% CI)

PFS, months (95% CI)

40 15

37.5 (22.7-54.2) 26.7 (7.8-55.1)

55.0 (38.5-70.7) 46.7 (21.3-73.4)

4.2 (2.6-5.8) 7.6 (6.7-9.0)

27 28

25.9 (11.1-46.3) 42.9 (24.5-62.8)

48.1 (28.7-68.1) 57.1 (37.2-75.5)

4.9 (2.1-7.6) 6.0 (3.9-7.6)

45 10

26.7 (14.6-41.9) 70.0 (34.8-93.3)

46.7 (31.7-62.1) 80.0 (44.4-97.5)

4.9 (2.6-6.7) 6.2 (2.6-8.3)

37 18

32.4 (18.0-49.8) 38.9 (17.3-64.3)

54.1 (36.9-70.5) 50.0 (26.0-74.0)

4.2 (2.6-6.7) 6.5 (2.6-9.7)


526s 8532

Lymphoma and Plasma Cell Disorders Poster Discussion Session (Board #12), Mon, 1:15 PM-5:15 PM and 4:45 PM-5:45 PM

Pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in patients (Pts) with relapsed and refractory multiple myeloma (RRMM): MM-002 phase II age subgroup analysis. Presenting Author: Sundar Jagannath, Mount Sinai Medical Center, New York, NY Background: POM demonstrated clinical efficacy and favorable tolerability in RRMM pts previously treated with lenalidomide (LEN) and bortezomib (BORT), in the randomized, multicenter, open label MM-002 phase II trial. This analysis evaluated whether the efficacy and tolerability of POM⫹LoDEX treatment is consistent across age subgroups. Methods: Pts with RRMM who had received ⱖ 2 prior therapies, including LEN and BORT, and were refractory to their last regimen were randomized to either POM⫹LoDEX (POM 4 mg/day, days 1–21 of a 28-day cycle; LoDEX 40 mg/week) or POM alone. End points included progression-free survival (PFS), response rate (based on EBMT criteria), response duration, and safety. A post-hoc analysis based on age (ⱕ 65 vs. ⬎ 65 yrs) was conducted. Results: A total of 221 pts with a mean age of 64 yrs (range 34 – 88) were randomized to POM⫹LoDEX (n ⫽ 113) or POM (n ⫽ 108). The efficacy outcomes and the most common treatment emergent grade 3/4 adverse events (AEs) for the age subgroups according to treatment arm are presented in the Table. Conclusions: Regardless of age (ⱕ 65 vs. ⬎ 65 yrs), POM with or without LoDEX was effective and generally well tolerated in heavily pretreated RRMM pts who had already received LEN and BORT. POM with or without LoDEX represents a new clinical option for pts previously treated with numerous lines of therapy. Updated data will be presented at the meeting. Clinical trial information: NCT00833833. Efficacy and safety outcomes. < 65 yrs Efficacy > PR (%) > MR (%) Median DoR (monthsa) Median PFS (months, range) Safety Hematologic AEs (%) Neutropenia Anemia Thrombocytopenia Nonhematologic AEs (%) Pneumonia Urinary tract infection

> 65 yrs

POMⴙLoDEX (n ⴝ 62) 31 47 10.1 4.7 (3.7–6.7)

POM (n ⴝ 69) 13 23 8.3 1.9 (1.8–2.7)

POMⴙLoDEX (n ⴝ 51) 37 43 7.7 3.7 (2.1–5.5)

POM (n ⴝ 39) 18 44 10.6 3.3 (2.8–5.5)

POMⴙLoDEX (n ⴝ 61)

POM (n ⴝ 68)

POMⴙLoDEX (n ⴝ 51)

POM (n ⴝ 39)

46 26 18

40 24 24

35 18 20

59 26 21

16 10

10 3

29 8

21 0


Lenalidomide in relapsed/refractory mantle cell lymphoma post-bortezomib: Subgroup analysis of the MCL-001 study. Presenting Author: Michael E. Williams, University of Virginia Health System, Charlottesville, VA Background: Lenalidomide, an immunomodulatory agent with antitumor and antiproliferative effects, demonstrated rapid and durable efficacy in patients with relapsed/refractory mantle cell lymphoma (MCL) post-bortezomib in the phase II multicenter MCL-001 study. The objective of this analysis was to explore the efficacy of lenalidomide across patient subgroups. Methods: Singleagent lenalidomide was administered at 25 mg/d PO on days 1-21 of a 28-day cycle until disease progression or intolerability; primary endpoints were overall response rate (ORR) and duration of response (DOR) determined by an independent central review committee per modified IWG criteria. Exploratory analyses of ORR and DOR for subgroups were predefined and prospectively conducted. Results: Patients with relapsed/refractory MCL (N⫽134) had a median age of 67 y, with a median of 4 prior therapies (range, 2-10). The ORR was 28% (7.5% CR/CRu) and DOR was 16.6 months (95% CI, 7.7-26.7). Lenalidomide treatment provided consistent ORR and DOR across all subgroups analyzed by demographics, baseline disease status and prior therapy (Table). High vs normal baseline LDH was the only significant factor by univariate and multivariate logistic regression analysis of ORR (odds ratio⫽0.193; p⫽0.002). Conclusions: Single-agent lenalidomide provided consistent clinical benefit in patients with relapsed/refractory MCL post-bortezomib irrespective of patient subgroups at baseline with the exception of LDH. Clinical trial information: NCT00737529. Subgroup analysis of lenalidomide in MCL. Subgroup Median age (>65 years) Sex Male Female High MIPI Normal LDH High LDH High tumor burden* Bulky disease† Refractory to bortezomib Refractory to last therapy Time from last systemic anti-lymphoma therapy 6 mo Prior high-dose/high-intensity treatment


Combined analysis of single-agent lenalidomide in relapsed/refractory mantle cell lymphoma. Presenting Author: Thomas E. Witzig, Mayo Clinic, Rochester, MN Background: Mantle cell lymphoma (MCL) is an aggressive form of nonHodgkin lymphoma (NHL) with poor prognosis. The immunomodulatory agent lenalidomide shows consistent activity with tolerable safety in multiple phase II studies of relapsed/refractory aggressive NHL (NHL-002 and NHL-003) and MCL post-bortezomib (MCL-001). This pooled analysis further examined the efficacy and safety of single-agent lenalidomide in patients with relapsed/refractory MCL. Methods: Single-agent lenalidomide was given 25 mg/d PO on days 1-21 of 28-day cycles as tolerated for 52 weeks (NHL-002) or until disease progression (NHL-003 and MCL-001). All MCL patients received ⱖ1 prior treatment, including bortezomib in MCL-001. Efficacy data were examined by independent central review for MCL-001 and NHL-003 and by investigators for NHL-002. Results: 206 patients with relapsed/refractory MCL were studied. The median age was 67 y (range 33-84; 63% ⱖ65 y), 91% stage III/IV disease and 51% had received ⱖ4 prior regimens (76% prior bortezomib). Overall response rate (ORR) with lenalidomide was 32% (10% CR/CRu), with a median time to response of 2.1 months and median duration of response (DOR) of 16.6 months (not yet reached in patients with CR/CRu; Table). Kaplan-Meier estimates for median PFS and OS were 5.4 and 23.9 months, respectively. Mean daily dose of lenalidomide was 21 mg. Grade 3/4 AEs included neutropenia (44%), thrombocytopenia (29%), anemia (11%), and fatigue (7%). Other any-grade AEs included tumor flare reaction (7%), venous thromboembolic events (7%), and invasive second primary malignancies (3%). Conclusions: Lenalidomide produced rapid and durable responses in patients with relapsed/refractory MCL, and exhibited a predictable safety profile among 3 phase II studies of lenalidomide in heavily pretreated patients, including prior treatment with bortezomib. Clinical trial information: MCL-001: NCT00737529; NHL-002: NCT00179660; NHL-003: NCT00413036. Efficacy of lenalidomide in relapsed/refractory MCL. Efficacy outcomes

a For pts who achieved ⱖ PR. DoR, duration of response; MR, minimal response; PR, partial response.

8534

8533

n

ORR, n (%)

Median DOR, mo (95% CI)

85 108 26

22 (26) 28 (26) 9 (35)

9.2 (5.8-16.7) 16.7 (9.2-NA) 7.7 (2.1-20.5)

39 84 47 77 44 81 74 96 36

10 (26) 32 (38) 5 (11) 22 (29) 13 (30) 22 (27) 20 (27) 23 (24) 14 (37)

7.7 (3.6-NA) 16.7 (14.8-NA) 5.8 (1.7-7.7) 14.8 (5.8-26.7) 14.8 (5.7-NA) 20.5 (7.7-NA) 26.7 (5.6-NA) 7.7 (3.6-26.7) 16.7 (14.8-NA)

44

12 (27)

16.7 (3.6-16.7)

*At least 1 lesion ⱖ5 cm or ⱖ3 lesions each ⱖ3 cm. ⬍sup⬎†⬍/sup⬎At least 1 lesion ⱖ7 cm.

(Nⴝ206)

ORR, % (95% CI) CR/CRu, % (95% CI) Median time to response, mo (95% CI) Median DOR, mo (95% CI) Median PFS, mo (95% CI) Median OS, mo (95% CI)

8535

32 (25-38) 10 (6-15) 2.1 (1.6-24.2) 16.6 (9.2-32.4) 5.4 (3.7-6.7) 23.9 (19.0-34.9)


A phase II study of single agent mocetinostat, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in patients with diffuse large cell B-cell (DLBCL) and follicular (FL) lymphomas. Presenting Author: Michael Crump, Princess Margaret Hospital, Toronto, ON, Canada Background: Mocetinostat (MGCD0103) is an orally available, isotypeselective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single-agent activity in Hodgkin’s lymphoma and in AML and MDS (in combination with 5-azacitidine). More than 430 patients have been treated to date. Methods: This open-label, phase II trial enrolled patients with DLBCL and FL. Patients received mocetinostat at doses ranging from 70-110 mg 3x/wk every 28 days. Anticancer activity, safety, pharmacokinetics and pharmacodynamics were evaluated. Results: Sixty-nine patients with DLBCL (n⫽41) and FL (n⫽28) were enrolled for treatment at starting doses of 85-110 mg. Median age was 62 years (range: 32 to 81). Median duration of treatment was ~3 months (range: ⬍1 to 24). Objective response rate in DLBCL and FL, respectively, was 7/41 (17%; including 2 unconfirmed PRs) and 3/28 (11%; including 1 CR). Median time to response was 2.0 mos (range 1.7-21.0) and 5.3 mos (range 4.3-6.0) respectively. Stable disease was achieved by 13/41 (32%) and 14/28 (50%), respectively, for a disease control rate of 49% and 61%, respectively. Mean duration of SD in patients with DBLCL was ~4.5 mos (range 2-12 mos), with 10 patients remaining stable for ⱖ3 mos. Among FL patients, mean duration of SD was approximately 4.1 mos (range 1.7-13 mos), with 9 patients remaining stable for ⱖ3 mos. The FL CR occurred in a 62-year-old female with paratracheal, subcarinal and portal target lesions who achieved a PR after 4 cycles and CR after 12 cycles that persisted through the remaining 4 mos on study. Study drug was discontinued for adverse events in 19/69 (28%). Fatigue, weight loss or anorexia were most common (n⫽4 each). A total of 26 drug-related SAEs were reported among 12 patients (17%; 1-6 events per pt). There were no drug related deaths. Enrollment is complete and final data will be presented. Conclusions: Single-agent mocetinostat has activity in DLBCL and FL. Fatigue, gastrointestinal, and cardiac symptoms are the most common adverse events resulting in discontinuation of dosing. Based on the acceptable tolerability and clinical activity further development is warranted. Clinical trial information: NCT00359086.




Long-term follow-up of the GELA LNH 03-7B study: A prospective phase II study of 150 patients over 80 years with diffuse large B-cell lymphoma (DLBCL) treated with RminiCHOP. Presenting Author: Frederic Peyrade, Centre Antoine Lacassagne, Nice, France Background: We report the outcome of patients included in the LNH 03-7B prospective phase II study of the GELA group which evaluated the tolerance and efficacy of a reduced dosage chemotherapy regimen (miniCHOP) associated with full dose rituximab in patients aged over 80 years with DLBCL. Methods: Patients were between 80 and 95 years (median 83 years), had disease stage I Bulky to IV and 65% had poor risk lymphoma according to IPI. Perfomance status was 0-2 in all cases. The majority of deaths and grade III/IV toxicity occurred during cycle 1 and 2. Response to treatment and early survival analyses were previously presented with 20 months median follow-up (Lancet oncol 2011;12:460-468). Results: At the time of this analysis, The median follow-up time was 41 months and 75 (50%) patients were alive. The 4-year estimated overall survival (OS) was 49.3% [95% CI: 40.8-57.3%] and the median OS was 38 months. The 4-year estimated PFS, EFS and DFS were 41.4% [95% CI: 33.1-49.5%], 39.4% [95% CI : 31.2-47.5%] and 57.9% [95% CI : 47.3-67.2%] respectively.]. During the additional follow-up, 8 patients relapsed (10% of CR patients) and 17 died. No long term toxicity was recorded. In a multivariate analysis an albumin level ⬎35 g/l remained significantly associated with a longer survival. Conclusions: These results show that very old patients with DLBCL treated with RminiCHOP could express long-term survival and probably be cured. Regarding the DFS and despite the early toxicity, it seems crucial to obtain the best possible response. This long term analysis confirm that in patient aged over 80y with DLBCL and with PS from 0 to 2, RminiCHOP is the treatment cornerstone. Clinical trial information: NCT01087424.

8538


Changes in the tumor microenvironment associated with transformation in follicular lymphoma. Presenting Author: Jacob Paul Smeltzer, Mayo Clinic, Rochester, MN Background: Follicular lymphoma (FL) is a heterogeneous disease with a variable prognosis. Transformation to an aggressive lymphoma is associated with a poor prognosis. Previous studies have identified tumor microenvironment cells such as CD68⫹ macrophages, PD-1⫹ and FOXP3⫹ cells as prognostic in FL. However, results have been conflicting and infrequently address the risk of transformation. In this study we analyzed various components of the microenvironment and their association with transformation. Methods: Patients with FL that later transformed were identified through Mayo Clinic lymphoma database. Tissue specimens at diagnosis were stained with CD68, CD11c, CD21, CXCL13, FOXP3, PD-1 and CD14 and characterized by pattern of location and semi-quantitative cell content. Time to transformation (TTT) and overall survival (OS) were assessed by Kaplan-Meir analysis. Significant variables were further analyzed by cox proportional hazards model. Results: 58 patients were included with a median TTT of 4.7 years (range, 0.4-20). Presence of CD14⫹ cells vs absence and their location (follicular vs non-follicular) were associated with shorter TTT (4.5 vs 6.2 yrs., p⫽0.037 and 3.8 vs 5.9 yrs. p⫽ 0.027, respectively). The quantity of PD-1⫹ cell content was not associated with TTT or OS. However, localization of PD-1 to the follicle compared to diffuse was associated with a longer TTT (6.1 vs 3.6 yrs. p⫽0.033) and superior OS (9.7 vs 4.6 yrs. p⫽0.009). On multivariate analysis, the pattern of CD14 and PD-1 staining remained significantly associated with shorter TTT (Table). Conclusions: In follicular lymphoma, a diffuse pattern of PD-1⫹ cells is associated with inferior TTT and OS. CD14⫹ cells localized to the follicle is associated with a shorter TTT. After accounting for FLIPI score, both these factors remained significant. These results identify two independent predictors of the rate of transformation in follicular lymphoma and suggest it is location rather than quantity of CD14⫹ or PD-1⫹ cells that influence outcomes. Multivariate analysis. TTT FLIPI PD-1 CD14

OS

HR

P value

HR

P value

2.3 (CI 1.4-3.8) 1.9 (CI 1.0-3.4) 3.0 (CI 1.5-6.1)

0.001 0.045 0.004

1.7 (CI 1.0-2.9) 2.5 (CI 1.2-4.8) 1.4 (CI 0.6-2.9)

0.05 0.012 0.37

8537

527s


Secondary efficacy subanalysis by histology from the phase III BRIGHT study: First-line bendamustine-rituximab (BR) compared with standard R-CHOP/R-CVP for patients with advanced indolent non-Hodgkin lymphoma (NHL) or mantle cell lymphoma (MCL). Presenting Author: Ian Flinn, Sarah Cannon Research Institute, Nashville, TN Background: BR was previously reported to be statistically noninferior to R-CVP/R-CHOP for complete response rate in the treatment of patients with indolent NHL or MCL. Evaluation of time-to-event outcomes is immature. This subanalysis reports response by histology. Methods: Indolent NHL or MCL was histologically confirmed ⬍6 months before study enrollment in patients who were therapy-naïve. Patients were stratified according to predetermined standard treatment (R-CHOP or RECVP) and lymphoma type, then assigned to receive BR (28-day cycles: bendamustine 90 mg/m2 on days 1 and 2, rituximab 375 mg/m2on day 1) or standard treatment (21-day cycles at standard doses) for 6-8 cycles. Responses were assessed by a blinded independent review committee. The primary efficacy measure was noninferiority of BR complete response (CR) rate for evaluable patients with ⱖ1 postbaseline efficacy assessment. If the noninferiority threshold was met, superiority was assessed. Secondary measures included tolerability. Results: Of 447 patients enrolled in the study, 213 receiving BR and 206 receiving R-CHOP/R-CVP were evaluable with postbaseline data (Table). BR achieved a statistically noninferior CR rate compared with R-CHOP/R-CVP in patients with indolent NHL and MCL. Conclusions: In patients with treatment-naïve indolent NHL and MCL, BR achieved the primary endpoint of noninferior CR rate. Most CR rates were numerically, but not significantly, higher with BR. Small subgroup results should be interpreted with caution. Support: Teva BPP R&D, Inc. Clinical trial information: NCT00877006. Response rates. CR ⴙ partial response

CR n/N (%) Indolent NHL Follicular Lymphoplasmacytic Marginal zone MCL

BR

R-CHOP/R-CVP

CR ratio [95% CI]

BR

R-CHOP/R-CVP

49/178 (28) 45/148 (30) 0/5 5/25 (20) 17/34 (50)

43/174 (25) 37/149 (25) 1/6 (17) 4/17 (24) 9/33 (27)*

1.11 [0.78, 1.59] 1.23 [0.85, 1.78] 0.39 [0.02, 7.88] 0.84 [0.26, 2.66] 1.76 [0.91, 3.42]

173/178 (97) 147/148 (⬎99) 3/5 (60) 23/25 (92) 32/34 (94)

160/174 (92) 140/149 (94) 6/6 (100) 12/17 (71) 28/33 (85)*

* R-CHOP, n ⫽ 22.

8539


Total therapy 5 (TT5) for newly diagnosed high-risk multiple myeloma (HRMM): Comparison with predecessor trials total therapy 3a and 3b (TT3 a/b). Presenting Author: Saad Zafar Usmani, Myeloma Institute for Research and Therapy, Little Rock, AR Background: HRMM has not benefited from advances achieved in the remainder 85% with low-risk MM. In order to guard against relapses during previous drug-free intervals in TT3, TT5 was designed as a dose-dense and less dose-intense program. Here we are reporting for the first time on the TT5 outcomes in comparison with TT3a/b results in HRMM. Methods: TT5 called for M-VTD-PACE induction with HPC collection. This was followed by tandem autologous stem cell transplants (ASCT) with hybrid regimens Mel80 plus VRD-PACE, sandwiched in between were 2 inter-transplant cycles of MEL20-VTD-PACE. Maintenance consisted of 3 years of alternating VRD and VMD (M, melphalan). As relapses were observed during maintenance, bortezomib was increased from 1.3mg/m2 to 1.5mg/m2 weekly. Results were compared with HRMM treated with TT3a/b (n⫽40/ 37). Data were compared with TT3 HRMM, involving 77 patients. Overall survival and progression free survival was analyzed employing KaplanMeier curves. Cox regression modeling was done for univariate and multivariate analyses. Results: Of 59 patients enrolled in TT5, CR was 66% including 10% with s-CR. The 18-mo OS was 92% v 74% with TT3 (p⫽0.009), whereas PFS was similar at 67% and 69%, respectively. A newly developed GEP-5 model distinguished 8 patients with a 36-mo OS estimate of 20% versus almost 90% for the remainder (p⫽0.04). On multivariate analysis that included TT5 and TT3, our GEP80 low-risk score, TT5 (vs TT3) and age ⬍65yr were independent features linked to superior OS. Conclusions: This isthe first report of a dose-dense chemotherapeutic approach for newly diagnosed HRMM, which also introduced a hybrid Mel80-VRDPACE hybrid preparative regimen for ASCT. TT5 represents an advance in the management of GEP70-defined HRMM compared to predecessor trials TT3a/b for similar patients, with significant improvement in overall survival and tolerability compared with TT3 a/b. Clinical trial information: NCT00081939, NCT00572169, NCT00869232.


528s 8540

Lymphoma and Plasma Cell Disorders Poster Discussion Session (Board #20), Mon, 1:15 PM-5:15 PM and 4:45 PM-5:45 PM

Early versus delayed autologous stem cell transplant (ASCT) in patients receiving induction therapy with lenalidomide, bortezomib, and dexamethasone (RVD) for newly diagnosed multiple myeloma (MM). Presenting Author: Ajay K. Nooka, Division of BMT, Emory University, Winship Cancer Institute - Hematology and Medical Oncology, Atlanta, GA Background: Lenalidomide, bortezomib and dexamethasone (RVD) is an active, tolerable induction regimen with superior response rates (ⱖVGPR rates of 80%) in newly diagnosed MM pts. However, the optimal timing of ASCT with this triplet combination is uncertain. We have evaluated our institutional experience to provide an insight for the best timing of ASCT, where specific patients were offered delayed ASCT based on risk, response and toxicity of therapy. Methods: 222 consecutive transplant-eligible pts with newly diagnosed MM that received at least 3 cycles of RVD and harvested stem cells were included in the analysis from May 2007 until October 2011. Patients underwent early ASCT (received planned ASCT immediately after stem cell harvest, n⫽136) or delayed transplant (received planned maintenance therapy after collection with intent to proceed with ASCT at first relapse, n⫽86). Results: Median age of the patients at the time of diagnosis is 60.5 yrs (32-77) vs. 60 yrs (22-73) for early vs. delayed groups. ISS stage 3 disease was seen in 31% patients and 10% patients; high risk cytogenetics were seen in 11% and 7% patients in early vs. delayed groups, respectively. Median time from initiation of induction therapy to ASCT in early group is 5.45 months (range, 3.19-12.68 months). In the delayed SCT group, 28 patients underwent ASCT at a median time of 26.21 months (range, 13.67-41.72 months) from initiation of therapy. At a median follow up of 32 months, 5-year overall survival from diagnosis was 68% and 88% in patients undergoing early and delayed ASCT, respectively (p ⫽ 0.106). Conclusions: Transplantation-eligible patients who receive RVD as initial therapy followed by early vs. delayed ASCT result in comparable overall survival. In carefully selected newly diagnosed myeloma patients with lower ISS stage receiving RVD as induction therapy, planned delayed ASCT results in 5-year survival rates close to 90%.

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Beneficial effect of complete response and type of therapy in multiple myeloma. Presenting Author: Shivlal Pandey, Mayo Clinic, Rochester, MN Background: Achievement of a complete response (CR) to treatment is an important predictor of outcome for patients (pts) with myeloma (MM). The goal of the current study was to assess whether the treatment that resulted in CR has any impact on the outcomes. Methods: We identified 462 pts with MM, who fulfilled the IMWG criteria for CR, seen at Mayo Clinic between 1991 and 2011. The treatment was classified into groups by the regimen that led to CR (Table), and also based on whether an autologous stem cell transplant (ASCT) was part of the regimen. The remaining 21 pts had a variety of regimens and are not included in the Table. Results: The median age at diagnosis was 58.5 yrs (27.1– 82.3 yrs) with 56% males. The overall survival (OS) from diagnosis for the entire cohort was 10.7 yrs (95% CI; 9.3, NR). The median interval from diagnosis to the recorded CR was 10.3 mos (range 1- 170), with 272 (58.4%) and 385 (82.7%) obtaining a CR in ⬍12 mos and ⬍24 months from diagnosis. We first compared the outcomes based on whether ASCT was part of the regimen; 328 had an ASCT while 117 pts received only chemotherapy. Median time to progression (TTP) following a CR was 5.1 yrs for the ASCT group compared with 5.5 yrs for the rest (P⫽0.3). Median OS from CR was 9.1 yrs for the ASCT group and 7.5 yrs for the rest (P⫽0.5) and OS from diagnosis was 10.1 yrs for the ASCT group and 12.6 for the rest (P⫽0.5). Examining the outcomes based on the regimen utilized showed that the TTP and OS from CR as well as OS from diagnosis were similar for all the groups (Table). Among pts who had a CR within a year of diagnosis, there were no differences in terms of the TTP or OS from the onset of CR or from diagnosis between the ASCT vs. chemotherapy groups or between the different regimens (P⫽NS for all comparisons). Conclusions: The current study highlights an important message regarding CR in MM. The results suggest that the prognostic value of CR is independent of the nature of therapy, and likely reflects the contribution of disease biology to obtaining a CR. Median from CR (yrs) Regimen Dexamethasone only Lenalidomide based Bortezomib based Lenalidomide ⴙ bortezomib based Thalidomide-based VAD

8543

N 48 145 101 41 72 36

TTP 4.8 5.5 4.5 3.5 5.0 4.3

OS 8.0 NR NR NR 8.7 12.1

Median from diagnosis (yrs) OS 8.7 NR 9.2 NR 10.7 12.6


Phase (Ph) I/II study of elotuzumab (Elo) plus lenalidomide/dexamethasone (Len/dex) in relapsed/refractory multiple myeloma (RR MM): Updated Ph II results and Ph I/II long-term safety. Presenting Author: Sagar Lonial, Emory University School of Medicine, Atlanta, GA

Treatment outcome with the combination of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) for newly diagnosed multiple myeloma (NDMM) after extended follow-up. Presenting Author: Andrzej J. Jakubowiak, University of Chicago Medical Center, Chicago, IL

Background: Elotuzumab (Elo) is a humanized anti-CS1monoclonal antibody that enhances natural killer cell mediated antibody dependent cellular cytotoxicity of CS1 expressing myeloma cells. This study included a dose finding Ph I cohort (N⫽28) and a Ph II cohort (N⫽73). Here we update Ph II data and provide long term safety data from both cohorts. Methods: Patients (pts) treated with ⱖ1 (Ph I) or 1–3 (Ph II) prior therapies received Elo ⫹ Len/dex as described previously (Lonial JCO 2012; Richardson ASH 2012) until disease progression, unacceptable toxicity, or death. All pts received a premedication regimen including methylprednisolone, diphenhydramine or equivalent, ranitidine or equivalent, and acetaminophen to mitigate infusion reactions. Adverse events (AEs) in Ph I/II pts occurring ⱕ18 months (mo) (N⫽98) were compared to AEs with a ⬎18 mo onset in a subgroup of pts treated ⬎18 mo (n⫽49). This safety analysis excluded 3 Ph I pts treated with Elo 5 mg/kg. Results: In the Ph II cohort (median 63 yr), objective response rate (ORR) was 84%; 92% with 10 mg/kg (n⫽36) and 76% with 20 mg/kg (n⫽37). At a median follow-up of 20.8 mo, median progression free survival (PFS) was not reached (10 mg/kg) and 18.6 mo (20 mg/kg). Most common treatment emergent grade ⱖ3 AEs were lymphopenia (19%), neutropenia (18%), thrombocytopenia (16%) and anemia (14%). Most common grade 3/4 AEs emerging ⱕ18 vs ⬎18 mo in Ph I/II cohorts are shown (Table). 15 pts discontinued due to AEs; none after 18 mo of treatment. There were 4 second primary malignancies; none were reported after 18 mo. Conclusions: Elo 10 mg/kg ⫹ Len/dex was generally well tolerated and resulted in a high ORR and encouraging PFS in pts with RR MM. AEs emergent after 18 mo of therapy were consistent with AEs during the initial 18 mo. Updated Ph II safety/efficacy data and long term safety data from Ph I/II cohorts will be presented.

Background: We previously reported results from a phase 1/2 trial of CRd in NDMM (NCT01029054), demonstrating a high rate (42%) of stringent complete response (sCR) and overall favorable efficacy /safety after a median of 12 cycles of treatment (tx) and a median follow-up of 13 mo (Jakubowiak et al Blood, 2012). Here we report updated results after extended tx and additional 12 mo of follow-up. Methods: Patients (pts) received 28-day (d) cycles of carfilzomib (CFZ) 20 –36 mg/m2 IV (d1, 2, 8, 9, 15, 16), lenalidomide (LEN) 25 mg PO (d1–21), and dexamethasone 40/20 mg PO wkly (cycles 1– 4/5– 8). For cycles 8 –24, CRd was given with a modified CFZ schedule (d1, 2, 15, 16) and then LEN alone after cycle 24. Stem cell transplant was an option after cycle 4. Response was assessed by IMWG plus nCR. Results: As of Nov 2012, 53 pts had received a median of 22 CRd cycles (range 2–24); 7 pts opted for transplant; 24 continued LEN maintenance for median 8 mo (range 1–10). Median follow-up was 25 mo (range 5–37). With extended tx, the CR rate was 64%; sCR improved from 42% to 53%, ⱖnCR from 62% to 72%, and ⱖVGPR from 81% to 87% (follow-up 13 vs 25 mo); ⱖPR remained at 98%. Immunophenotypic CR (IMWG) was achieved in 22/26 evaluated pts. Of pts in sCR, 25% had high-risk cytogenetics per IMWG. In pts who did not proceed to transplant (n⫽46), the sCR was 59%, CR 70%, ⱖnCR 78%, ⱖVGPR 91%, and ⱖPR 100%. Over the course of tx, depth of response improved. Median time to ⱖVGPR was 4 cycles (range 2–17), ⱖnCR 4.5 cycles (range 2–15), and sCR 10 cycles (range 4 –30); 2 pts converted to sCR during LEN maintenance. At 2 years, the estimated PFS rate was 94% and OS was 98%; for pts with sCR, rates were 96% and 100%, respectively. Adverse event types, rates, and dose modifications during extended tx were comparable with those previously reported. There was 1 death off study due to disease progression. Conclusions: Extended follow-up showed that depth of response continued to improve over the course of prolonged CRd tx, resulting in exceptional CR, sCR, and PFS. Extended tx continued to be well tolerated. The results compare favorably with historical studies in both transplant and non-transplant NDMM. Clinical trial information: NCT01029054.




Lenalidomide (LEN)-melphalan-prednisone induction followed by LEN maintenance (MPR-R) in newly diagnosed multiple myeloma (NDMM) elderly patients (Pts) with moderate renal impairment (RI): MM-015 trial post-hoc analysis. Presenting Author: John V. Catalano, Frankston Hospital and Department of Clinical Haematology, Monash University, Melbourne, Australia Background: The MM-015 pivotal phase III trial showed significant PFS benefit for MPR-R (31 mos) vs. MPR (14 mos) or MP (13 mos; both p ⬍ 0.001) followed by placebo in NDMM pts aged ⱖ 65 years. As NDMM pts with RI have poor prognosis, this retrospective analysis studied the efficacy and safety of MPR-R in pts with creatinine clearance (CrCl) ⬍ 60 mL/min. Methods: LEN starting dose for induction/maintenance was 10 mg/day (D1–21 of a 28-day cycle). Dose adjustments were not recommended for pts with RI. CrCl was calculated using the Cockcroft-Gault equation. Pts with severe RI (serum Cr ⬎ 2.5 mg/dL [221 ␮mol/L]) were excluded from the trial. Results: Pts with CrCl ⬍ 60 mL/min (median 47, interquartile range [IQR] 38 –55) were included in this analysis: 51% MPR-R, 45% MPR, and 49% MP. Median PFS was significantly higher with MPR-R (26 mos [95% CI 14 – 48]) vs. MPR (13 mos [95% CI 12–15]) or MP (14 mos [95% CI 12–16]; both p ⬍ 0.001). In a Cox proportional model of PFS, CrCl ⬍ 60 mL/min was not identified as a negative prognostic factor (p ⫽ 0.69). The most common Gr 4 adverse events (AEs) were hematologic and occurred predominantly during induction and are shown in the Table for pts with or without moderate RI. The number of deaths on study was similar: 10% (MPR-R), 7% (MPR), and 8% (MP); deaths associated with RI or disease progression were reported in ⱕ 1% of pts with RI across the arms. Conclusions: The benefit of continuous LEN treatment with MPR-R is not compromised in NDMM pts with moderate RI, consistent with the overall trial results. CrCl and AEs should be monitored closely in this population. Clinical trial information: NCT00405756.

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Results after long-term follow-up from the CAN2007 phase I/II study of weekly or twice-weekly bortezomib in patients (pts) with relapsed systemic light-chain (AL) amyloidosis. Presenting Author: Donna Ellen Reece, Princess Margaret Hospital, Toronto, ON, Canada Background: Data from multiple studies suggest that bortezomib alone or in combination regimens is active in newly diagnosed and relapsed AL. CAN2007 (NCT00298766) was the first prospective study of single-agent bortezomib in relapsed AL. Here we report outcome data at study closure after a median follow-up of 51.8 mos (median 46.1– 66.1 mos). Methods: 70 pts received bortezomib 0.7, 1.0, 1.3, or 1.6 mg/m2 on days 1, 8, 15, and 22 of 35-day cycles (QW) or 0.7, 1.0, or 1.3 mg/m2 on days 1, 4, 8, and 11 of 21-day cycles (BIW) for up to 8 cycles (or longer in pts with evidence of ongoing clinical benefit). The maximum tolerated dose was not reached on either schedule; 18 and 34 pts were treated at the maximum planned doses of 1.6 mg/m2 QW and 1.3 mg/m2BIW, respectively, and 18 pts were treated at lower doses. Posttreatment, pts were followed every 6 weeks until disease progression, and then every 3 mos for survival during the long-term follow-up phase. Results: Pts received a median (range) of 8 (1–39), 6 (1–57), and 8 (3–57) cycles of bortezomib in the 1.6 mg/m2 QW, 1.3 mg/m2 BIW, and lower-dose groups, respectively; overall, 32 (46%) pts received ⱖ8 cycles, and 4 pts were still on treatment and had received ⱖ39 cycles at study closure. Hematologic responses and outcomes are summarized below. Median (range) follow-up for survival was 51.8 (1– 68), 46.1 (1– 61), and 66.1 (2– 80) mos, and 7, 12, and 9 pts have died, in the 1.6 mg/m2 QW, 1.3 mg/m2BIW, and lower-dose groups, respectively. Median overall survival (OS) in all 70 pts was 62.7 mos, and 4-yr OS rate was 67.3%; data by dose group are shown below. Conclusions: Single-agent bortezomib produces durable hematologic responses and promising long-term OS data in pts with relapsed AL. Clinical trial information: NCT00298766. Bortezomib dose groups

AEs during induction according to baseline renal function MPR-R CrCl (mL/min)

CrCl > 60 (n ⴝ 71)

Median CrCI 84 (70–95) (mL/min) (IQR) Gr 4 hematologic AEs (%) Neutropenia 32 Thrombocytopenia 7 Anemia 1 Leukopenia 4 Febrile neutropenia 0 Gr 3–4 nonhematologic AEs (> 5%) (%) Pneumonia 1 Fatigue 1 Asthenia 0 Hypokalemia 3 Bone pain 1 Rash 4

8546

MPR

MP

CrCl < 60 (n ⴝ 77)

CrCl > 60 (n ⴝ 82)

CrCl < 60 (n ⴝ 69)

CrCl > 60 (n ⴝ 77)

CrCl < 60 (n ⴝ 75)

47 (38–55)

76 (68–85)

46 (37–54)

79 (68–92)

47 (34–55)

35 16 4 4 3

27 6 1 2 0

38 20 4 9 3

3 1 1 1 0

12 7 1 1 0

1 9 4 4 4 5

1 0 1 2 4 2

9 4 6 6 4 9

5 0 1 0 5 3

1 5 0 1 3 1


Patterns of failure in advanced-stage diffuse large B-cell lymphoma (DLBCL) patients treated with R-CHOP chemotherapy and the emerging role of consolidative radiotherapy. Presenting Author: Zheng Jane Shi, Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA Background: The role of consolidative radiotherapy (RT) after a complete response (CR) to R-CHOP for stage III-IV DLBCL patients is unclear. The goal of our study is to evaluate the Emory experience when consolidative RT is delivered to initial presenting nodal and extranodal sites or bulky sites in these patients. Methods: From 01/2000 to 05/2012, 211 histologically confirmed DLBCL patients with stage III-IV disease who received R-CHOP were identified at Emory University. Patterns of failure for patients who achieved CR to R-CHOP were analyzed. Local control (LC), distant control (DC), progression free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier method and compared between patients who received R-CHOP alone versus R-CHOP plus consolidative RT using Log-rank test. Multivariate analyses were also performed using Cox proportional hazards model. Results: 163 patients had detailed treatment records. After a median 6 cycles of R-CHOP, 110 patients (67.5%) achieved CR and were entered for analysis. Fourteen patients (12.7%) received consolidative RT to a median dose of 30.6 Gy as part of initial management. With a median follow up time of 32.9 months, 43.8% of patients who received R-CHOP alone failed at the initial presenting sites with or without distant recurrence (DR), whereas isolated DR only occurred in 3.2% of these patients. Consolidative RT was associated with significantly improved LC (91.7% vs 48.8%, p⬍0.0001), DC (92.9% vs 71.9%, p⬍0.0001), PFS (85.1% vs 44.2%, p⬍0.0001) and OS (92.3% vs 68.5%, p⬍0.0001) at 5-years when compared to patients with R-CHOP alone. In addition, the in-field control rate was 100% within irradiated sites for patients who received consolidative RT. On multivariate analysis, consolidative RT and non-bulky disease were predictive of increased LC and PFS, whereas bone marrow involvement was associated with increased risk of DR and worse OS. Conclusions: 44% of patients with advanced stage DLBCL failed at initial presenting sites despite achieving a CR to R-CHOP. Incorporation of consolidative RT as part of upfront treatment in these patients was associated with improved LC and PFS.

Best confirmed hematologic response rate, % Complete response, % Hematologic response duration >1 yr, % of responders Median (range) follow-up for hematologic disease, mos 2-yr hematologic disease progression-free rate, % Median OS, mos 4-yr OS rate, %

8547

1.6 mg/m2 QW, Nⴝ18

1.3 mg/m2 BIW, Nⴝ34

Lower doses, Nⴝ18

68.8

66.7

38.9

37.5 80

24.2 80

16.7 83.3

21.6 (0–35) 72.2

11.3 (0–18) 76.8

9.9 (2–49) 73.8

62.1 75.0

Not reached 63.0

63.2 69.7


The LIMD1-MYBL1 index as a composite marker for subtype classification and survival prediction for diffuse large B-cell lymphoma patients. Presenting Author: Qinghua Xu, Institut Mérieux Laboratory, Fudan University Cancer Hospital, Shanghai, China Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of B-cell lymphomas with wide variations in patient survival. Through gene expression profiling, DLBCL can be stratified into two major cell-of-origin subtypes with distinct prognoses: the favorable germinal center B-cell-like (GCB) and the unfavorable activated B-cell-like (ABC) DLBCLs. However, the current cell-of-origin signatures are not suitable for use in routine clinical practice. Our study aimed to identify a novel biomarker to facilitate the translation of research into clinical practice. Methods: We performed an integrative analysis of seven independent cohorts comprising 1,682 patients. The DLBCL-1 cohort was used for signature identification. The identified signature was then tested in the DLBCL-2 to DLBCL-7 cohorts. Results: Two genes (LIMD1 and MYBL1) were significantly differentially expressed between the ABC and GCB subtypes. We integrated these genes into a composite marker, the LIMD1-MYBL1 Index. In seven independent cohorts, the average concordance rate between the LIMD1MYBL1 Index and the cell-of-origin signature classification was 87% (range, 77% to 94%). Furthermore, the LIMD1-MYBL1 index is an independent prognostic factor for patients from different populations and for patients treated with a variety of therapies (Table). Conclusions: We identified the LIMD1-MYBL1 Index that has clinical value for DLBCL subtype classification and prognosis. Although little is known about the oncogenic roles of these genes, our findings prompt further research on the molecular mechanisms of DLBCL. Subtype classification Cohort DLBCL-1

DLBCL-2

DLBCL-3

DLBCL-4

DLBCL-5

DLBCL-6

DLBCL-7

Survival prediction

Subtype

COO

LIMD1-MYBL1

Concordance

Hazard ratio (95%CI)

P value

ABC GCB Unclassified ABC GCB Unclassified ABC GCB Unclassified ABC GCB Unclassified ABC GCB Unclassified ABC GCB Unclassified ABC GCB Unclassified

167 183 64 34 85 57 55 74 37 71 144 56 20 40 9 214 237 47 59 13 16

208 206

87%

2.3 (1.7-3.2)

0.001

85 91

84%

2.1 (1.3-3.5)

0.004

84 82

89%

2.0 (1.2-3.4)

0.01

134 137

85%

NA

NA

31 38

88%

4.5 (1.3-16.5)

0.02

257 241

77%

NA

NA

45 43

94%

2.4 (1.0-5.6)

0.04


530s 8548

Lymphoma and Plasma Cell Disorders General Poster Session (Board #47C), Sun, 8:00 AM-11:45 AM

8549


Dexabeam versus ICE salvage regimen prior to autologous transplantation for relapsed or refractory aggressive peripheral T-cell lymphoma: A retrospective evaluation of parallel patient cohorts of one center. Presenting Author: Jan-Henrik Mikesch, University Hospital Münster, Münster, Germany

Comparative outcomes of splenectomy and rituximab-based chemotherapy in elderly patients with splenic marginal zone lymphoma. Presenting Author: Adam J. Olszewski, Alpert Medical School of Brown University, Providence, RI

Background: High-dose chemotherapy (HDT) followed by autologous stemcell transplantation (ASCT) is considered standard in the treatment of patients with relapsed or refractory aggressive peripheral T-cell lymphoma (PTCL). However, the optimal salvage regimen before ASCT has not yet been established. Methods: We retrospectively analyzed 31 patients with relapsed or refractory aggressive PTCL after anthracycline based first-line chemotherapy who received either DexaBEAM (n⫽16) or ICE (n⫽15) regimen as first salvage chemotherapy followed by HDT and ASCT between 1996 and 2009. The median patient age was 46 years (range, 18-66) in the DexaBEAM group and 40 years (range, 17-59) in the ICE group. Patients were included independent of WHO stage and IPI score. Results: The overall response rate (OR) was significantly higher for patients treated with DexaBEAM (69%) as compared to the ICE group (20%; P⫽0.01), with higher complete response (CR; 38% vs. 7%) as well as partial response (PR; 31% vs. 13%) rate. Changing regimen due to failure of the first salvage therapy, 12 patients initially receiving ICE still achieved an OR of 58% (33% CR, 25% PR) with DexaBEAM as second salvage therapy, whereas in 3 patients receiving ICE after DexaBEAM failure only 1 patient achieved an OR (1 PR). Median progression-free survival (PFS) was significantly higher in the DexaBEAM group (6.4 vs. 2 months; P⫽0.01). Median overall survival (OS) was not different between the two groups (22.8 vs. 29.8 months; P⫽0.72), most likely due to the good response rate of patients to DexaBEAM as 2nd salvage regimen after failure of ICE chemotherapy. Major adverse event in both groups was myelosuppression with higher but tolerable treatment-related toxicity for patients in the DexaBEAM group. Conclusions: In this retrospective comparison DexaBEAM salvage chemotherapy was superior to ICE for patients with relapsed or refractory aggressive PTCL for remission induction prior to autologous transplantation, with higher but manageable treatment-related toxicity.

Background: Despite advances in diagnosis and therapy, over 50% of patients with splenic marginal zone lymphoma (SMZL) undergo splenectomy. The objective of this retrospective study was to compare outcomes in SMZL patients undergoing surgery or rituximab-containing chemoimmunotherapy (RCIT) based on the Surveillance, Epidemiology, and End ResultsMedicare linked database. Methods: Records of 521 SMZL patients diagnosed between 2000 and 2007 were extracted, excluding cases with incomplete Medicare coverage. Two treatment arms were defined by receipt of RCIT or splenectomy within 2 years of diagnosis. Factors confounding treatment selection or prognosis were balanced in both arms using a propensity score. The primary endpoint was lymphoma-related death, estimated using competing risk models, with overall survival (OS) and toxicities as secondary endpoints. Results: Of the 341 eligible patients (median age, 77 years), 67 (20%) were untreated, while 169 (50%) underwent splenectomy and 97 (28%) chemotherapy (64% single-agent rituximab) at median 1.4 months from diagnosis. Stage IE, treatment in a teaching hospital and good performance status were associated with a preference for splenectomy. There was no evidence of significantly different risk of lymphoma-related death after treatment with RCIT rather than surgery (hazard ratio, HR, 1.10, 95%CI 0.56-2.18, P⫽0.78). There was an excess of early mortality after splenectomy (7% within 90 days) but more later events with RCIT (OS at 3 years 69% vs. 67%, respectively). More patients required chemotherapy after surgery (38%) than vice versa (14%, P⬍0.001). Nursing home admissions were more common after splenectomy (22%, P⫽0.03). There were more inpatient hospitalizations after multidrug RCIT (P⫽0.003), but not after rituximab alone (P⫽0.65). Conclusions: Although SMZL is considered indolent, most elderly patients required treatment soon after diagnosis in this population-based study. Survival outcomes were similar after either RCIT or splenectomy. Complications of surgery or combination chemotherapy are significant, suggesting rituximab alone as a more suitable option in elderly patients.

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Nodular lymphocyte-predominant and classical Hodgkin lymphoma subtypes: Differences in biology, survival, and impact of radiotherapy. Presenting Author: Shihab Ali, Alpert Medical School of Brown University, Providence, RI

Phase I study of a novel humanized anti-CD20 antibody, BM-ca, in patients (pts) with relapsed or refractory indolent B-cell non-Hodgkin lymphoma (B-NHL) pretreated with rituximab. Presenting Author: Kensei Tobinai, National Cancer Center Hospital, Tokyo, Japan

Background: Hodgkin lymphoma (HL) is a heterogeneous disease, but differences between nodular lymphocyte predominant (NLPHL) and classical (CHL) subtypes were previously studied in small cohorts preventing adjustment for confounders. We studied those differences based on the Surveillance, Epidemiology and End Results (SEER) program data. Methods: We analyzed SEER HL cases aged 16 years and over, diagnosed between 1995 and 2009. We studied the following endpoints: crude probability of HL-related death (HLRD), relative survival (using individual data in multivariate flexible parametric models) and risk of secondary malignancies (using competing risk regression). We studied the impact of radiotherapy (RT) in early-stage disease using a propensity score, adjusting for treatment selection and immortal time bias. Results: We identified 25,903 patients, with disparate age, race and stage distributions between subtypes. In a multivariate model, NLPHL demonstrated significantly better crude and net survival outcomes (Table), but in contrast to all CHL subtypes, it showed a steady increase in mortality rate after 2 years. The risk of secondary non-Hodgkin lymphoma was significantly higher in both NLPHL (hazard ratio, HR, 2.28, P⫽0.002) and lymphocyte-rich (LR) CHL (HR 2.08, P⫽0.01) than in nodular sclerosis (NS). The risk of other secondary malignancies did not differ between subtypes. After balancing confounding factors in treatment arms, RT in stage I/II was associated with improved survival in NS (HR, 0.78, P⫽0.001) and LR-CHL (HR 0.36, P⬍0.001), but not in NLPHL (HR 0.98, P⫽0.94) or in the remaining CHL subtypes. Conclusions: Studies of NLPHL and CHL subtypes should account for their disparate biology and clinical course. Prospective evaluation of NLPHL treatment strategies without RT is justified.

Background: BM-ca is a novel humanized type-I/II anti-CD20 antibody, which is effective against rituximab-resistant cell line RC-K8, and has more potent anti-cell-proliferation activity than rituximab or ofatumumab when combined with cancer chemotherapeutics. The aim of this study was to evaluate the safety, efficacy, and PK profile of BM-ca in pts with indolent B-NHL. Methods: A total of 12 pts {age: median 61 (50-73), number of prior regimens: median 2 (1-13)} with indolent B-NHL relapsed after or refractory to rituximab-containing therapy underwent treatment by IV infusion of BM-ca weekly for 4 weeks at a dose of 5, 10, or 15 mg/kg. Initially, 3 pts were to undergo BM-ca therapy at a dose of 5 mg/kg using the conventional 3⫹3 dose escalation design. To minimize infusion reactions (IRs), pts were pretreated with acetaminophen and d-chlorpheniramine maleate. Allopurinol and/or hydrocortisone were also administered if necessary. Infusion was started at 50 or 100 mg/h and was gradually increased to a maximum of 400 mg/h. Since no DLTs were observed, all 12 pts completed weekly 4 doses of BM-ca. Results: The most frequent AE was IRs (11 of 12 pts), which occurred mostly in the first infusion, and the highest grade of AE was neutropenia (grade 4 in one pt of 15 mg/kg after the last infusion). Anti-BM-ca antibodies were not detected. Of the 12 pts examined, 2 achieved CR (10 mg/kg) and 2 PR (15 mg/kg); these 4 pts had follicular histology. The remaining 8 pts including one each of extranodal marginal zone, nodal marginal zone, and small lymphocytic histology were judged to achieve SD. The CR states in 2 pts continued at least ⬎14 and ⬎11 months, respectively. The PK properties of BM-ca were comparable to those of other naked anti-CD20 antibodies including rituximab (AUC and Cmax were proportional to the doses; Vdss⬇4 L; t1/2⬇750 h). Since at 10 mg/kg the response was the best and no grade 4 AE observed, 10 mg/kg was suggested as a recommended phase II dose. Conclusions: Four weekly IV administration of BM-ca up to 15 mg/kg was well tolerated and safe with promising preliminary anti-lymphoma activity in pts with indolent B-NHL. Further evaluation is warranted. Clinical trial information: 000004805.

Subtype NLPHL LR-CHL NS-CHL Mixed cellularity Lymphocyte-depleted

N

5-year risk of HLRD (95% CI)

P

Excess HR (95% CI)

1,018 806 15,387 3,558 350

5.6% (3.7-8.0) 14.6% (11.6-18.0) 13.2% (12.6-13.9) 25.3% (23.6-27.1) 48.9% (42.8-54.7)

⬍0.001 0.44 Reference ⬍0.001 ⬍0.001

0.29 (0.17-0.48) 0.82 (0.65-1.03) 1 1.18 (1.08-1.29) 2.17 (1.83-2.59)

P ⬍0.001 0.09 ⬍0.001 ⬍0.001




Impact of time from diagnosis to initiation of curative chemotherapy on survival of patients with diffuse large B-cell lymphoma (DLBCL). Presenting Author: Kevin A. Hay, Department of Medicine, University of British Columbia, Vancouver, BC, Canada Background: DLBCL is potentially curable with combination chemotherapy such as CHOP-R. Although it is generally regarded appropriate to start chemotherapy promptly after diagnosis, the impact of the time from diagnosis to treatment initiation on treatment outcome is unknown. Methods: Patients diagnosed with DLBCL and treated with at least one cycle of CHOP-R with curative intent during 2003 – 2008 in British Columbia were identified in the Lymphoid Cancer Database. Additional demographic data were obtained from the BC Cancer Registry. The BC Cancer Agency provincial pharmacy database was used to obtain dates of chemotherapy administration. The impact of the time interval from the date of pathologic diagnosis to treatment on overall survival (OS) and progression-free survival (PFS) was evaluated. Results: A total of 793 patients were identified: 199 (25%) received CHOP-R ⬍2 weeks after diagnosis, 244 (31%) at 2-4 weeks, 293 (37%) at 5-8 weeks, and 57 (7%) at ⬎8 weeks. High international prognostic index, primary mediastinal DLBCL, and hospitalization at the time of CHOP-R start were associated with earlier initiation of chemotherapy (p⬍0.001 for all factors). Distance to chemotherapy from home (p⫽0.237), rural vs. urban location (p⫽0.952), geographic region (p⫽0.458), and median household income (p⫽0.127) were not associated to treatment start. Five-year PFS and OS respectively were 54% (SD 4%) and 61% (SD 4%) for treatment ⬍2 weeks, 63% (SD 3%) and 66% (SD 3%) for 2-4 weeks, 70% (SD 3%) and 74% (SD 3%) for 5-8 weeks, and 60% (SD 7%) and for 61% (SD 8%) ⬎8 weeks, p⫽0.006 (PFS) and p⫽0.024 (OS). A multivariate analysis demonstrated no significant difference between the groups. Conclusions: In a publicly funded healthcare system, earlier initiation of chemotherapy was strongly associated with poor prognostic factors, as well as inferior PFS and OS. The timing of chemotherapy initiation appears to be related to clinical factors instead of system or socioeconomic barriers. Notwithstanding the lack of detrimental outcomes in those commencing CHOP-R after 8 weeks, clinicians should endeavor to initiate curative chemotherapy as soon as possible after a diagnosis of DLBCL is established.

8554


Dose-dense R-CHOP (administered every 2 weeks) with sargramostim in patients with newly diagnosed diffuse large B-cell lymphoma. Presenting Author: Preeti Chaudhary, University of Southern California Keck School of Medicine, Los Angeles, CA Background: R-CHOP administered every 3 weeks is standard of care for the treatment of diffuse large B-cell lymphoma (DLBCL). There are conflicting reports regarding the superiority of dose dense (DD) regimen (R-CHOP administered every 2 weeks), compared to the standard R-CHOP regimen. In a Phase II study, the tolerability and efficacy of DDRCHOP⫹Sargramostim was evaluated. Methods: All patients received intravenous rituximab, 375 mg/m2; cyclophosphamide, 750 mg/m2; doxorubicin, 50 mg/m2 and vincristine, 1.4 mg/m2 on day 1; prednisone 100 mg orally on days 1-5 and sargramostim 250 mg/m2subcutaneously on days 3-13. Chemotherapy cycles were repeated every 2 weeks. Results: We studied50 newly diagnosed, previously untreated DLBCL patients (median age 54.1 years, range 21.4-80.3 years). Stage III and IV disease was noted in 12 (24%) and 29 (58%) patients, respectively. Baseline characteristics included the following: high-intermediate or high-risk IPI score (n⫽38, 76%), extranodal involvement (n⫽32, 64%), bone marrow infiltration (n⫽5, 10%), B-symptoms (n⫽23, 46%), median LDH level (272, range 118-3797) and good baseline performance status (n⫽45, 90%). The median follow up from the start of treatment was 12.7 months (range 0.1-41.4 months). Among the 46 patients evaluated for response, complete response (CR) or unconfirmed CR (CRu) was observed in 36 (78%) patients, partial response (PR) or an unconfirmed PR in 9(20%) patients and 1 patient had stable disease. The probability of overall survival (OS) at 18 months was 0.84. The probability of disease free survival in complete responders at 9 months was 0.89. Neutropenia was the most common hematological toxicity and accounted for delays in 40 (20%) treatment cycles. There were no episodes of fever/sepsis in the 33 patients (66%) with grade 3 or 4 neutropenia. IgG, IgA and IgM levels decreased during therapy and returned to normal in 2-4 months post therapy. No opportunistic infections were reported. Conclusions: The administrationof DDRCHOP⫹Sargramostim regimen is safe, tolerable and effective in patients with newly diagnosed DLBCL. However, neutropenic episodes were significant, accounting in many cases for treatment delays.

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Radiotherapy for nasal cavity and Waldeyer ring natural killer/T-cell lymphoma: Analysis in 131 patients. Presenting Author: Yuan Zhu, Zhejiang Cancer Hospital, Hangzhou, China Background: Theaim of this study was to evaluate the efficacy and prognosis of chemotherapy and radiotherapy for patients with nasal cavity and Waldeyer ring natural killer/T cell lymphoma. Methods: Records of 131 patients who received chemotherapy or radiotherapy or chemoradiotherapy at Zhejiang Cancer Hospital between 2000 and 2010, were retrospectively reviewed. Ninety-eight patients received chemoradiotherapy. Thirty patients received radiotherapy, and three patients received chemotherapy. All patients had pathology and immunohistochemistry diagnosis. According to the Ann Arbor Staging System, majority of patients were staged as IE stage (116/131). 14 patients presented with IIE stage, and 1 IIIE stage. Thirty-four patients had B symptoms. Results: 109 patients were with nasal cavity NK/T cell lymphoma, and 22 patients with Waldeyer ring NK/T cell lymphoma. Complete response (CR) was achieved in 116 (89%) patients. The 5-year overall survival (OS) rate and disease-free survival (DFS) rate for all patients were 62.7% and 53.5%, respectively. 5-year OS in patients with RT dose ³a50Gy and ⬍ 50Gy were 64% and 45.4% respectively (p ⫽0.024). No survival difference was observed between patients with nasal cavity and Waldeyer ring, treated with radiotherapy and chemoradiotherapy, with or without B symptoms, CD56(⫹) and CD56(-), and between stage IE and IIE patients. On multivariate analysis, the level of lactate dehydrogenase (LDH) before treatment and dose of RT were correlated with prognosis (p⬍0.05). Conclusions: Radiotherapy, as the primary therapy, can result in a favorable outcome in the treatment of nasal cavity and Waldeyer ring natural killer/T cell lymphoma. The patients with the lower level of LDH before treatment, RT dose ⱖ50Gy had better prognosis. Addition chemotherapy to radiotherapy didn’t improve the survival.

8555


Interim FDG PET/CT to predict progression-free survival (PFS) better than clinical and baseline metabolic measurements in Hodgkin lymphoma (cHL). Presenting Author: Ashley Knight-Greenfield, Icahn School of Medicine at Mount Sinai, New York, NY Background: Previous studies in cHL have demonstrated that conventional methods to risk stratify patients into various prognostic groups and predict PFS may not be sufficient to individualize therapy. Metabolic parameters using FDG-PET may be helpful for developing a prognostic algorithm and predict PFS. Objectives: To determine the best predictor of PFS among various variables of tm metabolic measurements at baseline and at interim PET/CT compared to conventional methods in cHL patients. Methods: Retrospective evaluation of prospectively acquired data in 58 cHL pts, all stages [IIB-IV:41%, ⬎IPS-3:24%, unfavorable (UF):44%]. Eligibility: PET/CT prior to and after 1 cycle (PET1) ABVD therapy, imaging at 60min⫹15min, follow-up⬎24 mo. Baseline PET parameters including metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUVmax, and SULpeak were determined using gradient method (PETVCAR2, GE Healthcare, WI). Data were also evaluated at PET1 for %⌬MTV, %⌬SUVmax, %⌬TLG, PERCIST criteria and visually with Deauville 5-PS. Variables were correlated with PFS. Results: Median follow-up: 32.2 mo. Of 58 pts 14 relapsed (median PFS:6.5 mo). Results for PFS are displayed in the Table. No baseline conventional (stage, IPS, UF vs F) or PET variable was associated with PFS. The best predictor of PFS was Deauville 5-PS at PET1. PERCIST and %⌬TLG using gradient method trended toward significance. Conclusions: Deauville 5-PS best predicts PFS at PET1 in cHL. Neither baseline PET nor conventional prognostic factors correlated with PFS in this group of cHL pts. Risk-stratification of cHL using tumor metabolic volumetry and PERCIST criteria may require a larger sample size and further assessment of various methodologies. Variable Gradient method Baseline MTV (mL) Baseline SUVMAX Baseline TLG % decrease MTV % decrease SUVmax % decrease TLG PERCIST criteria Baseline SULpeak % decrease SULpeak Deauville PET1 Conventional Stage III or IV IPS >3 F vs UF (early stage only)

HR

Cutoff

P value

1.74 1.97 1.04 2.25 2.43 2.91

132 15.5 572 98% 83% 99%

0.34 0.23 0.95 0.15 0.14 0.06

1.98 3.09 5.61

9.15 84% 3

0.23 0.06 0.002

1.02 1.1 1.3

0.96 0.9 0.72


532s 8556


Efficacy of radioimmunotherapy-based conditioning with high-dose chemotherapy and autologous stem cell transplantation for transformed lymphoma. Presenting Author: Amrita Y. Krishnan, City of Hope, Duarte, CA Background: Transformed non-Hodgkin lymphoma (TF NHL) has a poor prognosis with median survival of 7-20 months. Studies have suggested the benefit of HDC. The series by Eide showed 47%, 5yr OS in 47 pts treated with HDC and ASCT (Br J Hem 2011). Our multicenter experience with RIT plus HDC (Yttrium 90 ibritumomab tiuxetan plus BEAM; carmustine, etoposide, cytarabine, melphalan ⬙ZBEAM⬙) demonstrated the safety and efficacy of the regimen in diffuse large cell lymphoma (DLCL). Therefore, the regimen was explored in other subtypes of NHL. Herein we report the outcome of 57 pts with TF NHL treated with ZBEAM conditioning and ASCT at three centers (City of Hope USA n⫽20, VUMC the Netherlands n⫽31, Chaim Sheba Med Center, Israel n⫽6.) between 2003- 2011. Methods: Histological confirmation of transformation was defined as dx of DLCL in pts with either a prior history or concomitant dx of follicular NHL. Results: Median age at ASCT was 59.6 yrs (range 41-69). Median number of prior regimens 2 (range 1-6), all pts received rituximab in at least one regimen. Disease status at ASCT: 1st CR 29, 1stPR 7,1st rel 9, IF 5, 2nd CR 5, 2nd rel 1, ⬎3CR 1. Median time from TF NHL dx to ASCT was 7.7 mo (range 2.8-116). Pts engrafted white cells at median of 12 days (range 8-33). Non relapse mortality was 3.5%. There were two second malignancies: 1 MDS and 1 SCC Skin. Median f/u for living pts was 29 mo (range 7-100). Two year PFS was 69.67% (95%CI 59.39 - 77.83) and OS 90.29% (95% CI: 79.63 - 95.52). On univariate analysis, number of prior regimens, time from TF NHL dx to ASCT and history of marrow involvement were not significant for PFS and OS. Disease status at ASCT was significant for PFS in 1st CR vs relapse disease ( p⫽0.03) The relapsed pts had a significant increase in risk of relapse/progression or death post ASCT compared to the 1CR patients. [HR ⫽ 2.9, (95% CI: 1.07 - 7.9)]. Conclusions: ZBEAM conditioning with ASCT is an active treatment for pts with TF NHL, and is particularly efficacious as consolidation for pts in 1st CR.

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Limited utility of surveillance imaging for detection of relapse in nonHodgkin lymphoma. Presenting Author: Quoc Van Truong, Mary Babb Randolph Cancer Center, West Virginia University School of Medicine, Morgantown, WV Background: Surveillance imaging with computerized tomography (CT) and positron emission tomography with CT (PET/CT) scans during follow-up after first-line therapies in patients with non-Hodgkin lymphoma (NHL) is commonly used in practice. However, most guidelines do not recommend surveillance imaging. We aimed to determine the value of routine imaging for the detection of first relapse in NHL patients in complete remission (CR) after first-line therapies. Methods: We retrospectively analyzed NHL patients referred to our center, who achieved CR after first-line therapies and subsequently relapsed. We evaluated whether the relapse was detected solely by routine CT or PET/CT or by patient-reported symptoms. Subgroup analysis was performed according to baseline histology (indolent vs. aggressive NHL). Data were also collected to determine the number of additional imaging, number of false positive scans, invasive procedures and iatrogenic complications, directly resulting from an abnormality detected on surveillance imaging. Results: Seventy-seven patients with first relapse of NHL between January 1, 2000 and December 31, 2010 were included. Majority of the relapses were detected by patient-reported symptoms as opposed to surveillance imaging (79.2% (n⫽61) vs. 20.8% (n⫽16); p⬍0.0001). There was no overall survival difference between the two groups (p⫽0.08). Patient-reported symptoms led to the detection of majority of relapses in aggressive (86.4% (n⫽45) vs. 13.6% (n⫽6); p⬍0.0001) and indolent NHL (69.7% (n⫽32) vs. 30.3% (n⫽10); p⫽0.037). There were greater number of scans done after a suspected relapse in the imaging versus symptoms group (1.94 versus 0.97; p⫽0.0004). Surveillance imaging led to 2 false positive scans/invasive procedures with one case of iatrogenic pneumothorax. Conclusions: Our limited retrospective analysis suggests that there is a limited role of surveillance imaging by CT or PET/CT for the detection of relapse in patients with NHL. There was no difference in survival outcome in our study between the two groups.

8559


Long-term survival with 90yttrium ibritumomab tiuxetan and rituximab as treatment for relapsed or refractory diffuse large B-cell lymphoma. Presenting Author: Jon E. Arnason, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA

Certification and role of local pathologists for diffuse large B-cell lymphoma (DLBCL) subtyping and eligibility determination in the phase II PYRAMID study. Presenting Author: Jonathan W. Said, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Los Angeles, CA

Background: Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) are salvaged with high dose chemotherapy followed by autologous stem cell rescue. Ibritumomab tiuxetan is an anti-CD20 antibody conjugated to the radionuclide 90yttrium. 90Y ibritumomab tiuxetan has demonstrated clinical efficacy in DLBCL with a favorable toxicity profile relative to transplant. Methods: This phase II trial investigated the overall response rate (ORR), event free survival (EFS), overall survival (OS) and toxicity of treatment with ibritumomab followed by rituximab in patients with relapsed or refractory DLBCL, not candidates for transplant. Patients were treated with an initial dose of rituximab (250 mg/m2) followed one week later by ibritumomab (0.4 mCi90Y/kg or 0.3 mCi90Y/kg based on plateles) followed by 4 weekly doses of rituximab (375mg/m2). All non-progressing patients received maintenance rituximab (375 mg/m2) weekly for 4 doses every 6 months for 4 cycles. Results: 25 patients were enrolled. Median age was 79 (range 45-95). 12 of 25 (48%) had stage 3 or 4 disease. 13 (52%) had 2 or more prior regimens. At 12 weeks 5 patients (21%) had a complete response (CR), 3 (13%) a partial response, 2 (8%) stable disease and 14 (58%) progressed for an ORR of 32% (8/25). At best response 7 patients obtained a CR. Median EFS was 2.5 months. Median OS was 8.1 months. No patient who obtained CR later relapsed, with follow up of 18.3-100.1 months. Deaths unrelated to treatment occurred in remission in 5 patients. 2 patients remain free of disease at 67.4 and 100.1 months. 11 (65%) patients had grade 3 or 4 thrombocytopenia, but no significant bleeding was observed. 9 (36%) patients had grade 3 non-hematologic toxicity. Grade 1 and 2 fatigue occurred in 41%. Patients who progressed through a rituximab containing regimen were at high risk of early progression. Conclusions: The ORR of ibritumomab as salvage therapy for DLBCL compares favorably to other regimens with acceptable toxicity. Those patients with disease refractory to rituximab are not likely to benefit. For a subset of patients not candidates for salvage with autologous transplant, this treatment can produce a durable remission. Clinical trial information: NCT00110149.

Background: The role of local pathologists in promoting patient (pt) accrual and evaluating eligibility criteria involving a complicated immunohistochemical (IHC) algorithm has rarely been investigated. The phase II PYRAMID trial (NCT00931918) is assessing R-CHOP ⫾ bortezomib for newly diagnosed pts with non-germinal-center B-cell (non-GCB) subtype DLBCL. In this trial, local pathologists were encouraged to perform DLBCL subtyping at the point of biopsy, identify suitable pts for the trial, and facilitate accrual. Methods: Determination of GCB vs non-GCB subtype is per the Hans method, an algorithm based on IHC for CD10, BCL-6, and IRF4/MUM1. In stage 1, pathologists demonstrated IHC subtyping proficiency by evaluating a tissue microarray (TMA) of 12 DLBCL cases; those with ⱖ80% of samples in agreement with central lab results were certified for determining trial eligibility. In stage 2, to broaden participation, pathologist certification occurred via teleconference outlining trial eligibility criteria, tissue subtyping requirements, and determining pathologists’ experience with the Hans method. Results: 182 pathologists have been certified for local subtyping, 50 via TMA and 132 by teleconference. 66/88 active study sites have ⱖ1 certified pathologist. Only 1 of the 10 top enrolling sites lacks a certified pathologist. 52% (84/162) of pts have been enrolled based on local pathologist subtyping prior to central lab confirmation. Discordance with central lab results occurred in 9/84 cases (11%). Enrollment rates pre- and post-local pathologist certification were 0.053 and 0.096 pts/site/month; an improvement of 81%. Trial accrual correlates with the presence of a certified local pathologist (p⫽0.0026). The rate of ineligible GCB cases sent for central lab testing was lower from sites with a certified pathologist (23% [69/299 cases] vs 38% [40/106 cases] for sites without). Conclusions: Engagement of local pathologists in trials requiring pathology selection can significantly improve accrual. This study demonstrates the effectiveness of various training modalities in improving selection by local pathologists using a complex IHC algorithm. Clinical trial information: NCT00931918.




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Y90-ibritumomab tiuxetan (Y90-IT) and high-dose melphalan as conditioning regimen before autologous stem cell transplantation (ASCT) for elderly patients with lymphoma in relapse or resistant to chemotherapy: A feasibility trial (SAKK 37/05). Presenting Author: Michele Voegeli, Medizinische Universitätsklinik, Liestal, Switzerland

Allogeneic hematopoietic cell transplantation (alloHCT) in diffuse large B-cell lymphoma (DLBCL) after nonmyeloablative (NMA) or reducedintensity (RIC) conditioning: Long-term outcome in 116 patients. Presenting Author: L. M. Poon, National University Cancer Institute, Singapore, Singapore

Background: Standard conditioning regimens for ASCT are often not tolerated by elderly patients. Single agent high-dose melphalan has been shown to be safe and active in elderly patients with multiple myeloma. Y90-IT is a well-tolerated lymphoma treatment and feasible in the transplantation setting. We therefore investigated this combination of high-dose melphalan and Y90-IT as a conditioning regimen for elderly patients. Methods: Patients ⱖ65 years with relapsed or chemotherapy resistant CD20-positive lymphoma in PR or CR after salvage chemotherapy could be enrolled prior to stem cell mobilization. Myeloablation regimen consisted of standard dose Y90-IT followed by melphalan at escalating doses (100, 140, 170 and 200mg/m2, with a 3⫹3 phase I design) and by ASCT. The primary objective was to identify the MTD of melphalan in combination with standard dose Y90-IT (as defined ⬍ 1 DLT in 3 patients); secondary endpoints were toxicity and CR rate 100 days after transplantation. Results: Between 2006-2012 twenty patients were included. Median age was 72 years (range 66-77). One patient was considered retrospectively ineligible and was evaluable for toxicity but not for DLT. Thirteen patients received the treatment and were transplanted. Eleven patients were evaluable for DLT. No DLT occurred. Non-hematological grade 3 or higher treatment related adverse events were: infection (n⫽6, including 2 cases of febrile neutropenia), diarrhea (n⫽3), mucositis, anorexia, viral hepatitis, hypokalemia, dehydration and multi-organ failure (n⫽1). Seven patients did not start treatment because of mobilization failure (n⫽3), progressive disease (n⫽2), worsening of cardiac failure (n⫽1) and grade 3 dyspnea (n⫽1). Seven patients achieved a CR/CRu and 2 patients were stable 100 days after transplantation. Conclusions: The combination ofstandard dose Y90-IT and high dose melphalan (200mg/m2) is a safe and feasible conditioning regimen before ASCT for patients ⱖ65 years. The results show promising activity. Clinical trial information: NCT00392691.

Background: The role of alloHCT and conditioning intensity in DLBCL remains unclear. In this retrospective study, we determined their effectiveness in 116 patients (pts) with DLBCL (de novo, n⫽59, transformed, n⫽57) receiving alloHCT at our institution, between 1998-2011. Methods: Median age was 51years (range, 19-70); median prior therapies was 4 (range 2-12). Disease status at alloHCT was complete response (CR) (n⫽22), partial response (PR) (n⫽58), stable (SD) (n⫽25) or progressive disease (PD) (n⫽11). 41 (35%) pts had previous autografts. 74 (64%) pts received RIC of melphalan/fludarabine (Flu) or BEAM, and 42 (36%) received a NMA conditioning of Flu/cyclophosphamide or cisplatin/ cytarabine/ Flu. Donor source was HLA-identical sibling (MRD) (65%), HLA-matched unrelated (MUD) (31%) or a 1-Ag mismatched donor (4%). Results: With median follow-up among survivors of 63 months (range 5-157), estimated 5-yr OS and PFS for the whole cohort was 41% and 34% respectively. On multivariate (MV) analysis, disease status was most significant predictor for OS, with chemo refractory disease (SD/PD) being associated with higher mortality rate (HR 3.7, 95% CI 1.6-8.6, p⫽0.002). Combined use of NMA conditioning and MRD was associated with significantly lower mortality rate (HR 0.4, 95% CI 1.6-8.6, p⫽0.005). OS was highest [69% (95% CI 49-82)} for pts in CR/PR after NMA with a MRD (n⫽29), and lowest [(12% (95% CI 3-29)] for SD/PD pts after RIC with a non MRD (n⫽32). Disease status was strongest predictor of PFS on MV analysis, with CR pts having improved PFS compared to SD/PD (5-year estimates of 58% and 13%, respectively (P⬍0.001). Pts in PR with early disease stage (⬍ Stage 4) and negative PET at alloHCT had PFS comparable to pts in CR (56% at 5 yr HR⫽1.3, p⫽0.6), while all other PR pts had PFS comparable to SD/PD pts (PFS⫽20%, p 0.1). Conclusions: Our study shows disease status, donor type and conditioning intensity are predictors of outcomes after alloHCT in DLBCL. Pts with chemosensitive disease and receiving NMA, MRD had improved survival rates compared to RIC alloHCT. PR pts with low volume PR had similar outcomes to CR pts.

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Markers of angiogenesis and hypoxia to cell of origin (COO) subtypes of DLBCL: Correlative studies from S0515, a phase II trial of R-CHOP plus bevacizumab. Presenting Author: Ambuga R. Badari, University of Arizona Cancer Center, Tucson, AZ Background: S0515 was a nonrandomized phase 2 trial of R-CHOP ⫹ bevacizumab in 64 patients with newly diagnosed DLBCL. No significant improvement in PFS or OS was observed compared with historic controls.Patients with higher baseline levels of plasma VCAM and urine VEGF had worse PFS and OS. Tumor-associated carbonic anhydrase, CA IX, is induced by hypoxia in various tumors and part of the hypoxia inducible factor -1/ hypoxia responsive element (HIF-1/HRE) system. We present additional correlative studies from S0515 including longitudinal plasma CAIX levels, and correlate expression of VEGF and VEGF receptors (VEGFR) to COO subtype [GCB vs. non-GCB] and urine VEGF and plasma VCAM. Methods: COO subtypes were determined by immunohistochemistry (IHC) using the Hans classification. VEGF and VEGFR expression was determined by IHC and scored on a scale of 0 (none) to ⫹3 (strong). Plasma VCAM, CAIX, urine VEGF levels were measured by ELISA and samples collected at baseline and before cycles 4 and 8 of therapy. Results: Baseline CAIX levels did not predict PFS (p ⫽ 0.95) or OS (p⫽.66) or change with therapy. Patients with lower baseline CAIX levels (below the median) had a statistically significant increase in CAIX over the course of therapy (median 34.1 to 52.4, p⫽.002), whereas in patients with higher baseline CAIX, levels decreased (median 96.7 to 78.2, p⫽.20). CAIX correlated with plasma VCAM (P⫽.006), but not COO subtype. 33 lymphoma samples were classified as GCB (n ⫽ 21) or non-GCB (n⫽12). COO subtype did not predict difference in PFS (p⫽.56) or OS (p⫽.67). Median urine VEGF and plasma VEGF levels trended higher in non-GCB vs GCB tumors (181 vs 144pg/mL and 1499 and 821ng/mL, respectively). Lymphoma expression of VEGF did not correlate with plasma VCAM or urine VEGF. VEGR2 expression was higher in non-GCB vs GCB tumors (33% vs 5% expression). Conclusions: Plasma CAIX levels, a marker of hypoxia and HIF1alpha activation, increased only in those patients with lower baseline levels in response to therapy. COO by IHC did not predict PFS or OS. However, non-GCB tumors had higher expression of VEGFR2, plasma VCAM, and urine VEGF compared to GCB tumors consistent with increased angiogenesis. Clinical trial information: SWOG S-0515.


Correlation of chemotherapy delivery and survival outcomes of follicular lymphoma in the immunchemotherapy era. Presenting Author: Kitsada Wudhikarn, University of Iowa Hospitals and Clinics, Iowa City, IA Background: Optimal initial treatment of follicular lymphoma (FL) is unknown. Rituximab as monotherapy (R) or as a component of immunochemotherapy (R⫹Chemo) is established as effective and it is now reasonable to re-examine the role of chemotherapy dosing. We explored clinical features, systemic treatment and chemotherapy delivery with comparative effectiveness of delivered dose intensity (DDI) on outcomes. Methods: We reviewed the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource database along with medical records on newly diagnosed grade I-IIIa FL who received systemic therapy from 2002 to 2009. Presenting clinicopathologic factors, outcomes and systemic therapy details including doses of chemotherapy were collected. The event-free (EFS) and overall survival (OS) effects of systemic therapy and chemotherapy DDI were analyzed with multivariate Cox regression. Confounding effects of FLIPI, grade, stage, and age were considered in the analysis. Results: From 2002 to 2009, 631 newly diagnosed FL were enrolled. Median follow up duration was 52.7 months. We identified 322 grade I-IIIa FL treated with systemic therapy including 93 R and 229 R⫹Chemo. Age and stage were similarly distributed between the R and R⫹Chemo groups; however, patients in the R group had lower grade (p⬍0.01) and FLIPI (p⫽0.03). Multivariate analysis showed no significant differences in EFS (HR⫽1.24, p⫽0.28) or OS (HR⫽0.55, p⫽0.13) for R compared to R⫹Chemo. Among R-CVP or R-CHOP treated FL, DDI data were collected for 73 doxorubicin (dox) and 137 cyclophosphamide (cyc) patients. Eighty-five percent of patients received 90% or more pre-planned DDI. After controlling for confounding factors, higher cycDDI was associated with improved EFS (HR 0.55, P⫽0.04) and OS (HR 0.74, P⫽0.03). No significant OS or EFS effects of doxDDI were observed. Conclusions: Addition of chemotherapy to rituximab was not associated with a detectable difference in survival outcomes in grade I-IIIa FL at a median follow-up of 52.7 months. Among R⫹Chemo treated FL, chemotherapy was delivered completely in most patients and more completed delivery of cyclophosphamide was associated with improved EFS and OS.


534s 8564


A phase II study of gemcitabine, ifosfamide, and oxaliplatin (GIFOX) as upfront treatment for high-risk, non-anaplastic large cell, peripheral T-cell lymphomas. Presenting Author: Gaetano Corazzelli, Hematology-Oncology and Stem Cell Transplantation Unit, Istituto Nazionale Tumori, Fondazione, Naples, Italy Background: Patients (pts) with peripheral T/NK cell lymphomas (PTCL) and intermediate-high/high IPI risk have a 5-yr overall survival ⬍ 20%. Current chemotherapy is unsatisfactory while benefit of upfront autologous transplantation (ASCT) is limited by high pre-transplant progression rates and pts advanced age. We evaluated efficacy and stem cells (SCs)mobilizing activity of a biweekly regimen of gemcitabine (G), ifosfamide (Ifo) and oxaliplatin (Ox) (GIFOX), as an upfront strategy ensuring fast cytoreduction and early ASCT access or an effective alternative to CHOPlike programs in transplant-inelegible pts. Methods: Six biweekly courses of GIFOX [G 1000 mg/m2 D1, Ox 130 mg/m2 D2, Ifo 5 g/m2 D2 as 24h infusion (fractionated over days 2-4 in pts⬎65 yrs), G-CSF DD 7-11] were planned for all pts, with SCs mobilization at course 3 in ASCT-eligible pts. Simon’s minimax two-stage design was adopted with the primary and secondary endpoints of response rate (RR) and progression-free survival (PFS), respectively. Results: Thirty-four pts (median age 63 yrs, r 42-80) [PTCL, nos (n⫽16), AITL (n⫽7), extranodal NK/T-cell (n⫽5), SS (n⫽6)], with IPI score intermediate-high (62%) or high (38%) were accrued [stage IV: 71%; BM involvement: 38%; E-site ⬎1: 47%; hi LDH: 71%; ECOG⬎1: 38%; B-symptoms: 44%]. A total of 172 courses was delivered (median 6, r 2-6). Only 5 pts received ⬍4 courses, due to progression (n⫽4) or early death (n⫽1). Overall RR was 82% [95% CI, 66-92; 22 complete (CR) and 6 partial (PR) responses]. Twelve pts mobilized SCs (median CD34⫹ cells harvest: 4.36x106/kg) and 8 (7CRs,1PR) underwent ASCT, 6 to 13 weeks after the 6th course. Estimated 5-yr PFS was 48% (95%CI: 28-65); median PFS for non-transplanted pts was 15 mo.s. Estimated 4-yr disease-free survival was 58%. Relevant toxicities were G4 thrombocytopenia (13%), G4 anemia (23%), G3/G4 infection (29%/6%), G3 encephalopathy (6%). Conclusions: Response and survival rates of GIFOX in high-risk PTCL compared more than favorably to CHOP-based regimens. Effective cytoreduction and prompt access to ASCT were ensured, together with safe delivery of a full induction program to transplant-ineligible pts.

8566


The role of radiotherapy and intrathecal CNS prophylaxis in extralymphatic craniofacial diffuse large B-cell lymphoma. Presenting Author: Niels Murawski, Saarland University Medical School, Homburg, Germany Background: The role of radiotherapy and intrathecal prophylaxis in extralymphatic craniofacial involvement of aggressive B-cell lymphoma remains to be determined in the rituximab era. Methods: In a retrospective subgroup analysis of 9 consecutive prospective DSHNHL trials covering all DLBCL risk groups from 18 to 60 years of age, patients with and without craniofacial involvement were compared with respect to clinical presentation, event-free and overall survival. Results: 336 sites of extralymphatic craniofacial involvement were observed in 284/3840 (7.4%) patients (orbita: 30, paranasal sinuses: 90; main nasal cavity: 38, tongue: 26, remaining oral cavity: 99, salivary glands: 53). In a multivariable analysis adjusting for IPI risk factors the addition of rituximab improved EFS and OS in both patients with and without craniofacial involvement. The 141 responding patients who received radiotherapy to sites of craniofacial involvement had a similar 3-year event-free (79% vs 79%; p⫽0.835) and 3-year overall survival (88% vs. 85%; p⫽0.311) when compared with the 56 patients who did not receive radiotherapy. Without rituximab, the 2-year-rate of cumulative risk of CNS disease was increased in 205 patients with compared to 2586 patients without craniofacial involvement (4.2% vs. 2.8%; p⫽0.038), while this difference disappeared in patients who received CHOP(like) chemotherapy in combination with rituximab (1.7% in 77 patients with compared to 2.9% in 946 patients without craniofacial involvement; p⫽0.868). Of 85 patients with craniofacial involvement who received intrathecal prophylaxis with methotrexate, the 2-year-rate of cumulative risk of CNS disease was 4.3% compared to 2.3% in 189 patients who did not (p⫽0.995). Conclusions: Rituximab eliminates the increased risk for CNS disease in patients with craniofacial involvement. As a practical consequence intrathecal prophylaxis and radiotherapy to sites of craniofacial involvement should not be given any more.

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Different safety profiles of first-line bendamustine-rituximab (BR), R-CHOP, and R-CVP in an open-label, randomized study of indolent non-Hodgkin lymphoma (NHL) and mantle cell lymphoma (MCL): The BRIGHT study. Presenting Author: David MacDonald, Dalhousie University, Halifax, NS, Canada Background: The BRIGHT study demonstrated that first-line BR was non-inferior to R-CHOP/R-CVP in terms of complete remission rate in indolent NHL and MCL. This is the first detailed analysis of the safety and tolerability of the study regimens. Methods: Patients were preselected for R-CHOP or R-CVP, and then randomized to 6-8 cycles of BR (28-d cycle) or the preselected standard regimen (21-d cycles). BR dosing was bendamustine 90 mg/m2/d as a 30-min infusion on days 1 and 2 plus rituximab 375 mg/m2given before bendamustine on day 1. Colony stimulating factors (CSFs) and antiemetics were given per local standards. Results: In patients preselected for R-CHOP, 103 received BR and 98 R-CHOP. In patients preselected for R-CVP, 118 received BR and 116 R-CVP. For all regimens, ⱖ 88% of patients received the planned 6 cycles. Main differences in adverse events (AEs), all grades, are shown in the Table. Incidence of grade 3/4 AEs was 69% for R-CHOP vs 56% BR, and 50% for R-CVP vs 56% BR. Grade 3/4 drug hypersensitivity, neuropathy, and rash were infrequent. Antiemetic use was similar between groups except use of aprepitant as an adjunct to 5-HT3 antagonists was higher with R-CHOP (23% [19% in cycle 1]) than BR (9% [2%]) or R-CVP (3% [2%]). CSF use was higher with R-CHOP (61%) than BR (29%) or R-CVP (27%). Analyses of event prevalence over the treatment period and by region will also be presented. Conclusions: BR, R-CHOP, and R-CVP have significantly distinct AE profiles. More nausea, vomiting, and hypersensitivity occurred with BR while more constipation, neuropathy, and alopecia occurred with RECHOP/R-CVP. Support: Teva BPP R&D, Inc. Clinical trial information: NCT00877006. All-grade AEs. Preselected for R-CHOP

Nausea Vomiting Constipation Drug hypersensitivity a Infection a Grade >3 infection Opportunistic infection a Pneumonia / respiratory infection a Peripheral neuropathy / paresthesia a Rash / urticaria a Alopecia

Preselected for R-CVP

BR (n ⴝ 103) %

R-CHOP (n ⴝ 98) %

BR (n ⴝ 118) %

R-CVP (n ⴝ 116) %

63 29 32 17 55 12 10 18 9 20 4

58 13 * 40 6* 57 5 7 14 44 † 12 51 †

63 25 27 13 53 7 12 14 14 24 3

39 † 13 * 44 * 3* 50 7 9 13 47 † 16 21 †

a From multiple preferred terms. * P ⬍0.05; † P ⬍0.005.

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A matched pair analysis of conditioning BuEM versus BEAM in autologous haematopoietic cell transplantation for lymphomas in terms of toxicity and efficacy. Presenting Author: Ioanna Sakellari, George Papanicolaou Hospital, Thessaloniki, Greece Background: In autologous hematopoietic cell transplantation (AHCT) for lymphomas, the optimal conditioning regimen is currently investigated. The standard conditioning used is BEAM. During 2009-2011 a new alternative Busulphan-based conditioning regimen constructed in our unit, consisting of Busilvex (9.6 mg/Kg), Etoposide (9.6 mg/Kg) and Melphalan (140mg/m^2) (BuEM) was used. We retrospectively analysed the outcome of patients (pts) conditioned with BEAM and BuEM regimen, in terms of toxicity and efficacy, in a matched pair analysis. Methods: A matched paired analysis on a 1:2 ratio was performed. Thus, 2 control cases (receiving BEAM regimen) were matched to each patient treated with BuEM according to: phase of transplant, age, lines of previous chemotherapy. The first 50 consecutive pts treated with BuEM were matched to a random sample from the historical BEAM control population. Ninety-three BEAM pts that fulfilled the matching criteria were eventually randomly selected. Concerning pts characteristics there were no statistical significant differences except from more chemoresistant disease in the BuEM cohort (p⫽0.008). Thus a second matched pair analysis was conducted upon stratification by disease chemosensitivity instead of age as a risk factor. Results: Progression free survival and overall survival (OS) were 70.6% and 81.8% for the BEAM vs 68.9% and 83% for the BuEM cohort respectively (p⫽ns). In the BuEM cohort a borderline significantly better OS was noted in Hodgkin’s pts receiving BuEM (p⫽0.05). In terms of early toxicity a significantly faster neutrophil engraftment was found in the BEAM cohort, but there was a significantly less need of red blood cells, platelet transfusions and GCSF infusion in the BuEM cohort. BEAM regimen was also associated with: reduced incidence of infections (p⫽0.02), less severe (grade 3-4) mucositis (p⫽0.000) and liver toxicity (p⫽0.004). Conclusions: BEAM regimen was correlated with a favourable reduced early toxicity profile, ie severe mucositis and liver impairment. On the other hand, BuEM was found to be equally efficacious and moreover offered improved overall survival in Hodgkin’s lymphoma pts.




Screening for coronary artery disease after mediastinal irradiation in Hodgkin lymphoma survivors. Presenting Author: Laurien Aletta Daniëls, Leiden University Medical Center, Department of Clinical Oncology, Leiden, Netherlands Background: Cardiovascular diseases are the most common non-malignant cause of death in Hodgkin Lymphoma (HL) survivors, especially those who had mediastinal irradiation as part of their treatment. We investigated the role of CT coronary angiography (CTA) as a screening tool for coronary artery disease (CAD) in asymptomatic HL survivors, related findings to stress testing and subsequent interventions. We also evaluated acceptance of screening. Methods: Patients were eligible if at least 10 years disease-free and treated with mediastinal radiotherapy. All patients were screened with ECG, stress testing and CTA. Primary endpoint was significant CAD (stenosis ⬎50%) on CTA. A sample size of 50 patients would achieve ⱖ80% power to detect a difference of 13% (ⱖ20% vs a population proportion of 7%) using a two-sided binominal test. Allowing for nonevaluable and false-positive scans, we considered CTA screening to be indicated for testing in a larger population if in ⱖsix patients revascularization would be necessary. Results: Fifty-two patients were included, 48 patients underwent CTA. Median age was 47 years, time since HL diagnosis 21 years. Most patients had no risk factors for CAD. There were 45 evaluable scans. Prevalence of significant CAD on CTA was found in 20% (N⫽9), and significantly increased compared to the 7% expected abnormalities (p⫽0.01, 95% CI 8.3-31.7%). In 5 of the 8 patients who underwent conventional angiography, significant CAD was confirmed, and revascularization performed. Two patients were started on medication. Stress testing was inaccurate for determining CAD: all participants were asymptomatic and 1 patient with significant CAD had signs of ischemia. Ninety percent of the participants were content with the screening offered in this study, regardless whether the CTA showed abnormalities or not. Conclusions: Prevalence of significant CAD among HL survivors is high. In our participants even the most severe and life-threatening CAD was not preceded by typical symptoms. In symptomatic cardiac patients revascularization improves survival. This might justify both screening by CTA and intervention in this asymptomatic population, but needs to be further evaluated in a larger cohort. Clinical trial information: NCT01271127.

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Association of 25-OH vitamin D deficiency with worse outcome for elderly patients with aggressive B-cell lymphomas treated with CHOP plus rituximab (R): An analysis of the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Presenting Author: Joerg Thomas Bittenbring, Saarland University Hospital, Homburg, Germany Background: Vitamin D deficiency was shown to be is associated with a worse outcome in patients with non-Hodgkin’s lymphoma (Drake et al., 2010) To study whether this observation could be confirmed in patients with aggressive B-cell lymphomas treated uniformly within a prospective trial, we analyzed 25-OH vitamin D serum levels in patients treated within the RICOVER-60 trial of the DSHNHL. Methods: 25-OH Vitamin D serum levels were determined with a commercial chemoluminescence immunoassay in the serum from elderly patients of the RICOVER-60 trial which compared 6 or 8 cycles of CHOP, both with and without rituximab. Results: 193 of 359 pts (53.8%) had vitamin D deficiency (⬍10 ng/ml) and 165/359 patients (46.0%) had vitamin D insufficiency (10-30 ng/ml) according to current definitions. When treated with R-CHOP, patients with vitamin D levels ⱕ8 ng/ml had a 3-year EFS of 59% compared to 79% of patients with vitamin D serum levels ⬎8 ng/ml; the respective figures for 3-year overall survival were 70% and 82%, respectively. In R-CHOP pts these differences were significant in a multivariable analysis adjusting for IPI risk factors with a hazard ratio (HR) of 2.1 (p⫽0.008) for EFS and a HR of 1.9 (p⫽0.040) for OS. In pts treated without R effects of vitamin D deficiency were significant only for OS (HR 1.8; p⫽0.025), but not with respect to EFS (HR 1.2; p⫽0.388). These results were confirmed in an independent validation set of 63 patients treated within the prospective RICOVER-noRx study. Conclusions: Vitamin D deficiency is a significant risk factor for patients with aggressive B-cell lymphomas treated with R-CHOP. The stronger adverse effect of vitamin D deficiency in patients receiving rituximab suggests that vitamin D deficiency interferes with the R mechanisms of this antibody. A prospective study evaluating the effects of vitamin D substitution on outcome of patients receiving R-CHOP is warranted. Supported by Deutsche Krebshilfe.

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Differential impact of sex in young and elderly patients with DLBC: Correlation with rituximab (R) pharmacokinetics. Presenting Author: Michael Pfreundschuh, Saarland University Medical School, Homburg, Germany

Infectious disease associations in advanced stage, indolent lymphoma (follicular, FL, and nonfollicular, nFL): A prospective trial of antibiotic therapy. Presenting Author: Carol S. Portlock, Lymphoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY

Background: Sex and weight independently influence R clearance in elderly DLBCL pts (Mueller et al., Blood 2012). Methods: We analyzed the impact of sex on R pharmacokinetics and outcome of 1,222 elderly pts of the RICOVER-60, 823 young (18 to 60 years) aaIPI⫽0,1 pts of the MInT, and 375 aaIPI⫽2,3 pts of the Mega-CHOEP trials. R pharmacokinetics was determined by ELISA in 33 young and 49 elderly patients. Population pharmacokinetic modeling was performed with nonlinear mixed-effect modeling software (NONMEM VI). Results: R clearance was independent of tumor mass (IPI), but weakly correlated (0.2, R2linear⫽0.045) with increasing age in male, and moderately inversely correlated (-0.5, R2linear⫽0.207) with age in female DLBCL patients, resulting in similar R clearances in young female and male patients (9.88 vs. 10.38 ml/h; p⫽0.238), but a significantly faster R clearance in elderly males compared to females (10.50 vs 8.25 ml/h; p⫽0.006). In the RICOVER-60 trial, elderly females had a higher 3-year PFS (68% vs. 61%) and OS (74% vs. 68%) than male pts. due to a greater outcome improvement by the addition of R in females. In a multivariable analysis adjusting for IPI, the hazard for progression in male compared to female pts. was not significantly increased after CHOP (HR⫽1.1; p⫽0.348), but was significantly higher after R-CHOP (OR⫽1.6; p⫽0.004). In contrast, young males treated in the MInT and Mega-CHOEP trials benefitted as much as females from the addition of rituximab, with a similar hazard for male pts. after CHOP and R-CHOP (HR⫽1.2) with no significant difference to female patients (HRPFS⫽1.2, p⫽0.552; HROS⫽1.0; p⫽0.898). Conclusions: While no differences in R clearance and benefit from rituximab were found in young female compared to male patients, the reduced benefit of adding R to CHOP in elderly male DLBCL pts. who have a shorter rituximab serum half life and hence lower serum levels suggests that this subpopulation is suboptimally dosed when R is given based on body surface area at 375 mg/m2. Ongoing studies of the DSHNHL investigate whether higher R doses for pts. with a shorter R serum half life can improve the outcome of the respective patients. Supported by Deutsche Krebshilfe and Roche.

Background: The antigen-drive association of gastric MALT with H. pylori (HP) is well recognized. Successful antibiotic (Ab) can result in lymphoma remission. We have studied a 3 mo course of clarithromycin (substituting lansoprazole/amoxicillin/clarithromycin, Prevpak, in the first 2 wks if HP ⫹) in non-bulky, advanced stage indolent lymphoma as the first step to such a lymphoma treatment/prevention strategy. Methods: Patients with new diagnosis indolent lymphoma (FL and nFL), stages II (abdominal), III and IV fulfilling GELF criteria for observation were eligible. Stool HP done in all patients. Hepatitis B and C positive excluded. All patients had CT and PET prior to and 1 mo post Ab. Results: 32 evaluable patients were enrolled: 14 females, 18 males; median age, 53.5 years (36- 81); 22 FL, 10 nFL; stage II (2), III (16), and IV (14). HP ⫹ patients: 4 (3 FL, 1 nFL). We have observed lymphoma responses 1 mo post Ab in 7 of 32 (Table). With continued followup post Ab, best response to date in 9 of 32: PET CR ( 2 FL; 2 nFL); CT CR/PR ( 1/3 FL, 1/0 nFL). Median followup for all patients, 23.7 mos; and for those not needing lymphoma treatment, 54.9 mos. To date, no patient with PET CR has required lymphoma treatment (22.5⫹ to 62.8⫹ mos). Among 22 with FL, 8 have progressed, 3 had histologic transformation, possibly suggesting a different biology. Conclusions: H pylori eradication/3 mos clarithromycin has achieved lymphoma responses in advanced stage indolent lymphoma. PET negative CRs have been durable for 22.5 – 62.8 ⫹ mos following Ab alone. This prospective study may be a first step toward developing a lymphoma prevention strategy and deserves further clinical/biological study. Clinical trial information: NCT00461084. H Pylori ⴙ FL H Pylori - FL H Pylori ⴙ nFL H Pylori - nFL

PET neg CR

CT CR

CT PR

1 0 0 1

1 0 1 1

0 0 2 0


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Impact of rituximab on the course of low-grade follicular lymphoma. Presenting Author: Jairam Krishnamurthy, University of Nebraska Medical Center, Omaha, NE

Prognostic value of PET/CT scans on early chemo-cycle in diffuse large B-cell lymphoma: Prospective study. Presenting Author: He Huang, Sun Yat-sen University Cancer Center, Guangzhou, China

Background: Rituximab has revolutionized the treatment of lymphomas and has been shown to improve clinical outcomes in patients with follicular lymphoma. Our study evaluated the progression free survival (PFS) and overall survival (OS) in patients with grades I and II follicular lymphoma when rituximab was used as initial therapy, as salvage or if no rituximab was used. Methods: Patients with grades I and II follicular lymphoma treated between June 1981 and January 2010 were included. Disease and treatment related variables were compared based on type of treatment (No rituximab-Group I, rituximab as salvage-Group II, Rituximab as initial treatment-Group III) using the Kruswal Wallis or chi-square tests. Univariate probabilities of PFS and OS were estimated using the Kaplan Meier method. Multivariate analyses were performed using Cox proportional hazards regression analysis to evaluate differences in risk of treatment failure and mortality in the three groups while adjusting for covariates. Results: There were 226 patients in group I, 84 in group II and 110 in group III. Significant differences were found in some of the disease and treatment related variables. Univariate analysis is shown in the Table. The relative risk of treatment failure for group II was 0.82 (p⫽0.26) and 2.63 (p⫽0.0001) respectively in the first 10 years and after 10 years while it was 0.52 (p⫽0.0003) and 3.97 (p⫽0.001) respectively for group III in the first 10 years and after 10 years. The relative risk of mortality in group II was 0.63 (p⫽0.008) and group III was 0.32 (p⬍0.0001). Conclusions: Overall survival for patients with low grade follicular lymphoma is significantly improved when rituximab is used as initial treatment or as salvage when compared with no rituximab.

Background: To evaluate the prognostic value of positron emission tomography/computed tomography (PET/CT) scan on early chemo-cycle in newlydiagnosed diffuse large B cell lymphoma (DLBCL) patients. Also to distinguish the variation in outcome of early-responder (ER), lateresponder (LR) and non-responder (NR). Methods: Newly diagnosed 149 DLBCL patients were treated with R-CHOP regimen for 2-8 cycles (mean: 5.49 cycles) in our center (Feb 2008 –Jan 2013). The median age at diagnosis was 47 years (range, 17-80 years); 78 males (52.35%) and 71 females (47.65%); 63 stage I-II (42.3%) and 86 stage III-IV (57.7%); 45 B symptoms (30.2%); 90 IPI 1-2 scores (60.4%) and 59 IPI 3-5 scores (39.6%). All the patients with bulky disease, extranodal invasions and residual disease underwent baseline PET/CT scan and repeated after every 2 chemo-cycles. Results: After 2 subsequent cycles, the PET/CT evaluation showed complete remission (CR) in 82/149 (early-responder, 55.03%), and non-CR in 67/149 (44.97%) patients. Among 67 non-CR patients, 39 achieved CR (late-responder), 21 partial remission (PR), 3 stable disease (SD) and 4 progressive diseases (PD) (non-responder). After a follow-up of median 618 days (range 45-1816 days), the 1st and 2nd year progressionfree survival (PFS) rate in NR were significantly different from ER (61.3% vs 92.6% , 52.5% vs 86.6%, p ⬍ 0.001) and LR (61.3% vs 91.6%, 52.5% vs 75.9%, p⫽0.023), and no significant differences were found between ER and LR (p⫽0.329). The 1st and 2nd year overall survival (OS) were 98.5%, 91.9% in ER; 97.3%, 97.3% in LR and 89.8%, 60.0% in NR respectively with significant differences between NR and ER (p⫽0.005), between NR and LR (p⫽0.008), but there was no statistically significant difference between ER and LR (p⫽0.558). The 1st and 2nd year disease free survival (DFS) rate did not differ between ER and LR (92.6% vs 84.6%, 86.9% vs 76.7%, p⫽0.250). Conclusions: The PET/CT findings in early chemo-cycle response might predict PFS advantage, but the difference of DFS and OS between ER and LR were not so obvious, and NR showed poor prognosis according to our current data. Clinical trial information: CTR-TRC-11001687.

Outcomes PFS (years) 5 10 20 Median (95% CI) OS (years) 5 10 20 Median (95% CI)

Group I (95% CI)

Group II (95% CI)

Group III* (95% CI)

53(46-59) 38(32-45) 16(10-23) 5.79(3.77-8.35)

65(54-74) 43(32-54) 1(⬍1-6) 9.72(7.68 – 10.50)

80(70-87) 47(33-59) Follow-up short 9.54(8.62-10.96)

71(64-76) 49(42-56) 20(13-27) 9.78(8.16-11.50)

90(82-95) 68(56-77) 22(6-43) 16.68(12.70-18.56)

90(82-94) 82 69-90) Follow-up short Not yet attained

P value 0.12

⬍0.0001

* Longest follow-up is only up to 13.5 years.

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Single ascending dose escalation study of the specific Syk inhibitor P505-15 investigating pharmacokinetics, pharmacodynamics, and safety in healthy male volunteers. Presenting Author: Greg Coffey, Portola Pharmaceuticals, Inc., South San Francisco, CA

A phase I dose-escalation trial of ublituximab (TG-1101), a novel antiCD20 monoclonal antibody (mAb), for rituximab relapsed/refractory B-cell lymphoma patients. Presenting Author: Changchun Deng, Columbia University Medical Center / New York Presbyterian Hospital, New York, NY

Background: The spleen tyrosine kinase (Syk) regulates immune cell activation in response to ligation of a variety of receptors, making it an intriguing target for inflammatory and autoimmune disorders, as well as certain B cell malignancies. Here we present data from our first human study aimed at characterizing the pharmacokinetics (PK), pharmacodynamics (PD), and safety of P505-15, a selective Syk inhibitor in male volunteers following single oral administration. Methods: This study was a single center, blinded, randomized, placebo-controlled, ascending, single dose study of oral P505-15 suspension or its matching placebo, administered to healthy male volunteers. Dosing was initiated at 3mg and escalated to 400mg over seven cohorts. Serial blood samples for PK and PD evaluations were analyzed. The PD assays were designed to determine the potency and specificity of Syk inhibition. Potency for Syk inhibition was determined by measuring B cell receptor- (BCR) mediated ERK Y204 phosphorylation and cellular activation (CD69), as well as Fc␧RI-mediated basophil degranulation. Results: PK data indicate that P505-15 has a long terminal half life (~50-60 hrs), a Tmax of about 2 hrs, and oral exposure more than dose proportional up to the 200mg dose. Complete inhibition of all three Syk-dependent assays was observed in the 200mg and greater dose levels. PD effect in the basotest approximated IC50 at 24 hours post-dose, and returned to pre-dose levels by 72 hours. At all dose levels, no inhibition of PMA or fMLP induced signaling and leukocyte activation was observed, consistent with a high degree of selectivity for Syk. Analysis of the PK/PD relationship indicated an IC50of 208nM (95% confidence interval of 190-225) for inhibition of BCR-mediated B cell activation, and 124nM (95% confidence interval of 117-131) for inhibition of Fc␧RImediated basophil degranulation. Conclusions: P505-15 was safe and well tolerated across the entire range of doses. These data show that P505-15 has a favorable PK profile, and demonstrate its utility to safely and potently suppress Syk kinase function in humans.

Background: Anti-CD20 therapy (rituximab or RTX) in treating patients (pts) with B-cell lymphomas has resulted in significant improvement in treatment response and clinical outcomes. Despite advances, pts continue to relapse from, or are refractory to, RTX-based regimens. Ublituximab (UTX) is a novel, chimeric mAb targeting a unique epitope on the CD20 antigen. UTX has been glycoengineered to enhance affinity for all variants of Fc␥RIIIa receptors, and therefore demonstrates greater ADCC activity than RTX (Le Garff-Tavernier, 2011). UTX displayed greater antitumor activity compared to RTX in NHL in vivo models and in low CD20 expressing tumors (ASH 2011). A phase I trial with UTX used as a single agent in pts with relapsed/refractory CLL reported a response rate of 45%. Herein we report on the phase I dose-escalation of UTX in pts with RTX relapsed/refractory B-cell lymphoma. Methods: Eligible pts have B-cell lymphoma relapsed or refractory to a RTX containing regimen. Pts are required to have measurable/ evaluable disease, ECOG PS ⬍ 2 and no active hepatitis B/C. The phase I dose-escalation uses a sequential 3⫹3 design in dose cohorts of 450mg, 600mg and 900mg respectively. UTX is administered once weekly for 4 infusions followed by monthly maintenance therapy. PK and correlative PD data are being collected. Primary endpoint: Maximum Tolerated Dose (MTD) and Dose Limiting Toxicities (DLT). Efficacy is a secondary endpoint. Results: Nine pts (5 FL, 3 MZL, 1 MCL) have been enrolled (3 each cohort). Median age 63; 3/6 (M/F). Median prior Rx ⫽ 4 (2-6). RTX refractory (44%). 8/9 pts are evaluable for safety; no DLT’s observed and no Grade 3/4 AE’s to date. 7/9 pts have had at least one response assessment (8 wk scan), which includes: 1 CR (rituximab refractory MZL); 2 PR’s (1 MZL, 1 FL); 2 SD (FL) and 2 PD (1 transformed FL, 1 MCL). PK analysis is ongoing. Conclusions: UTX has been well tolerated to date with no G 3/4 AE’s with demonstrated early clinical activity at all doses. 7/9 patients continue to receive UTX treatment (range 1–25 wks). Enrollment in the 900mg expansion cohort is now open with an emphasis on RTX relapsed/ refractory indolent or low CD20-expressing lymphomas. Clinical trial information: NCT01647971.




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Whole genome sequencing of sporadic Burkitt lymphoma in HIV-infected and uninfected patients. Presenting Author: Deborah Ritter, Baylor College of Medicine, Houston, TX

EBV-negative post-transplant lymphoproliferative disorder: Clinical characteristics, response to therapy, and survival. Presenting Author: Daniel S. Heil, Hospital of the University of Pennsylvania, Philadelphia, PA

Background: Burkitt Lymphoma is defined by canonical translocations between MYC and immunoglobulin IgH, IgK or IgL (8:14, 8:2, 8:22, respectively), and is commonly associated with HIV. The identification of HIV from sequenced samples is critical to understanding HIV-associated Burkitt Lymphoma. While recent novel gene mutations (ID3 and TCF3) have been implicated in functional roles, concomitant genomic structural variants and the interaction of HIV with structural variation is less well defined. Methods: We sequenced the whole genomes of 15 patients with 100bp paired-end reads on Illumina Hi-Seq platform, resulting in an average insert size of 278 (⫹/- 63) and coverage of 60X tumor and 30X normal. We included 7 HIV-negative, and 8 HIV-positive subjects. Sequencing reads were mapped to the reference genome using BWA. Large-scale structural variation was detected by the BreakDancer and Crest programs. Functional annotation was used to prioritize structural variants for validation. Single nucleotide variants and small insertions and deletions were detected by CARNAC, a somatic variation discovery pipeline. The subset of WGS reads that failed to align to the human reference genome were tested for the presence of HIV sequences by comparing the unmapped reads to a database of viral DNA sequences which included the common subtypes of HIV defined by Los Alamos. Reads matching HIV or EBV with an expectation value of ⬍10-4 were analyzed to determine virus coverage and viral integration sites. Results: Canonical MYC-IgH translocations were identified in 9/15 (60%) tumor samples, with 2 additional subjects harboring either a deletion or an inversion near exon1 of MYC; 4 had no MYC rearrangement. MYC translocations occurred equally in both groups. TP53 and SMARC4 point mutations were observed recurrently in the HIV uninfected group but not in the HIV infected patients. Variable levels of HIV DNA sequence were observed in normal tissue of all HIV infected patients. Conclusions: Whole genome sequencing has identified known somatic variants in HIV infected and uninfected patients. Two genes, TP53 and SMARC4, appear to be differentially mutated, but additional samples are needed to achieve statistical significance.

Background: Post-transplant lymphoproliferative disorder (PTLD) is a potentially life-threatening complication of solid organ transplantation. PTLD is frequently linked with Epstein-Barr virus (EBV) and it was suggested that EBV negativity is associated with a poor prognosis and lack of response to reduction of immunosuppression (RI). We conducted a case-control study to identify the characteristics, outcome and response to therapy of EBVpos and EBVneg PTLD over a 20-year period. Methods: We reviewed data on patients diagnosed with PTLD at U. Penn. between 1982 and 2012. We determined EBV positivity on tumor samples according to WHO criteria. We compared clinical and pathologic characteristics, response to therapy, and survival of EBVpos and EBVneg patients. Results: Of 222 patients diagnosed with PTLD, we verified the EBV status of 169 patients, of whom 35% were EBVneg and 65% were EBVpos. Mean follow-up was 46.7 months. Median time from transplant to PTLD was 23.1 mo. in EBVpos vs. 59.3 mo. in EBVneg (p⫽0.003) with 42% of EBVpos patients being diagnosed within the first year after transplant vs. 15% in the EBVneg group (p⬍0.001). EBVneg PTLD was more likely to occur in non-thoracic vs. thoracic transplants (p⫽0.006). 28% of patients with EBVpos PTLD presented with disease originating from the graft vs. 14% in the EBVneg group (p⫽0.03). In terms of histology, 36% of EBVpos patients had polymorphic PTLD vs. 7% of EBVneg patients (p⬍0.001). Of patients who were treated with RI alone (40% of patients in both groups), the overall response rates were 50% and 48% in EBVpos and EBVneg patients respectively (p⫽NS). Response rates to rituximab were also similar. There was no difference in the mortality risk between groups (HR⫽1.04; p⫽0.84). The 5-year survival rates were 47% and 51% in EBVpos and EBVneg PTLD respectively (p⫽NS). Conclusions: In a large single-center series, EBVneg PTLD was associated with late occurrence after transplant, monomorphic histology and similar outcome in comparison with EBVpos PTLD. Importantly, the response of EBVneg PTLD to RI and rituximab was no different than EBVpos PTLD. These results have implications for the management of solid organ transplant recipients with PTLD.

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Effect of phosphotidylinositol 3-kinase-delta inhibitor idelalisib (GS-1101) on signaling in primary non-Hodgkin lymphoma cells: Correlative studies from NCT01306643. Presenting Author: Adriana Arita, Mount Sinai Medical Center, New York, NY Background: Studies of GS-1101, an oral phosphatidylinositol 3-kinase (PI3K)d-specific inhibitor, in heavily pre-treated patients with indolent-nonHodgkin’s lymphomas (iNHL) have shown marked clinical activity [Kahl BS, et al., Blood 2010]. We have shown that GS-1101 blocks both constitutive and inducible signaling events proximally downstream of PI3K [Lannutti BJ, et al., Blood 2011]. We hypothesized that flow-cytometric interrogation of PI3Kd-inhibition in iNHL samples might demonstrate signaling differences between patients that can be correlated with clinical outcomes. Methods: Single-cell suspensions of biopsy specimens from patients were incubated with or without GS-1101, B-cell receptor stimulated and stained with lineage markers and phospho-specific antibodies targeting signaling nodes proximally (e.g. pAkt S473) or distally (e.g. pS6 S235/6) downstream, or ⬙parallel⬙ to (e.g. pErk1/2) described PI3K pathways. Results: Healthy and iNHL B cells demonstrated complete or near-complete inhibition of PI3K proximal downstream signaling by GS1101. PI3K distal downstream signaling was completely inhibited by GS-1101 in healthy B cells. The degree inhibition of distal downstream signaling was variable between iNHL patients. iNHL showed marked variability in the degree of PI3K distal downstream signaling amongst tumor cells within the same sample, suggesting an admixture of ⬙PI3Kdependent“ and ⬙PI3K-independent⬙ tumor cells. We also observe variable PI3K-independence amongst other NHL histologies such as mantle cell lymphoma. Additionally, combining inhibition of PI3K with that of other signaling nodes shows additive distal downstream effects. Conclusions: We demonstrate that GS-1101 blocked both constitutive and invoked signaling proximally downstream of PI3K in primary iNHL cells. By correlating clinical outcomes in the ongoing study with signaling readouts between patients we may develop predictive rules for response. Ongoing studies will focus on studying the change in intratumoral cell subsets which develop in vivo as patients progress on PI3Kd inhibitor therapy.


Use of stem cell transplantation (SCT) as initial therapy in multiple myeloma (MM) and impact of sociodemographic factors in the era of novel agents: Analysis of 137,409 patients using the National Cancer Data Base (NCDB). Presenting Author: Mohammed Al-Hamadani, Gundersen Lutheran Medical Foundation, La Crosse, WI Background: Novel agents for MM became available in the past decade. Our study aim was to determine whether the rate of SCT utilization as part of initial therapy in patients with MM had changed in the US after the introduction of novel agents. We also determined the impact of various sociodemographic factors. Methods: De-identified patient level data were obtained from the NCDB bParticipant User File. NCDB is a nationwide oncology outcomes database, which comprises approximately 70% of all newly diagnosed cancer cases in the United States. Results: A total of 137,409 MM patients were included in the study. The median age was 68 years (range, 18-90⫹). The population was predominantly male (54%), white (79%), non-Hispanic (87%), and living in a metro (78%), low- or middle-income (annual income ⬍ $46,000; 63%), and low- or moderateeducation (⬎ 14% without high school diploma; 66%) areas. Most patients had minimal or no co-morbidities (Charlson-Deyo score of 0-1; 93%) and treated in the community setting (62%). The rate of SCT use as initial therapy consistently increased annually from 5% in 1998 to 12% in 2010. This was true for all socio-demographic subgroups except for those who were age ⬎ 75 years, treated in the Northeast, and the medically uninsured. Multivariate logistic regression showed that the following characteristics were significant main predictors of lower likelihood of SCT use (odds ratio): age ⬎ 65 years (0.18), non-white race (0.57), Hispanic ethnicity (0.68), lack of high education (0.89), annual income ⬍ $30,000 (0.76), diagnosed before the era of novel agents (1998-2003) (0.70), covered by a non-managed care insurance (0.57), treatment in a nonacademic facility (0.28), residence at a non-metro area (0.88), and treatment facility located outside of the Midwest or West (0.62). In contrast, sex was not significant. Conclusions: Even after the introduction of novel agents, the rate of SCT as initial therapy in MM continues to increase annually in the US. Significant disparity exists in the rate of SCT use by demographic, social, and geographic factors as well as the type of treatment facility.


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Lymphoma and Plasma Cell Disorders General Poster Session (Board #53B), Sun, 8:00 AM-11:45 AM

Measures of immune recovery following autologous stem cell transplantation for multiple myeloma and outcome. Presenting Author: Livia Hegerova, Mayo Clinic, Rochester, MN Background: Autologous stem cell transplant (ASCT) improves survival in patients with multiple myeloma (MM). Recent studies have elucidated the relationship in ASCT between absolute lymphocyte count (ALC) recovery and improved survival, highlighting the importance of immune recovery. We conducted a retrospective analysis of patients with multiple myeloma to observe the impact of different measures of immune recovery at day 100 post-ASCT on outcome. Methods: Retrospective analysis of data from the existing clinical databases identified 1184 patients with multiple myeloma that underwent ASCT at Mayo Clinic between 1987-2011. Markers of immune recovery analyzed on day 100 status-post ASCT included ALC, monocyte count, and immunoglobulin levels. Kaplan Meier analysis was performed to determine progression free survival (PFS) and overall survival (OS). Results: Among the 1184 patients, median age at diagnosis of multiple myeloma was 57 (range, 23-75 yr), and median age at time of transplantation was 59 (range, 24-75 yr); 59% were male. The median OS and PFS post-transplant were 80 months and 34 months respectively. 62% of patients were alive 5-years post-transplant. The median OS was not improved with normal vs. abnormal IgG levels at day 100 (p⫽.298). In contrast, monocyte recovery was a significant predictor of OS. Patients with normal monocyte counts of greater than 0.3 x 10⁹ cells/L at day 100 showed superior survival (65 vs. 37 months, p⫽ .001). Similarly, patients with normal monocyte recovery at day 15 post-transplant showed a significant survival benefit (68 vs. 50 months, p⫽.007). Early ALC recovery, which has been shown to be a positive prognostic indicator at day 15 post-transplant, was not prognostic at day 100 (p⫽ .960). Conclusions: The present study further elucidates prognostic indicators after ASCT for MM highlighting the importance of various markers of immune recovery. Immunoglobulin recovery was not associated with superior survival, while monocyte recovery at day 15 and day 100 post-transplant translated to an improved survival and requires further study. It may be hypothesized that early immune system reconstitution may have a positive effect against disease post-transplant.

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Effect of a novel agent, SL-401, targeting interleukin-3 (IL-3)-receptor on plasmacytoid dendritic cell (pDC)-induced myeloma cell growth and drug resistance. Presenting Author: Dharminder Chauhan, Dana-Farber Cancer Institute, Boston, MA Background: Multiple myeloma (MM) remains incurable despite novel therapies, highlighting the need for further identification of factors mediating disease progression and drug resistance. The bone marrow (BM) microenvironment confers growth, survival, and drug resistance in MM cells. Our recent study utilized in vitro and in vivo MM xenograft models to show that plasmacytoid dendritic cells (pDCs) were significantly increased in MM BM and promote MM growth (Chauhan et al., Cancer Cell 2009, 16:309). Importantly, we found increased IL-3 levels upon pDC-MM interaction, which in turn, trigger MM cell growth and pDCs survival. IL-3R is highly expressed on pDCs. We utilized SL-401, a novel biologic conjugate that targets IL-3R, to examine whether abrogation of IL-3–IL-3R signaling axis affects pDC-MM interaction and its tumor promoting sequelae. Methods: MM cell lines, patient MM cells, and pDCs from healthy donors or MM patients were utilized to study the anti-MM activity of SL-401. MM cells and pDCs were cultured alone or together in the presence or absence of SL-401, followed by analysis of cell growth or viability. Results: SL-401 significantly decreased the viability of pDCs at low concentrations (IC50: 0.83 ng/ml; P ⬍ 0.005, n ⫽ 3). SL-401 also decreased the viability of MM cells at clinically achievable doses. Coculture of pDCs with MM cells induced growth of MM cell lines; and importantly, low doses (0.8 ng/ml) of SL-401 blocked MM cell growthpromoting activity of pDCs. MM patient-derived pDCs induced growth of MM cell lines and primary MM cells as well; conversely, SL-401 inhibited pDC-triggered MM cell growth (P ⬍ 0.005, n⫽ 5). Tumor cells from 3 of the 5 patients were from patients whose disease was progressing while on bortezomib, dexamethasone, and lenalidomide therapies. In agreement with these results, SL-401 blocked pDC-induced growth of dexamethasoneresistant MM cell lines. Conclusions: Our study therefore provides the basis for directly targeting pDCs or blocking the pDC-MM interaction, as well as targeting MM, in novel therapeutic strategies with SL-401 to enhance MM cytotoxicity, overcome drug-resistance, and improve patient outcome.

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Quality of life (QOL) improvements for pomalidomide plus low-dose dexamethasone (POM ⴙ LoDEX) in relapsed and refractory multiple myeloma (RRMM) patients (pts) enrolled in MM-003. Presenting Author: Kevin W. Song, Vancouver General Hospital, Vancouver, BC, Canada

MM-005: A phase I trial of pomalidomide, bortezomib, and low-dose dexamethasone (PVD) in relapsed and/or refractory multiple myeloma (RRMM). Presenting Author: Paul Gerard Guy Richardson, Dana-Farber Cancer Institute, Boston, MA

Background: Poor prognosis and therapy exhaustion have been associated with reduced QOL in RRMM. In MM-003, a randomized, multicenter, open-label phase 3 trial, POM ⫹ LoDEX (n ⫽ 302) significantly improved progression-free and overall survival vs. high-dose dexamethasone (HiDEX; n ⫽ 153) in pts who failed lenalidomide (LEN) and bortezomib (BORT) and progressed on their last therapy. This analysis evaluated QOL changes in these pts. Methods: To assess pt-reported outcomes, cross-sectional and longitudinal analyses were performed. Minimal important differences for 5 clinically relevant EORTC QLQ-C30 domains (Global Health Status, Physical Functioning, Fatigue, Emotional Functioning, and Pain) were calculated as meaningful change thresholds (1 standard error of measurement) from baseline through cycle (C) 5. Time to QOL worsening was compared between arms using the Kaplan-Meier method. Results: Favorable trends were observed for POM ⫹ LoDEX vs. HiDEX in each of the 5 relevant domains. The cross-sectional analysis indicated statistically or marginally significant (P ⬍ .10) differences favoring POM ⫹ LoDEX in Global Health Status (C2, 4), Physical Function (C2, 3, 4), Emotional Function (C2, 3, 4), and Fatigue (C2) scores. Longitudinal comparisons between arms confirmed the significance of score changes for Global Health Status (C2; P ⫽ .01), Physical Functioning (C3 and 4; P ⫽ .018 and .028, respectively), Emotional Functioning (C3; P ⫽ .018), and Fatigue (C5; P ⫽ .008) for POM ⫹ LoDEX vs. HiDEX. HiDEX pts exhibited clinically meaningful worsening in Global Health Status and Physical Functioning scores vs. POM ⫹ LoDEX by C2 (P ⫽ .04) and C3 (P ⫽ .02), respectively. POM ⫹ LoDEX extended median time to meaningful worsening vs. HiDEX for Global Health Status (114 vs. 85 days, P ⫽ .05), Physical Functioning (174 vs. 106 days; P ⫽ .09), Fatigue (113 vs. 60 days; P ⫽ .02), Emotional Functioning (190 vs. 124 days; P ⫽ .04), and Pain (147 vs. 113 days; P ⫽ .2). Conclusions: In heavily pretreated pts who failed LEN and BORT, POM ⫹ LoDEX resulted in better clinical outcomes as well as improvement in clinically relevant QOL measurements over the course of treatment. Clinical trial information: NCT01311687.

Background: Combinations of lenalidomide (LEN), bortezomib (BORT), and dexamethasone (DEX) have demonstrated preclinical and clinical activity in patients (pts) with multiple myeloma. Pomalidomide with low-dose DEX (LoDEX) has demonstrated efficacy in RRMM pts treated with prior LEN and BORT. MM-005 was designed to identify the optimal PVD dose for a phase 3 trial comparing PVD vs BORT ⫹ LoDEX (VD) in RRMM (MM-007). Methods: Eligible pts had RRMM with 1-4 prior therapies including ⱖ 2 consecutive cycles of LEN and a proteasome inhibitor. Pts must have been refractory to LEN (progressive disease [PD] during or within 60 days of LEN treatment), but not refractory to BORT (at 1.3 mg/m2 twice-weekly). The maximum tolerated dose (MTD) was determined using a 3 ⫹ 3 design in 5 cohorts. Each cohort received 21-day cycles of POM 1-4mg/day on D1-14; BORT 1-1.3mg/m2on D1, 4, 8, 11; and LoDEX 20mg/day on D1-2, 4-5, 8-9, 11-12. An expansion cohort was enrolled at the MTD. Treatment was continued until PD or unacceptable toxicity. Dose-limiting toxicities (DLTs) were assessed during cycle 1. The primary endpoint was MTD; secondary endpoints were safety, overall response rate (ORR; ⱖ partial response), duration of response, and time to response (TTR). Results: As of Dec 31, 2012, 21 pts were enrolled (3 pts per escalating dose cohort; 6 in the expansion cohort). Median age was 57 years (36-75). All were LENrefractory and had prior BORT. No DLTs were observed at any dose level. The most common grade 3/4 adverse events (AEs) were neutropenia (32%) and thrombocytopenia (21%). With thromboprophylaxis, no deep vein thrombosis was observed. 17 pts remain on study and no pts have discontinued treatment due to AE. Thus far, the ORR was 72% (n ⫽ 18 evaluable) and responses were rapid (median TTR, 2 cycles). Conclusions: PVD was well-tolerated in RRMM with no DLTs and no discontinuations due to AE to date. PVD has promising activity with a current ORR of 72%. The maximum planned dose of POM 4mg/day on D1-14; BORT 1.3mg/m2 on D1, 4, 8, and 11; and DEX 20mg on D1-2, 4-5, 8-9, 11-12 of a 21-day cycle has now been incorporated into the MM-007 phase III trial comparing PVD with VD in RRMM pts (N ⫽ 782 planned). Clinical trial information: NCT01497093.


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MM-008 trial: Pharmacokinetics (PK) and tolerability of pomalidomide plus low-dose dexamethasone (POM plus LoDEX) in relapsed/refractory multiple myeloma (RRMM) patients with renal impairment (RI). Presenting Author: Jeffrey Matous, Colorado Blood Cancer Institute, Denver, CO Background: POM ⫹ LoDEX has shown significant clinical activity in RRMM pts including those refractory to lenalidomide and bortezomib. Renal impairment is a common comorbidity for MM pts, occurring in ⬎ 40%. POM is extensively metabolized with less than 5% renally eliminated as parent drug. Thus, renal function may not substantively affect parent drug exposure. Previous POM trials excluded pts with severe renal impairment. MM-008 is a phase 1, multicenter, open-label study designed to assess the PK and safety of POM ⫹ LoDEX in RRMM pts and normal or impaired renal function. Methods: RRMM pts (ⱖ 1 prior therapy [Tx]) with creatinine clearance (CrCl) ⱖ 60 ml/min (cohort A) or severe renal impairment (CrCl ⬍ 30 ml/min [cohort B]) not requiring dialysis were included. Cohort A received POM 4 mg and cohort B received POM 2 mg or 4 mg D1-21/28day cycle following a standard 3 ⫹ 3 dose-escalation design. Both cohorts received DEX 40 mg (20 mg for pts aged ⬎ 75 y) D1, 8, 15, and 22. Cohort C will assess pts with severe renal impairment (CrCl ⬍ 30 ml/min) requiring dialysis (up to 14 pts planned). Pts were not permitted to enroll in more than 1 cohort. G-CSF was not permitted in cycle 1. Tx continued until progressive disease or unacceptable toxicity. Results: As of Feb 5, 2013, 11 pts have been treated (8 pts in cohort A; 3 pts in cohort B at 2 mg). Age ranged from 46-71 y (cohort A) and 57-64 (cohort B). 5 pts were aged ⬎ 65 y in cohort A (aged 66, 69 [n ⫽ 3], and 71 y); none in cohort B. 7 pts in cohort A have received ⬎ 1 cycle of Tx; 5 pts have received ⱖ 3 cycles. One pt in cohort B has received ⬎ 3 cycles. All 3 pts in cohort B have completed 1 full cycle of Tx with no dose-limiting toxicities reported. Dose escalation is planned. The most common grade 3/4 adverse events (AEs) in cohort A were neutropenia (n ⫽ 3) and pneumonia (n ⫽ 2). No grade 3/4 AEs have been observed for pts in cohort B to date. POM dose reduction due to AE occurred in 2 pts (both in cohort A), all pts remain on study. PK and updated AE data will be presented at the meeting. Conclusions: MM-008 is an ongoing trial evaluating PK and safety in pts with renal impairment. Early tolerability data are encouraging. Clinical trial information: NCT01575925.

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Continued monoclonal protein response beyond day 100 after autotransplantation for multiple myeloma. Presenting Author: Wilson I. Gonsalves, Mayo Clinic, Rochester, MN Background: Patients (pts) undergoing an auto-transplant (ASCT) for multiple myeloma (MM) have disease assessment approximately 100 days later. This result may direct decisions of further therapy versus observation. However, some pts continue to experience a decline in their serum or urine monoclonal (M) - protein after day 100 without more therapy. Little is known about the prevalence and significance of this phenomenon. Methods: We identified 903 MM pts who underwent ASCT within 12 months (mos) of diagnosis (Dx) at our institution. Their day 100 post-ASCT M-protein from serum and urine electrophoresis with immunofixation as well as serum free light chains were compared to subsequent values during follow-up. The IMWG criteria were used to evaluate response. Results: Of the pts included, 510 (56%) were male and median age at ASCT was 59 (range 28-76). Median follow up from Dx and ASCT was 82 mos (95% CI; 75 - 86) and 74 mos (95% CI; 70 - 79) respectively. There were 453 (50%) pts seen in follow-up who had not achieved a CR at Day 100 nor initiated on maintenance therapy. Of these pts, 167 (37%) had a further decrease in their M-protein after day 100 at a median of 9.4 mos (95% CI; 8 – 10) post-ASCT. Given the time taken for maximal response, we assessed patients’ clinical response at one year post-ASCT. Compared to patients who did not have further clinical response between day 100 and 1 year, pts experiencing further response had a longer time to next therapy (TTNT) (43 mos vs. 17 mos, P ⬍ 0.001) as well as overall survival (OS) (96 mos vs. 62 mos, P ⬍ 0.001). Positive predictors for continued response included having an IgG isotype, evolution from a pre-existing MGUS, smoldering myeloma or solitary plasmacytoma and a Day 100 bone marrow plasma cell ⬍ 3%. In a multivariate analysis, elevated creatinine at Dx and lack of continued response predicted for shorter TTNT and OS post-ASCT. Older age and high-risk MM by FISH also predicted a shorter OS. Conclusions: In MM pts undergoing ASCT, continued M - protein response was seen in a third of the pts lacking a CR at day 100. This phenomenon appears prognostic and must be considered when interpreting studies evaluating post-ASCT response and the need for further therapy.

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Changes in patient-reported outcomes in patients diagnosed with and treated for multiple myeloma in the Connect MM registry. Presenting Author: Chris L. Pashos, United BioSource Corporation, Lexington, MA Background: Little is known about the impact of treatment on patientreported outcomes (PROs) and health-related quality of life (HRQoL) in multiple myeloma (MM) patients (pts). The change in PROs of MM pts between baseline and 1 year was assessed relative to their baseline International Staging System (ISS) stage and Eastern Cooperative Oncology Group (ECOG) performance status (PS) score. Methods: Connect MM is a prospective US registry of MM pts initiated in 2009. Clinicians reported pt demographics, ECOG PS score, and ISS stage. PROs were collected at baseline and at 1 year utilizing the Functional Assessment of Cancer Therapy (FACT)-MM, EQ-5D, and Brief Pain Inventory (BPI). Changes in FACT-MM, EQ-5D, and BPI scores were analyzed by ISS stage and ECOG PS score in 636 pts meeting CRAB criteria from 189 centers. Results: Most pts were male (58%) and white (84%). Mean age was 66 years (⫾ 11). Pts were treated in community (81%), academic (17%), or veterans/military (2%) settings. ISS stages of pts were: I (29%), II (35%), and III (35%). ECOG PS scores were 0 (37%), 1 (49%), 2 (11%), and 3 (3%). Improvements in overall HRQoL as shown by the FACT-MM and FACTGeneral (G) total scores, were observed across all ISS stages (P ⫽ 0.03 to ⬍ 0.0001) with no significant differences between stages. Improvements in FACT-MM and FACT-G total scores were observed with ECOG PS scores 1–3 (P ⫽ 0.03 to 0.005). Pts with poorer ECOG PS scores tended to have greater improvement in EQ-5D domains of mobility, self-care, and usual activities. HRQoL/functional ability improved in 4 of 5 FACT domains (except social/family; all others P ⬍ 0.0001), and in 4 of 5 EQ-5D domains (except pain/discomfort; all others, P ⫽ 0.01 to ⬍ 0.0001). BPI showed that overall average pain improved (P ⬍ 0.0005) over 1 year, but statistically significant differences by ISS stage or ECOG PS score were not observed. Conclusions: Connect MM data showed that overall HRQoL of MM pts improved between baseline and 1 year, with a consistent benefit observed across pts with different ISS stages and ECOG PS scores. Additional analysis should examine which disease- and treatment-related factors are associated with these HRQoL improvements.

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Long-term safety and efficacy of pomalidomide (POM) with or without low-dose dexamethasone (LoDEX) in relapsed and refractory multiple myeloma (RRMM) patients enrolled in the MM-002 phase II trial. Presenting Author: David Samuel DiCapua Siegel, John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ Background: MM-002 is a randomized, open-label, multicenter phase II trial evaluating the safety and efficacy of POM with or without LoDEX in advanced RRMM pts. Methods: Pts who had received ⱖ 2 prior therapies, including lenalidomide (LEN) and bortezomib (BORT), and were refractory to their last treatment were randomized to POM⫹LoDEX (POM 4 mg/day, days 1–21 of a 28-day cycle; LoDEX 40 mg/week) or POM alone. End points included progression-free survival (PFS), response rate (according to EBMT criteria and investigator assessment), response duration, overall survival (OS), and safety. The efficacy outcomes are based on the intent-to-treat population (POM⫹LoDEX, n ⫽ 113; POM, n ⫽ 108). Results: The median number of prior therapies in each group was 5 (range 1–13). In the POM⫹LoDEX arm, 30 (27%) pts had high-risk cytogenetics, including del(17p13) and/or t(4p16/14q32). The overall response rate (ⱖ partial response) was 34% and 15% with POM⫹LoDEX and POM, respectively, with a median duration of 8.3 (95% CI: 5.8 –10.1) and 8.8 (95% CI: 5.5–11.4) mos, respectively. At least minimal response was observed in 45% and 31% of pts, respectively. Median PFS was 4.6 (95% CI: 3.6 –5.5) and 2.6 (95% CI: 1.9 –2.8) mos with POM⫹LoDEX and POM, respectively, with a median follow-up of 16.0 and 12.2 mos. Median OS was 16.5 (95% CI: 12.4 –18.5) and 13.6 (95% CI: 9.6 –18.1) mos, respectively. The most common treatment emergent Gr 3/4 adverse events (AEs) reported in the safety population (n ⫽ 219) were neutropenia (44%), anemia (23%), thrombocytopenia (21%), and pneumonia (18%); there were no reports of Gr 3/4 peripheral neuropathy. The incidence of deep-vein thrombosis was low (2%). AEs were managed through dose reductions or interruptions, and supportive care with G-CSF (52%), RBC transfusions (47%), and platelet transfusions (17%). Discontinuations due to AEs were 10%. Conclusions: POM with or without LoDEX is clinically effective and generally well tolerated in RRMM pts who have received multiple prior treatments, including LEN and BORT. AEs were predictable and manageable. Updated data will be presented at the meeting. Clinical trial information: NCT00833833.


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Evaluating results from the multiple myeloma subset of patients treated with denosumab or zoledronic acid (ZA) in a randomized phase III study. Presenting Author: Noopur S. Raje, Center for Multiple Myeloma, Massachusetts General Hospital Cancer Center, Boston, MA

Longitudinal whole body MRI (wbMRI) in monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma. Presenting Author: Maximilian Merz, Department of Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg, Germany

Background: Denosumab (dmab) is a fully human monoclonal antibody against RANKL and is superior to ZA in preventing skeletal-related events (SREs) as shown in 3 identically designed phase 3 trials (N⫽5723). Overall survival (OS) was balanced between treatment groups in the overall study populations of these trials. In the trial of patients (pts) with solid tumors (excluding breast and prostate) and multiple myeloma (MM), OS was longer for dmab pts with lung cancer, shorter for pts with MM, and balanced for pts with other solid tumors. This analysis further characterizes the results from the MM subset of this trial. Methods: Pts with solid tumors or MM were randomized (1:1) to receive 120 mg of SC dmab or 4 mg of IV ZA Q4W. Daily calcium and vit D supplements were strongly recommended. The primary endpoint was the time to first on-study SRE; results from the primary endpoint and lung cancer subset were previously reported. Results: Of 1776 randomized pts, 10% had MM (93 ZA, 87 dmab). OS favored ZA (hazard ratio: 2.26; 10 subject difference in deaths). 1-year OS was 83% dmab, 97% ZA. Imbalances in baseline prognostic characteristics were observed. More pts in the dmab arm had low baseline renal function (CrCl ⬍ 40 mL/min) (ZA 2 [2%], dmab 9 [10%]) and more ZA pts underwent stem cell transplant (ZA 23 [25%], dmab 15 [17%]). Additionally, more ZA pts had stage I tumors at diagnosis (ZA 13 [14%], dmab 9 [10%]) and better performance status (ECOG ⫽ 0; ZA 30 [32%], dmab 21 [24%]). Study discontinuations due to consent withdrawal or lost to follow-up were also higher in the ZA group (ZA 17 [18%], dmab 11 [13%]) and occurred earlier in the ZA arm (ZA 59%, dmab 45% within 9 months of randomization). Conclusions: In this SRE study of dmab vs ZA, pts were stratified by baseline characteristics known to affect SRE outcomes, but not by prognostic factors or concurrent anticancer therapy that may impact survival in MM. OS results in the MM cohort are difficult to interpret due to small sample size and imbalances in baseline disease characteristics, stem cell transplant therapy, and consent withdrawal or loss of follow-up that favored ZA. A phase 3 trial is currently underway, which controls for these factors in pts with MM. Clinical trial information: NCT00330759.

Background: The detection of bone marrow focal lesions (FLs) by MRI at the initial work up has prognostic significance in multiple myeloma (MM), smoldering MM as well as MGUS. Currently, there are no data available on the predictive relevance of new FLs or FLs increasing in size in longitudinally performed wbMRIs for the follow-up of sMM and MGUS. Methods: We retrospectively analyzed 87 patients (sMM n⫽65; MGUS n⫽22) that received at least 2 (up to 5) wbMRIs for follow-up. The date of progression into MM requiring systemic therapy was defined as event for the analysis of progression free survival (PFS). Radiological progressive disease (rPD) was defined as the appearance of novel FLs or increase in size of preexisting FLs. Kaplan-Meier plots of PFS for patients with rPD and patients without rPD were analyzed using the log-rank test for significant differences. Results: Median follow-up was 61 months (9.8-101) with a median time between follow-up wbMRIs of 15.8 months (1-73). Progression from sMM/MGUS into MM was found in 28 patients (sMM 40%; MGUS 9%). Using wbMRI, rPD was found in 21 patients (sMM 32%; MGUS 0%). Of all patients, 76% (n⫽16) with rPD and 16% (n⫽ 9) without rPD progressed into MM during the observation period. Analysis of Kaplan Meyer plots for PFS revealed a highly significant shorter PFS for patients with rPD (32 months) compared to patients with radiological stable disease in wbMRI (PFS not reached; p⬍0.0001). New appearance or progression of diffuse bone marrow infiltration was not associated with a shorter PFS (not reached; p⬎0.05). Conclusions: In our study, the appearance of novel FLs or progression of preexisting FLs was highly predictive for progression from sMM into MM requiring systemic treatment. We conclude that wbMRI is effective for the longitudinal follow-up of patients with sMM and MGUS and identifies a group of patients at risk for progression into MM.

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Promotion of human multiple myeloma cell growth in vitro and bone marrow invasion in vivo by Notch receptors and the CXCR4/SDF1 axis. Presenting Author: Maurizio Chiriva-Internati, Texas Tech University Health Sciences Center, Lubbock, TX

Strategies to overcome barriers to accrual (BtA) to NCI-sponsored clinical trials: A project of the NCI-Myeloma Steering Committee Accrual Working Group (NCI-MYSC AWG). Presenting Author: Matthias Weiss, Marshfield Clinic, Marshfield, WI

Background: Multiple myeloma (MM) originates from post-germinal center B cells, and is caused by malignant plasma cells accumulating in the bone marrow. Interactions of MM cells with the bone marrow stroma promote tumor growth, migration and drug resistance. The chemokine receptor CXCR4 and its ligand SDF1 are critical regulators of this process. MM cells frequently hyper-express CXCR4 and respond to SDF1,2 enhancing MM cell infiltration, proliferation and osteolysis. Notch receptors similarly promote MM cell growth, drug resistance and the associated osteolytic process. We hypothesized that the CXCR4/SDF1 axis mediates the effects of Notch signals in MM. Methods: We used real-time PCR, flow-cytometry, E.L.I.S.A. and chemotaxis assay to explore the effects of CXCR4 in cultured human MM cell lines after Notch inhibition or over-stimulation. Additionally, we validated our findings in a NOD/SCID murine model xenografted with human MM cells. Results: Our results show that Notch blocking reduced CXCR4 and SDF1 expression by MM cells. Further, Notch activation was required for MM cell chemotactic and proliferative response to SDF1 in vitro. We then investigated the outcome of anti-Notch treatment on human MM cells bone invasion in NOD/SCID mice. Interfering with Notch activity dramatically reduced xenografted MM cell ability to infiltrate the bone marrow, ultimately resulting in diminished tumor burden. Notably, such effect was associated with a decrease of CXCR4 expression. Conclusions: This was the first time that Notch receptors were reported to regulate the CXCR4/SDF1 axis and bone marrow invasion in human MM. These findings indicate that specific Notch-tailored therapies may effectively hamper CXCR4-mediated bone infiltration and associated lesions, and are expected to significantly improve treatment outcome and survival.

Background: Accrual to NCI clinical trials(CT)is often slower than planned at times mandating premature closure resulting in loss of valuable resources and delay of scientific progress. Methods: The NCI-MYSC AWG identified 10 potential BtA. SWOG, ECOG and Alliance investigators were queried and agreed that these barriers impede accrual (results stratified for academic and community sites). The MYSC AWG developed in collaboration with NCI and FDA strategies to overcome these barriers. Results: Strategies listed for the 3 most often cited BtA: 1. Reimbursement for CT related expenses:increase awareness of improved reimbursement for phase II CT; tailor reimbursement according to CT complexity; request funds from industry and other sources (http://biqsfp.cancer.gov) for qualifying ancillary CT components. 2. Spectrum of available treatment options influences CT participation: educate patients and providers about the significance of a new CT using social media, presentations at national meetings and by adding educational material to CT protocol; encourage opinion leaders and advocacy groups not to promote a new therapy as “standard” in the absence of phase III data. 3. Requirement of CT specific therapy at NCI designated sites only: “MYSC AWG Drug Administration Table” describes NCI/FDA approved rules for CT specific drug administration; CT protocol will outline which standard treatment components of a CT can be administered at any site as long as protocol specific guidelines are followed and conduct is supervised by enrolling investigator. Examples of additional strategies to overcome identified BtA: determine feasibility, indication and insurance coverage of CT specific tests during protocol development; discourage narrow eligibility criteria; avoid competing CT; allow up to 1 cycle of commercially available therapy prior to enrollment; CIRB support for phase II CT. Conclusions: The MYSC Accrual Working Group developed in collaboration with NCI and FDA strategies to overcome barriers to myeloma clinical trial accrual. These strategies may be applicable to NCI-sponsored clinical trials evaluating interventions in other diseases.




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Early versus late treatment for smoldering (asymptomatic) multiple myeloma: A systematic review. Presenting Author: Mubarak Salem Alahamdi, University of Ottawa, Ottawa, ON, Canada

Profile of multiple myeloma in the inner city: Disease presentation and clinical course. Presenting Author: Adam Goldrich, SUNY Downstate Medical Center, Brooklyn, NY

Background: Expectant management remains the current standard of care for patients with smoldering multiple myeloma (SMM). Recent appreciation of ⬙high risk⬙ smoldering myeloma and the advent of novel therapeutic agents may allow one to better tailor the timing of therapeutic interventions. Herein, we performed a systematic review of the literature, summarizing the available randomized controlled trial (RCT) evidence for treatment of SMM. Methods: Our systematic search strategy includes MEDLINE, EMBASE, Cochrane Database, and relevant bibliographies where the following search concepts were used: RCT, SMM as defined as per the IMW Criteria, and treatment. Two reviewers independently extracted data on study design, population, sample size, treatment, clinical outcomes, and trial quality, were any discrepancies were discussed and resolved. Results: We identified 7 RCTs (2 articles and 5 abstracts) representing 869 patients. Six articles compared early versus deferred treatment for SMM; 2 studies compared early Melphalan plus Prednisone (MP) versus deferred MP. 3 studies compared bisphosphonates versus abstention while one study compared lenalidomide with dexamethasone to therapeutic abstention. Further, one study compared thalidomide with zoledronate to zoledronate alone. The median age is 66. Four studies received a Jadad score of 3 while three studies received a score of 2. Allocation concealment was described in four studies. Risk of disease progression was lower in patients receiving therapy compared to abstention OR 0.5(0.38-0.68). The events that demonstrate disease progression were not clearly defined. Further, the use of combination therapy compared to a single intervention decreased the risk of progression OR 0.23(0.11-0.51). No difference in OS was noted in patients receiving therapy compared to abstention OR 0.95(0.57-1.57). Conclusions: Early treatment of SMM compared with abstention decreases the risk of disease progression. However, OS was not improved by earlier intervention. High risk SMM may benefit from early intervention. The optimal intervention(s) remains to be defined, and further studies are warranted in this understudied population.

Background: Multiple myeloma (MM) is the most common hematologic neoplasm in blacks in the US. Based on SEER data of all Americans, the disease is more common in men, has a median diagnosis age of 70 and median survival of 3-6 years. The subclinical syndrome MGUS precedes MM, and blacks have a 2-3-fold higher risk of developing MGUS and MM. Further, recent improvements in survival observed for white patients are not observed in blacks. To gain new insight into pathogenesis and to optimize patient care, we characterized our inner city, largely Caribbean-African population in Brooklyn, NY, in terms of disease presentation and course. Methods: MM patients were identified by tumor registries based on histopathology. Data including survival were collected from records of patients diagnosed between 2001-2011 (n⫽242). Data analysis was performed using SPSS Advanced Statistics. Results: Median age was 64 (range 35-91), male: female ratio was 0.70. The most common presenting pathology was the presence of multiple skeletal lesions with fractures (67% of patients). Spinal cord compression and spinal compression fractures occurred in 33% and 32% of patients, respectively. Renal disease was present in 26%, indicated by serum creatinine ⬎2 mg/dL. Consistent with advanced stage and renal failure, median serum beta-2 microglobulin was 4.25 (range 0.96-82.8). Chromosome banding and FISH was available on 133 patients and showed no cytogenetic abnormalities in 53%; hyperdiploidy (30.4%). Common trisomies included chr 1, 5, 15 and 19. Other abnormalities were del 13 (13%) and chr 14 translocations (11%). Comorbidities include hypertension (65%), diabetes (35%) and obesity (BMI over 30 in 24%). While recent improvements in acquiring health insurance have improved access, less than 10% of patients received HDCT and ASCT. As of October 1, 2012, 36% of all patients are living. Survival analyses are underway. Conclusions: MM presents at an advanced stage and affects younger AA’s in the Downstate community. Strategies for identifying and treating patients with progressive MGUS and at earlier disease stages may enhance survival.

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Retrospective analysis of cardiovascular (CV) events following compassionate use of carfilzomib (CFZ) in patients (Pts) with relapsed and refractory multiple myeloma (RRMM). Presenting Author: Shebli Atrash, Myeloma Institute for Research and Therapy, Little Rock, AR Background: Herein, we report CV events observed in late-stage, heavily pretreated pts who received salvage CFZ under a compassionate use protocol. Methods: Pts received IV single-agent CFZ (20-45 mg/m2) over 2-30 min on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C) or CFZ with weekly dexamethasone (4-40 mg) during C1, along with other agents (eg, lenalidomide, thalidomide, cyclophosphamide, doxorubicin, cisplatin, vorinostat) during C2 and beyond. CV events were grouped according to preferred terms. Serious CV events were defined as those that required hospitalization. B-type natriuretic peptide (BNP) values were measured at baseline; peak values were recorded during C1. Results: 143 pts (median age, 61 years old; 70% were male) received treatment. Prior to enrollment, pts received a median of 7 prior lines of therapy (range, 2-15), including doxorubicin (range, 0-360 mg/m2). Most pts (92%) had prior autologous stem cell transplants (ASCT), with 74% receiving ⱖ2 ASCT (range, 0-5). Pts received CFZ for a median of 2C (range, 1-36). Of pts with available BNP values at baseline and during C1 (n⫽69; 48.3%), the median peak BNP increase from baseline was 407 pg/ml (P⬍0.001). 27 pts (18.9%) experienced a serious CV event, 21 (77.7%) of which had preexisting CV risk factors. Of these 27 pts, 11 pts (7.7%) developed CHF or worsening of existing CHF (confirmed by echocardiogram [ECHO] ⱕ1 month from diagnosis), and 13 (9.1%) required hospitalization for hypotension (n⫽6), arrhythmia (n⫽2), hypertension (n⫽2), pulmonary edema (n⫽1), pulmonary embolism (n⫽1), or pulmonary hypertension (n⫽1). Additionally, 3 pts (2.1%) experienced cardiopulmonary arrest. Of the 11 CHF pts, 10 had a baseline ECHO (recorded ⱕ6 months before study); left ventricular ejection fraction decreased from a median of 55% (pretreatment) to 33% (posttreatment). Conclusions: Late-line, heavily pretreated pts with RRMM occasionally experienced CV events following administration of CFZ with or without other antimyeloma agents. Given the number of confounding factors and the uncontrolled nature of these data, causality for these CV events could not be definitively determined.


Early mortality (EM) for newly diagnosed multiple myeloma (NDMM) in the Connect MM U.S. registry. Presenting Author: Howard R. Terebelo, Providence Cancer Institute, Southfield, MI Background: EM occurring ⱕ 6 mos from diagnosis of MM has been reported in several NDMM studies. Incidence of EM in the pre-noveltherapy era was 10 –14% of patients (pts); causes included infection/ pneumonia, renal failure, refractory disease, and cardiac events. Identifying risk factors and improving response rates (RR) could lower EM. Established risk factors only have a sensitivity of 61% and specificity of 74%. Introduction of novel therapies is improving RRs and changing the profile of morbidity risk factors. Fewer indwelling catheters, better antibiotics, and bisphosphonates have reduced morbidity and mortality in MM. This analysis aims to better understand the causes of EM in this new era. Methods: Connect MM is a prospective observational registry of NDMM pts. Since 2009, 1494 pts in 228 US centers have been enrolled. Baseline characteristics were compared for pts who died ⱕ 6 mos after enrollment vs pts who survived ⬎ 6 mos. Multivariate logistic analyses identified significant associations between baseline characteristics and EM. Results: Most pts received novel therapies (91%). In the entire cohort, EM occurred in 103 pts (7%), of which 93 were treated (6.5%). EM associated characteristics by multivariate analyses (P⬍ 0.05) were: age, ISS disease stage, PS, history of hypertension, hypercalcemia, lower clonal bone marrow cells (subject to further study), and platelet count. Venous thromboembolism and cytogenetics were not risk factors. Causes of the 103 early deaths were: MM progression (38%), cardiac failure (13%), infection (7%), pneumonia (6%), renal failure (4%), sudden death (3%), vascular event, bleeding, pulmonary embolism (1% each), other (15%) and unknown (13%). Conclusions: It is important to recognize EM as a distinct entity in MM. Better understanding of the biology and pt characteristics is required to further reduce its incidence. This is the first assessment of EM in a registry where almost all pts received novel agents. Of the 103 early deaths, 38% were due to MM, representing a 2.6% incidence in the total cohort (under further review). Although the 7% EM in Connect MM is encouraging, there is still room for improvement. Additional analyses on improvements and causes of death should be performed.


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Altered cytokine profiles in multiple myeloma (MM) and precursor disease: Predictors of progression and potential targets for treatment. Presenting Author: Nishant Tageja, Metabolism Branch, NCI, NIH, Bethesda, MD Background: Presently, there is no reliable biomarker for predicting clinical progression from smoldering (SMM) to symptomatic MM for individual patients. To improve our understanding on the pathogenesis from SMM to MM, we conducted a screening study of circulating cytokines using peripheral blood (PB) and bone marrow supernatant (BM) collected from treatment naïve SMM and MM patients as well as healthy donors as controls. Methods: PB samples from 14 SMM and 38 MM patients and 7 controls and BM obtained from 17 MM patients and 9 controls were assayed in duplicates using ultra-sensitive Human TH1/TH2 10-plex multi-spot plate and multi-array plate for interleukin-(IL)-6. Two-tailed Mann-Whitney test was used for statistical analysis. Results: PB of SMM patients (vs controls) had increased levels of several cytokines, including IL-8 (p⫽0.008) and IFN-gamma (p⫽0.002). In PB, MM patients (compared to SMM patient and controls) had increased levels of IL-6 (p⫽0.006 and 0.001, respectively), IL-8 (p⫽0.0001 and 0.008), IL-10 (p⫽0.02 and 0.02), TNF-alpha (p⫽0.01 and 0.009), and IFN-gamma (p⫽0.01 and 0.02). Analysis of BM revealed a similar profile with increased levels of IL-2, IL-6, IL-8, and TNF-alpha in MM patients compared with controls (p⫽0.007, p⫽0.0003, p⫽0.0001 and p⫽0.0008). Conclusions: We found significantly increased levels of key cytokines associated with progressive disease state (controls¡SMM¡MM). Patterns of cytokines were similar in BM and PB, suggesting that serum based cytokines may have a future role as biomarkers for disease progression, and could potentially be assessed as novel targets for treatment.

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Results of a phase I/II study (NCT01365559) of carfilzomib (CFZ) replacing bortezomib (BTZ) in BTZ-containing regimens for BTZ-treated patients (pts) with relapsed and refractory multiple myeloma (MM). Presenting Author: James R. Berenson, Institute for Myeloma and Bone Cancer Research, West Hollywood, CA Background: Recent data has shown that single-agent CFZ can produce responses among MM pts refractory to previous treatment regimens including those containing BTZ. We conducted an intrapatient phase I/II trial investigating the safety and efficacy of CFZ as a replacement for BTZ in BTZEcontaining regimens to which pts have progressed. Methods: Eligible pts progressed while receiving their most recent BTZEcontaining regimen after at least 4 doses of BTZ at ⱖ1.0 mg/m² in ⱕ4 weeks per cycle. CFZ replaced BTZ in each regimen via intravenous administration over 30 min on days 1, 2, 8, 9, 15, and 16 of each cycle. Treatment continued using the same dose(s) and schedule(s) of each drug administered in the BTZEcontaining regimen. CFZ doses were escalated on each of the first 4 cycles from 20 to 27, 36, and 45 mg/m² or until a maximum tolerated dose (MTD) was reached for that regimen. Results: Of 37 enrolled pts, 33 were evaluable for efficacy and 37 for safety. Pts received a median of 4 prior treatments (range, 1-23) and 2 different BTZ-containing regimens (range, 1-13). Pts were treated with CFZ and a variety of different combinations of agents, including: bendamustine, clarithromycin, cyclophosphamide, dexamethasone, melphalan, methylprednisolone, pegylated liposomal doxorubicin, thalidomide, lenalidomide, and ascorbic acid. Pts have completed a median of 3 cycles with 12 pts going on to maintenance. One of 14 combinations, CFZ ⫹ ascorbic acid ⫹ cyclophosphamide, has reached a MTD at 45 mg/m2. Clinical benefit was seen in 23 (70%) evaluable pts (complete response ⫽ 6%; very good partial response ⫽ 18%; partial response ⫽ 21%; minor response ⫽ 24%) with another 18% showing stable disease. The median time to progression is 8.8 mo. (95% CI: 6.4-11.1 mo.) with 21 pts progressing overall and 9 progressing on study treatment. The most common ⱖ G3 adverse events were lymphopenia (35% of pts), thrombocytopenia (19%), neutropenia (11%), and anemia (8%). Conclusions: These results suggest that replacement of BTZ with CFZ in a BTZ-containing combination regimen to which a MM patient is failing often leads to responses and is well-tolerated. Clinical trial information: NCT01365559.

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A phase I/II study (NCT01541332) of pomalidomide (POM), dexamethasone (DEX), and pegylated liposomal doxorubicin (PLD) for patients with relapsed/refractory (R/R) multiple myeloma (MM). Presenting Author: James D. Hilger, Oncotherapeutics, West Hollywood, CA Background: POM is a newer IMiD immunomodulatory compound with high in vitro potency that has shown promise in combination with DEX as an effective treatment option for R/R MM patients (pts), even those refractory to bortezomib and lenalidomide (LEN). We conducted a phase I/II trial investigating the safety and efficacy of POM in combination with IV DEX and PLD using a modified dose and longer 28-day schedule in R/R MM pts. Methods: Phase I pts had progressive MM at the time of enrollment that was R/R to at least one anti-MM regimen. Phase II pts had to be refractory to LEN (singe-agent or in combination) demonstrated by progressive disease while receiving LEN or relapse within 8 weeks of its last dose. During phase I, POM was administered orally at 2, 3, or 4 mg daily in 3 successive cohorts of 3 pts each on days 1-21 of each 28-day cycle. DEX was administered IV at 40 mg over 30 min and PLD was administered at 5 mg/m2as an IV infusion over 30-90 min on days 1, 4, 8, and 11 of each cycle. POM doses were escalated until maximum tolerated dose (MTD) was reached. Once MTD was reached, all subsequent pts were enrolled at that dose. Results: To date, 27 pts have been enrolled, with 18 evaluable for efficacy and 19 for safety. Pts received a median of 5 prior treatments (range, 1-18) with a median of 1 prior PLD regimens (range, 0-2). Pts have completed a median of 1 cycle (range: 0-8) with a median of 1.4 months of follow up (range: 0-7.1). No DLTs were seen during phase I, which established the MTD at 4 mg. Phase II has enrolled 16 pts at 4 mg so far. Clinical benefit was seen in 7 (39%) of evaluable pts (partial response ⫽ 22%; minor response ⫽ 17%) with another 44% showing stable disease. Common ⱖ G3 adverse events included leukopenia (32% of pts), neutropenia (32%), lymphopenia (26%), and hyponatremia (16%). Neutropenia at ⱖ G3 occurred in more than half of patients on the phase II trial (4 mg POM). Conclusions: The combination of pomalidomide with dexamethasone and PLD on a 28-day cycle shows efficacy for R/R MM pts. However, because of excessive ⱖ G3 neutropenia, POM is being reduced to 3 mg for newly enrolled patients. Clinical trial information: NCT01541332.

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Clinical outcomes after intensive VDT-PACE therapy for relapsed multiple myeloma. Presenting Author: Preet Paul Singh, Mayo Clinic, Rochester, MN Background: The combination of bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide (VDTPACE) was developed as an intense regimen for disease control prior to tandem transplantation for multiple myeloma (MM) in total therapy protocols. The regimen is very effective in this setting, and since has also been used in the relapsed setting. We examined the outcomes of a set of patients undergoing VDTPACE therapy for relapsed MM at our institution. Methods: We identified 71 patients who received VDTPACE for relapsed MM, at Mayo Clinic from 7/2006 to 7/2012. Plasma cell leukemia was excluded. All data was extracted from clinical records. Results: The median age of patients was 59 years (range, 39-80); 48 (67.6%) were male. The median time from diagnosis to initiation of VDTPACE was 38.2 months (range, 2-125). The median number of cycles given was 1 (range, 1-9). The overall response rate after one cycle was 57.1% (14.3% VGPR, 22.2% PR and 20.6% MR) in the 63 patients in whom the response was evaluable. The median overall survival (OS) post-VDTPACE was 8.2 months (95% CI, 5.7-10.9). Eighteen (25.4%) patients went on to autologous stem cell transplantation (SCT), and 7 (9.9%) received matched allogeneic SCT following VDTPACE, and the median OS post-VDTPACE was significantly longer for these groups compared to those who were not transplanted (15.3 and 20.5 months, respectively vs 5 months, p-value ⬍0.001). Thirty eight of 66 (57.6%) patients were rehospitalized after initial admission for infusion therapy for a median duration of 6 days (range, 1-26). The median platelet and red cell transfusions were 4 (range, 0-21) and 5 (range, 0-22) units, respectively. Renal toxicity was seen in 13/62 (21%) patients and 27/65 (41.5%) patients developed neutropenic fever. The median duration to absolute neutrophil and platelet count recovery was 18 (range 12-42) and 27 (range, 12-42) days, respectively. Three (4.2%) patients died within 30 days and 11 (15.5%) within 8 weeks of initiating VDTPACE. Conclusions: VDTPACE is an effective therapy in relapsed MM but is associated with significant morbidity and short-term mortality. It appears to be more effective when followed by an autologous or allogeneic SCT.




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A comparison between next-generation sequencing and ASO-qPCR for minimal residual disease detection in multiple myeloma. Presenting Author: Hiroyuki Takamatsu, Kanazawa University, Graduate School of Medical Science, Kanazawa, Japan

Phase I study of TH-302, an investigational hypoxia-targeted drug, and dexamethasone in patients with relapsed/refractory multiple myeloma. Presenting Author: Irene M. Ghobrial, Dana-Farber Cancer Institute, Boston, MA

Background: Although molecular CR in multiple myeloma (MM) can be assessed by allele-specific oligonucleotide (ASO)-PCR, this technique requires preparation of clonotype-specific primers for each individual which is laborious and time-consuming. The usage of the LymphoSIGHT method, a next-generation sequencing (NGS)-based platform, may overcome these challenges and increase sensitivity and specificity. We compared the LymphoSIGHT approach with ASO-qPCR for minimal residual disease (MRD) detection in autografts in the autologous peripheral blood stem cell transplantation (ASCT) setting. Methods: Seventeen Japanese patients with newly diagnosed MM who received various induction regimens prior to ASCT were retrospectively analyzed. All patients had achieved a PR or CR after ASCT. Bone marrow (BM) slides from 13 MM patients and fresh BM cells from 4 MM patients at diagnosis as well as autografts were obtained for DNA extraction. Using universal primer sets, we amplified IGH variable (V), diversity (D), and joining (J) gene segments, IGH-DJ, and IGK from genomic DNA. Amplified products were subjected to deep sequencing using NGS. Reads were analyzed using standardized algorithms for clonotype determination. Myeloma-specific clonotypes were identified for each patient based on their high frequency in BM samples. The presence of the myeloma clonotype was then assessed in follow-up samples. Results: MRD in autografts was detected in 6 of 17 (35%) by ASO-qPCR and 13 of 17 (76%) by NGS. When MRD was assessed by NGS, 6 MRD (⫹) cases received post-ASCT therapy while 4 MRD (-) cases and 7 MRD (⫹) cases were followed without post-ASCT therapy. The MRD (-) cases tended to show a better PFS than the MRD (⫹) cases with post-ASCT therapy (P ⫽ 0.26) and those without post-ASCT therapy (P ⫽ 0.09) although overall survival rates were comparable among the three groups. There was no difference in PFS between MRD (-) and MRD (⫹) cases when MRD was assessed by ASO-qPCR (P ⫽ 0.6). These studies will be extended in 30 additional MM patients, and results will be presented. Conclusions: MRD-negativity in autografts revealed by NGS may be more closely associated with durable remission of MM than that revealed by ASO-qPCR.

Background: TH-302 is an investigational 2-nitroimidazole prodrug of the DNA alkylator Br-IPM designed to be selectively activated in hypoxia. In multiple myeloma (MM) mouse models, diseased animals demonstrate a marked expansion of areas of hypoxia in the bone marrow. TH-302 exhibited anti-tumor activity against MM in vitro and in vivo and synergism was seen when combined with bortezomib (Hu et al, Blood 2010; Chesi et al, Blood 2012). Based on these findings, a phase I/II study of TH-302 plus dexamethasone (dex) was initiated for patients (pts) with relapsed/ refractory MM. Methods: Eligible pts in the study (NCT01522872) had ECOG PS ⱕ 2, receipt of at least two prior therapies, and acceptable hepatorenal function and hematologic status. A standard 3⫹3 dose escalation design was used with a fixed oral 40 mg dose of dex and 40% dose increments of TH-302. TH-302 was administered IV with dex on days 1, 4, 8, and 11 of a 21-day cycle. The objectives were to determine DLTs and the MTD; assess the safety, tolerability and preliminary clinical activity of TH-302 plus dex; and study the relationship between hypoxia within the bone marrow and response to TH-302. Results: Eleven pts have been treated: 7M/4F with a median age 61 years (range: 53 – 86) and 6 prior therapies (range: 3 – 10). All received both bortezomib and lenalidomide/ thalidomide containing regimens. TH-302 was dosed at 240 (n⫽5), 340 (n⫽4), and 480 (n⫽2) mg/m² for a median of 5 cycles. No DLTs were reported at 240 or 340 mg/m². Two pts treated at 480 mg/m² had DLTs of grade 3 mucositis, exceeding the definition of MTD. A dose expansion is thus ongoing at 340 mg/m2. Two patients had SAEs related to TH-302 (pneumonia). Five pts continue on study after a median of 7 cycles (range: 2–11). Nine pts have had efficacy evaluations: 2 pts with partial responses, 2 pts with minimal responses, and 5 pts with stable disease, for an overall response rate (of MR or better) of 44%. Conclusions: TH-302 can be administered at 340 mg/m2 biweekly ⫹ dex, with dose limiting mucositis seen at higher doses. Initial clinical activity has been noted with an ORR of 44% in heavily pretreated MM pts who are relapsed/refractory to both bortezomib and lenalidomide. Clinical trial information: NCT01522872.

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Cure candidates: Characteristics of >10yr progression-free survivors (PFS10) and continuous CR (CCR-10) after total therapy 1 and 2 (TT1, TT2) for multiple myeloma (MM). Presenting Author: Sarah Waheed, Myeloma Institute for Research and Therapy, Little Rock, AR Background: Our TT studies demonstrate that long term progression free survival is achievable in MM pointing to the possible curability of MM. We report here on the base line characteristics of 33/231 TT1 patients and 109/475 TT2 patients qualifying for PFS-10, including 45/245 randomized to the control arm and 64/230 randomized to thalidomide. Methods: Baseline and response levels were compared between ⬍10yr and ⬎⫽10yr survivors and logistic regression applied to identify the critical features linked to PFS-10 status. Results: Compared to the remainder, PFS⬎⫽10yr and CCR⬎⫽10yr were characterized by lower frequencies of cytogenetic abnormalities (CA), B2M⬎⫽3.5mg/L and age ⬎⫽65yr. More females and more patients with platelets ⬎150.000/uL qualified for the ⬎⫽10yr category. Finally, timely administration of 2 transplants was also overrepresented in these patients. Conclusions: Long-term survival PFS-10 and CCR-10 were adversely affected by by CA and elevated B2M levels. Females more frequently attained PFS-10. Assessment of MRD by 8-color flow cytometry in these patients is in progress and will be presented at the meeting. Clinical trial information: NCT00580372, NCT 00083551. Patient characteristics by PFS10 and CCR 10 categorization, TT1ⴙ2 patients. Factor Age >ⴝ 65 yr Female B2M >ⴝ 3.5 mg/L B2M > 5.5 mg/L Prestudy CA Received transplant 1 Received transplant 2

PFS10 years

P value

Not CCR at 10 years

CCR at 10 years

P value

107/601 (18%) 218/601 (36%) 232/601 (39%) 118/601 (20%) 210/589 (36%) 490/601(82%) 383/601(64%)

16/160 (10%) 74/160 (46%) 39/160 (24%) 18/160 (11%) 28/157 (18%) 148/60(93%) 123/160(77%)

0.017 0.021 ⬍.001 0.014 ⬍.001 ⬍.001 0.002

111/646(17%) 237/646(37%) 244/646(38%) 123/646(19% 219/632(35%) 526/646(91% 406/646(63%)

12/15(10%) 55/115(48%) 27/115(23%) 13/115(11%) 19/114(17%) 114/115(99%) 100/115(87%)

0.070 0.024 0.003 0.046 ⬍0.001 ⬍0.001 ⬍0.001

Logistic regression 10-year PFS

Multivariate

Variable

N

Female B2M ⬎⫽ 3.5 mg/L Prestudy CA

743 743 743

With factor 73/286 (26%) 37/261 (14%) 28/238 (12%)

Without factor 82/457 (18%) 118/482 (24%) 127/505 (25%)

OR (95% CI)

P value

1.57 (1.09, 2.26) 0.58 (0.38, 0.88) 0.44 (0.28, 0.70)

0.0152 0.0107 0.0004


HM1.24/CD317-directed immunotoxin to eliminate malignant plasma cells in vitro and in vivo. Presenting Author: Martin Gramatzki, Division of Stem Cell Transplantation and Immunotherapy, 2nd Department of Medicine, University of Kiel, Kiel, Germany Background: Targeted immunotherapy, based on antibodies against tumorassociated antigens, is a promising approach for the treatment of multiple myeloma (MM). Recently, antibody-based strategies delivering a toxic payload have documented impressive clinical activity in hematological malignancies. In particular, surface molecules overexpressed on malignant plasma cells and efficiently internalized represent promising targets for developing myeloma-directed immunoconstructs. Here, the identification of CD317 (HM1.24) as a potent target structure and the characterization of a novel CD317-directed single-chain immunotoxin, HM1.24-ETA’, is described. Methods: Using a novel screening tool, a panel of antibodies against MM-associated antigens was evaluated for their ability to mediate antigen-dependent delivery of a truncated version of Pseudomonas exotoxin A (ETA’) to MM cells. HM1.24-ETA’ was generated by genetic fusion of a CD317-specific single-chain Fv antibody and ETA’. The anti-myeloma activity of the E. coli-expressed immunotoxin was evaluated in vitro and in a xenograft mouse model. Results: By screening a panel of antibodies including CD38, CS1, IL-6R, CD138 and CD317, CD317 was identified as a suitable receptor to deliver ETA’ to MM cells. The subsequently designed recombinant HM1.24-ETA’ immunotoxin efficiently inhibited growth of MM cell lines with halfmaximal growth inhibition at concentrations of less than 1 nM. Antigen-specific MM cell killing occurred via induction of apoptosis. The proliferation of IL-6 dependent INA-6 cells was completely inhibited by HM1.24-ETA’ even in the presence of bone marrow stromal cells that otherwise strongly support tumor cell growth. Importantly, HM1.24-ETA’ strongly triggered apoptosis (up to 80%) in freshly isolated tumor cells from 7 out of 7 MM patients. In a xenograft SCID mouse model, establishment of INA-6 plasma cell tumors was efficiently abrogated by treatment with HM1.24-ETA’ immunotoxin (p ⬍ 0.04). Conclusions: The HM1.24-ETA’ immunotoxin in vitro and in the preclinical xenograft model in vivo demonstrates that the CD317 antigen may represent a promising target structure for immunotherapy of MM using immunoconjugates with toxic payloads.


544s 8605


Minimal residual disease (MRD) status pre- and post- high-dose therapy/ autologous stem (HDC/ASCT) cell transplantation for multiple myeloma (MM) in the era of novel agents. Presenting Author: Adetola Kassim, Vanderbilt University Medical Center, Nashville, TN Background: MRD assayed by multi-parameter flow cytometer (MFC), has prognostic significance after HDT/ASCT for MM (Paiva et. al. 2008). The frequency of MRD negativity (-) after induction therapy using novel agents such as immunomodulatory drugs like lenalidomide (IMiDs), and proteasome inhibitors like bortezomib, is unknown. The impact of HDT/ASCT on MRD status in this patient group has not been studied. Methods: We performed a retrospective study of all MM patients undergoing HDT/ASCT (January 2010 - December 2012) in our institution. No restrictions on inclusion were made based on the International Myeloma Working Group response criteria. All patients had novel agents as part of their initial induction regimen. Statistical analysis was by SPSS software (V 12.0). MRD status was determined by MFC on bone marrow samples preHDC/ASCT [M1] and post- HDC/ASCT (D100 [M2] and I year [M3]). MFC was done with antibodies against CD45, CD19, CD138, CD38, CD20, CD56, and anti-k and l cytoplasmic antibodies. Results: MRD status was available on 91 patients pre-transplant. Of these patients, 80 had MFC recorded at M2 and 17 patients had MFC recorded at M3. Fifty-eight percent were male and 76% were Caucasian. Forty percent received IMiDs, while 60% got proteasome based therapies. Of the 91 patients with MRD pre-HDC/ASCT, 58% (53/91) were MRD (-), and of these patients 89% (41/46) remained MRD (-) at M2. 48 patients were MRD positive (⫹) pre-HDC/ASCT, 58% (20/34) became MRD (-) at M2. Age, cytogenetic risk, disease stage, number of chemotherapy cycles or immunofixation status had no impact on MRD status. There were only 6 relapses in the cohort, thus the impact of MRD status on progression-free survival could not be studied. Conclusions: Novel agents improve depth of response pre-transplant. HDC/ASCT increases MRD negativity post-transplant. MRD status could aid better timing of HDC/ASCT or adoption of a risk-adapted strategy for high-risk patients. MRD status validation in a prospective cohort is underway at our center (NCT01215344). With future follow-up, the impact of MRD on progression-free survival in the era of novel agents will be determined.

8606


Implications of rapidity of response to initial therapy in multiple myeloma. Presenting Author: Krishna Bilas Ghimire, Mayo Clinic, Rochester, MN Background: The rapidity of response to initial therapy in multiple myeloma (MM) depends on a variety of factors. There is limited data on its implications on long term outcomes in patients (pts) with newly diagnosed MM. Methods: We retrospectively examined the outcomes in a cohort of 454 pts with newly diagnosed MM between Jan 2000- Dec 2011 undergoing induction therapy. Results: The median age at diagnosis was 66 yrs (29-92). Pts had measurable serum M-spike (⬎⫽ 1 g/dL), dFLC (⬎⫽10 mg/dl) or 24 hour urinary M protein excretion (UrM; ⬎⫽200 mg) in 70, 63 and 39% respectively. We first examined the relationship between the response to first cycle of therapy and overall survival (OS). We divided pts into quartiles based on their % reduction in the serum M spike, dFLC or UrM. The median OS (Table) was poorest for pts with the least reduction of serum M protein (P⬍0.001) and of dFLC. The cutoffs for Q1 was 25, 40and 40% decrease for serum M spike, dFLC and 24 hr UrM respectively. Among various baseline characteristics only higher age was predictive of a poor (Q1) response. Given the trend toward worse OS among the Q 4 group (maximum decrease in serum M spike), we examined the relationship to cytogenetic risk. Among 232 pts with FISH data available, proportion of pts with high-risk disease was 27, 12, 22 and 31% respectively in quartiles 1 4). In a multivariate analysis, quartile 1 and 4 of serum M-protein response and the high-risk FISH were independent risk factors associated inferior OS. Conclusions: Both shallow and very deep response to therapy in cycle 1 is a strong indicator of eventual disease outcome and should be considered as marker of high-risk disease, likely through different mechanisms. For the shallow responders, prospective trials should assess if a change in therapeutic management will alter the outcome of these pts. The rapid deep responders also appear represent a different high-risk biology, emphasizing the fact that pts with high-risk disease often have excellent initial responses, but poor long term outcomes. Median overall survival from diagnosis (mo). Quartile (based on protein reduction) 1 Lowest 2 3 4 Greatest P value

Serum M-spike

dFLC

40

51

91 89 65 ⬍ 0.001

88

⬍0.001*

61 69 81 0.16

24-hour urinary M protein 40 65

0.04*

74 61 88 0.5

67

0.13*

* Quartile 1 vs. Q2-4.

8607


Risk-adapted maintenance therapy (MaintRx) after ASCT in first-line therapy for multiple myeloma (MM). Presenting Author: Jonathan L. Kaufman, Emory University, Atlanta, GA Background: Maintenance lenalidomide improves survival in patients who have undergone induction therapy and then autologous stem cell transplant (ASCT) as first line management for MM. We studied how the extent of cytoreduction after induction therapy à ASCT (as measured by CR, VGPR, or PR as best response) influences MAINTRX prescribing preferences among American Hematology-Oncology physicians (AHOP). Methods: We studied 284 individual AHOPs using a proprietary, live, case-based market research tool to assess prescribing preferences. A core case scenario and variations based on extent of response to induction à ASCT was constructed. Preference data were acquired using blinded audience response technology. All responses for each scenario were obtained contemporaneously prior to any display of respondent selections. All sources of research support were double blinded. The core scenario involved a 59-year-old patient (42% plasma cells in BM, no cytogenetic abnormalities, CrCl 65ml/min, B2M 5.8, PS 1) treated with induction therapy of choice à ASCT. The same query was then posed in each of 3 settings: Following CR (or following VGPR or following PR) as best response, what, if any, further therapy would you recommend now? Results: See Table. Conclusions: Among patients with myeloma getting first-line therapy, MaintRx is almost uniformly preferred by AHOPs. Specific single or doublet therapy preferences are dependent upon best response to induction à ASCT treatment. Compared to the CR setting, preferences for 2 drug MaintRx are significantly increased in patients with VGPR (p ⬍.0.001) or with PR (p ⬍ 0.001)] as best overall response. The potential for benefit from intensified MaintRx in these response subsets needs prospective phase III testing. Best response after induction à ASCT Post ASCT options Bortezomib fixed interval [FI] Bortezomib to progression [PD] Lenalidomide FI Lenalidomide PD Daily lenalidomide and intermittent bortezomib both for FI Daily lenalidomide and intermittent bortezomib both to PD Total with plans to use a maintenance strategy Observe post ASCT Other

CR Nⴝ282

VGPR Nⴝ281

PR Nⴝ284

6% 4% 25% 48% 2% 1% 86% 12% 2%

1% 10% 8% 63% 2% 10% 94% 4% 2%

1% 10% 3% 45% 5% 31% 95% 1% 4%

8608


Outcomes of patients with solitary plasmacytomas (SP) in the era of PET imaging and serum-free light chain (sFLC) testing: A single institution experience. Presenting Author: Abby L. Koch, University of South Florida, Morsani College of Medicine, Tampa, FL Background: SP can occur in bone (SPB) or in extramedullary sites (EMP) and generally accounts for ~ 3-5% of plasma cell dyscrasias. Up to 50% of SPB and 15% of EMP will progress to multiple myeloma (MM). We evaluated the utility and prognostic significance of positron emission tomography (PET) imaging and SFLC ratio (sFLCr). Methods: We retrospectively reviewed electronic medical records of patients with SP evaluated at Moffitt Cancer Center between 1990-2012. The diagnosis of SP was per IMWG criteria (BJH 2003, 121:749) (biopsy proven single site, negative skeletal survey, bone marrow biopsy with no more than 10% plasma cells). Initial and post therapy sFLCr as well as PET findings were correlated with progression to symptomatic MM (PFS). Radiation therapy (XRT) was at the discretion of the treating physician. Results: 135 patients were identified and 91 (67%) were males. The median age was 58 years (range 20-82). Consistent with prior reports, the PFS of the entire cohort was 43 months (95% CI 17.8-70). 23 patients had PET prior to progression. All patients had uptake in the primary lesion (except 4 who had resection of the primary). 8 patients had additional PET findings in other bony structure (PET⫹), and 15 did not (PET-). 2 and 6 of the PET- and PET⫹ patients progressed (median PFS Not reached (NR) vs. 8.1 months, p⫽0.021) respectively. Of the 49 patients with available sFLC data, 32 had an abnormal ratio (17 progressed) and 17 patients had a normal ratio (2 progressed). Abnormal baseline sFLCr was associated with progression (median PFS 19 months vs NR, p⫽0.012). Post XRT, 44 patients had an available sFLCr, of which 23 had an abnormal ratio and 21 a normal ratio. A persistent serum/urine m spike after XRT was associated with progression to MM (median PFS 20.8 months vs NR, p⬍0.0001). However, the association between Post XRT sFLCr and progression to MM was not statistically significant (median PFS 19 vs 43 months (abnormal vs normal ratio) p⫽0.2). Conclusions: PET imaging and sFLC are predictors of outcomes in SP and their routine inclusion in the diagnostic work up of patients with SP will result in a stage migration where patients outcomes are improved compared to historical controls.




Survival outcomes of plasma cell leukemia (PCL) in the United States: A SEER analysis. Presenting Author: Hari Prasad Ravipati, Morehouse School of Medicine, Atlanta, GA

8610

545s


Factors that predict successful remobilization after autologous hematopoietic progenitor cell transplant (aHCT) for multiple myeloma. Presenting Author: Xenofon Dimitrios Papanikolaou, Myeloma Institute for Research and Therapy, Little Rock, AR

Background: Plasma cell leukemia (PCL) is an aggressive plasma cell disorder that is associated with poor outcomes. Previous studies have shown improved survival with bortezomib-based regimens in this subset of patients undergoing stem cell transplant (SCT), but this may reflect referral bias. Current knowledge evaluating outcomes of PCL is limited in the era of novel agents. Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER) database from 18 registries for survival characteristics in PCL stratified by age, sex, race and the era of diagnosis. International Classification of Diseases for Oncology 3rd edition histology code 9733 was used to identify cases. Results: From 1973 to 2009, 74826 cases of myeloma and 479 cases of PCL were recorded. Survival data was available for 397 PCL patients. The median overall survival (OS) was 6 months (95% Confidence Interval (CI): 4.8 months – 7.2 months); and 1-year, 2-year, and 4-year OS rates were 34%, 20%, and 9% compared to corresponding myeloma survival rates of 66%, 52%, and 32%, respectively. Median overall survival differences were observed for women vs. men (7 months vs. 5 months, p⫽0.026); black vs. white patients (7 months vs. 5 months, p⫽0.01); and patients aged ⬍60 years vs. ⱖ 60 years (9 months vs. 4 months; P⫽0.01), respectively. In addition, patients diagnosed after 2005 had superior median OS compared with patients diagnosed prior to 2005 (7 months vs. 3 months; P⫽0.005). Conclusions: Black patients, women and patients aged ⬍60 years have improved OS compared to white patients, males and patients aged ⱖ 60 years. The survival benefit seen in patients diagnosed after 2005 may be attributed to the benefit conferred by access to new agents, but OS remains poor. Newer treatment approaches for managing PCL are clearly needed.

Background: aHCT is a proven therapeutic modality in treating relapsed multiple myeloma (MM). However, previously transplanted patients may have no hematopoietic progenitor cells (HPC) left in storage. Methods: Collection of HPC after aHCT was studied in 221 MM patients who underwent 333 mobilization attempts between 10/2000 and 06/2012. Results: The median number of CD34⫹ collected was 4.7 ⫻106/kg, with 74% of collections yielding at least 2.5⫻106/kg. Mobilization with chemotherapy and G-CSF was most efficient, yielding a median of 6.84⫻106/kg (p⬍0.001). Growth factor-only mobilization was least effective, with a median of 3.01⫻106/kg (p⬍0.001). The addition of plerixafor yielded a significant increase if there was a previous “poor” (⬍2.5⫻106/kg) collection (1.83 vs. 3.43⫻106/kg, p⬍0.001). In univariate statistical analysis female sex (p⫽0.048), platelets (PLT) ⱕ100⫻106/L (p⬍0.001), hemoglobin ⱕ11g/dL (p⫽0.032), and albumin ⱕ3.5 g/dL (p⫽0.003) prior to mobilization correlated with a “poor” collection. In multivariate analysis only PLT ⱕ100⫻106/L was significant (p⬍0.001). Of the 221 patients collected, 154 underwent subsequent aHCT. Infusion of HPC procured after previous aHCT did not yield a difference in treatment-related mortality (p⫽0.766). Use of only cells collected after aHCT was related to a delayed platelet engraftment ⱖ50⫻106/L (p⬍0.001). Conclusions: Remobilization and collection of an adequate number of HPC after previous aHCT is feasible. PLT ⱕ100⫻106/L suggest the need for plerixafor for a successful collection. Infusion of the graft procured is safe and effective, but use of only cells collected after aHCT is associated with delayed platelet engraftment ⬎50⫻106/L.

TPS8611

TPS8612


Phase III trial of brentuximab vedotin and CHP versus CHOP in the frontline treatment of patients (pts) with CD30ⴙ mature T-cell lymphomas (MTCL). Presenting Author: Owen A. O’Connor, Columbia University Medical Center / New York Presbyterian Hospital, New York, NY Background: MTCL including systemic anaplastic large cell lymphoma (sALCL) are aggressive neoplasms. Anthracycline-based multiagent chemotherapy regimens have demonstrated response rates ranging from 76 to 88%. Five-year overall survival rates range from 12 to 49% depending on the histologic subtype. Brentuximab vedotin is an antibody drug conjugate that has shown efficacy in a pivotal phase 2 study as a single agent in relapsed sALCL (Pro et al., J Clin Oncol, 2012) and evidence of clinical activity in combination with CHP in the frontline treatment of MTCL including sALCL in a phase 1 study (Fanale et al., ASH 2012). Methods: This randomized, double-blind, placebo-controlled, multicenter, phase 3 study (NCT01777152) is evaluating the safety and efficacy of 1.8 mg/kg brentuximab vedotin with CHP (A⫹CHP) vs CHOP for frontline treatment of CD30⫹ MTCL. Pts must have FDG-avid disease by PET and measureable disease of at least 1.5 cm by CT. Approximately 300 pts will be randomized 1:1 to receive A⫹CHP or CHOP for 6 – 8 cycles (q3wk). Randomization will be stratified by ALK⫹ sALCL vs other histologic subtypes and IPI score (0 –1, 2–3, or 4 –5). The target proportion of pts with a diagnosis of sALCL will be 75%. The primary objective is to compare progression-free survival (PFS) between the 2 treatment arms as determined by an independent review facility (IRF). Secondary objectives include comparisons of PFS per IRF in sALCL patients, safety, overall survival, and complete remission rate between the 2 arms. After completion of treatment, pts will be followed for disease progression, medical resource utilization, quality of life, and survival. Post-treatment stem cell transplant is permitted. Efficacy assessments will use the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). CT and PET scans will be performed at baseline, after Cycle 4, and after the completion of treatment. CT scans will also be performed at regular intervals during follow-up until disease progression, death, or analysis of the primary endpoint. Safety assessments will occur throughout the study until 30 days after last dose of study treatment. Enrollment for this global trial began in early 2013. Clinical trial information: NCT01777152.


Phase III study of brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (AⴙAVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as front-line treatment for advanced classical Hodgkin lymphoma (HL). Presenting Author: Anas Younes, The University of Texas MD Anderson Cancer Center, Houston, TX Background: Brentuximab vedotin, a CD30-targeted antibody-drug conjugate, has conditional approval in Europe for relapsed/refractory (RR) CD30-positive HL following autologous stem cell transplant (ASCT) or following ⱖ2 prior therapies when ASCT or multi-agent chemotherapy is not a treatment option. ABVD, a common front-line regimen for advanced HL, achieves complete response (CR) rates of 70 – 80%. However, 10 – 20% of patients (pts) are refractory to front-line treatment and up to 35% relapse after front-line multi-modality therapy. In pts with relapsed HL post-ASCT, single-agent brentuximab vedotin yields an objective response rate of 75% (CR, 33%; Chen ASH 2012). In a phase 1 study in treatment-naïve HL pts, A⫹AVD was associated with manageable toxicity and a CR rate of 96%; brentuximab vedotin ⫹ ABVD was contraindicated due to pulmonary toxicity (Ansell ASH 2012). We hypothesized that substituting bleomycin with brentuximab vedotin would eliminate bleomycin-associated pulmonary toxicity and improve progression-free survival (PFS) compared to a standard ABVD regimen. Methods: This ongoing, open-label, randomized, multicenter study (NCT01712490) will compare A⫹AVD vs ABVD in 1040 pts with stage III/IV classical HL. Primary endpoint: modified (m) PFS (death, progression, and receipt of chemotherapy or radiotherapy by pts not in CR after completing A⫹AVD or ABVD will count as progression event). Key secondary endpoint: overall survival. Key inclusion criteria: histologically-confirmed previously untreated stage III/IV classical HL. Pts will be stratified by region and International Prognostic Score, and will be randomized 1:1 to receive A⫹AVD (brentuximab vedotin 1.2 mg/kg with each dose of AVD) or ABVD administered intravenously on Days 1 and 15 of 28-day cycles, for up to 6 cycles. Disease status and survival will be evaluated regularly until study closure. Safety assessments: incidence and severity of adverse events, changes to physical and laboratory tests. Clinical trial information: NCT01712490.


546s TPS8613^


A phase III study of ibrutinib in combination with bendamustine and rituximab (BR) in elderly patients with newly diagnosed mantle cell lymphoma (MCL). Presenting Author: Michael Wang, The University of Texas MD Anderson Cancer Center, Houston, TX Background: MCL is a distinct subtype of B-cell non-Hodgkin lymphoma (NHL) accounting for approximately 6% of NHL diagnoses. Current immunochemotherapy followed by rituximab maintenance results in a prolonged duration of remission, but a constant relapse pattern is still observed. Ibrutinib, an oral Bruton’s tyrosine kinase(BTK) inhibitor, demonstrated promising single-agent activity in 115 patients with relapsed or refractory MCL who were enrolled in the phase II study PCYC-1104. The overall response rate (ORR) was 68%, with 46% of patients achieving partial response (PR) and 22% achieving complete remission (CR) (Wang ASH 2012). Blum et al (ASH 2012) demonstrated that ibrutinib can be safely combined with BR in a phase I combination study in relapsed or refractory NHL and that it enhanced BR’s clinical activity with an ORR in 5 evaluable MCL patients of 100% (80% CR, 20% PR). These data suggest that combining ibrutinib with BR will improve the outcome of these patients. Methods: The SHINE study, PCI-32765MCL3002, is a phase III double-blind study of ibrutinib in combination with BR versus BR for the treatment of patients with newly diagnosed MCL. The study aims to enroll 520 patients (approximately 260 patients per arm). All patients will receive BR therapy for 6 cycles; those patients achieving a CR or PR will receive R maintenance for 2 years. In addition to BR and R, all patients will receive an oral daily dose of 560 mg ibrutinib or placebo concomitant with the chemotherapy and ongoing as a single agent until disease progression or unacceptable toxicity. The primary objective is to evaluate if the addition of ibrutinib to BR will result in prolongation of progression-free survival, with secondary objectives of ORR (CR⫹PR), CR rate, duration of response, safety, and overall survival. The study will enroll patients aged 65 years or older who are not suitable for high-dose chemotherapy. Key exclusion criteria include diagnosis or treatment for malignancy other than MCL, requirement for treatment with warfarin or equivalent vitamin K antagonists, and treatment with strong CYP3A4/5 inhibitors. Approximately 200 sites globally will enroll patients. Enrollment began in Q1 of 2013. Clinical trial information: NCT01776840.

TPS8615


AHL 2011: A Lysa randomized phase III study of a treatment driven by early PET response compared to a standard treatment in patients with Ann Arbor stage III-IV or high-risk IIB Hodgkin lymphoma. Presenting Author: Rene-Olivier Casasnovas, Hôpital Le Bocage, Dijon, France Background: ABVD is the most widely chemotherapy regimen used as standard treatment of advanced Hodgkin lymphoma (HL). The escalated BEACOPP (BEAesc) regimen which delivers more drugs at higher dose intensity was shown to improve patient’s PFS but not OS when compared to ABVD (Federico M, 2009; Viviani S, 2011; Carde P, 2012). The better efficiency of BEAesc is associated to a marked immediate hematologic toxicity and a higher risk of secondary myelodysplasia/leukemia. Also, the gonadal toxicity which is a real concern in young women, is quite higher when using BEAesc. So, to better manage HL treatment we need to identify early responding patients able to benefit from a strategy of dose intensity decrease after upfront BEAesc, without impairing the disease control. PET performed after 2 cycles of chemotherapy (PET2) might identify such a population suitable for receiving ABVD after 2 cycles of upfront BEAesc, and was implemented in the present study. Methods: The AHL 2011 trial (NCT01358747) was designed to test in 16 to 60 years old HL patients with Ann Arbor stage III, IV or high risk IIB, a treatment strategy driven by PET after 2 cycles of BEACOPPesc, delivering 4 cycles of ABVD for PET2 negative patients and 4 cycles of BEAesc for PET2 positive patients, compared to a treatment not monitored by PET, delivering the best BEAesc schedule consisting in 6 cycles of this regimen (Engert A, 2012). A baseline PET is mandatory before treatment and PET2 are centrally reviewed within 48 hours and interpreted according to Deauville criteria. The allocation of treatment in the experimental arm is based on the PET2 central review result. PFS is the primary endpoint of the study with an hypothesis of non-inferiority of the experimental arm with a margin of 10% (85% 5y-PFS in the control arm vs ⬎75% in the experimental arm). With a 6-year of accrual period, inclusion of 405 patients in each arm would have 80% power to detect a HR of 1.77 using a one-sided log rank test with significance level of 0.025. The trial started in May 2011 and to date, 385 patients have been enrolled. The DSMC reviewed the trial in November 2012 and suggested that the trial continue as planned. Clinical trial information: NCT01358747.

TPS8614^


An open-label phase II study of ibrutinib in patients with refractory follicular lymphoma. Presenting Author: Gilles A. Salles, Centre Hospitalier Lyon Sud, Oullins, France Background: Follicular lymphoma (FL) is the second most common nonHodgkin lymphoma (NHL) and comprises approximately 22% of all NHL cases. Most patients treated eventually relapse and subsequent responses and duration of responses become shorter. Patients ultimately become resistant to chemoimmunotherapy and repeated treatment-related toxicity commonly outweighs the benefit of treatment. Ibrutinib is a potent inhibitor of BTK (downstream of the B-cell receptor, BCR) that binds covalently to Cys-481 in the active site, abrogating intrinsic survival pathways (eg, ERK1/2, NF-kB, AKT) as well as survival signals from the microenvironment (eg, TNF family members: BAFF, CD40L; cytokines from T-cells: IL4, IL6, IL10, TNF␣). Irish et al (2010) have also shown that up to 60% of FL patients display BCR signaling addiction. Early indications from study PCYC-04753 suggest activity of the BTK inhibitor ibrutinib in FL. Three CR and 3 PR were observed in 11 patients at a dose of 2.5 mg/kg or higher that achieved full BTK occupancy (Fowler, ASH 2012). Methods: The DAWN study, PCI-32765FLR2002, is a phase II, single-arm study of ibrutinib in refractory FL. The study aims to enroll 110 patients with chemoimmunotherapy-resistant FL. Patients will receive an oral daily dose of 560 mg ibrutinib. Patients must have been treated with at least 2 prior lines of therapy, at least 1 rituximab-containing combination chemotherapy regimen, and the last prior line of therapy included an anti-CD20 monoclonal antibody-containing chemotherapy regimen. The primary objective of the study is to evaluate the ORR (CR ⫹ PR), with secondary objectives of duration of response, progression-free survival, overall survival, and safety. To better understand the mechanism of action of ibrutinib, blood and tumor samples will be collected and, where feasible, characterized by GEP, SMA, IHC, or other technology as applicable. These evaluations aim to identify biomarkers associated with response or resistance to ibrutinib in subjects with FL and results may assist in the development of this drug in this and potentially other indications. Approximately 64 sites in the US and Europe will enroll patients. Enrollment began in 1Q of 2013. Clinical trial information: NCT01779791.

TPS8616


ROCHOP study: A phase III randomized study of CHOP compared to romidepsin-CHOP in untreated peripheral T-cell lymphoma. Presenting Author: Richard Delarue, Hopital Necker, Paris, France Background: Peripheral T-cell lymphomas (PTCL) account for 10-15% of lymphomas. They share an aggressive clinical behaviour and a poor prognosis when treated by CHOP-like regimen which is nevertheless consider as a standard because others regimens failed to demonstrate survival advantage. Romidepsin is a histone deacetylase inhibitor with promising results in PTCL. First trials showed a response rate of 38% in heavily pre-treated PTCL patients. These results were confirmed with 15% of patients reaching a CR/CRu, 89% of them without disease progression at 13 months. Adverse events include gastrointestinal, hematologic and asthenic conditions. A phase I study of romidepsin combined with CHOP was conducted by LYSA. A total of 18 patients were included. The recommended dose was 12 mg/m² administered at day 1 and day 8 of each cycle. Methods: Ro-CHOP study is an international phase III study comparing 6 cycles of CHOP21 with 6 cycles of romidepsin-CHOP21 (EUDRACT 2012-001580-68). Primary endpoint is Progression-Free Survival assessed independently. Secondary objectives include overall survival, other efficacy parameters, analysis of response rate according to 18FDG-PET, safety, quality of life and biological ancillary studies. A total of 420 subjects aged from 18 to 80 years will be enrolled in the study. Main inclusion criteria are untreated PTCL whatever Ann Arbor stage and a performance status of 0-2. Main exclusion criteria are other subtypes of lymphoma, HTLV1 positivity, any cardiac abnormality, poor renal, hepatic and marrow functions unless related to lymphoma. Patients are randomized 1:1 between the two regimens. A stratification is performed with IPI score, age and histology. The first patient has been included in January 2013. A recruitment of 10.5 patients per month is anticipated, with a total duration of the study of 60 months. An update on enrolment will be presented at the meeting. Clinical trial information: 2012-001580-68.


Lymphoma and Plasma Cell Disorders TPS8617


TPS8618

547s


A phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib (GS-1101) in combination with rituximab for previously treated indolent non-Hodgkin lymphomas (iNHL). Presenting Author: John Leonard, Weill Cornell Medical College, New York, NY

A phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of idelalisib (GS-1101) in combination with bendamustine and rituximab for previously treated indolent non-Hodgkin lymphomas (iNHL). Presenting Author: Sven De Vos, University of California, Los Angeles Medical Center, Los Angeles, CA

Background: PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3K␦ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, targeted, highly selective, oral inhibitor of PI3K␦ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues (Lannutti et al, 2011). Phase 1 trials demonstrated that idelalisib is highly active in pts with heavily pretreated iNHL: pts experienced reductions in disease-associated chemokines, profound and rapid reductions in lymphadenopathy, and durable clinical benefit with acceptable safety profile (de Vos et al, 2011). Methods: 375 pts with previously treated iNHL, who have measurable lymphadenopathy, have received prior anti-CD20-antibody-containing therapy, and who have iNHL that is not refractory to rituximab (R) are randomized in a 2:1 ratio into Arm A or Arm B. In Arm A, pts receive idelalisib at 150 mg BID continuously ⫹ R at 375 mg/m2 (weekly x 4 then every 8 weeks x 4). In Arm B, pts receive placebo BID instead of idelalisib. Stratification factors include tumor type (follicular lymphoma vs others), tumor burden (high vs low), and time since completion of last prior therapy for iNHL (⬍18 months vs ⱖ18 months). The primary endpoint is PFS and key secondary endpoints include ORR, lymph node response rate, CR rate, and OS. This is an event-driven trial and primary endpoint evaluation will be based on independent central review. For the primary efficacy analysis, the difference in PFS between the treatment arms will be assessed in the ITT analysis set using Kaplan-Meier methods and the stratified log-rank test. The study opened for enrollment in Dec 2012 (NCT01732913). Clinical trial information: NCT01732913.

Background: PI3K-delta is critical for activation, proliferation and survival of B cells and plays a role in homing and retention in lymphoid tissues. PI3K␦ signaling is hyperactive in many B-cell malignancies. Idelalisib is a first-in-class, selective, oral inhibitor of PI3K␦ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues (Lannutti et al, 2011). Phase I trials demonstrated that idelalisib is highly active in pts with heavily pretreated iNHL: pts experienced reductions in disease-associated chemokines, profound and rapid reductions in lymphadenopathy, and durable clinical benefit with an acceptable safety profile (de Vos et al, 2011). Methods: 450 pts with previously treated iNHL, who have measurable lymphadenopathy, require therapy for iNHL, have received prior anti-CD20-antibody-containing therapy and chemotherapy, and who have iNHL that is not refractory to bendamustine (B) are randomized in a 2:1 ratio into Arm A or B. In Arm A, pts receive idelalisib at 150 mg BID continuously ⫹ rituximab (R) at 375 mg/m2 every 28 days for 6 cycles ⫹ B at 90 mg/m2 on days 1 and 2 of each 28-d cycle. In Arm B, pts receive placebo BID instead of idelalisib. Stratification factors include tumor type (follicular lymphoma vs others), tumor burden (high vs low), and time since completion of last prior therapy for iNHL (⬍18 months vs ⱖ18 months). The primary endpoint is PFS, and key secondary endpoints include CR rate, ORR, lymph node response rate, and OS. This is an event-driven trial and primary endpoint evaluation will be based on independent central review. For the primary efficacy analysis, the difference in PFS between the treatment arms will be assessed in the ITT analysis set using Kaplan-Meier methods and the stratified log-rank test. The study opened for enrollment in Dec 2012 (NCT01732926). Clinical trial information: NCT01732926.

TPS8619


A randomized, multicenter, open-label, phase III study of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) versus ofatumumab in patients (pts) with relapsed or refractory (RR) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): RESONATE. Presenting Author: John C. Byrd, The Ohio State University, Columbus, OH Background: Chemoimmunotherapy (CIT) treatment approaches such as FCR have markedly improved outcomes for CLL pts when administered as initial or second-line therapy. Despite this progress, virtually all pts relapse and effective salvage regimens that induce durable remissions or can be administered safely to elderly pts or those with comorbidities are lacking. BTK, an essential mediator of B-cell receptor signaling, is a novel target in CLL. Ibrutinib, a first-in class inhibitor of BTK, promotes apoptosis and inhibits proliferation, migration and adhesion in CLL cells. Phase II data of ibrutinib monotherapy in RR CLL demonstrated an estimated PFS and OS of 75% and 83% respectively at 26 months (Byrd Abst #189 ASH 2012). These findings confirmed BTK as an important target in CLL and supported initiation of a pivotal phase III study in pts with RR CLL/SLL. Methods: PCYC-1112-CA is an ongoing international Phase 3 randomized controlled study of ibrutinib versus ofatumumab for treatment of pts with RR CLL/SLL. The study is enrolling 350 planned pts in 9 countries. Pts are randomized 1:1 to receive ibrutinib 420 mg orally once daily or ofatumumab per the package insert at 300 mg for the first dose, then 2000 mg for a total of 12 doses over 24 weeks. Pts are stratified based on del 17p and disease refractory to purine analogs. Key inclusion criteria include RR CLL/SLL with ⬎⫽ 1 prior line of therapy including pts who experienced a short remission duration to purine analog based CIT, pts who are older or have comorbidities, and pts with del 17p. Pts must have active disease meeting criterion for requiring therapy and measurable nodal disease by CT. Key exclusion criteria include Richter’s transformation, stem cell transplantation within 6 months, GVHD or immunosuppression, platelet count ⬍30,000 cells/ul or use of warfarin The primary objective of the study is PFS evaluated by an IRC. Other outcomes include ORR, OS, hematologic improvement, and safety. An independent DMC is monitoring the study. Clinical trial information: NCT01744691.


548s LBA9000

Melanoma/Skin Cancers Oral Abstract Session, Sat, 1:15 PM-4:15 PM

AVAST-M: Adjuvant bevacizumab as treatment for melanoma patients at high risk of recurrence. Presenting Author: Philippa Corrie, Oncology Centre, Addenbrooke’s Hospital, Cambridge, United Kingdom


9002


9001


Adjuvant radiotherapy after lymphadenectomy in melanoma patients: Final results of an intergroup randomized trial (ANZMTG 0.1.02/TROG 02.01). Presenting Author: Michael A. Henderson, Peter MacCallum Cancer Center, Melbourne, Australia Background: The role of adjuvant radiotherapy following lymphadenectomy in melanoma patients identified as at high risk for further recurrence has been controversial. This final report of a multicenter randomized trial updates survival and lymph node field (LNF) control, and reports long term treatment toxicity, lymphedema and quality of life (QOL) (Lancet Oncol 2012;13:589-97). Methods: Patients at high risk of LNF relapse (ⱖ1 parotid, ⱖ2 cervical or axillary or ⱖ3 groin positive nodes; or extra-nodal spread of tumour; or minimum metastatic node diameter of 3cm (neck or axilla) or 4cm (groin)) received adjuvant radiotherapy (ART) (48Gy in 20 fractions) or observation (OBS). LNF relapse, as a 1st relapse, was the primary endpoint; morbidity, QOL, patterns of relapse, disease free and overall survival were secondary endpoints. A target sample size of 250 enabled detection of a difference in 3 year relapse rates of 30% and 15% to be detected (2-sided logrank test, power of 80%). Results: 250 patients from 16 centres were randomized from Mar 02 to Sept 07 (123 ART; 127 OBS) with 217 fully eligible (109 ART, 108 OBS). Mean follow-up 73 months (range 21–116). LNF recurrence was reduced in the ART arm (HR⫽0.52 (0.31- 0.88) p⫽0.023) but there was no difference in survival (HR⫽1.13 (0.82 – 1.55) p ⫽0.21). QOL was assessed by comparison of area under the curve from baseline to 5 years (or recurrence) with the FACT-G tool using both total score and the 4 major domains (physical, social, emotional and functional wellbeing), no difference. Regional symptoms (standardised questionnaire) were higher in the ART arm (p⫽0.035). Limb volumes were higher in the ART arm (leg 7.3% difference p⫽0.014, arm 3.4% p⫽0.25). Grade 2-4 RT toxicity was common for head ⫹ neck: skin (33%); axilla: skin (44%), subcutaneous tissue (41%); Groin: skin (46%), subcutaneous tissue (67%), other (38%). Conclusions: RT reduced the risk of LNF relapse by 52% but there was no impact on survival. In the ART arm loco-regional symptoms were worse, limb volumes were somewhat increased and Grade 2 - 4 long term RT toxicity was relatively common. However QOL as assessed by a validated tool (FACT-G) was similar in both groups. Clinical trial information: NCT00287196.

CRA9003


Next-generation sequencing of genomic and cDNA to identify a high frequency of kinase fusions involving ROS1, ALK, RET, NTRK1, and BRAF in Spitz tumors. Presenting Author: Phil Stephens, Foundation Medicine, Inc., Cambridge, MA

Phase II study of selumetinib (sel) versus temozolomide (TMZ) in gnaq/ Gna11 (Gq/11) mutant (mut) uveal melanoma (UM). Presenting Author: Richard D. Carvajal, Memorial Sloan-Kettering Cancer Center, New York, NY

Background: Spitz tumors are melanocytic neoplasms with characteristic morphologic features that can overlap with melanoma. Predicting biologic behavior, which can range from an indolent disease to metastasis confined to regional lymph nodes and infrequent incidences of widespread metastatic disease with lethal outcome, is unreliable based on histopathological criteria and the genetic underpinnings of the disease as a whole are poorly understood. Methods: Genomic DNA and total RNA was isolated from 40 microns of FFPE sections from 20 benign Spitz nevi and 8 atypical Spitz tumors (with morphological features inconsistent with HRAS or BRAF/ BAP1 mutations) in a CLIA-certified lab (Foundation Medicine). DNA sequencing was performed for 3230 exons of 182 cancer-related genes plus 37 introns of 14 genes commonly fused on indexed hybridizationcaptured libraries to an average unique coverage of 997x, with 99.96% of exons being sequenced at ⱖ100x coverage. RNA sequencing was performed on indexed libraries captured using the cDNA Kinome hybridization kit (Agilent) generating ⬎50,000,000 unique pairs per specimen. Results: Only a single case harbored a point mutation in a gene known to be recurrently mutated in melanocytic neoplasms, HRAS Q61L and no known alterations were found in BRAF, NRAS, KIT, GNAQ or GNA11. Remarkably, genomic rearrangements were observed in 19/28 (68%) of cases. The rearrangements fused the intact kinase domains of ROS1 (36%), ALK (14%), RET (7%), NTRK1 (7%) and BRAF (4%) to a wide range of predominantly novel 5’ partners including PWWP2A, PPFIBP1, ERC1, MYO5A, CLIP1, HLA-A, ZCCHC8, DCNT1, LMNA and CEP89. These gene rearrangements, which were all expressed, formed constitutively activated chimeric oncogenes. All fusions occurred in a mutually exclusive pattern and were more common in younger patients compared to patients whose tumors did not harbor fusions (median age 14 versus 24 years, p⫽0.02). Conclusions: Next generation sequencing identified gene fusions in two thirds of Spitz tumors which are likely to be useful as diagnostic markers that may also serve as therapeutic targets for the rare subset of these tumors that metastasize.



Melanoma/Skin Cancers 9004


549s

9005


Phase II double-blind, randomized study of selumetinib (SEL) plus dacarbazine (DTIC) versus placebo (PBO) plus DTIC as first-line treatment for advanced BRAF-mutant cutaneous or unknown primary melanoma. Presenting Author: Mark R. Middleton, Oxford University Hospitals NHS Trust, Oxford, United Kingdom

BRAF inhibitor (BRAFi) dabrafenib in combination with the MEK1/2 inhibitor (MEKi) trametinib in BRAFi-naive and BRAFi-resistant patients (pts) with BRAF mutation-positive metastatic melanoma (MM). Presenting Author: Jeffrey Alan Sosman, Vanderbilt University Medical Center, Nashville, TN

Background: BRAF mutations play an oncogenic role in melanomas. Selumetinib (AZD6244, ARRY-142886) inhibits MEK1/2 downstream of B-Raf and may have an additive effect to chemotherapy. We prospectively evaluated SEL ⫹ DTIC vs PBO ⫹ DTIC in patients with stage III-IV BRAF mutation-positive advanced cutaneous or unknown primary melanoma (NCT00936221). Methods: Eligible patients (pts) received iv DTIC 1000 mg/m2, and po SEL 75 mg or matched PBO bd as first-line treatment. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety and tolerability. Results: A total of 385 pts were screened across 44 centers; 91 patients were randomized (SEL ⫹ DTIC, 45; PBO ⫹ DTIC, 46). One pt from each group did not receive the randomized treatment. Baseline characteristics were balanced between the two groups, with the exception of histology, gender and previous medications. At data cut-off, 66 deaths had occurred (73% maturity) and median follow-up was 12.3 mo. OS was longer for SEL ⫹ DTIC vs PBO ⫹ DTIC (median 13.9 vs 10.5 mo), but this did not meet statistical significance (HR 0.93; 80% CI 0.67, 1.28; 1-sided p⫽0.3873). PFS was significantly improved for SEL ⫹ DTIC vs PBO ⫹ DTIC, median 5.6 vs 3.0 mo (HR 0.63; 80% CI 0.47, 0.84; 1-sided p⫽0.021). ORR was 40% with SEL ⫹ DTIC vs 26% with PBO ⫹ DTIC. Most frequent adverse events (AEs) observed with SEL ⫹ DTIC were: nausea (64%), dermatitis acneiform (52%), diarrhea (48%), vomiting (48%), and peripheral edema (43%). AEs that led to hospitalization were higher for SEL ⫹ DTIC vs PBO ⫹ DTIC (36 vs 13%), and were mostly infections and gastrointestinal disorders. The incidence of grade ⱖ3 AEs (68 vs 42%), serious AEs (50 vs 18%) and discontinuation of the randomized treatment due to AEs were higher for SEL ⫹ DTIC vs PBO ⫹ DTIC (16 vs 4%). Conclusions: Clinical activity was observed in patients with BRAF mutation-positive melanoma treated with SEL ⫹ DTIC, reflected by a nonsignificant improvement in OS and a significant benefit in PFS. Tolerability of this combination was generally consistent with the monotherapy safety profiles. Clinical trial information: NCT00936221.

Background: Dual inhibition of the MAP kinase (MAPK) pathway with dabrafenib (D) and trametinib (T) in combination has demonstrated clinical benefit compared to D alone in a randomized Phase II trial in V600 BRAF-mutant MM pts, thus delaying the development of BRAFi resistance. Little is known about the efficacy of D ⫹ T after BRAFi resistance has been acquired. This analysis evaluates the ability of D ⫹ T combination to treat acquired resistance compared to the D ⫹ T combination as first-line treatment. Methods: These data from a phase I/II study include 1. BRAFi-resistant group: pts who received 150/2 D⫹T in Part B (n⫽26) and Part C (n⫽43) following progression on BRAFi monotherapy (mono); 2. BRAFi-naïve group: pts who received initial 150/2 D⫹T in Part B (n⫽24) and Part C (n⫽54). Results: Baseline characteristics (ECOG PS, M staging, LDH) were similar across all groups.In the Part B BRAFi-resistant group, 93% of pts previously received D or vemurafenib and all pts received D prior to D⫹T in Part C. In BRAFi-resistant group, prior best response of CR/PR (38%, 56%), SD (35%, 27%), PD (27%, 7%) was observed in Parts B and C respectively. In BRAFi-resistant group, the ORR and PFS with D⫹T was lower than initial D⫹T in BRAFi-naive group. Median duration of response (DoR) in BRAFi-resistant group cannot be calculated due to small no. of pts responding. Median DoR for BRAFi-naïve pts was 11.3 mo and 10.5 mo in Parts B and C respectively. In Part C, the 12-mo overall survival rates in BRAFi-naïve (150/2) pts was 79% vs 70% for pts initially on D mono, despite 80% pts crossing over to D⫹T combination. Conclusions: The clinical activity for 150/2 D⫹T combination is consistently superior in BRAFi-naive group vs BRAFi-resistant group in both Parts B and C. Dual MAPK blockade can delay clinical resistance to BRAF inhibition. However, once BRAFi resistance has occurred, the combination of BRAFi ⫹ MEKi is far less effective. Clinical trial information: NCT01072175.

CRA9006^


BRAFi resistant Cohort Treatment group PFS, median, months ORR, %

CRA9007

BRAFi naive

Part B

Part C

Part B

Part C

150/2 combination N⫽26 3.6 15%

Mono X-over 150/2 combination N⫽43 3.6 9%

150/2 combination N⫽24 10.8 63%

150/2 combination N⫽54 9.4 76%


Survival and long-term follow-up of safety and response in patients (pts) with advanced melanoma (MEL) in a phase I trial of nivolumab (anti-PD-1; BMS-936558; ONO-4538). Presenting Author: Mario Sznol, Yale Cancer Center, New Haven, CT

Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus ipi alone in metastatic melanoma: E1608. Presenting Author: F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA




550s LBA9008

Melanoma/Skin Cancers Oral Abstract Session, Sat, 1:15 PM-4:15 PM

OPTiM: A randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma. Presenting Author: Robert Hans Ingemar Andtbacka, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT


9010


9009


Clinical efficacy and safety of lambrolizumab (MK-3475, Anti-PD-1 monoclonal antibody) in patients with advanced melanoma. Presenting Author: Antoni Ribas, Med-Hematology & Oncology, University of California, Los Angeles, Los Angeles, CA Background: Programmed death-1 (PD-1) is an inhibitory T-cell co-receptor that may lead to suppression of antitumor immunity. Lambrolizumab is a humanized monoclonal IgG4 antibody against PD-1. This study explored the safety and clinical activity of lambrolizumab in patients (pts) with advanced melanoma (MEL). Methods: In this ongoing phase 1b expansion study of MEL pts with or without previous ipilimumab (IPI) treatment, lambrolizumab was administered IV every 2 or 3 weeks until disease progression or unacceptable toxicity. Tumor response was assessed every 12 weeks by independent, central, blinded radiographic review per immunerelated response criteria and RECIST 1.1. Results: As of December 1, 2012, 294 pts with MEL were enrolled, including 179 IPI-naive and 115 IPI-pretreated. Pts received lambrolizumab 10 mg/kg (n ⫽ 183) or 2 mg/kg (n ⫽ 111). Preliminary data from the first 85 consecutive pts dosed before April 25, 2012, who had independent radiologic review available as of December 3, 2012, indicate a confirmed overall response rate per RECIST 1.1 of greater than 35%, pooled across all doses and schedules and including both IPI-naive and IPI-pretreated patients. The median duration of response has not been reached as only 2 pts who had initial response discontinued due to disease progression, but the duration of confirmed responses range from 28⫹ to 240⫹ days (up to 8⫹ months). Among 133 pts who were dosed with lambrolizumab before July 31, 2012, and evaluable for adverse events (AEs) as of September 28, 2012, fatigue (22%), rash (18%), and pruritus (14%) were the most common drugrelated AEs (mostly grade 1/2). The incidence of drug-related grade 3/4 AEs was 10% (24% regardless of attribution). Four drug-related cases of pneumonitis were reported, all of grade 1/2. Grade 3/4 drug-related hypothyroidism (n ⫽ 1) and hyperthyroidism (n ⫽ 1) were noted. Conclusions: Preliminary data suggest that lambrolizumab has significant antitumor activity and is well tolerated with manageable side effects in both IPI-naive and IPI-pretreated MEL pts. These data have led to an ongoing, international, randomized study of lambrolizumab versus chemotherapy in IPIpretreated MEL. Clinical trial information: NCT01295827.

9011


Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic melanoma (mM). Presenting Author: Omid Hamid, The Angeles Clinic and Research Institute, Los Angeles, CA

Phase I/II trial of PD-1 antibody nivolumab with peptide vaccine in patients naive to or that failed ipilimumab. Presenting Author: Jeffrey S. Weber, Moffitt Cancer Center, Comprehensive Melanoma Research Center, Tampa, FL

Background: mM is an immunotherapy responsive disease where PD-L1 overexpression is prevalent. MPDL3280A, a human monoclonal antibody containing an engineered Fc-domain designed to optimize efficacy and safety, targets PD-L1, blocking PD-L1 from binding its receptors, including PD-1 and B7.1. Initial antitumor activity observed during dose escalation supported further expansion in mM with MPDL3280A as monotherapy and in combination with targeted therapy. Methods: Pts with mM of any histologic subtype received MPDL3280A administered IV q3w for up to 1 y. Objective response rate (ORR) was assessed by RECIST v1.1. Reported ORR includes u/cCR and u/cPR. In addition, a separate Ph 1b was initiated to evaluate the safety and efficacy of MPDL3280A with vemurafenib (vem) in pts with BRAF-V600 mutated mM. Results: As of Jan 10, 2013, 45 mM pts were treated at ⱕ1 (n⫽4), 10 (n⫽10), 25 (n⫽20) and 20 mg/kg (n⫽11) and evaluable for safety. Median pt age was 63 y (range 21-83 y), 100% were PS 0-1, 91% had prior surgery and 64% received prior systemic therapy. Pts received MPDL3280A treatment for a median duration of 127 days (range 1-282). The incidence of all G3/4 AEs, regardless of attribution, was 33%, including hyperglycemia (7%), elevated ALT (7%) and elevated AST (4%). No G3-5 pneumonitis was reported. No treatment-related deaths occurred on study. 35 mM pts who initiated treatment at doses of 1-20 mg/kg and enrolled prior to Jul 1, 2012, were evaluable for efficacy. An ORR of 26% (9/35) was observed, with all RECIST responses ongoing or improving. Further, some responding pts experienced tumor shrinkage within days of initial treatment. The 24-week PFS was 35%. Several additional pts had delayed antitumor activity after apparent radiographic progression and were counted as PD for the above analyses. Analysis of mandatory archival tumors showed a correlation between PD-L1 status and efficacy. Further, of three initial pts treated with MPDL3280A and vem, 2 experienced tumor shrinkage, including 1 CR. Conclusions: MPDL3280A was well tolerated as monotherapy, and durable ORs were observed. Therefore, further assessment of MPDL3280A as monotherapy and combination therapy is warranted. Clinical trial information: NCT01375842.

Background: Nivolumab, an IgG4 fully human monoclonal antibody against checkpoint protein PD-1, is active in metastatic melanoma, renal cell and non-small cell lung cancer. It was administered with a multi-peptide vaccine to patients (pts) with unresectable melanoma who failed at least one regimen for metastatic disease and were ipilimumab naïve, or failed ipilimumab, to assess the toxicity and tolerability of the combination and perform correlative immune assays. Methods: Three cohorts of 10 HLA A0201 positive ipilimumab-naïve pts received nivolumab at 1, 3 or 10 mg/kg, then three additional cohorts of pts who had failed prior ipilimumab received nivolumab at 3 mg/kg: two cohorts of 10 pts each who were A0201 positive and had either grade 2 or less ipilimumab toxicity, or grade 3 dose limiting ipilimumab toxicity; finally 40 pts were treated with antibody who had grade 2 or less ipilimumab toxicity and were not HLA restricted. Pre-treatment archived tumor tissue as well as pre- and post-treatment peripheral blood cells were collected. Results: Median age for all pts was 59;76% were M1c. Response rates by RECIST were 28% in 34 pts naïve to, and 32% for 46 pts who failed prior ipilimumab. Nivolumab did not induce the same irAEs in pts with prior ipilimumab induced toxicity. No cohort had more than one dose limiting toxicity. 2 pts had grade 3 pneumonitis. Three of ten pts who failed nivolumb had stable disease or a partial response to subsequent ipilimumab. Biomarker studies showed that elevated NY-ESO 1 and MART-1 specific CD8 T cells pre-treatment were associated with non-response (p⬍0.005 and ⬍0.001), and that CTLA-4 positive CD4 T cells and T regulatory cells were elevated after treatment in non-responders (p⬍0.01). Immunohistochemical analysis of pre-treatment tumors indicated that PD-L1 staining was associated with response, but responses were also observed in pts whose tumors did not stain. Conclusions: Objective responses to nivolumab were observed after failing ipilimumab, and to ipilimumab after failing nivolumab. Elevation of CTLA-4 after nivolumab in non-responders suggest that sequential therapy with the combination should be tested. Tumor PD-L1 was associated with but not predictive of response. Clinical trial information: NCT01176461.


Melanoma/Skin Cancers 9012^


Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO4538) in combination with ipilimumab in patients (pts) with advanced melanoma (MEL). Presenting Author: Jedd D. Wolchok, Memorial SloanKettering Cancer Center, New York, NY Background: CTLA-4 and PD-1 are critical immune checkpoint receptors. In MEL pts, ipilimumab (anti-CTLA-4) prolonged survival in two phase III trials, and nivolumab (anti-PD-1) produced an objective response rate (ORR) of 31% (n⫽106) in a phase I trial. PD-1 is induced by CTLA-4 blockade, and combined blockade of CTLA-4/PD-1 showed enhanced antitumor activity in murine models. Thus, we initiated the first phase 1 study to evaluate nivolumab/ipilimumab combination therapy. Methods: MEL pts with ⱕ3 prior therapies received IV nivolumab and ipilimumab concurrently, q3 wk ⫻ 4 doses, followed by nivolumab alone q3 wk ⫻ 4 (Table). At wk 24, combined treatment was continued q12 wk ⫻ 8 in pts with disease control and no DLT. In two sequenced-regimen cohorts, pts with prior standard ipilimumab therapy were treated with nivolumab (q2 wk ⫻ 48). Results: As of Dec. 6, 2012, 69 pts were treated. We report efficacy data on 37 pts with concurrent therapy in completed cohorts 1-3 (Table); ORR was 38% (95% CI: 23-55). In cohort 2 (MTD), ORR was 47% and 41% of pts had ⱖ80% tumor reduction at 12 wk (Table) with some pts showing rapid responses, prompt symptom resolution, and durable CRs. Related adverse events (rAEs) for concurrent therapy were similar in nature with some higher in frequency than those typically seen for the monotherapies and were generally manageable using immunosuppressants. Cohort 3 exceeded the MTD (DLT: gr 3-4 1 lipase). At the MTD, gr 3-4 rAEs occurred in 59% of pts and included uveitis/choroiditis, colitis, and reversible lab abnormalities. Conclusions: Nivolumab and ipilimumab can be combined with a manageable safety profile. Clinical activity for concurrent therapy appears to exceed that of published monotherapy data, with rapid and deep tumor responses (ⱖ80% tumor reduction at 12 wk) in 30% (11/37) of pts. A phase III trial is planned to compare concurrent combination dosing with each monotherapy. Clinical trial information: NCT01024231. Ipilimumab (mg/kg) ⴙ CRb PRb Cohort nivolumab (mg/kg) na (n) (n) 1 2 3 2a 6 7

3 ⫹ 0.3 3⫹1 3⫹3 1⫹3 Prior ⫹ 1 Prior ⫹ 3

14 17 6 12 14 6

1 3 0

2 5 3

ORR (%) [95% CI]

>80% Tumor reduction at 12 wk (%)

21 [5-51] 4/14 (29) 47 [23-72] 7/17 (41) 50 [12-88] 0/6 (0) Ongoing Ongoing Ongoing

9013

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An update on BREAK-3, a phase III, randomized trial: Dabrafenib (DAB) versus dacarbazine (DTIC) in patients with BRAF V600E-positive mutation metastatic melanoma (MM). Presenting Author: Axel Hauschild, University Medical Center Schleswig-Holstein, Kiel, Germany Background: Dabrafenib is a selective BRAF inhibitor with demonstrated efficacy in BRAF V600E-positive mutation in MM. The primary analysis of BREAK-3 (NCT01227889) compared progression-free survival (PFS) in patients (pts) with BRAF V600E-positive mutation MM treated with dabrafenib or DTIC. Methods: Median PFS for dabrafenib of 5.1 months (mo) and study methods were previously described (Hauschild A, et al. Lancet. 2012,380:358 –365). Independent review ended at the primary analysis. PFS was updated in Jun 2012 at median follow-up of 10.5 mo for dabrafenib (67% of PFS events), and 9.9 mo for DTIC. Median overall survival (OS) was not reached, so another analysis of OS and safety was performed with data as of Dec 2012, at which time the median follow-up was 15.2 (dabrafenib) and 12.7 (DTIC) mo. PFS of subjects who crossed over was also evaluated at that time. Results: PFS hazard ratio was 0.37 [95% CI; 0.23, 0.57]; median PFS was 6.9 mo dabrafenib and 2.7 mo DTIC. In Dec 2012, 36/63 DTIC pts crossed over; median PFS was 4.3 [95% CI; 4.1, 6.1] mos. OS is presented in the Table.The four most common adverse events (AE) on the dabrafenib arm were hyperkeratosis (39%), headache (35%), arthralgia (35%), and pyrexia (32%). Serious AEs ⱖ 5% on the dabrafenib arm included cutaneous squamous cell carcinoma/ keratoacanthoma (10%) and pyrexia (5%). Conclusions: Longer follow-up confirms the benefits of dabrafenib on PFS and response rate. Median OS in the dabrafenib arm was over 18 mo and over 15 mo in the DTIC arm. OS results are confounded by crossover of DTIC pts to dabrafenib and likely by subsequent therapy after progression. The effects of subsequent therapy results will be investigated. The safety profile had no significant changes. Clinical trial information: NCT01227889.

OS

# Deaths Median [95% CI] HR [95% CI]

25 Jun 2012 Dabrafenib DTIC

18 Dec 2012 Dabrafenib DTIC

55/187 (29%) NR [NR, NR]

78/187 28/63 (42%) (44%) 18.2 15.6 [16.6, NR] [12.7, NR] 0.76 [0.48, 1.21]

21/63 (33%) NR [11.3, NR] 0.75 [0.44, 1.29]

NR ⫽ not reached. DTIC patients were not censored at crossover.

Total treated; bmWHO criteria.

9014


9015


Coexistence of multiple escape mechanisms in a BRAFV600E-mutated cutaneous melanoma treated with vemurafenib. Presenting Author: Olivier Michielin, University Hospital Lausanne, Oncology, Lausanne, Switzerland

Whole exome and whole transcriptome sequencing in melanoma patients to identify mechanisms of resistance to combined RAF/MEK inhibition. Presenting Author: Nikhil Wagle, Dana-Farber Cancer Institute, Boston, MA

Background: Mechanisms of acquired resistance to vemurafenib are the subject of intense research. Here we report, for the first time, two coexisting yet mutually exclusive mechanisms of escape in a melanoma patient who presented an excellent clinical response following reintroduction of vemurafenib. Methods: To investigate the mechanisms of resistance to vemurafenib, we performed whole-exome sequencing using the Illumina technology of a pre-treatment paraffin-embedded lymph node metastasis (Pre) and of two progressing subcutaneous snap-frozen metastases of the right arm (PV1 and PV2). The tumor samples, along with germline controls, were sequenced at high coverage (mean range 268x-356x). Results: We identified 107 exonic somatic Single Nucleotide Variants (SNVs) in Pre, 139 SNVs in PV1, and 127 SNVs in PV2, generating a set of 202 different SNVs, 82 of which were common to all 3 samples. The non-synonymous to synonymous ratios were higher for PV1 (1.82) than for PV2 (1.46), and lower for Pre (1.31). C⬎T transitions, largely predominated in the samples, indicating light-induced damage. Two independent NRAS escape mutations (Q61K and Q61R) where observed in PV1, whereas appearance of a BRAF splice variant (lack of exon 4-10) was present in PV2. Most importantly, these 2 escape mechanisms were mutually exclusive, i.e. no BRAF splice variant was observed by PCR in PV1 and no NRAS mutation found in PV2. Conclusions: Our results clearly demonstrate that multiple molecular escape mechanisms can be both coexistent and mutually exclusive. These findings have clinical implications: firstly, local treatment of isolated progressing lesions and continuation of vemurafenib could be supported by the fact that the resistance mechanisms are not necessarily shared. This approach is currently being tested within clinical trials with preliminary results that seem to support this hypothesis. Secondly, the coexistence of divergent escapes within the same patient strongly argues that single biopsy analysis at progression might not reflect the molecular complexity of tumor progression, and therefore might not be sufficient to guide selection of second-line optimal combination therapy.

Background: The RAF inhibitors vemurafenib and dabrafenib (D) and the MEK inhibitor trametinib (T) improve survival as monotherapies in BRAFmutant melanoma. Since clinical mechanisms of resistance (MoR) result in MAPK pathway reactivation, recent efforts have focused on combined targeting of RAF and MEK. The combination of D and T (D/T) increased progression-free survival and response rate compared with D alone (Flaherty et al, NEJM, 2012). The MoR to this combination remain unknown. Methods: To look for clinical MoR to combined RAF/MEK inhibition, we performed whole exome (WES) and whole transcriptome sequencing (RNASeq) on tumors from 4 patients (pts) with acquired resistance and 1 pt with intrinsic resistance to D/T. Pre-treatment and post-resistance tumors from all pts were analyzed for point mutations, insertions/deletions, copy number alterations, alternatively spliced transcripts, rearrangements, and expression changes. Results: In 2 of 4 pts with acquired resistance, WES identified mutations in MEK1 and MEK2 that were undetectable in the pre-treatment tumors. In the 3rd pt, RNASeq identified an alternatively spliced isoform of BRAF lacking exons 2-10, also undetectable in the pre-treatment tumor. In the 4th pt, no obvious MoR were seen, though multiple alterations were enriched in the post-resistance tumor. The pt with intrinsic resistance had several alterations in genes that conferred resistance to RAF/MEK inhibition when overexpressed in BRAF-mutant cell lines. Integration of WES and RNASeq data also identified several coexisting alterations that may synergize to increase resistance. Conclusions: Analysis of combined WES and RNASeq data from pt samples provides a more complete picture of clinical MoR to MAPK-targeted therapy. Postresistance tumors from 3 of 4 pts with acquired resistance to D/T had alterations in MAPK genes not detectable in the pre-treatment tumors, suggesting that resistance involves reactivation of the MAPK pathway despite combined RAF/MEK inhibition. Alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.


552s 9016

Melanoma/Skin Cancers Poster Discussion Session (Board #4), Mon, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

Comparison of BRAF inhibitor (BRAFi)-induced cutaneous squamous cell carcinoma (cuSCC) and secondary malignancies in BRAF mutationpositive metastatic melanoma (MM) patients (pts) treated with dabrafenib (D) as monotherapy or in combination with MEK1/2 inhibitor (MEKi) trametinib (T). Presenting Author: Jonathan S. Cebon, Ludwig Institute for Cancer Research, Melbourne, Australia Background: The MAP kinase (MAPK) pathway is of critical importance for keratinocyte proliferation and maturation and is essential for epidermal homeostasis. Occurrence of hyperproliferative skin lesions including keratoacanthomas (KA) and cuSCC are considered a class effect of BRAFi [Anforth 2012, Chu 2012, Mattei 2012]. These effects, as well as promotion of pre-existing RAS-driven malignancies, may be caused by paradoxical activation of the MAPK pathway downstream of BRAF in wild-type BRAF cells. As MEK inhibition blocks downstream MAPK signaling, it was hypothesized that addition of a MEKi to a BRAFi would abrogate these effects [Su, 2012]. Methods: This 4-part phase I/II study enrolled 365 BRAFV600E/Kmutated MM pts in Parts B-D. In part C, 162 pts (BRAFi and MEKi treatment-naïve, ⱖ 18 yrs; ECOG PS ⬍2; RECIST measurable disease) were randomized to D monotherapy 150mg BID (D mono) vs. the combination of D (150 mg BID) and T (1 mg or 2 mg QD). Primary endpoints included safety and efficacy. Occurrence of cuSCC (including KA) across three arms in Part C and secondary malignancies with D⫹T across all Parts are provided below. Results: The difference in incidence of cuSCC between D mono and the D⫹T (150/1) was statistically significant, whereas the difference in incidence between D mono and D⫹T (150/2) was not. The median time to onset of cuSCC was 30 days in D mono compared to 282 and 152 days with D⫹T (150/1 and 150/2, respectively). Of 365 pts who received D⫹T, 2 (⬍1%) cases of new cancers (colorectal and gliobastoma) and 2 (⬍1%) cases of new primary malignant melanoma were reported. Conclusions: These data support the experimental hypothesis that the occurrence of cuSCC (including KA) can be substantially reduced and delayed by the addition of a MEKi to BRAFi therapy. Clinical trial information: NCT01072175. Treatment groups for Part C D T N Any cuSCC including KA, n (%) Reduction P value (2-sided)

9018

150 mg BID -53 10 (19) ---

150 mg BID 1 mg QD 54 1 (2) 89% 0.0040

150 mg BID 2 mg QD 55 4 (7) 63% 0.0901


9017


NRAS and BRAF mutations in atypical melanocytic lesions arising in melanoma patients treated with vemurafenib. Presenting Author: Emily Y. Chu, Hospital of the University of Pennsylvania, Philadelphia, PA Background: BRAF inhibition with targeted therapy has demonstrated improved overall survival in patients with BRAF mutant melanoma. The use of the selective BRAF inhibitors vemurafenib and dabrafenib are associated with a range of known and predictable cutaneous side effects, including squamous cell carcinomas often associated with RAS mutations. Preclinical evidence indicates that BRAF inhibitors may give rise to non-melanoma tumors by promoting MAPK activation in the tissues that lack mutant BRAF. Here we report atypical melanocytic lesions arising in patients treated with the BRAF inhibitor vemurafenib. Methods: To characterize the mutations of both the melanoma tumors and the atypical melanocytic lesions arising in patients with BRAF V600E/K melanoma treated with vemurafenib, a custom Sequenom panel designed to detect 74 mutations in 12 genes known to play a role in the pathogenesis of melanoma was applied to both melanoma and atypical melanocytic lesions for each patient. Results: We observed a total of six atypical melanocytic lesions (melanoma in situ and severely dysplastic nevi) in three patients undergoing treatment with vemurafenib. Mutations analysis in both pre-treatment tumor samples and on-treatment melanocytic lesions was feasible in two of the three patients. One patient with BRAF V600E metastatic melanoma developed two new melanoma in situ lesions while on vemurafenib, diagnosed 10 and 23 weeks after starting vemurafenib. Both on-treatment melanoma in situ lesions were found by Sequenom analysis to be BRAF wild-type, with a NRAS Q16R detected in one of the two lesions. Another patient’s pre-treatment primary melanoma demonstrated synchronous BRAF kinase domain mutations V600K and G466A, and CTNNB1 D32E mutation; a severely dysplastic nevus which arose after 25 weeks on vemurafenib in this patient showed only a BRAFG466A mutation. Conclusions: We identified an NRAS mutation and a rare BRAF kinase domain mutation in atypical melanocytic lesions that arose in patients treated with vemurafenib. Further studies are warranted to demonstrate a causal relationship between BRAF inhibition and the development or accelerated growth of atypical melanocytic lesions.

9019


Identification of changing melanocytic lesions in patients on BRAF inhibitor therapy. Presenting Author: Sarah Yagerman, Memorial Sloan-Kettering Cancer Center, New York, NY

NRAS mutation: A potential biomarker of clinical response to immunebased therapies in metastatic melanoma (MM). Presenting Author: Douglas Buckner Johnson, Vanderbilt-Ingram Cancer Center, Nashville, TN

Background: Patients treated with BRAF inhibitors (BRAFi) have been observed to develop new primary melanomas. In addition, these patients often develop new nevi and involuting nevi. It remains a challenge to detect clinically subtle and histopathologically early melanomas in a background of such increased nevus volatility. In this study, we sought to quantify and describe the new, changing, and involuting melanocytic lesions observed in these patients. Methods: A retrospective chart and image analysis was conducted for all BRAFi treated patients referred to the Dermatology service at Memorial Sloan-Kettering Cancer Center. Initial overview and follow-up images were compared in MIRROR Body Mapping image system, DermaGraphiX software (Canfield Imaging Systems, Fairfield, NJ). A total count of new, changing, and involuting melanocytic lesions was determined in four anatomic areas: upper back, lower back, chest, and abdomen. Dermoscopy images of all changing lesions that were biopsied were evaluated for dermoscopic pattern and for the presence or absence of any melanoma specific features. Results: Average photography follow-up was 261 days (n⫽21). The average number of combined new and changing melanocytic lesions was 13.1, 16.4, 9.5, and 6.1 for the upper back, lower back, chest, and abdomen respectively. The average number of involuting melanocytic lesions was 8.0, 4.0, 4.3, and 3.4 for the upper back, lower back, chest, and abdomen respectively. Of all new and changed lesions, 38 were biopsied revealing 31 benign melanocytic lesions and 7 melanomas (18% of lesions biopsied). All 7 melanomas revealed at least one melanoma specific structure, with the most significant dermoscopic discriminate being negative network. Conclusions: Given the setting of highly volatile melanocytic changes in BRAFi treated patients and that 18% of biopsied lesions were melanomas; we propose the use of total body photography and dermoscopy as a method for the identification and monitoring of secondary atypical pigmented lesions.

Background: NRAS mutant (mut) MM comprises a distinct, molecularly defined cohort of this disease that appears to have a poor prognosis compared to other genetic subsets. In contrast to BRAF mut MM, there are no effective small molecule inhibitors specifically targeting NRAS. Immune based therapy (IT) has become a mainstay in MM treatment, especially in BRAF wild type (WT) patients (pts). Biomarkers to predict which pts will benefit from IT have not been validated. The goal of this study was to evaluate whether genetic subtype (specifically NRAS) has a role in predicting benefit from IT in BRAF WT MM. Methods: We identified 173 pts from 3 institutions who underwent clinical genotyping (exome or PCR based) for NRAS and BRAF mutation from 1/09 – 8/12 and were treated with IT (defined as IL-2, ipilimumab (ipi), or anti-PD-1 (nivolumab, MK3475)/ PD-L1 (MPDL3280A)). Only BRAF WT pts were included. Primary endpoints were response rate (RR) and clinical benefit rate (CBR), defined as RR ⫹ stable disease lasting ⬎24 wks to IT (best response as assessed by treating clinicians in any line of IT). Secondary endpoints were overall survival (OS) and progression-free survival (PFS) from first line IT. Results: Of the 173 pts, 59 had NRAS mut MM compared to 114 WT/WT (no mutation in NRAS or BRAF). Improved clinical outcomes were seen in the NRAS mut compared to WT/WT cohort in terms of RR (32% vs. 18%, p⫽0.042), and CBR (49% vs. 30%, p⫽0.012). Improvements in PFS and OS did not reach statistical significance. By specific IT, NRAS mutation predicted benefit compared to WT/WT for anti-PD-1/PD-L1 (RR 78% vs. 19%, p⫽0.002; CBR 78% vs. 29%, p⫽0.013, n⫽30) and ipi (RR 18% vs. 12%, p⫽0.315; CBR 41% vs. 22%, p⫽0.018, n⫽137). No significant differences were observed with IL-2 (RR 33% vs. 28%, p⫽0.730; CBR 33% vs. 39%, p⫽0.741, n⫽33). Conclusions: This study demonstrates that pts with NRAS mut MM achieve increased clinical benefit from IT compared to pts with BRAF/NRAS WT MM. A larger, prospective analysis is necessary to validate and expand on these results, including those with BRAF mut and KIT mut MM. However, our data suggest that NRAS mutation status may be a biomarker of response to IT in MM and that molecularly targeted immunotherapy may be feasible.




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Tumor-specific circulating cell-free DNA (cfDNA) to predict clinical outcome in BRAF V600 mutation-positive melanoma patients (pts) treated with the MEK inhibitor trametinib (T) or chemotherapy (C). Presenting Author: Dirk Schadendorf, Universitätsklinikum Essen, Essen, Germany

Genetic variation in immunomodulatory genes as markers of melanoma recurrence-free and overall survival. Presenting Author: Justin Rendleman, Department of Population Health, New York University School of Medicine, New York, NY

Background: Tumor-derived cfDNA in the blood is a potential alternative source to derive tumor mutation (mut) status and could be a useful biomarker of therapeutic response. Data from METRIC (NCT01245062), an open-label randomized Phase III study evaluating the efficacy and safety of T vs C, were used to assess: correlation between baseline tumor and cfDNA BRAF muts; correlation between baseline cfDNA levels and tumor burden (i.e., the sum of target lesion diameters); and efficacy based on baseline cfDNA BRAF mut status. Methods: BRAF mut status was established for 322 pts using an allele-specific PCR assay in tumor samples. Baseline plasma samples were available for 305/322 pts. cfDNA BRAF mut status was evaluated by Inostics GmBH using BEAMing technology. Spearman correlation coefficients were used to determine the association between cfDNA fraction (mut DNA molecules ⬎ 0.01%) and baseline tumor burden. A Cox proportional hazards model was used to assess the association between cfDNA mut status and progression-free survival (PFS). Results: The overall agreement between tumor and cfDNA BRAF V600E and V600K mut status was 77%, and 96% respectively. V600E or V600K cfDNA mut fraction did not correlate with baseline tumor burden (R⫽0.38 and 0.23, respectively). Benefit of T vs C was observed regardless of cfDNA BRAF mut status (HR⫽ 0.42, 0.41, 0.47 for V600E, V600K, and not detectable (cfDNA ND) subgroups). Interestingly, cfDNA ND pts had longer PFS vs cfDNA V600E/K pts, independent of treatment (HR⫽0.37 for cfDNA ND vs V600E/K, p⫽⬍0.0001). For T cfDNA ND median PFS was not reached (n⫽52), however the first quartile was 4.5 months; for V600E (n⫽127) and V600K (n⫽21) median PFS was 3.5 and 4.4 months, respectively. For C median PFS was 3.5, 1.4, and 1.5 months for cfDNA ND (n⫽28), V600E (n⫽69), and V600K (n⫽7), respectively. Similarly, higher response rates were seen in cfDNA ND pts vs cfDNA V600E/K pts across both treatment arms. Conclusions: Free circulating DNA can be used to detect BRAF V600 muts. cfDNA mut fraction was not linked to tumor burden. The absence of circulating BRAF mut DNA in BRAF V600 pts may be a marker of a better outcome. Clinical trial information: NCT01245062.

Background: Small reported studies have provided some evidence implicating immune related genes in melanoma susceptibility and prognosis; however candidate selection of these prior efforts has been limited. In this study, we performed an analysis of germline variants in immunomodulatory genes for their association with melanoma survival in a well characterized cohort of prospectively accrued melanoma patients. Methods: Germline DNA isolated from blood samples of 817 melanoma patients was genotyped for 94 SNPs tagging 55 immuno-modulatory genes using Sequenom iPLEX. Cox models were used to test associations between each SNP and recurrence-free and overall survival (RFS and OS), with adjustments for age, gender, subtype, thickness, ulceration, and anatomic site. ROC curves were constructed from different SNP/clinical covariate combinations and the area under the curve (AUC) was used to assess their utility in the classification of 3-year recurrence. Results: The SNP rs2796817 in TGFB2 had strong associations with both RFS (HR⫽3.8, CI 95%: 1.3-11, p⫽0.02) and OS (HR⫽5.5, CI 95%: 1.6-19, p⫽0.029). Other interesting associations with OS came from IRF8 (rs4843861, HR⫽0.62, CI 95%: 0.39-0.99, p⫽0.017), CCL5 (rs4796120, HR⫽7.6, CI 95%: 2.3-25, p⫽0.035), and CD8A (rs3810831, HR⫽2.4, CI 95%: 0.91-6.2, p⫽0.048). A multivariate model including stage, subtype, and one of the SNPs (rs3810831 from CD8A), was shown to improve the AUC when compared to a model including only stage and subtype (0.77 vs. 0.79). Conclusions: We identified several immune-related loci associated with melanoma RFS and OS. The strongest association, rs2796817, maps in TGFB2, which among other functions suppresses IL-2 dependent T-cell growth. In addition to other associations found in the study these findings provide evidence for the involvement of immuno-modulatory genes in melanoma prognosis and suggest further investigations of immune related genes in disease progression. This is currently underway in the second stage validation analysis, which includes an expanded set of immune target genes as well as an additional independent cohort of melanoma patients.

9022

9023


Gene expression profile of primary cutaneous melanomas to distinguish between low and high risk of metastasis. Presenting Author: David H. Lawson, The Winship Cancer Institute of Emory University, Atlanta, GA Background: Wide variability exists in metastatic rates of primary cutaneous melanoma (CM), even within TNM stage groupings. We developed an RT-PCR based gene expression profile (GEP) test to predict distant metastases in early stage CM. Methods: RNA was isolated from formalinfixed, paraffin embedded biopsies or wide excisions of primary CM from patients with stage 1-4 CM (87% stage 1-2) converted to cDNA and analyzed using RT-PCR. All analyses were done using JMP Genomics and WinSTAT. Radial Basis Machine (RBM) modeling was used to predict metastasis-free survival (MFS) for the training set of 149 samples. Independent validation was performed on an additional 107 CM samples. RBM reports a binary Class 1 (low risk) and Class 2 (high risk). Results: Analysis of the training set resulted in a model with 85% receiver operating characteristic (ROC) and sensitivity of 82%. Prediction of metastatic risk for the validation set resulted in a 90% ROC and sensitivity of 89%. 30 of 33 stage 1-3 cases with a known metastatic event were accurately called Class 2. Kaplan-Meier analysis showed 5-year MFS rates of 88% and 25% for predicted Class 1 and Class 2, respectively, in the training set (p⬍0.0001, overall MFS⫽60%). Similarly, MFS was 95% and 26% for Class 1 and Class 2, respectively, in the independent validation set (p⬍0.0001, overall MFS⫽67%). Univariate Cox regression analysis of the validation set revealed that GEP, AJCC stage, Breslow thickness, and ulceration were each predictors of metastatic risk (HR⫽27.2, 11.4, 3.0, and 11.6, respectively, p⬍0.002 for each). Multivariate analysis showed GEP and AJCC stage were independent predictors of risk (HR⫽8.4 and 6.4 respectively, p⬍0.007 for both). Conclusions: This GEP signature provides an accurate stratification of metastatic risk in the training and validation samples independent of all other histologic factors. This test may serve as a prognostic tool for outcomes in patients with melanoma and for stratifying patients for clinical trials.


Analysis of plasma-based BRAF and NRAS mutation detection in patients with stage III and IV melanoma. Presenting Author: David Polsky, The Ronald O. Perelman Department of Dermatology, NYU Langone Medical Center, New York, NY Background: Patients with metastatic melanoma are eligible for BRAF inhibitor therapy if the BRAF V600E mutation can be identified in their tumor specimen. Patients lacking an available specimen for genotyping are unable to receive inhibitor therapy. We developed two mutation-specific genotyping platforms and tested their ability to detect BRAF and NRAS mutations in archived plasma and tumor samples to determine the potential utility of blood-based tumor genotyping in melanoma. Methods: We analyzed a group of 96 patients with stage III or IV melanoma, prospectively enrolled and followed in the NYU Melanoma Biorepository program. Each patient had a plasma sample and one or more tumor samples available for analysis. We used a combination of allele-specific PCR (Taqman) and SNaPshot assays to identify BRAF V600 and NRAS Q61 mutations in the tumor and plasma samples. Results: Among the 96 patients, 51 had stage III disease at the time of analysis; 45 had stage IV disease. Seventy-two patients had 2 or more tumor samples available for analysis, for a total of 204 tumors analyzed. In total, 52/96 (54%) patients had one or more BRAF or NRAS mutant tumors, including one patient with separate BRAF and NRAS mutant tumors (BRAF, n⫽35 (36%); NRAS, n⫽18 (19%)). We successfully amplified plasma DNA from 39/52 (75%) patients with tumor-associated mutations. Among those patients with amplifiable plasma DNA we detected mutations in 7 (18%) patients including 3 BRAF V600E, one V600K, 2 NRAS Q61K and one Q61L. Plasma-based mutations matched tumor-associated mutations in all 7 patients. All 7 patients had active disease at the time of blood draw. There were 32 patients with tumor-associated mutations in which a mutation could not be detected in the plasma. Only 15 of those 32 (47%) had active disease at the time of blood draw. There were no mutations detected in the plasma of the 44 patients whose tumors lacked BRAF or NRAS mutations. Conclusions: These data suggest that plasma-based detection of BRAF and NRAS mutations has a high specificity for tumor-associated mutations. It may prove to be a useful adjunct to tumor-based genotyping in patients with active disease, especially those lacking an available tumor specimen.


554s 9024


9025


Pretreatment levels of absolute and relative eosinophil count to improve overall survival (OS) in patients with metastatic melanoma under treatment with ipilimumab, an anti CTLA-4 antibody. Presenting Author: Katja Schindler, Medical University of Vienna, Vienna, Austria

Analysis of BRAF and NRAS mutation status in advanced melanoma patients treated with anti-CTLA-4 antibodies: Association with overall survival? Presenting Author: Joanna Mangana, University Hospital Zurich, Dermatology, Zurich, Switzerland

Background: Ipilimumab, a fully human monoclonal Ab directed against the CTLA-4 receptor on T-cells, has shown significant improvement in OS for patients with metastatic melanoma in randomized phase III trials. Eosinophilia in peripheral blood of those patients has been observed, but its clinical significance as a prognostic factor has not been assessed. Methods: We report on a retrospective multi-center analysis of 123 patients who received ipilimumab in three centers between 2010 and 2013. Patients treated had AJCC unresectable stage III or stage IV melanoma of any origin and received ipilimumab in first- and second-line setting at the approved standard dosage of 3mg/kg (4 times q21d). Four patients were excluded due to missing baseline values in eosinophil count (EC). Results: Median OS for patients in final analysis (n⫽119) was 9.57 months. Based on cut-offs assessed by ROC curves, OS was estimated by Kaplan-Meier curves. Baseline absolute eosinophil count (AEC) ⱖ 0.1 (109/l) was significantly associated with improved OS (p⫽ 0.002) with 6-, 12- and 18-month survival rates of 79%, 60% and 48% compared to rates of 48%, 37% and 19% for pts with baseline AEC below 0.1. Baseline relative eosinophil counts (REC) of ⱖ 1.75% showed an even stronger significance (p⬍0.0001) with 6-, 12- and 18-months survival rates of 79% vs. 52%, 60% vs. 40% and 51% vs. 17.1% respectively. Conclusions: This retrospective analysis elucidates the possible association of baseline EC with OS of patients treated with Ipilimumab. Improvement of OS was highly significant in both analyses considering AEC (p⫽ 0.002) and REC (p⬍0.0001). Since easily detectable biomarkers could be of great potential value, further effort on understanding the potential role of eosinophil granulocytes as possible effector cells in the immune-mediated response to anti CTLA-4 abs should be undertaken.

Background: Ipilimumab and tremelimumab are human monoclonal antibodies against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival with durable-long-term responses for advanced melanoma patients both in first-and second-line setting. Up to date, there is no proven association between the BRAF-V600E mutation and the disease control rate (DCR) in response to Ipilimumab. Moreover, significantly shorter survival rates have been reported in patients harboring an NRAS mutation than in those without. This retrospective analysis was carried out to assess if BRAF (V600) and NRAS mutation status affects the clinical outcome of Ipilimumab-treated melanoma patients. Methods: This is a retrospective multi-center analysisof 71 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The cut-off for the estimation of overall survival was end of November 2012. Results: The median overall survival of BRAFV600/ NRAS mutant patients (n⫽44) was 1,41 years compared with 2.67 years in BRAF/NRAS wild-type patients (n⫽27). Although this difference was not statistically significant there was a trend for improved survival in wild-type patients. Of the 71 patients analyzed, 56 received chemotherapy prior to Ipilimumab. In the BRAF/NRAS mutant cohort, 12 patients received Ipilimumab following either a BRAF- or a MEK- inhibitor. Of those 12 patients, 8 progressed and were unable to complete Ipilimumab. Of the 4 patients who completed 4 cycles of Ipilimumab, 2 were subsequently treated with a BRAF inhibitor. Furthermore out of the 71 patients, 8 patients received a BRAF or a MEK inhibitor after progression; 5 of them are still alive. Conclusions: This is the first retrospective study to evaluate the association of both BRAF and NRAS mutational status with the overall survival of Ipilimumab-treated patients. There was a trend towards an improved survival in the BRAF/NRAS wild-type subpopulation. Additional patients will be examined to foster these preliminary results.

9026

9027


A phase II study of the multitargeted kinase inhibitor lenvatinib in patients with advanced BRAF wild-type melanoma. Presenting Author: Steven O’Day, The Beverly Hills Cancer Center, Beverly Hills, CA Background: Lenvatinib is an oral receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFR␤. Melanoma responses in the phase I study led to this multicenter phase II trial of lenvatinib in separate cohorts of BRAF mutant and BRAF wild-type (wt) melanoma to provide an estimate of efficacy and to identify molecular correlates of clinical benefit. Primary analyses of clinical outcomes for the BRAF wt cohort are reported here; the BRAF mutant cohort will be presented at a later date. Methods: Eligible patients (pts) had stage IV or unresectable stage III BRAF wt melanoma with ⱖ1 prior treatment (26/96 [27%] pts received ⱖ3 treatments) and no prior VEGF-targeted therapy. Lenvatinib 24 mg once daily with dose reduction for toxicity was administered until disease progression or unmanageable toxicities. Primary endpoint was response rate by independent review (IRR) using RECIST 1.1. Archival tumor tissue and baseline and posttreatment serum samples were collected for molecular analysis. Results: 93 pts were treated (median [m] age: 64 y; male: 69%; 95% AJCC stage IV). Confirmed partial responses (PRs) were observed in 8 pts (9%) with a clinical benefit rate (CR⫹PR⫹durable SD ⱖ23 wks) of 32% by IRR. mPFS was 3.7 mos (95% CI, 2.5-4.0) by IRR and mOS was 9.5 mos (95% CI, 8.3-12.9); 46% pts required dose reduction for management of toxicity; 12% were withdrawn from therapy due to toxicity. Treatment-related adverse events reported in ⱖ20% pts included hypertension 59% (34% Gr 3/4), fatigue 58% (16% Gr 3/4), nausea 44% (3% Gr 3/4), diarrhea 43% (2% Gr 3/4), decreased appetite 38%, vomiting 29% (2% Gr 3), dysphonia 27%, and proteinuria and headache 26% each (4% and 1% Gr 3/4). Serum biomarker analysis showed baseline levels of serum angiogenic factors, such as angiopoietin-2, correlated with OS. More extensive biomarker analyses are reported in an accompanying abstract. Conclusions: Lenvatinib administered to pts with advanced BRAF wt melanoma was associated with frequent but manageable toxicity. Clinical benefit was seen in some pts. Predictive biomarkers for response to lenvatinib, such as the serum level of angiogenic factors, may be useful for future clinical trials. Clinical trial information: NCT01136967.


Lenvatinib combined with dacarbazine versus dacarbazine alone as firstline treatment in patients with stage IV melanoma. Presenting Author: Michele Maio, Azienda Ospedaliera Universitaria Senese U.O.C. Immunoterapia Oncologica, Viale Bracci 16, Siena, Italy Background: Lenvatinib (E7080; LEN) is an oral, receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFR␤ . In a phase I study qd dosing of ⬎/⫽ 20mg LEN demonstrated PRs and prolonged SD in patients (pts) with advanced melanoma. Dacarbazine (DTIC) upregulates the proangiogenic factor VEGF and has been shown to confer resistance in melanoma cell lines (Lev, JCO 2004; 22:2092-2100). Treatment of melanoma pts with LEN ⫹ DTIC may potentiate the therapeutic effects of DTIC. Methods: This was a phase II study in pts with metastatic melanoma randomized 1:1 to receive LEN (20 mg QD) ⫹ DTIC (1000 mg/m2 Q 21 d) or DTIC (1000 mg/m2Q 21 d). Pts were stratified by LDH level and stage IV subclass. Eligible pts were ECOG PS 0/1 and had no prior systemic therapies. BRAF status was determined from circulating tumor DNA. The primary endpoint was PFS by independent assessment. Results: In a modified ITT analysis,a total of 78 of 81 pts were evaluable for efficacy; 59% were male, 59% were Stage IV M1c, 22% had elevated LDH, 29% had prior adjuvant therapy and 49% BRAF wild-type (wt). Most common AEs in the LEN ⫹ DTIC arm were hypertension (48%), nausea (38%), constipation (33%), and diarrhea (31%). Most common Grade 3/4 AEs in LEN ⫹ DTIC were hypertension (26%) and neutropenia (10%). There were no deaths due to an AE. Median PFS increased in LEN ⫹ DTIC compared to DTIC alone (see Table). An improvement in median PFS was observed in BRAFwt pts on the combination. Conclusions: A 2.7-fold increase in the median PFS was observed in pts administered LEN ⫹ DTIC compared to single agent DTIC. A 2.5 fold increase in the median PFS was observed in the combination arm in pts with BRAFwt melanoma. The AE profile observed with the LEN ⫹ DTIC was consistent with observed LEN monotherapy studies. These data suggest further evaluation of LEN ⫹ DTIC in BRAFwt melanoma is warranted. Clinical trial information: NCT01133977. LEN ⴙ DTIC (nⴝ40)

DTIC (nⴝ38)

# Events (%) Median PFS, wks (95% CI) HR (95% CI)

30 (75) 19.1 (9.6, 25.6)

30 (79) 7.0 (5.6, 15.6)

BRAFwt, median PFS, wks (95% CI) (# events/# pts w/BRAFwt) BRAFmut, median PFS, wks (95% CI) (# events/# pts w/BRAFmut)

23.9 (6.1, 42.4) (n⫽11/17)

9.3 (5.3, 16.9) (n⫽18/20)

6.3 (5.3, 42.0) (n⫽5/5)

6.0 (5.3, 9.3) (n⫽3/4)

0.4 (0.23, 0.75) p value ⫽ 0.0033




Initial results from a phase I, open-label, dose escalation study of the oral BRAF inhibitor LGX818 in patients with BRAF V600 mutant advanced or metastatic melanoma. Presenting Author: Reinhard Dummer, University Hospital Zurich, Zurich, Switzerland Background: LGX818, a potent and selective BRAF inhibitor (BRAFi) being investigated in BRAF V600 mutant melanoma, has unique biochemical properties with a dissociation half-time ⬎ 10 times longer than other BRAF inhibitors. Methods: A phase I trial of LGX818 administered orally once (qd) or twice (bid) daily in BRAF V600 tumors was initiated to define the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) and to assess pharmacokinetics and clinical activity in BRAFi–naive or pretreated patients with BRAF V600 mutant advanced melanoma. Baseline assessment of biomarkers from MAPK/PI3K pathways and pharmacodynamics were also evaluated. Results: Fifty-four patients have been enrolled in the dose-escalation phase (dose levels [DLs], 50-700 mg qd [n⫽42] and 75-150 mg bid [n⫽12]). LGX818 plasma concentrations increased proportionally by dose with a mean t1/2 of 4 hours and steady state in ⬇ 15 days. The MTD/RP2D (450 mg qd) was well tolerated. Seven patients had a dose limiting toxicity (DLT): 5 at qd (1 each with hand-foot skin reaction [HFSR], foot pain, fatigue, diarrhea/rash, insomnia/asthenia) and 2 at bid (1 facial paresis/confusion, 1 musculoskeletal pain/neuralgia). All DLTs were grade 3 and reversible. The most common adverse events (ⱖ 20%) suspected to be treatment related were cutaneous (rash, dry skin, HFSR, pruritus, keratosis pilaris, alopecia), pain in extremity, arthralgia, and fatigue. Squamous cell carcinoma was observed in 2 patients (1 naive and 1 pretreated). As of 30 Sept 2012, the preliminary efficacy (all DLs) in patients with at least 1 postbaseline tumor assessment was 16 partial responses [PRs] (67%; 12 confirmed) out of 24 BRAFi–naive patients and 2 PRs (8.3%; 1 confirmed) among 24 BRAFi–pretreated patients. Responses were seen at all DLs from 50 to 550 mg qd. Updated safety and efficacy including time to event endpoints will be reported. Conclusions: Initial results from this study identified the MTD/RP2D as 450 mg/day and provided an early sign of promising activity in advanced melanoma. Expansion cohorts are ongoing in BRAFi–naive and BRAFi–pretreated melanoma and colorectal cancer. Clinical trial information: NCT01436656.

9030


A phase III trial of nab-paclitaxel versus dacarbazine in chemotherapynaive patients with metastatic melanoma: A subanalysis based on BRAF status. Presenting Author: Evan Hersh, University of Arizona Cancer Center, Tucson, AZ Background: Activating mutations of BRAF V600 can be found in 40%50% of melanomas and are related to poor prognosis. In a phase 3 trial for the treatment of metastatic melanoma (MM) in chemotherapy-naive patients, nab-paclitaxel (nab-P) vs dacarbazine (DTIC) demonstrated a significant improvement in the primary endpoint of progression-free survival (PFS), assessed by independent radiological review (IRR), and a trend toward prolonged overall survival (OS) at the interim survival analysis. The study also explored the effect of BRAF status on the efficacy parameters. Methods: Chemotherapy-naive patients with stage IV melanoma (M1c stage 65%; elevated LDH 28%) and ECOG performance status 0-1 were randomized to nab-P 150 mg/m2 on days 1, 8, and 15 of a 28-day cycle (n ⫽ 264) or DTIC 1000 mg/m2 on day 1 of each 21-day cycle (n ⫽ 265) independent of BRAF status. Prespecified subgroup analyses of final PFS and interim OS in subgroups by BRAF status (V600E mutant, wild-type, or unknown) were performed. Results: BRAF mutation status was balanced between the treatment arms, with 36% and 38% of patients with known BRAF mutation status in the nab-P and DTIC arms, respectively. Patient characteristics were also balanced within BRAF subgroups. As shown in the Table, advantage in the nab-P arm vs DTIC arm was observed for both PFS and interim OS regardless of BRAFmutation status. Poststudy BRAF inhibitor treatment was also balanced. Conclusions: In this phase III trial, treatment effect was independent of BRAF mutation status, benefiting all patients who received nab-P vs DTIC. Therefore nab-P should be considered in the armamentarium for all chemotherapy-naive patients with MM. Clinical trial information: NCT00864253.

N

nab-P Median, mo (95% CI)

N

DTIC Median, mo (95% CI)

HR

PFS by IRR 116 5.4 (3.5-5.7) 108 2.5 (1.9-3.7) 0.715 Wild type V600E 65 5.3 (3.5-7.5) 67 3.5 (1.9-5.5) 0.883 Unknown 83 3.7 (2.8-5.6) 90 2.2 (1.9-3.6) 0.684 Interim OS 116 12.7 (10.0-15.5) 108 11.1 (9.5-14.7) 0.845 Wild type V600E 65 16.9 (11.6- NE) 67 11.2 (8.3-15.3) 0.688 Unknown 83 11.1 (7.9-13.2) 90 9.9 (6.2-14.1) 0.837

9029


Preliminary results from a phase Ib/II, open-label, dose-escalation study of the oral BRAF inhibitor LGX818 in combination with the oral MEK1/2 inhibitor MEK162 in BRAF V600-dependent advanced solid tumors. Presenting Author: Richard Kefford, Melanoma Institute Australia, Westmead Institute for Cancer Research and Westmead Hospital, The University of Sydney, Sydney, Australia Background: Clinical data indicate that combining a BRAF and a MEK inhibitor (BRAFi, MEKi) may be more effective than BRAFi monotherapy in BRAF-mutant metastatic melanoma and that a MEKi may overcome or delay resistance to a BRAFi. Methods: This ongoing phase 1b/2 study is evaluating the combination of LGX818, a potent, selective BRAF inhibitor, and MEK162, a selective MEK1/2 inhibitor, in BRAFi-naive and -pretreated patients with BRAF-mutant tumors. The objective of the phase 1b part is to determine the maximum tolerated dose and/or recommended phase 2 dose (RP2D) for oral, daily LGX818 ⫹ MEK162 in BRAF V600 –mutant advanced solid tumors. A Bayesian logistic regression model with overdose control guides the treatment dose escalation. Results: As of January 8, 2013, 20 patients (7 BRAFi-naive melanoma; 9 BRAFipretreated melanoma; 2 BRAFi-naive thyroid cancer; 1 BRAFi-naive metastatic colorectal cancer; 1 BRAFi-pretreated colorectal cancer) were treated with LGX818 qd ⫹ MEK162 bid at the following dose levels (DLs): 50 mg ⫹ 45 mg, 100 mg ⫹ 45 mg, 200 mg ⫹ 45 mg, and 400 mg ⫹ 45 mg. No dose-limiting toxicity has been observed at these DLs. The next DL of 600 mg ⫹ 45 mg is under investigation. The single agent RP2Ds for LGX818 and MEK162 are 450 mg and 45 mg, respectively. The most common adverse events (ⱖ 20%, all grades) suspected to be treatment related were nausea, abdominal pain, and headache. No events of fever, hand-foot-skin reactions, hyperkeratosis, or squamous cell carcinoma were observed. In patients with at least 1 post-baseline CT scan available for investigator-determined response, a complete response was observed in 1/7 (14%) BRAFi-naïve melanoma patients and partial responses were observed in 5/7 (71%) BRAFi-naive melanoma patients, 2/9 (22%) BRAFi-pretreated melanoma patients (starting at 50 mg ⫹ 45 mg DL), and 1/2 thyroid cancer patients. Conclusions: Preliminary data from this study indicate that LGX818 ⫹ MEK162 can be safely combined with promising clinical benefit. No febrile events or photosensitivity were reported suggesting a distinct safety profile for this BRAFi/MEKi combination vs others. Clinical trial information: NCT01543698. 9031


Sunitinib versus dacarbazine as first-line treatment in patients with metastatic uveal melanoma. Presenting Author: Joseph J Sacco, Clatterbridge Cancer Centre, Merseyside, United Kingdom Background: Uveal melanoma (UM) is a rare cancer with a propensity for metastasis. There are no effective systemic therapies for metastatic UM, although dacarbazine is commonly used in practice. Sunitinib is a tyrosine kinase inhibitor with activity against several targets including c-Kit and VEGF receptors, both of which have been implicated in the pathogenesis of UM. Methods: In this randomized multicentre, phase II study (SUAVE), patients (pts) with metastatic UM, ECOG PS 0-2, and no prior systemic therapy for advanced disease, were randomized 1:1 to sunitinib (50mg daily for 28 days, followed by a 14 day break), or dacarbazine (1000 mg/m2once every 21 days). Crossover was permitted on progression. The primary endpoint was PFS; secondary endpoints included response rate and OS. A sample size of 124 was planned, with a power of 0.9 to detect an increase in 3 month PFS from 0.2 to 0.4 (HR: 0.563) and a one-sided alpha of 0.05. A preplanned futility analysis was performed after 50% of events, and recruitment stopped early, due to low conditional power (0.17% under current trend). Presentation of results was approved by DMC. Results: 74 pts from 12 centres were randomized over 24 months. Overall response rates of 0% and 8% were observed in the sunitinib and dacarbazine arms; while stable disease was observed in 24% of pts on sunitinib, and 11% on dacarbazine. PFS and OS were not improved with sunitinib (see Table). 11 pts in the sunitinib arm and 23 in the dacarbazine arm underwent crossover on progression. No unexpected AEs were observed, and no deaths due to toxicity occurred. Conclusions: In these preliminary results sunitinib did not have significant clinical activity in metastatic UM. This trial is one of the largest undertaken in metastatic UM and demonstrates that timely recruitment to collaborative multicentre randomized trials is achievable in this rare disease. Clinical trial information: 75033520.

P value 0.088 0.656 0.066 0.330

555s

PFS OS

Sunitinib (nⴝ 38) Median in months (95% CI)

Events

2.76 (2.63 to 4.67) 6.35 (3.29 to 8.42)

28 24

Dacarbazine (nⴝ 36) Median in months (95% CI) 3.88 (2.7 to 8.06) 8.65 (6.25 to 13.55)

Hazard ratio (sunitinb:dacarbazine) Events

(95% CI)

25 21

1.09 (0.62 to 1.92) 1.59 (0.86 to 2.96)

Analysis performed on an ITT basis using Cox regression stratified on Helsinki Prognostic Index.

0.132 0.381

NE ⫽ upper limit was not estimable.


556s 9032


Final efficacy results of NCIC CTG IND.202: A randomized phase II study of recombinant interleukin-21 (rIL21) in patients with recurrent or metastatic melanoma (MM). Presenting Author: Teresa M. Petrella, Odette Cancer Centre, Sunnybrook Health Sciences Centre; University of Toronto, Toronto, ON, Canada Background: rIL21 is a T-cell derived cytokine with antitumor activity dependent on NK cells or CD8⫹ T cells through induction of central and effector memory cells. A previous phase II study demonstrated an ORR of 22.5% in previously untreated patients with MM. We conducted a multicentre randomized phase II study of MM evaluating the efficacy, toxicity, pharmacokinetics, immunogenicity, and biomarkers of rIL21 versus dacarbazine (DTIC). Methods: Eligible patients: Recurrent or MM, with either maximum tumour lesion size of ⬍ 50 mm or LDH ⬍ 2.5 x ULN and prior therapy with BRAF/MEK inhibitors allowed. Patients were treated with either rIL-21, 30 ␮g /kg/day dose IV daily x 5 days weeks 1, 3, 5 q 8 weeks or dacarbazine (DTIC) 1000 mg/m2 IV q 3 weeks. The primary objective was to compare progression free survival (PFS). The trial was designed to detect a hazard ratio of 1.75 with one-sided alpha of 0.1; 58 progression events were required to provide 80% power. Results: 64 patients were randomized, 32 in the rIL-21 arm and 32 in the DTIC arm. The Table summarizes key demographic and efficacy endpoints. Common rIl21 related adverse events were fatigue, rash, diarrhea, nausea, myalgia and elevated liver enzymes. At least one dose reduction/ interruption or discontinuation occurred in 32 (100%) and 27 (96.4%) of rIL21 and DTIC patients. Conclusions: Despite encouraging efficacy in prior phase I/II studies, the results suggest that rIL-21 is comparable to DTIC in this patient population. Additional biomarker analysis from this study is pending and combination studies are currently ongoing. Clinical trial information: NCT00514085. Demographic Patients randomized n Patients treated n ECOG PS n (%) 0 1 Female Male

rIL-21

DTIC

Total

32 32

32 28

64 60

21 ( 65.6) 11 ( 34.4) 9 ( 28.1) 23 ( 71.9)

22 ( 68.8) 10 ( 31.3) 9 ( 28.1) 23 (71.9)

43 ( 67.2) 21 ( 32.8) 18 ( 28.1) 46 ( 71.9)

Efficacy PFS median (months) 1.8(95% CI 1.7, 3.5) 2.0 (95% CI 1.7, 3.5) PFS 6 months 19% 30% PFS HR (95% CI) 1.1 (0.60, 2.01); p⫽0.76 OS median (months) 6.6 (95% CI 5.9, 12.3) 7.3 ( 95% CI 5-0, inf) OS 12 months 32% 35% OS HR (95% CI) 0.8 (0.38, 1.68); p⫽0.55 Response rate (CRⴙPR) 4/30 ⫽ 13.3% 4/28 ⫽ 14.3% 95% CI 3.8, 30.7 4.0, 32.7 Median duration response (months) 5.2 NR

9034


Preoperative imaging for staging of cutaneous melanoma in the United States: A population-based analysis. Presenting Author: Dana Haddad, Mayo Clinic, Phoenix, AZ Background: Routine imaging for staging of early stage cutaneous melanoma is not recommended by National Comprehensive Cancer Network (NCCN) guidelines. Besides the low probability of finding metastatic disease, detrimental aspects include false-positives and additive cost. We sought to investigate the use of imaging for staging of cutaneous melanoma in the United States. Methods: Patients with newly diagnosed clinically node negative cutaneous melanoma between 2000-2007 were identified from the Surveillance Epidemiology End Results-Medicare registry. Any imaging performed within 90 days following diagnosis was considered a staging study. Patients with metastatic disease were excluded. Results: A total of 25,643 patients were identified, of whom 10,775 (42%) underwent imaging. The mean age was 76.1 years, with the majority being male (61.8%) and Caucasian (98.4%). Breakdown by T classification of the primary was as follows: T1 (63%), T2 (17%), T3 (12%), and T4 (8%). A chest Xray was performed for 9,737 (38.0%), while 3,176 (12.4%) underwent advanced staging imaging studies; PET (7.2%), CT (5.9%), MRI (0.6%), and Ultrasound (0.4%). The use of advanced imaging steadily increased over the period of our study from 9.0% in 2000 to 16.3% in 2007 (p⬍0.001). When stratified by T classification, advanced imaging was used for 8.9% of T1, 14.5% of T2, 18.8% of T3 and 27.0% of T4 tumors (p⬍0.001). Similarly, node positive patients (4.7%) underwent advanced imaging 33.4% of the time compared to 11.3% for node negative patients (p⬍0.001). On multivariate analysis, factors predictive of advanced imaging include higher T classification (OR 3.12 T4 vs. T1, CI 2.77-3.52, p⬍0.001), node positivity (OR 2.70, CI 2.36-3.09, p⬍0.001), more recent year of diagnosis (OR 2.01 2007 vs. 2000, CI 1.71-2.37, p⫽0.006), high school education (OR 1.62, CI 1.43-1.83, p⬍0.001), non-Caucasian race (OR 1.37, CI 1.05-1.77, p⫽0.018), and male gender (OR 1.12, CI 1.03-1.21, p⫽0.006). Conclusions: Contrary to current recommendations, performance of advanced imaging for staging of early stage cutaneous melanoma is increasing in the Medicare population. Further research is needed to identify factors driving this increase.

9033


Observation after a positive sentinel lymph node biopsy in patients with melanoma. Presenting Author: Zubin M. Bamboat, Department of Surgery Memorial Sloan-Kettering Cancer Center, New York, NY Background: The therapeutic benefit of completion lymph node dissection (CLND) in melanoma patients with a positive sentinel lymph node (SLN) remains unknown. This study describes the natural history of selected patients undergoing nodal observation (no-CLND) after a positive SLN biopsy and compares outcomes with those undergoing immediate CLND. Methods: A prospective database was used to identify melanoma patients with a positive SLN biopsy from 1994 to 2012. Patient and tumor characteristics, reasons for not undergoing CLND, patterns of initial recurrence, and melanoma-specific survival data were analyzed. Results: Of 4319 patients undergoing SLN biopsy, 505 (12%) had a positive SLN. 170 (34%) patients underwent nodal observation and 335 (66%) had an immediate CLND. Patients in the no-CLND group were older (65 vs. 56 years, p⬍0.001) and more likely to have lower extremity lesions (43% vs. 30%, p⫽0.004). There were no differences in tumor thickness, Clark level of invasion, presence of ulceration, or degree of SLN tumor between groups. In 89% of cases, the reason to forgo CLND was due to doctor and/or patient decision. Median follow up was 23.5 and 78.5 months for no-CLND and CLND groups and median time to first recurrence was similar at 9 and 12 months (p⫽NS) respectively. There was no difference in regional recurrence rates between groups (20%). Nodal disease as a site of first recurrence occurred in 16% of patients in the no-CLND group compared with 7% of CLND patients (p⬍0.001). In contrast, systemic disease as first site of recurrence occurred in 8% of no-CLND patients compared with 27% of CLND patients (p⬍0.001). While median relapse-free survival was better after CLND (34.5 vs. 20.9 months, p⫽0.02), melanoma-specific survival was similar (not reached, no-CLND vs. 110 months, CLND, p⫽0.14). Conclusions: Immediate CLND after a positive SLN biopsy is associated with fewer initial nodal basin recurrences but similar melanomaspecific survival. These results support ongoing equipoise in the two arms of MSLT-II.

9035


Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: Data from the Italian cohort of ipilimumab expanded access programme (EAP). Presenting Author: Paolo Antonio Ascierto, Melanoma Unit, Fondazione Pascale - National Cancer Institute, Naples, Italy Background: Ipilimumab and vemurafenib have recently been approved as single agents for the treatment of unresectable or metastatic melanoma. Currently, limited data exist on the sequential treatment with these agents in patients (pts) with the BRAF mutation; here we evaluate the efficacy outcomes of pts enrolled in the EAP in Italy who sequentially received a BRAF-inhibitor and ipilimumab, or vice versa. Methods: Ipilimumab was available upon physician request for pts aged ⱖ16 years with unresectable stage III/stage IV melanoma who had either failed systemic therapy or were intolerant to ⱖ1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for 4 doses. Tumour assessments were conducted at baseline and after completion of induction therapy using immune-related response criteria. Patients were considered for this analysis if they tested positive for the BRAF mutation and had received a BRAF-inhibitor before or after ipilimumab treatment. Results: In total, 855 Italian pts participated in the EAP from June 2010 to January 2012 across 55 centres. Out of 173 BRAF positive pts, 93 (53.7%) were treated sequentially with both treatments: 48 pts received a BRAF inhibitor upon disease progression with ipilimumab and 45 pts received ipilimumab upon disease progression with a BRAF inhibitor. As of December 2012, median overall survival was 14.5 months (11.1-17.9) and 9.7 months (4.6-14.9) for the two groups, respectively (p⫽0.01). Among the 45 BRAF inhibitors pretreated pts, 18 (40%) had rapid disease progression (median overall survival: 5.8 months) and were unable to complete all four induction doses of ipilimumab, while the remaining 27 (60%) pts had slower disease progression (median overall survival: 19.3 months) and were able to complete the therapy with ipilimumab. Conclusions: These preliminary results suggest that, in BRAFmutated pts, to start the sequential treatment with ipilimumab can provide a better survival than the reverse sequence. These findings deserve confirmation in a prospective study.




9037

557s


Vismodegib, a Hedgehog pathway inhibitor (HPI), in advanced basal cell carcinoma (aBCC): STEVIE study interim analysis in 300 patients. Presenting Author: Jean Jacques Grob, Department of Dermatology and Skin Cancer, Timone Hospital, Marseille, France

Long-term safety and efficacy of vismodegib in patients with advanced basal cell carcinoma (aBCC): 18-month update of the pivotal ERIVANCE BCC study. Presenting Author: Aleksandar Sekulic, Mayo Clinic, Scottsdale, AZ

Background: Therapy options are limited for locally advanced (la) and metastatic (m) BCC. Aberrant Hedgehog (Hh) signaling is the key driver in BCC pathogenesis. Vismodegib, a first-in-class HPI, is approved in the US for use in adults with aBCC. STEVIE is an ongoing study focusing on safety of vismodegib therapy in patients with aBCC. We present data from the third interim analysis (data cutoff: 19 October 2012), which also permits a preliminary assessment of efficacy of vismodegib in the largest study ever conducted in patients with aBCC. Methods: Adult patients with laBCC or mBCC received oral vismodegib 150 mg QD until progressive disease, unacceptable toxicity, or withdrawal. Safety is the primary objective of STEVIE (Common Terminology Criteria for Adverse Events 4.0). Secondary endpoints include efficacy variables. Recruitment is ongoing. Results: This analysis included 300 patients with locally advanced (n⫽278) or metastatic (n⫽22) BCC from 11 countries with potential for ⱖ3-month follow-up. Median treatment duration, including vismodegib interruption, was 176.5 days (range 1-455 days). Common treatment-emergent AEs (TEAEs), typically ⱕ grade 2, included muscle spasm (59.3%), alopecia (49.3%), and dysgeusia (41.0%) and were comparable to prior analysis. Serious TEAEs occurred in 53 patients (17.7%). 131 (43.7%) discontinued from the study, mainly due to patient or investigator request (n⫽41), AEs (n⫽35), disease progression (n⫽18) or death (n⫽13; 7 due to AEs assessed by the investigator as unrelated to study drug, 3 due to AEs not possible to be assessed, 3 due to disease progression). Preliminary best overall response in patients with available tumor assessments (n⫽251) included complete response (17.5%), partial response (39.8%), stable disease (39.0%) and progressive disease (2.8%). Patient recruitment and monitoring is ongoing. Conclusions: This third interim analysis of STEVIE confirms the previously observed vismodegib safety profile but can also provide further information about the high rate of tumor control with vismodegib in a large series of patients with aBCC. Clinical trial information: 2011-000195-34.

Background: Therapies for aBCC, which includes metastatic (m) and locally advanced (la) BCC, are limited. Abnormal Hedgehog pathway signaling is a key driver in BCC pathogenesis. Primary analysis of the pivotal ERIVANCE BCC trial of vismodegib, an oral hedgehog pathway inhibitor (HPI), demonstrated an objective response rate (ORR) of 30% and 43%, in mBCC and laBCC patients, respectively, with a median duration of response (DOR) of 7.6 months. We present safety and investigator (INV) assessed efficacy results 18 months (29 May 2012) after primary analysis (26 Nov 2010). Methods: Multicenter, international, nonrandomized study in patients (N⫽104) with radiographically measurable mBCC or laBCC (surgery inappropriate due to multiple recurrence, or substantial morbidity or deformity anticipated) receiving 150 mg oral vismodegib daily until disease progression or intolerable toxicity. Key secondary endpoints included INV-assessed ORR, progression-free survival (PFS), DOR, overall survival (OS), and safety. Results: At data cutoff, 21 patients continued to undergo protocol-specified assessments and 56 patients were in survival follow-up. The median dose intensity was comparable with primary analysis. ORR was 48.5%, mBCC; 60.3%, laBCC, comparable with primary analysis. However, median DOR improved (mBCC⫽14.7; laBCC⫽20.3 months). The median OS for mBCC was 30.9 months but not estimable in laBCC. Adverse events remained consistent, with muscle spasm, alopecia, dysgeusia, weight decrease, and fatigue most frequently reported. Eleven more deaths were reported in the update period after primary analysis; these occurred in survival follow-up and were not drug-related. Conclusions: Vismodegib is the first FDA-approved HPI; thus, long-term efficacy and safety data are particularly relevant. 18-month update data confirmed prolonged responses and consistent safety in vismodegib-treated aBCC patients. Clinical trial information: NCT00833417.

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9039


Phase II study of low-dose peginterferon alfa-2b antiangiogenic therapy in patients with metastatic melanoma overexpressing basic fibroblast growth factor: An Eastern Cooperative Oncology Group study (E2602). Presenting Author: Ronald S. Go, Gundersen Lutheran Health System, La Crosse, WI Background: FGF-2 plays an important role in the pathogenesis and progression of melanoma. In particular, FGF-2 and its receptor are expressed in melanoma cells. We investigated the use of graded dosages Peg-IFN in patients with stage IV melanoma overexpressing FGF-2. Primary objective: suppression of plasma FGF-2 to normal levels (⬍ 7.5 pg/mL). Secondary objectives: clinical efficacy of Peg-IFN and its association with angiogenic factor levels (FGF-2 and vascular endothelial growth factor /VEGF). Methods: Patients were eligible if they had stage IV melanoma from any primary site. Prior systemic therapies (⬍ 4) were allowed including IFN. Plasma FGF-2 was measured at baseline (Step 1) and patients with levels ⬎ 15 pg/mL allowed to receive study treatment (Step 2). Peg-IFN was given weekly at starting dose of 0.5 mcg/kg/wk with increments every 3 weeks (maximum dose: 5 mcg/kg/wk) based on serial FGF-2 levels. Results: 207 patients entered into Step 1 and 45 (22%) overexpressed FGF-2 with a median level of 22 pg/dL (range, 15-216). 29 eligible patients enrolled into Step 2 and received treatment. The median age was 64 years and most had ⬎ 2 prior therapies. FGF-2 decreased in 28 (97%) patients with suppression to normal level in 10 (35%). The median time to FGF-2 suppression was 30 days (range, 14-116). The best clinical responses were PR (7%) and stable disease (17%). The median PFS and OS were 2.0 and 9.7 months, respectively. Patients who achieved FGF-2 suppression were more likely to have a response or stable disease compared to those who did not (50% vs 11%; P⫽.03). Landmark analysis at 63 days showed similar OS between those who achieved FGF-2 suppression and those who did not (7.8 vs 7.7 months; P⫽.31). VEGF decreased in 27 patients (93%) during treatment and the levels paralleled those of FGF-2 over time. We did not find a compensatory rise in VEGF level among those with FGF-2 suppression. Conclusions: Graded dose Peg-IFN suppresses FGF-2 and has activity against metastatic refractory melanoma. Complete suppression of plasma FGF-2 was observed in 35% of the patients and correlated with clinical response but not OS. Clinical trial information: NCT00049530.


Toward an miRNA signature for predicting outcome in patients with melanoma. Presenting Author: Colette R Pameijer, Stony Brook University Hospital, Stony Brook, NY Background: Melanoma remains a clinical challenge, as an aggressive and often unpredictable tumor. The incidence continues to increase, but treatment options are limited. One significant challenge is predicting which patients with stage I or II disease will have a poor outcome. We sought to develop a tool to assist in risk stratifying patients with melanoma. Methods: This is a prospective trial in which patients with melanoma at least 0.5mm deep were enrolled between 2007-2011. Tissue was collected from primary tumors, bulky nodes and metastatic deposits. RNA was extracted, labeled and hybridized to a miRNA microarray (Affymetrix). Hierarchical cluster method was used to find similarities among samples. A clinical patient database was maintained. Results: This study looks at 58 intermediate and high risk subjects. The median depth of melanoma was 3mm. The median age was 69 (range 26-95) and most patients (48/58, 83%) were treated with surgery alone, with ten receiving adjuvant therapy. All patients underwent wide excision, and 43 patients had sentinel node biopsy. Twenty-seven patients developed a recurrence (47%), and 19 (33%) patients have died, 14 from melanoma. The median length of follow-up is 21 months (range 1-76 months). A total of 112 probes are differentially expressed at a p value of 0.005. The largest number of differentially expressed probes relate to location of the tumor. Other significant differences are origin of the specimen (primary versus node), mitotic rate and subject age. High expression of miR-193b was correlated with death from melanoma, p⫽0.05. Parameters with no differential expression include gender, tumor depth and subtype, and ulceration. Conclusions: Microarray analysis of miRNAs is a reliable platform to obtain prognostic information about melanoma. The miRNA signatures found in this patient population reinforce some well described differences among patients with melanoma, and fail to find a difference between other groups thought to be clinically important. Tumor genetic profiling may provide better risk stratification of patients with melanoma than clinical parameters alone.


558s 9040

Melanoma/Skin Cancers General Poster Session (Board #44C), Sat, 8:00 AM-11:45 AM

Adjusting for treatment crossover in the METRIC metastatic melanoma (MM) trial for trametinib: Preliminary analysis. Presenting Author: Keith R. Abrams, Department of Health Sciences, University of Leicester, Leicester, United Kingdom Background: In METRIC, a randomized phase III study, trametinib significantly improved PFS (hazard ratio [HR]⫽0.44 [95% CI 0.31– 0.64; p⬍0.001]) vs chemotherapy (chemo) in patients (pts) with BRAF V600E⫹ MM and no brain metastases. Median overall survival (OS), a secondary endpoint, has not yet been reached. OS results are likely to underestimate the effect of trametinib as pts progressing on chemo could cross over to experimental treatment (trt). This analysis attempts to adjust for confounding effects of trt crossover on OS in the overall population and first line (1L) subgroup using current METRIC results. Methods: Randomization-based crossover adjustment methods – Rank Preserving Structural Failure Time Models (RPSFTM) and the Iterative Parameter Estimation (IPE) algorithm – were used. We conducted two sets of analyses testing different assumptions regarding the durability of the trt effect. “Trt group” analyses adjusted for crossover under the assumption that the trt effect is maintained until death regardless of trt duration; “On trt – observed” analyses adjusted for crossover under the assumption that the trt effect disappears upon trt discontinuation. Results are presented as HRs. Results: 178 and 95 MM pts were randomized to trametinib and chemo, respectively; 49.5% of chemo pts crossed over to trametinib as of data cut off (Oct. 2011). Median follow-up was 4.9 months and 19.8% deaths occurred across both arms. Crossover adjustment results are presented in the Table. Conclusions: RPSFTM and IPE “trt group” analyses resulted in OS HR point estimates that represented greater trt effects in the overall population and 1L subgroup compared to the unadjusted HRs. Results are exploratory because few deaths have been observed in the current dataset. Future analyses on a mature dataset should produce more robust estimates of the OS trt effect after crossover adjustment. Assumption

Adjustment method

Baseline unadjusted RPSFTM IPE On trt – observed RPSFTM IPE Trt group

9042

HR (95% CI) Overall pts IL pts 0.53 (0.30, 0.94) 0.45 (0.23, 0.87) 0.45 (0.23, 0.90) 0.48 (0.26, 0.88) 0.49 (0.26, 0.91)

0.55 (0.26, 1.13) 0.46 (0.20, 1.07) 0.47 (0.21, 1.05) 0.56 (0.30, 1.05) 0.57 (0.31, 1.03)


Investigation of the diagnostic precision and utility of sentinel lymph node biopsy in the treatment of patients with Merkel cell carcinoma (MCC). Presenting Author: Elena Mantas Paulus, University of Tennessee Health Science Center, Memphis, TN Background: Merkel cell carcinoma (MCC) is a relatively uncommon and aggressive cutaneous neuroendocrine neoplasm with a high incidence of local recurrence and regional and distant metastasis. The management and identification of prognostic factors remains of value in the treatment of these patients. Although the optimal multidisciplinary treatment of MCC has yet to be determined, the purpose of this study was to investigate whether sentinel lymph node biopsy confers a lower risk of recurrent disease in patients with Merkel cell carcinoma at our institution. Methods: After obtaining institutional review board approvals, all patients with a diagnosis of MCC from 2002-2012 were obtained from our tumor registries. Clinical features, pathologic characteristics, management modalities, and patient outcomes were retrospectively reviewed. Results: Of 20 patients with MCC, nine patients underwent sentinel lymph node biopsy, another four received therapeutic lymph node dissections, and seven patients did not have lymph node evaluation at the initial operation. The most common nodal basins involved were cervical and axillary. Recurrent disease was observed in seven patients (35%). Three patients underwent complete regional lymph node dissection after developing clinically positive nodal disease subsequent to only wide local excision at the index operation (15%). Three patients developed locoregional recurrence and the seventh patient developed metastatic disease to the liver. Of these seven patients with recurrent disease, only two (28.57%) had initial lymph node evaluation. Twelve patients (60%) received adjuvant therapy with chemotherapy (carboplatin/etoposide) and/ or radiation therapy. Conclusions: Merkel cell carcinoma continues to demonstrate its propensity for high rates of recurrence and metastatic disease. Of the seven patients with recurrent locoregional and/or nodal disease in our study, only two patients had initial lymph node evaluation, which was statistically significant with a p value of 0.01175. Further analysis focusing on additional prognostic factors is necessary to optimize our management algorithms and patient outcomes.

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Ipilimumab retreatment following induction therapy: The expanded access program (EAP) experience. Presenting Author: Kim Allyson Margolin, University of Washington, Seattle, WA Background: Phase III study MDX010-020 for patients (pts) with advanced melanoma showed that retreatment (ReRx) with ipilimumab (Ipi) upon disease progression could result in further clinical benefit (Hodi et al. NJEM 2010). The Ipi EAP (CA184-045), conducted from 3/2010 to 3/2011, allowed ReRx with Ipi for a subset of pts with progression after benefit from their initial Ipi (SD for ⱖ3 months or objective response). Methods: Pts with unresectable stage III/IV melanoma who progressed on ⱖ1 systemic therapies or had no alternative treatment options were eligible for the EAP. Pts who received 3 mg/kg Ipi i.v. q 3 wks up to 4 doses on the EAP were eligible for ReRx using the same regimen if they had not experienced unacceptable toxicity requiring Ipi discontinuation (e.g., grade 4 any severe adverse events (AEs), grade 3/4 immune-related AEs (excluding endocrinopathies)), and had disease progression after clinical benefit defined as ⱖ3 months SD or objective response, or delayed response following progressive disease not requiring a different interval therapy. Endpoints of this retrospective analysis were clinical benefit defined by objective response or SD ⱖ3 months and toxicities measured by occurrence of serious adverse events (SAEs), irAEs, or death on study. Results: 108/2155 pts (5%) met the eligibility criteria for ReRx. Among these 108 pts, grade 3 drug-related SAEs during initial therapy were endocrinopathies only (4%). During ReRx, grade 3 drug-related SAEs, all ⬍2%, were colitis, diarrhea, GI hemorrhage, fatigue and dehydration, similar to the toxicities of Ipi in the full EAP cohort of 2155 pts. Three pts (3%) of the 108 in this ReRx cohort had drug-related GI SAEs leading to discontinuation of Ipi. Among these pts who underwent ReRx, the median OS from the 1st initial therapy dose was 21.1 months. Conclusions: In this analysis of EAP pts who experienced benefit from initial Ipi therapy (including those with durable SD who subsequently progressed) and received ReRx with Ipi, no new safety signals were identified. The potential benefit of Ipi ReRx on OS will be prospectively evaluated in an ongoing phase II study in which pts who qualify are randomized to Ipi ReRx or physician’s choice alternative therapy. Clinical trial information: NCT00495066.

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Differential genomic profiles of tumor-involved and tumor-free sentinel lymph nodes in patients with melanoma. Presenting Author: Ahmad A. Tarhini, University of Pittsburgh Medical Center, Pittsburgh, PA Background: For clinical stage I and II node negative melanoma the histologic status of the sentinel lymph node (SLN) is the most significant predictor of survival. Molecular characterization of node positive and node negative SLNs through gene expression profiling may improve the understanding of the molecular mechanisms of metastasis and identify specific gene signatures for SLN⫹/SLN- that correlate with clinical outcome. Methods: We characterized 15 SLN⫹ and 15 SLN- melanoma patients (T3a/b, T4a/b) who underwent SLN dissection for routine staging using transcriptome profiling analysis on 5␮ sections of fresh LN samples. The primary endpoint was mRNA expression profiling using the U133A 2.0 Affymetrix gene chips. Significance Analysis of Microarrays v.4 was used to perform non-parametric analysis and statistical comparison for each transcript corrected for false discovery rate (q value) to control for type 1 errors arising from multiple tests. Pathway analysis was performed using Ingenuity Pathway Analysis software. Results: Tumor size ranged from 1-2mm in size. Twenty-one genes were expressed at significantly (q value ⬍0.056) higher levels in SLN⫹ vs SLN-. These included CCNA2, CEP55, DCT, FEN1, HMMR, MLANA, PAICS, PBK, POSTN, RAB27A, RRM2, SHCBP1, SILV, TYR, CENPE, CCL20, CHEK1, LINS, TPX2, TTK, TYRP1. Pathway analysis (39 genes ⬎1.4 fold; q ⬍ 0.12) identified the top disease categories as “Cancer” (26 genes, p ⫽ 5.7x10-9) and “Dermatological” (14 genes, p ⫽ 3.9x10-6). The top functional categories included “Cell Cycle” (21 genes p⫽ 2.3x10-12) and “Cell Growth and Proliferation” (26 genes p⫽9x10-9). The relevant canonical pathways were “Eumelanin Biosynthesis” (p⫽3x10-5) and “Cell Cycle: G2/M DNA Damage Checkpoint Regulation” (p⫽1.2x10-4). Conclusions: We identified a 21 gene signature that is consistent with metastatic melanoma and its microenvironment and is differentially expressed in SLNs that are tumor involved. These gene families provide a signature of nodal involvement that may assist in diagnosis, and may be further explored towards prediction of outcome and development of therapy. A validation study is ongoing with clinical outcome association analyses as follow up is mature.




Adjusting for treatment crossover in the BREAK-3 metastatic melanoma trial for dabrafenib: Preliminary analysis. Presenting Author: Nicholas Latimer, School of Health and Related Research, University of Sheffield, Sheffield, United Kingdom Background: In BREAK-3, dabrafenib improved PFS (hazard ratio [HR]⫽0.30 [95% CI 0.18 – 0.51; p⬍0.0001] as of Dec 19, 2011) vs dacarbazine (DTIC) in patients (pts) with previously untreated BRAF V600E⫹unresectable or metastatic melanoma. In an updated analysis (data as of June 25, 2012), PFS HR⫽0.37 (95% CI 0.24 – 0.58; p⬍0.0001). Overall survival (OS) results may underestimate the effect of dabrafenib as DTIC pts could cross over to dabrafenib at progression. This analysis attempts to adjust for confounding effects of crossover on OS using BREAK-3 results from June 2012 data. Methods: Randomization-based crossover adjustment methods – Rank Preserving Structural Failure Time Models (RPSFTM) and the Iterative Parameter Estimation (IPE) algorithm – were used. We conducted 2 sets of analyses testing different assumptions regarding the durability of the treatment (trt) effect. “Trt group” analyses adjusted for crossover under the assumption that the trt effect is maintained until death regardless of trt duration; “On trt – observed” analyses adjusted for crossover under the assumption that the trt effect disappears upon trt discontinuation. Results are presented as HRs. Results: 187 and 63 pts were randomized to dabrafenib and DTIC, respectively. At the time of this analysis, 55.6% of DTIC pts crossed over to dabrafenib. Median duration of follow-up was 10.5 months and 76 (30.4%) pts died. Median OS has not yet been reached. Crossover adjustment results are presented in the Table. Conclusions: All RPSFTM and IPE analyses resulted in point estimates for the OS HR that represented a substantial increase in trt effect compared with the unadjusted HR of 0.75. Results are exploratory, as the OS data are not mature. Analyses will be updated when further data are available. Assumption Trt group On trt – observed

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Adjustment method

HR (95% CI)

Baseline unadjusted RPSFTM IPE RPSFTM IPE

0.75 (0.44, 1.29) 0.52 (0.17, 1.61) 0.52 (0.18, 1.55) 0.57 (0.22, 1.50) 0.60 (0.26, 1.41)


9045

559s General Poster Session (Board #44H), Sat, 8:00 AM-11:45 AM

Current management of advanced melanoma: A European perspective. Presenting Author: Clare Frances Jones, PRMA Consulting Ltd, Fleet, United Kingdom Background: Melanoma is a rare but serious subtype of skin cancer that can infiltrate deep skin layers and commonly metastasizes. Although it makes up only a small proportion (⬍5%) of all skin cancer cases, it causes 75% of deaths from skin cancer. Melanoma affects all ages with 38% of patients less than 55 years old causing significant work productivity and life impact. Median survival of patients with advanced (unresectable or metastatic) melanoma is less than a year. Conventional chemotherapy provides no overall survival benefit. Within the last 2 years, the EMA approved two new drugs for advanced melanoma: ipilimumab for second-line and vemurafenib for patients with BRAF mutation-positive tumors; both drugs provide survival benefits. The objective of this study was to investigate physicians’ perceptions of the unmet need in the treatment of advanced melanoma in the new treatment landscape. Methods: 150 oncologists and dermatologists from France, Germany, Italy, Spain, and the UK who had treated at least 12 patients with advanced melanoma in the last 12 months prior to September 2012 were asked by a web-based survey to describe their treatment of advanced melanoma and the current issues in treatment. Results: Overall, 76% of respondents had used ipilimumab and 79% had used vemurafenib in the 12 months prior to September 2012. Toxicity and tolerability of treatment was the most commonly mentioned issue (cited by 43% of respondents). Limited treatment effectiveness (29% respondents) was also highlighted by respondents in all countries. Limited treatment options were identified as a key issue by 30% of respondents in Germany, France, and the UK. Other commonly mentioned issues were low response rates and poor survival. Conclusions: The majority of physicians surveyed had experience using vemurafenib and ipilimumab. However, a number of issues remain in the treatment of advanced melanoma, suggesting that unmet need remains high.

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Open-label, multicenter safety study of vemurafenib in patients with BRAFV600 mutation–positive metastatic melanoma. Presenting Author: James M. G. Larkin, The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom

Biomarker study in patients with resectable AJCC stage IIIc or stage IV (M1a) melanoma treated in a randomized phase II neoadjuvant trial. Presenting Author: Nitin Chakravarti, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: Vemurafenib (VEM), a BRAF kinase inhibitor, has demonstrated high response rates and improved progression-free and overall survival in pts with BRAFV600mutation–positive metastatic melanoma (mM). We present interim results from predefined subgroups from a large multicenter, open-label safety study of VEM in pts with mM (NCT01307397). Methods: Pts with BRAFV600mutation–positive histologically confirmed mM received VEM (960 mg BID) as first-line therapy or subsequent to previous therapies. Assessments for safety and efficacy were made every 28 days. Results: As of Feb 29, 2012, 2,265 pts have received VEM. Pts had a median age of 54.0 (13-95) yrs and median time since diagnosis of mM of 6.2 (0-351.9) mos. 59% had received prior systemic therapy. Median time of exposure to VEM as of the cut-off date was 3 (0.03-11.24) mos for the overall population and majority of subgroups, and approximately 2.5 mos for pts with ECOG ⱖ2 and age ⱖ75 yrs. 1537 (68%) pts were still receiving VEM at the cut-off date. 728 (32%) pts discontinued, most frequently because of PD (538/728 pts; 74%). Adverse events (AEs) were reported for 87% of all patients, with arthralgia (32%) and rash (26%) the most frequent. The incidences of AEs in the subgroups are summarized (Table). Although efficacy analyses are limited by the short duration of follow-up, six-month OS rate was 76% (95% CI 72-79%) and median PFS was 4.1 mos (95% CI 3.9-4.5 mos). Postbaseline tumor assessments were available for 63% and 30% of pts at wk 8 and 16, respectively. At wk 8 CR: 2%, PR: 57%, SD: 30%, PD: 6%. At wk 16 CR: 3%, PR: 46%, SD: 31%, PD: 15%. Conclusions: Although the overall safety profile of VEM in this study was consistent with previous clinical data, interim analyses of subgroups suggest that very elderly pts may be at higher risk of G3 AEs. Clinical trial information: NCT01307397. AEs, % (95% CI) Subgroups N G3 G4 Leading to withdrawal

Background: Fewer than 30% of patients with resectable stage IIIC or IV (M1a) metastatic melanoma (MetM) who undergo surgical resection will achieve long-term survival. This study was designed to administer neoadjuvant systemic therapy prior to definitive surgery to explore potential predictive and prognostic biomarkers in patients with MetM. Methods: Fifty patients with resectable MetM were randomized to receive temozolomide (TMZ) alone at 150 mg/m2/day x 7 days every other week (Arm A, n⫽26) or with pegylated interferon (PGI) at 0.5 mcg/kg weekly (Arm B, n⫽24). After a pre-treatment tumor biopsy, patients received 8 weeks of neoadjuvant therapy before undergoing surgery. Endpoints were clinical response, tolerability, and biomarker analysis by immunohistochemistry and gene array. In particular, we examined PD-1, PD-L1, pAKT, pMAPK, Ki67, and caspase 3. Patients with response (complete-, partial-, or stable disease) received up to 3 additional cycles of the assigned regimen as adjuvant therapy. Results: Overall response to neoadjuvant therapy was 38% [1 CR, 15 PRs, 3 SDs]: 31% in Arm A (95% CI 14% - 52%) and 46% in Arm B (95% CI 26% - 67%). Estimated 4-year overall survival was 52.52% (95% CI 35.86 - 66.74%). Only 5 patients did not undergo definitive surgery after neoadjuvant treatment due to development of distant metastasis. Preliminary data indicate that in Arm B, responders had higher PD-1 membranous expression in tumor infiltrating lymphocytes (TILs) (p⫽0.029). Furthermore, low PD-L1 cytoplasmic expression in TILs (p⫽0.002) as well as low nuclear PD-L1 expression in tumor cells (p⫽0.025) had better overall survival. Conclusions: Comparing with historical data, neoadjuvant therapy has a potential to improve overall survival in patients with resectable MetM. Biomarker analysis may predict response to neoadjuvant treatment as well as overall survival. Clinical trial information: NCT00525031.

Overall BM No Yes LDH Normal Elevated ECOG 0-1 >2 Prior ipilimumab Age (yrs) 75

2,265 1,673 555 1,037 1,159 1,992 236 236 2,089 176

31 (29-33) 30 (28-32) 35 (31-39) 31 (28-33) 32 (29-35) 31 (29-33) 37 (31-43) 40 (34-46) 30 (28-32) 44 (36-51)

2 (1-3) 1 (1-2) 3 (2-5) 2 (1-3) 2 (2-4) 2 (1-2) 4 (2-7) 4 (2-7) 2 (1-3) 2 (1-6)

4 (3-5) 4 (3-5) 4 (3-6) 3 (2-4) 5 (3-6) 3 (3-4) 7 (4-11) 3 (1-5) 3 (3-4) 13 (8-18)


560s 9048


9049


Impact of BRAF mutation and effectiveness of BRAF inhibitor on the brain metastases in patients with metastatic melanoma. Presenting Author: Tulasi Gummadi, University of Minnesota, Minneapolis, MN

Prognostic implication of KIT mutations in melanoma. Presenting Author: Katherine G. Roth, The University of Texas Health Science Center at Houston, Houston, TX

Background: Brain metastases continue to be the major cause of morbidity and mortality in patients with metastatic melanoma. The impact of BRAF mutations and effectiveness of BRAF inhibitors on the brain metastases in these patients is lacking. Methods: Preclinical studies were conducted to assessthe steady-state brain and plasma distribution of vemurafenib, a BRAF inhibitor in FVB wild-type and Mdr1a/b-/-Bcrp1-/- mice deficient in the drug efflux transporters, p-glycoprotein (P-gp) and breast cancer resistant protein (BCRP). A retrospective analysis of patients with metastatic melanoma treated at University of Minnesota from August 2011 to December 2012 was conducted. A similar analysis of cases treated at Mayo Clinic is underway. Results: The preclinical studies in mice show that both P-gp and BCRP play a significant role in limiting the brain distribution of vemurafenib. Retrospective analysis was performed on 57 patients with Stage IIIc /IV cutaneous and mucosal melanoma. Patients with BRAF mutation had a higher incidence rate of brain metastases compared to patients without BRAF mutation, although it was not statistically significant (Incidence ratio⫽1.56; 95% CI⫽0.70-3.48; P⫽0.27). Vemurafenib neither reduced the incidence of brain metastases (Incidence ratio ⫽ 0.89; 95% CI: 0.30-2.60; P⫽0.83) nor made significant difference in overall survival. It was observed that treatment with BRAF inhibitor led to improvement in extracranial disease but did not affect progression of intracranial disease. Conclusions: In concordance with preclinical data which indicates that P-gp and BCRP play a significant role in limiting the brain distribution of vemurafenib, the retrospective analysis shows that there is improvement in extracranial disease but progression in intracranial disease with treatment with BRAF inhibitor in patients with metastatic malignant melanoma with BRAF mutation. Development of BRAF inhibitors that are not substrates for P-gp and BCRP or concomitant use of P-gp and BCRP inhibitors with vemurafenib, may be needed in order to control or prevent intracranial disease in these patients. Further analysis to improve statistical power of our observation is underway.

Background: The natural history of BRAF and NRAS mutant (mut) melanoma (mel) has been described, but prognostic implications of KIT mut mel have not. Methods: We performed a single-center retrospective review of 180 patients (pts) enriched for mucosal, acral or chronic sun-damaged skin (CSD) mel and screened for KIT, BRAF, and NRAS mut from 4/07 - 4/10 as a part of a phase II imatinib study. Pt/disease characteristics were compared using the Kruskal-Wallis or Chi-square tests. Factors associated with outcomes were assessed by Kaplan-Meier methods and multivariable Cox regression. Results: Median age, 63.7 years; 54.4% male. Primary site: 40% mucosal, 29% acral, 22% CSD, 9% others. Mut rate: 18% KIT, 16% BRAF, 14% NRAS, 52% wild-type (wt). Pathologic subtype differed by genetic subgroup (p⬍.001) while age, gender, and stage did not (all p⬎0.05). 18/26 (69%) KIT mut pts received imatinib in the metastatic (met) setting; 6/18 received ⬎ 1 other KIT inhibitor. 3/25 (12%) BRAF mut pts received vemurafenib. 8/27 (30%) KIT mut, 4/27 (15%) BRAF mut, 6/20 (30%) NRAS mut, and 6/20 (30%) wt pts received ipilimumab. 149/180 (83%) pts developed mets at a median of 2.15 years (95% CI: 1.72, 2.72). Median follow-up (FU) of pts not developing mets was 3.91 yrs (range: 0.25, 14.34). Older age (HR: 1.02, 95% CI: 1.00, 1.03) and pathologic subtype (mucosal vs CSD HR: 1.70, 95% CI: 1.02, 2.84; non-CSD/unknown vs CSD HR: 2.05, 95% CI: 1.00, 4.21) were associated with increased risk of mets but not with time from mets to death. Of 149 pts who progressed, 123 (83%) died during FU. Median time from met to death was 1.21 years (95% CI: 0.91, 1.67). Median FU from time of mets among those alive at last FU was 2.53 yrs (range: 0.06, 6.85). Mut status including KIT mut was not associated with time to first met or time from met to death. Pts who received ipilimumab from time of first distant met had reduced risk of death (HR: 0.55, 95% CI: 0.36, 0.87) independent of mut status. No impact was observed with KIT inhibition. Conclusions: KIT mut status is not an independent predictor of time to mets or survival in pts with mets. Ipilimumab improved pt outcomes regardless of mut status. The lack of impact of KIT inhibitors is likely due to the heterogeneity of KIT mut in mel but does not preclude efficacy in appropriately selected pts.

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9051



Safety and efficacy of ipilimumab in melanoma patients who received prior immunotherapy on phase III study MDX010-020. Presenting Author: Howard Kaufman, Rush University Medical Center, Chicago, IL

Melanoma of ocular, mucosal, and genital sites: Epidemiology and survival outcomes. Presenting Author: Kenneth Bishop, Rhode Island Hospital, Providence, RI

Background: MDX010-020 was a phase III comparison of ipilimumab (Ipi), gp100 vaccine or the combination for advanced melanoma. A subset of patients (pts) received other immunotherapy (IM) for advanced disease prior to receiving Ipi, providing the opportunity to evaluate safety and efficacy of Ipi following IM. A prior analysis has shown that pts receiving prior IL-2 had a similar overall survival (OS) to pts who had not received prior IL-2 [Hodi et al NEJM2010]; we now report expanded results for pts receiving any prior IM (interferons and/or interleukin). Methods: Eligible pts (n⫽676) had unresectable stage III/IV melanoma and were randomized 3:1:1 to q3 wks x 4 doses of Ipi ⫹ gp100 or Ipi ⫹ placebo or gp100 ⫹ placebo. All Ipi doses were 3 mg/kg i.v. OS was retrospectively analyzed for pts receiving any prior IM; immune-related adverse events (irAEs) during induction were evaluated for pts who received any prior IM (322 pts, 48%) and for pts who received prior IL-2 (154 pts, 23%). Results: Demography and OS are summarized below. irAEs of any grade were reported for 60% (Ipi) and 54% (Ipi ⫹ gp100) of pts receiving any prior IM. Those receiving prior IL-2 specifically had 73% (Ipi) and 58% (Ipi ⫹ gp100) incidence of any grade irAEs. Incidence was similar for those not receiving prior IM or prior IL-2. Diarrhea, rash, and pruritus were the most common events in all groups. Conclusions: Results for OS in this subgroup analysis were similar for both those receiving any prior IM and those who did not receive prior IM and to the overall 020 population. In addition, safety profiles were similar irrespective of prior immunotherapy. Clinical trial information: NCT00094653.

Background: Melanomas arising from noncutaneous sites are rare entities with poorly defined staging, prognosis and no evidence-based treatment guidelines. Methods: We analyzed melanoma cases in the Surveillance, Epidemiology and End Results database between 1988 and 2007. Differences in clinical and pathologic features, treatment, and mortality were studied according to primary site of disease. The risk of melanomarelated death was calculated from life tables based on expected survival. Relative survival was compared in a multivariable parametric model using individual data. Results: We identified 209,861 cases of melanoma, of which 9,267 (4.4%) were noncutaneous. These were notable for older age, higher proportion of women, racial minorities, and advanced-stage disease. Mortality was high, even in subgroups with localized stage at diagnosis. Mucosal melanomas of the gastrointestinal and genitourinary tract had the highest excess mortality hazard ratios (HR) in the multivariate model. A substantial proportion of patients underwent organ-specific radical resection (32% eye enucleation, 40% radical head/neck surgery, 31% gastrectomy, 23% abdominoperineal resection). Conclusions: Melanoma arising from mucosal sites portends markedly worse prognosis than cutaneous melanoma. Prospective studies of systemic adjuvant treatment are needed for this disease, which is rarely curable even with aggressive local therapy.

Ipi ⴙ gp100 nⴝ403 N (%) receiving prior IM 194 (48%) Male/female, % 66/34 Mean age (range), yrs 54 (24-78) ECOG 0/1/2/3, % 59/39/1/1 Stage III/IV/M1c, % 2/98/73 Prior IM, OS hazard ratio (95% CI) Ipi vs gp100 Ipi ⴙ gp100 vs gp100 No prior IM, OS hazard ratio (95% CI) Ipi vs gp100 Ipi ⴙ gp100 vs gp100

Ipi ⴙ placebo nⴝ137 55 (40%) 66/34 54 (24-78) 60/40/0/0 2/98/73

gp100 ⴙ placebo nⴝ136

73 (53%) 55/45 54 (23-79) 58/40/3/0 1/99/74 n⫽322 0.54 (0.36, 0.82) 0.71 (0.53, 0.96) n⫽354 0.69 (0.48, 0.99) 0.66 (0.49, 0.90)

Site Skin Eye Nasal cavity Sinuses Oral cavity Pharynx Stomach/esophagus Anus/rectum Urinary tract Vagina Vulva Male genitals Other sites

N

5-year risk of melanoma death

95%CI

Excess HR

95% CI

P value

200,594 6,482 420 207 183 41 59 491 46 281 741 77 239

10.0% 19.0% 58.9% 75.4% 50.1% 81.3% 92.1% 75.5% 67.7% 79.6% 40.9% 25.5% 72.8%

(9.8-10.2) (17.7-20.4) (53.1-64.3) (68.0-81.3) (41.2-58.4) (66.4-90.1) (85.9-95.7) (70.9-79.4) (51.3-79.6) (73.9-84.1) (36.5-45.2) (13.5-39.3) (65.8-78.6)

Reference 1.19 1.42 1.86 1.25 1.53 3.58 2.72 3.05 2.22 2.23 0.89 2.29

(1.09-1.30) (1.19-1.69) (1.55-2.23) (0.96-1.63) (1.03-2.28) (2.60-4.94) (2.39-3.09) (1.94-4.79) (1.87-2.63) (1.93-2.57) (0.50-1.58) (1.93-2.73)

-0.0001 0.0001 ⬍0.0001 0.1 0.04 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 ⬍0.0001 0.69 ⬍0.0001




Pharmacodynamic effect of ipilimumab on absolute lymphocyte count (ALC) and association with overall survival in patients with advanced melanoma. Presenting Author: Michael Andrew Postow, Memorial SloanKettering Cancer Center, New York, NY Background: Ipilimumab (Ipi) is a fully human monoclonal antibody that augments antitumor T-cell responses. Ipi has been shown to improve overall survival (OS) in 2 phase (ph) III trials of advanced melanoma, as monotherapy at 3 mg/kg in previously treated patients (pts) (MDX010-20) or at 10 mg/kg with dacarbazine in previously untreated pts (CA184-024). In preclinical and clinical studies, inhibition of CTLA-4 by Ipi resulted in increases in activation and proliferation of peripheral T cells and increases in ALC. Baseline ALC may be a prognostic biomarker in several cancer types. The current analyses aim to increase understanding of changes in ALC with Ipi treatment and association of these changes with OS. Methods: Data were from 6 studies of Ipi with chemotherapy (CT) (ph I 078; N⫽59) or without CT (ph III MDX010-20; ph II trials 004, 007, 008, and 022; N⫽1203), and Ipi monotherapy in an Expanded Access Program (N⫽117) or with commercially available Ipi (N⫽71) or BRAF inhibitors (N⫽39). ALC was measured at baseline, prior to each dose during induction (weeks 1, 4, 7, and 10) and at the end of induction (week 13). Cox proportional hazards models were used to estimate and test associations between ALC measures and OS. Results: In all studies, mean ALC increased significantly over time in pts who received Ipi, with or without CT (P⬍.0001 to P⫽.03). There was no significant mean increase in ALC in pts who received gp100 or BRAF-inhibitor monotherapy. In study MDX010-20, pts with a greater rate of change in ALC from baseline to week 7 tended to have longer OS (P⫽.0003). A similar association was found between OS and ALC ⱖ1000/␮L after 2 Ipi doses. However, pts in MDX010-20 had an OS benefit from Ipi relative to gp100, regardless of rate of change in ALC (P⫽.14). Conclusions: In these analyses, consistent with inhibition of CTLA-4, Ipi induced an increase in mean ALC, even with the addition of CT. A positive association between rate of ALC increase and OS was observed, but this was not specifically predictive of OS benefit from Ipi. Therefore, ALC cannot currently be used to guide clinical management with Ipi. However, further prospective investigation may be warranted.

9054


9053


Long-term survival in patients with metastatic melanoma who received ipilimumab in four phase II trials. Presenting Author: Celeste Lebbé, Hôpital Saint-Louis, Paris, France Background: Ipilimumab (Ipi) has shown improved overall survival (OS) in two phase III trials of patients (pts) with metastatic melanoma (MM), with survival follow-up of ⬎4 years in one trial. The present analyses provide survival follow-up of ⬎5 years in four phase II trials of Ipi in MM. Methods: Pts with MM were enrolled in one of four phase II trials: (1) CA184-004, a biomarker study with Ipi at 3 or 10 mg/kg in treatment-naive (TN) and previously treated (PT) pts; (2) CA184-007, with Ipi at 10 mg/kg ⫹/- prophylactic budesonide in TN and PT pts; (3) CA184-008, a single-arm study with Ipi at 10 mg/kg in PT pts; and (4) CA184-022, a dose-ranging study of Ipi at 0.3, 3, or 10 mg/kg in PT pts (crossover from lower dose groups to 10 mg/kg was allowed upon disease progression). Ipi was administered q3 wk x4 (induction), followed by maintenance (q12 wk from week 24) in eligible pts. Some pts were retreated with Ipi at 10 mg/kg upon disease progression. Along with survival data collected through March 2012 for studies 007, 008, and 022, we report updated 5-year OS data for study 004 collected through September 2012. Results: Five-year OS rates for TN and PT pts are reported in studies 007, 008, and 022, with combined analyses for TN and PT pts within each dose group in study 004 (Table). The results show that survival rates reach a plateau beginning at year 3. Conclusions: In pts who received Ipi at 3 or 10 mg/kg in phase II studies, regardless of prior treatment, a proportion (12.3– 49.5%) remained alive 5 years after the start of treatment. These results demonstrate long-term survival with Ipi therapy in MM. An ongoing phase III trial will compare OS for Ipi at 3 vs 10 mg/kg in pts with MM. Clinical trial information: NCT00162123. Trial

N (prior Tx)

004

42 (14 TN, 28 PT) 40 (14 TN, 26 PT) 155 (PT) 72 (PT) 72 (PT) 73 (PT) 57 (total) 32 (TN) 25 (PT) 58 (total) 21 (TN) 37 (PT)

008 022

007

9055

OS rate, %

Ipi dose (mg/kg)

Median OS, months

1-yr

2-yr

3-yr

4-yr

5-yr

10

11.2

45.2

27.7

20.1

17.6

17.6

3

12.8

52.0

31.2

22.7

22.7

17.0

10 10 3 0.3 10 ⫹ placebo

10.2 11.4 8.7 8.6 19.3 30.5 14.8 17.7 45.0 8.5

47.2 48.6 39.3 39.6 62.4 71.4 50.8 55.9 65.9 49.9

32.8 29.8 24.2 18.4 41.8 56.6 24.2 41.1 57.7 31.6

23.3 24.8 19.7 13.8 34.4 42.5 24.2 38.7 57.7 28.4

19.7 21.5 18.2 13.8 32.0 37.7 24.2 36.2 49.5 28.4

18.2 21.5 16.5 12.3 32.0 37.7 24.2 36.2 49.5 28.4

10 ⫹ budesonide


Impact of age on treatment of primary melanoma patients. Presenting Author: Nathaniel H. Fleming, New York University School of Medicine, New York, NY

Role of the immunoglobulin constant region in the antitumor activity of antibodies to cytotoxic T-lymphocyte antigen-4 (CTLA-4). Presenting Author: Alan J. Korman, Bristol-Myers Squibb, Redwood City, CA

Background: Although patient age at diagnosis is not currently included in guidelines for treatment of primary melanoma, several lines of evidence suggest that patient age is an important, yet understudied, factor when considering treatment options. Here, we attempt to address the limited knowledge of the impact of age on primary melanoma treatment. Methods: In a prospectively enrolled and followed-up cohort of melanoma patients at NYU, we used logistic regression models to evaluate the association between patient age at diagnosis, tumor baseline characteristics, including BRAF and NRAS mutation status, and likelihood of receiving and responding to adjuvant therapy. We examined adjuvant therapy effectiveness using recurrence and melanoma-specific survival as endpoints. Results: 444 primary melanoma patients were included in the study (median follow-up: 6.3 years; age range: 19-95 years). Age was categorized into three groups spanning the range of age at presentation: younger (19-45 years; 24%), middle (46-70 years; 50%), and older (71-95 years; 26%). Older patients were significantly more likely to have advanced stage, nodular subtype (P ⬍ 0.01, both variables), and BRAF wildtype tumors (P ⫽ 0.04). Controlling for these factors as well as gender, older patients experienced a higher risk of recurrence (HR older vs. younger 3.34, 95% CI 1.53-7.25; P ⬍ 0.01). Of the 128/444 (29%) patients who were eligible for adjuvant treatment (clinical stage ⱖ IIB), only 67/128 (52%) received treatment. Using a propensity score that accounts for stage at presentation, patients in the middle age group were more likely to receive adjuvant therapy than those in the older group (OR 2.61, 95% CI 1.12-6.08; P ⫽ 0.03). In addition, a trend suggesting benefit from adjuvant therapy (defined as longer melanomaspecific survival) was observed only in the middle age group (P ⫽ 0.07). Conclusions: Our data suggest that older melanoma patients, despite having a significantly worse prognosis, are less likely to receive and benefit from adjuvant therapy. Further work is needed to understand the biological variables contributing to the limited response to treatment in elderly primary melanoma.

Background: Anti-CTLA-4 therapy enhances antitumor T-cell responses by both cell-intrinsic and cell-extrinsic mechanisms. Effector T-cell (Teff) activation is increased directly by interfering with CTLA-4-B7 interactions that negatively regulate T cells and by interfering with CTLA-4 expressed on regulatory T cells (Tregs), which function to inhibit immune responses. To analyze in greater detail the mechanism of action of anti-CTLA-4 antibodies (Abs), we examined the role of the immunoglobulin constant region in the antitumor activity of anti-CTLA-4 Abs in mouse tumor models. Methods: The activity of anti-CTLA-4 Abs with different mouse IgG constant regions were compared in several mouse tumor models, and intratumoral and peripheral T cells were analyzed by FACS. DNA samples from 488 patients with metastatic melanoma who received ipilimumab in a phase III clinical trial, MDX010-20, were analyzed for polymorphisms in the IgG fragment c receptor (FcR) at FCGR3A (V158F) and FCGR2A (H131R) loci. Results: In subcutaneous MC38 and CT26 colon tumor models, an anti-CTLA-4 Ab containing the mouse IgG2a constant region exhibited enhanced antitumor activity compared to an anti-CTLA-4 Ab containing the IgG2b constant region, while anti-CTLA-4 Abs containing mouse IgG1 or a mutated mouse IgG1 D265A constant region showed no activity. Anti-CTLA-4-IgG2a caused a dramatic reduction of Tregs at the tumor site that resulted in a greater Teff/Treg ratio. In contrast, all isotypes resulted in expansion of Tregs in the periphery. These results point to an important role for FcR in the action of anti-CTLA-4 Abs. In patients from study MDX010-20, there was no association between the 2 FcR polymorphisms (FCGR3A and FCGR2A) and overall survival. Conclusions: These preclinical studies reveal a novel dual activity of anti-CTLA-4 Abs consisting of intratumoral reduction of Tregs together with activation of Teff cells. This effect is mediated by the constant region and is presumably due to antibodydependent cellular cytotoxicity. The data suggest that FcR-bearing cells at the tumor site, as well as the presence of intratumoral Tregs, may be important factors in the antitumor activity of anti-CTLA-4 Abs.


562s 9056^


9057


Safety and efficacy of adjuvant anti-PD1 therapy (nivolumab) in combination with vaccine in resected high-risk metastatic melanoma. Presenting Author: Geoffrey Thomas Gibney, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL

BEVATEM: Phase II study of bevacizumab (B) in combination with temozolomide (T) in patients (pts) with first-line metastatic uveal melanoma (MUM): Final results. Presenting Author: Sophie Piperno-Neumann, Institut Curie, Paris, France

Background: Nivolumab (BMS-936558), a fully human monoclonal antibody targeting the programmed death-1 (PD-1) receptor, has demonstrated clinical activity in advanced metastatic melanoma patients (pts). In this phase I study, the safety and activity of nivolumab plus a multipeptide vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma pts. Methods: HLA-A*0201 positive pts with HMB-45, NYESO-1, and/or MART-1 positive tumors received nivolumab (1mg/kg, 3mg/kg, or 10mg/kg IV) with a multipeptide vaccine (gp100, MART-1, NY-ESO-1, Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 3 months (8 doses) or until disease recurrence. The primary objective was safety and determination of maximum tolerated dose (MTD). Secondary objectives were immunologic response and relapse free survival. Results: 33 pts were enrolled: 12 pts at 1mg/kg, 10 pts at 3mg/kg, and 11 pts at 10mg/kg nivolumab. Median age was 47 yrs; 55% male and 52% M1c disease (2 IIIc, 7 M1a, 7 M1b, and 17 M1c pts). As of January 16, 2012, median follow up time was 14 months and median number of doses was 12 (20 pts still receiving therapy). A MTD was not reached. Grade 2-3 related adverse events (AEs) occurred in 27 pts with the most common AEs being fatigue, rash/pruritis, and endocrinopathies. 4 pts experienced grade 3 AEs: (colitis/diarrhea (3), rash (1)). No drug related grade 4 or higher AEs occurred. 7/33 pts have relapsed to date. One pt with biopsy-proven relapse on trial had spontaneous disease regression. Non-relapsing pts had higher pre-treatment PD-1 expression on Treg and TCD4⫹ cells (p⫽0.053) and a greater increase in Treg cells after 12 weeks on treatment (p⫽0.027). Among all pts, treatment led to a rise in Treg cells (p⫽0.015) and decreased PD-1 expression on TCD4⫹ and TCD8⫹cells (p⫽0.014 and p⬍0.001, respectively). Conclusions: Nivolumab is well tolerated in combination with vaccine and preliminary data demonstrates immunologic and clinical activity as adjuvant therapy, justifying a randomized phase III study in resected high risk melanoma pts. Clinical trial information: NCT01176474.

Background: Overall survival (OS) of MUM pts remains poor (median 12 months), stressing the lack of effective therapies in this rare cancer. Targeting angiogenesis seems to be promising in uveal melanoma (UM). Antiangiogenic agents are used to treat neovascular ocular diseases such as age-related macular degeneration or proliferative diabetic retinopathy. B suppressed in vitro growth and in vivo hepatic establishment of micrometastases in experimental UM. Preclinical data suggest a potential clinical benefit of the combination of dacarbazine and B. Methods: Two-stage phase II trial; expected 6-month progression-free rate (PFR) of 40% with BEVATEM versus 15% with chemotherapy (power 94%, ␣ risk 3%). Primary endpoint: 6-month PFR according to RECIST. Secondary objectives: response and survival rates, safety; liver perfusion CT for functional imaging of response; impact of VEGF-A gene polymorphisms on B pharmacodynamics. Treatment schedule: T 150mg/m2 d1-d7 and d15-d21 oral route, B 10 mg/kg d8 d22 IV infusion, 6 cycles (d1⫽d28) then B maintenance until toxicity or progression. Results: 35 evaluable pts have been enrolled from May 2010 to May 2012. First step analysis showed 3/17 first patients with disease control at 6 months and good tolerance. The final population consisted of 19 men and 16 women, median age 55 (29-72). PS was 0 in 28 and 1 in 7 pts, and the median time to metastasis was 38 months (17-62). Liver was the sole metastatic site in 29 pts.With an administered dose-intensity similar to the planned schedule, 7 and 9 pts experienced grade 3 (neutropenia 4, thrombocytopenia 1, constipation 1, pruritis 1) or grade 4 toxicities (neutropenia 3, thrombocytopenia 4, thrombosis 1) respectively. Despite no objective response, 9/35 pts showed stable disease, and the 6-month PFR was 26% [95%CI 13-41]. With a median follow-up of 18 months, 5 pts (14%) had long lasting non progressive disease with B maintenance (10⫹ to 29⫹ months). Finally, the median PFS and OS were 3 and 12 months respectively. Conclusions: BEVATEM regimen in first line MUM patients showed safety and 6-month PFR of 26% including 14% of pts with durable clinical benefit. Clinical trial information: 2009-011751-46.

9058

9059



Analysis of serum biomarkers and tumor genetic alterations from a phase II study of lenvatinib in patients with advanced BRAF wild-type melanoma. Presenting Author: Pallavi Sachdev, Eisai Inc., Woodcliff Lake, NJ

Ipilimumab (Ipi) retreatment at 10 mg/kg in patients with metastatic melanoma previously treated in phase II trials. Presenting Author: Bart Neyns, UZ Brussel, Brussels, Belgium

Background: Lenvatinib is an oral receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFR␤. Phase I and II studies of lenvatinib demonstrate that a subset of advanced melanoma patients (pts) appears to derive benefit from lenvatinib treatment (tx), prompting a need to identify predictive biomarkers for response to lenvatinib. Methods: Serum and archival tumor samples were collected from 93 enrolled pts in the BRAF wild-type (wt) cohort of the lenvatinib phase II study of advanced melanoma. Concentrations of 50 factors were measured in pre- and post-tx serum samples; 58 archival tumor tissues were obtained and gene mutation (mut) (n⫽53) and gene expression profiling (GEP) (n⫽39) analyses were performed. For mut analysis, targeted resequencing was performed on a select panel of genes using the Ion PGM Sequencer and mut validation studies were performed. For GEP analysis, the nCounterAnalysis System was used to measure the expression level of 330 genes. Results: Clinical benefit rate (32%) and objective response rate (9%) by independent radiologic review were observed in the BRAF wt cohort. In serum biomarker analysis, lenvatinib tx resulted in a decrease in soluble VEGFR2 and increase in VEGF and PlGF levels consistent with target engagement. Correlation with clinical outcome demonstrated that baseline (BL) levels of Ang-2, IL8, PlGF, and PDGFBB associated with OS, but only pts with low BL Ang-2 levels also demonstrated improved response. High BL levels of FLT3LG and eotaxin associated with longer OS and improved response. In GEP analysis, expression levels of a set of genes including TARBP2, ZNF544, and NF1 (targets identified in phase I and preclinical studies) associated with OS. In gene mut analysis, NRAS mut showed a trend towards longer OS. Pts with NRAS mut along with wt PIK3CA status demonstrated longer OS. Conclusions: Lenvatinib demonstrated limited response in BRAF wt advanced melanoma pts. A subset of pts may derive extended clinical benefit. NRAS mut/PIK3CA wt status and low BL Ang-2 levels appear to associate with improved clinical outcome in this pt population and require further study to assess their predictive value. Clinical trial information: NCT01136967.

Background: Ipi is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4 to augment antitumor immune responses. In phase III study MDX010-20, where patients (pts) could be retreated if they met safety criteria and achieved an objective response or stable disease ⱖ3 months from the end of the induction period (q3 weeks for 4 doses), 21 of 31 pts (68%) retreated with Ipi reestablished disease control. CA184-025 is a roll-over study of extended Ipi treatment or survival follow-up in pts who received Ipi in phase II trials, with the primary objective of evaluating safety during extended treatment. We report the safety profile in pts retreated with Ipi in study 025. Methods: Eligible pts in phase II trials CA184-004, -007, -008, -022, MDX010-08, or -015 were enrolled in study 025 (N⫽248) to receive retreatment (at the time of progression), extended maintenance (if no prior progression), or survival follow-up only. Pts were ineligible for retreatment if they had experienced a grade 3-4 non-skin toxicity during prior Ipi therapy. Ipi was administered at 10 mg/kg, q3 weeks for 4 doses, to 111 pts who initially received Ipi induction at 0.3, 3, or 10 mg/kg in a parent study. Results: In this selected population of eligible pts, the nature and frequency of immune-related adverse events (irAEs) during retreatment were similar to those reported in previous studies, which most commonly affected the GI tract and skin (Table). There were no new types of drug-related irAEs and no grade 5 irAEs upon retreatment. Conclusions: Retreatment with Ipi at 10 mg/kg in these pts was generally well tolerated and the safety profile was similar to that during induction dosing in the parent studies. The higher frequencies of irAEs at lower doses should be interpreted with caution given the small sample sizes. An ongoing, randomized phase II trial will evaluate the clinical benefit of Ipi retreatment. Clinical trial information: NCT00162123. irAEs Any grade Grade 3-4 GI grade 3-4 Skin grade 3-4 Liver grade 3-4 Endocrine grade 3-4

Ipi dose in parent study with retreatment at 10 mg/kg, n (%) 0.3 mg/kg, nⴝ24 3 mg/kg, nⴝ34 10 mg/kg, nⴝ53 18 (75.0) 6 (25.0) 3 (12.5) 1 (4.2) 1 (4.2) 1 (4.2)

23 (67.6) 2 (5.9) 1 (2.9) 1 (2.9) 0 (0.0) 0 (0.0)

30 (56.6) 7 (13.2) 2 (3.8) 2 (3.8) 2 (3.8) 1 (1.9)




9061


Vemurafenib (VEM) in patients (pts) with BRAF-mutant melanoma and brain metastases (mets). Presenting Author: James J. Harding, Memorial Sloan-Kettering Cancer Center, New York, NY

Health behaviors and survivorship needs of short- versus long-term melanoma survivors. Presenting Author: Susan M. Swetter, VA Palo Alto Health Care System; Stanford University Medical Center, Stanford, CA

Background: Emerging data suggest that RAF inhibitors are an effective therapy for pts with BRAF-mutant melanoma and brain mets. Although reported efficacy is encouraging, these data are derived from case reports or early stage trials enriched with physiologically fit pts. It is therefore of interest to assess the “real world” experience of VEM in this population. Methods: Records of all BRAF-mutant melanoma pts treated with RAF inhibitors at our center from 2007 to 2012 were reviewed retrospectively. We determined the best overall response rate (BORR) and, when applicable, the overrall intracranial response rate (OIRR) by RECIST v1.1, progression-free survival (PFS), and overall survival (OS) to RAF inhibition. Pretreatment formalin-fixed, paraffin-embedded tumor was assessed using an exon capture assay able to sequence coding exons of 279 cancerassociated genes. Results: 21 (18%) of 119 pts with BRAF-mutant melanoma treated with VEM had active brain mets (age range: 25-86, sex: 52% men, median ECOG PS: 1, proportion with extracranial mets: 90%, BRAF mutation: 86% V600E and 14% V600K). 10/21 pts had no prior intracranial (IC) therapy; 11/21 pts received whole brain radiotherapy (WBRT, 7/21), stereotactic radiosurgery (1/21), metastasectomy (2/21) or multimodality therapy (1/21) prior to VEM. 12/21 pts received ipilimumab sometime during their disease course. For radiographically evaluable pts (N⫽17), the BORR was 65% (95% CI: 43-88) and the OIRR was 40% (95% CI: 15-65). For 4 pts, the BORR and OIRR were discordant⫺3 pts had IC progression but visceral tumor shrinkage, 1 pt had IC disease control but visceral progression. VEM was effective in pts whether or not they had received prior local brain therapy. The estimated median PFS and OS for all brain mets pts (N⫽21) were 4 and 8 months, respectively. Pretreatment tumor is available for exon sequencing in approximately half of these patients. This analysis is ongoing. Conclusions: In routine clinical practice, the OIRR to VEM was 40% which is higher than historical response rates to WBRT. VEM may be preferable to WBRT as a first-line therapy for pts with BRAF-mutant melanoma and brain mets. Whether RAF inhibitor treatment improves OS in this population will require further study.

Background: Little is known about melanoma survivors and their long-term symptoms, sun protection practices and support needs from health professionals. Methods: Melanoma survivors previously treated at Stanford Cancer Center completed a quality improvement survey to explore the value of a melanoma survivorship clinic, as part of the Stanford Cancer Survivorship Program. The survey period ranged from July 2012 to September 2012, and 17% of the 893 invited survivors responded. We compared responses of melanoma survivors diagnosed between 2006-2011 (shortterm) and 1995-2005 (long-term). Results: 153 cancer survivors (41% short- and 59% long-term) completed the survey. On average, they were 62 years of age (SD⫽15.1), 94% Caucasian, 47% female, and 68% underwent local excision alone. Long- vs. short-term survivors were less likely to receive routine skin screening every 3-6 months (38% vs. 83%, p⬍0.001) or follow-up for their melanoma in the last 6 months (54% vs. 76% p⫽0.045). Sun protection practices were similar between groups; however, long-term survivors decreased their use of tanning beds (33% vs. 18%, p⫽0.03) and time seeking a tan relative to short-term survivors (72% vs. 48%, p⫽0.002). Overall, survivors rated anxiety as the most prevalent symptom (33%), followed by numbness of the scar site (31%), forgetfulness (26%), sleep problems and depression (23%), pain and fatigue (17%). Sixty-eight percent of all survivors reported their symptoms were not addressed by their health provider, and of those stating their provider addressed their symptoms (32%), the survivor initiated the conversation 71% of the time. In general, survivors desired education about the long-term effects of melanoma (41%), family risk of skin cancer (28%), and protecting their skin from further damage (20%). Twenty percent of all survivors requested treatment for the long term effects of melanoma, and 12% wanted emotional support. Conclusions: Melanoma survivors experience continuing symptoms long after treatment, namely anxiety, and express a need for information about long-term melanoma effects, psychosocial support, and prevention of further skin cancer. Clinicians should routinely assess survivorship needs to improve quality of life.

9062

9063


Clinical characteristics and survival of BRAF-mutant (BRAFⴙ) metastatic melanoma patients (pts) treated with BRAF inhibitor (BRAFi) dabrafenib or vemurafenib beyond disease progression (PD). Presenting Author: Matthew Chan, Westmead Hospital, University of Sydney, Sydney, Australia Background: Accelerated tumor growth has been demonstrated on BRAFi cessation in BRAFi-resistant melanoma cell lines. In BRAFi-treated pts initial response rates are high but most have PD at 6⫹ months. The benefit of ongoing BRAFi after PD is unknown. We sought to describe the characteristics of pts treated beyond progression (TBP) vs those not TBP, and whether TBP prolongs survival. Methods: Clinicopathologic data were collected on 112 pts enrolled in phase I-IV clinical trials at Westmead Hospital and Melanoma Institute Australia from July 2009 to Sept 2012 with unresectable stage IIIC or IV BRAF⫹ melanoma treated with single agent dabrafenib or vemurafenib. TBP was defined as ongoing BRAFi ⬎28 days beyond RECIST PD. Pt and disease characteristics at baseline and at PD were examined, as well as survival data. Results: 92/112 (82%) pts had RECIST PD. 36/92 (39%) pts were TBP (mean 144 days, median 93 days, range 29 –572 days). Pts TBP were significantly more likely to have achieved a RECIST response (CR/PR) prior to PD, have a lower ECOG at PD, presence of brain metastases at PD, have PD treated locally and a smaller RECIST sum of diameters (SoD) at PD, compared with those not TBP (all p⬍0.05). Median OS from commencement of BRAFi in those TBP was longer than those not TBP (15.0 vs 6.5 months, p⬍0.001), as was OS from RECIST PD (7.4 vs 1.9 mo, p⫽0.001). In multivariate analysis of all pts, TBP improved OS from RECIST PD (HR 0.32, p⫽0.012) even after adjusting for other potential prognostic factors at PD (see table). Within the TBP cohort, RECIST SoD at PD was the only factor that influenced OS from PD (p⫽0.009), and presence of brain metastases did not. Conclusions: Treatment with BRAFi may be continued after RECIST PD in selected pts, and is associated with a prolonged OS compared with ceasing treatment at PD. Factors at progression TBP SoD at PD (mm) Brain metastasis present ECOG (>1) LDH (>ULN) PD treated locally

Hazard ratio

95% CI

P value

0.32 1.005 2.79 1.13 1.98 0.97

0.13-0.78 1.001-1.009 1.13-6.89 0.56-2.25 0.74-5.33 0.38-2.49

0.012 0.009 0.026 0.736 0.176 0.952


Evaluating the safety of anti-CTLA-4 therapy in the elderly with unresectable melanoma. Presenting Author: Sunandana Chandra, New York University School of Medicine, New York, NY Background: Anti-CTLA-4 monoclonal antibodies demonstrated an improvement in overall survival in patients with metastatic melanoma and ipilimumab (ipi) was FDA approved in 2011. We performed a retrospective analysis of 74 elderly (age ⱖ 65) patients (pts) who were treated with anti-CTLA-4 therapy (tx) and evaluated their treatment related adverse events (AEs) as well as clinical response. Methods: 65 pts were treated with ipi 3 mg/kg x 4, among whom 8 pts were re-treated with ipi 3 mg/kg x 4; 3 pts were treated with ipi 10 mg/kg x 4 with 2 pts who went on to receive maintenance tx; 2 pts were treated with tremelimumab (treme) 15 mg/kg q 3 months; 4 pts are currently undergoing tx with ipi 3 mg/kg x 4. There were 17 treatment naïve pts, and 57 pts were previously treated with 1-4 prior therapies. Thirty-nine pts received all 4 doses of ipi. There were 46 males and 28 females. Ages ranged from 65 to 90, median age 74. Melanoma subtypes included: 55 cutaneous, 8 mucosal, 7 ocular, 3 acral, and 1 unknown primary. Ten pts had M1a, 18 M1b, and 45 M1c disease. One pt had unresectable stage IIIC disease. Results: The most common tx related AEs included rash (33 AEs ⱕ grade 3), diarrhea/colitis (21 AEs ⱕ grade 3, with 1 grade 4 AE), fatigue (17 AEs ⱕ grade 2), and pain at tumor site (17 AEs ⱕ grade 2). There were 3 hepatotoxicity-related AEs, including 1 grade 5 AE; and 3 endocrinopathy-related AEs, including 1 grade 4 hypopituitarism. Toxicities were managed with corticosteroids, anti-histamines, antimotility agents, analgesics, thyroid and cortisol supplementation. Of the 69 pts evaluable for response, 16 pts (23%) had complete response (CR) or partial response (PR), and 9 pts (13%) had stable disease (SD) as measured radiographically using mWHO criteria at least 12 weeks post completion of treatment. When analyzed within melanoma subtypes, 17 cutaneous pts (31%) had tumor response (CR, PR, SD), 6 mucosal (75%), and 2 ocular (29%). Conclusions: Anti-CTLA-4 tx, including ipi and treme, was safe and well tolerated by the elderly population. Reported adverse events and response rates were consistent with published data in younger cohorts.

LDH; lactate dehydrogenase; ULN; upper limit of normal.


564s 9064


Survival patterns following brain metastases for patients with melanoma in the targeted therapy era. Presenting Author: Daniel A. Wattson, Harvard Radiation Oncology Program, Boston, MA Background: Survival from metastatic melanoma (MM) has been significantly prolonged with the introduction of molecularly targeted therapy, including BRAF inhibitors (BRAFi) for patients (pts) with the V600E mutation. Here, we present the first data describing patterns of survival after diagnosis of brain metastases (BM) in a large cohort of these pts with long follow-up. Methods: A retrospective review of 191 MM pts accrued on multiple prospective trials between 2008 –2012 was conducted. These trials assessed novel immunologic and targeted therapies in pts with both BRAF mutant (n⫽70) and wild type/unknown (n⫽121) tumors. We evaluated pt characteristics and the impact of systemic and BM-directed treatments. Results: Of 98 pts who developed BM, median follow-up after first BM was 7.7 months (15.5 months for the 25 living pts), and 33 were treated with BRAFi. Median duration of BRAFi use was 5.9 months (range 0.7–27.1), which preceded BM in 30%, was concurrent with first BM in 18%, and followed first BM in 52%. Ipilimumab or anti–PD-1/PD-L1 immunotherapy was given to 58% of pts who received a BRAFi and 95% of those who did not. Limited intracranial disease on initial BM presentation (defined as ⱕ3 lesions) occurred in 70% of BRAFi-treated pts and 74% of non-BRAFi pts, and 70% of BRAFi pts received at least one focal BM treatment (stereotactic radiosurgery or resection) compared to 75% of non-BRAFi pts. As shown in the Table, actuarial survival after BM diagnosis was prolonged among pts treated with a BRAFi. This is due primarily to the nearly 2-year median survival of pts for whom a BRAFi was initiated after BM were diagnosed. Conclusions: Survival for pts with BM from BRAF mutant MM can significantly exceed the often anticipated 4 – 6 months, particularly if a BRAFi is initiated after BM arise. This supports BRAFi activity in intracranial disease, and helps to inform trials currently under way testing BRAFi use among MM pts with previously diagnosed BM. BRAF mutant, with BRAFi BRAFi started pre-BM BRAFi started post-BM BRAF mutant, no BRAFi BRAF wild type BRAF unknown

9066

Median survival, months (95% CI)

Number of pts

13.2 (7.6 – 23.2) 5.6 (0.8 – 14.1) 23.2 (10.2 – 27.8) 6.7 (2.3 – 12.1) 8.0 (5.6 – 21.0) 6.5 (3.5 – 9.4)

33 16 17 7 34 24

Log-rank p ⫽ 0.02


Efficacy, safety, and pharmacokinetics (PK) of the BRAF inhibitor dabrafenib (D) hydroxypropyl methylcellulose (HPMC) capsule formulation in combination with the MEK1/2 inhibitor trametinib (T) in patients (pts) with BRAF mutation-positive metastatic melanoma (MM). Presenting Author: Lynn Mara Schuchter, University of Pennsylvania, Philadelphia, PA Background: Preclinical studies ofD ⫹ T show enhanced activity in BRAF mutant MM vs either drug alone. D ⫹ T safety and efficacy were evaluated in a 4-part (A–D) phase I/II study. Part D assessed the impact on efficacy, safety and PK of a more stable HPMC capsule formulation of D alone, and in combination with T, instead of the gelatin capsule used in Parts A–C. Methods: 110BRAFV600E/KMM pts with RECIST measurable disease were randomized to 4 cohorts. Doselimiting toxicities (DLTs) were evaluated for the first 3 weeks of treatment. PK sampling was done on Days 1 and 21. Primary endpoints were PK and safety; secondary endpoints were response rate (RR) and overall survival (OS). Results: Median age was 54 years, 58% male, 65% ECOG PS 0, 88% V600E, 68% M1c stage, 97% no prior brain metastases, and 45% LDH ⬎ ULN. Treatment (tx) with D HPMC ⫹ T had little impact on ratio of D Cmax (1.16) and D AUC (1.23) vs D tx alone; but led to higher ratio of D Cmax(1.51) but similar D AUC (1.10) vs D gelatin ⫹ T seen in Part B. Median progression-free survival (PFS) and RR are in Table. Median PFS not reached in D4. No DLTs occurred in the first 15 subjects enrolled in D4. Most common AEs (ⱖ40%) for all cohorts were pyrexia, nausea, chills, vomiting, arthralgia, and fatigue. Most common grade ⬎3 AEs (all 5%) were hypertension, pyrexia, increased GGT, and hyponatremia. 11% of pts discontinued treatment due to an AE. There were no major differences in toxicities between cohorts and Parts A–C. Conclusions: The D ⫹ T combination had an acceptable safety profile with clinically manageable side effects. D HPMC ⫹ T had little impact on D Cmax and D AUC vs D alone. D HPMC led to higher D Cmaxbut similar D AUC vs gelatin ⫹ T. Meaningful clinical activity was seen in all dose combinations with D HPMC ⫹T; PFS, RR, and duration of response were consistent with other study parts. Phase 3 studies with D HPMC ⫹ T are ongoing. Clinical trial information: NCT01072175. Part D dabrafenib HPMC dose cohorts. Dabrafenib dose Trametinib dose Cohort (mg BID) (mg QD)

N

Median PFS (months)

RR (%)

12

6.9

67

16

9.3

69

75

2 (starting Wk 4) 2 (starting Wk 4) 2

43

7.5

74

150

2

39

NR

67

D1

75

D2

150

D3 D4

9065


Correlation between efficacy and toxicity in pts with pretreated advanced melanoma treated within the Italian cohort of the ipilimumab expanded access programme (EAP). Presenting Author: Anna Maria Di Giacomo, Medical Oncology and Immunotherapy, University Hospital of Siena, Siena, Italy Background: Ipilimumab was the first agent approved for the treatment of unresectable or metastatic melanoma that showed an overall survival benefit in randomised phase III trials. Early clinical studies explored the potential relationship between immune-related adverse events (irAEs) associated with ipilimumab and antitumor activity but no definitive conclusion has been reached. Here, we evaluated the possible correlation between efficacy of ipilimumab treatment and irAEs in patients (pts) enrolled in the EAP in Italy. Methods: Ipilimumab was available upon physician request for pts aged ⱖ16 years with unresectable stage III/stage IV melanoma who had either failed systemic therapy or were intolerant to ⱖ1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for 4 doses. Tumour assessments were conducted at baseline and after completion of induction therapy using immune-related response criteria. Pts were monitored for adverse events (AEs), including immunerelated AEs (irAEs), using Common Terminology Criteria for Adverse Events v.3.0. Results: In total, 855 Italian pts participated in the EAP from June 2010 to April 2012 across 55 centres. Among 833 evaluable pts, 278 pts (33.4%) reported an irAE and 555 (66.6%) did not. As of December 2012, the disease control rates among pts with or without irAEs were 35.3% and 33.9% respectively. We noted that there was a difference in the distribution of pts with or without irAEs among pts who experienced a fast progression, thus not being able to receive at least 3 cycles, and pts with slow progression. In fact, due to the mechanism of action of the drug and consequent delayed onset of irAEs, pts with irAEs among fast and slow progressors were 22% and 37% respectively. Therefore, median overall survival was evaluated by adjusting the 2 groups for this factor and results showed a comparable survival between pts who reported an irAE and pts who did not (10.0 vs 9.7 months respectively). Conclusions: This exploratory analysis of EAP data suggest that activity and efficacy of ipilimumab is not related with the occurrence of irAEs.

9067


The clinical and biologic impact of PPP6C mutations in melanoma. Presenting Author: Heidi L. Gold, New York University School of Medicine, New York, NY Background: PP6C binds to regulatory units to affect a number of important pathways including cell proliferation and DNA repair. Recently two independent groups reported for the first time the presence of somatic mutations in the PPP6C gene in ~10% of short term cultures and limited number of human melanoma tissues. However, the clinical or biological relevance of PPP6C mutations in melanoma patients is unknown. Our objectives were to examine the clinical relevance of PPP6C mutations in a well characterized cohort of melanoma specimens linked to extensive, prospectively-collected clinical information and to explore the functional consequence of different categories of mutations. Methods: Sanger dideoxy sequencing was performed on PCR-amplified DNA from macro-dissected FFPE tumors. Associations between PPP6C mutations and baseline characteristics, recurrence, survival, and BRAF/ NRAS mutational status were examined. The impact of mutations on binding PP6C regulatory units was assessed as well as the effect on additional downstream pathways. Results: 308 primary melanoma patients (118 Stage I, 92 Stage II, and 98 Stage III) were examined (median follow up: 5.3 years). 50 PPP6C mutations in 33 patients (10.7%) were identified with 11 tumors harboring more than one mutation. One mutation (R301C) was identified in 6 patients. PPP6C mutations occurred with similar frequencies across stages and showed no association with BRAF or NRAS mutations. Mutations were categorized into 3 groups: Mutations resulting in premature stop codon (n⫽9), those occurring in the active site (n⫽16) and others (n⫽8). 8/9 (89%) patients with stop mutations recurred and developed visceral metastases. Functional studies revealed that PPP6C mutants also behaved differently; some PPP6C mutations led to decreased binding to regulatory subunits, others, including the R301C mutation did not. Conclusions: Our data suggest that PPP6C mutation is an early event in melanoma progression and independent of BRAF or NRAS mutations. Data also suggest different biologic and clinical impact of PPP6C mutations, with stop mutations showing association with development of visceral metastases that requires further clinical and functional study.




DOC-MEK: A double-blind randomized phase II trial of docetaxel with or without selumetinib (AZD6244; ARRY-142886) in wt BRAF advanced melanoma. Presenting Author: Avinash Gupta, Oxford University Hospitals NHS Trust, Oxford, United Kingdom Background: Inhibitors of mutant BRAF have transformed the treatment of melanoma for the 40% of patients whose tumors harbor V600 mutations. ERK1/2 is constitutively active in melanoma cells regardless of mutation status, and plays key roles in cell cycle entry, invasion, angiogenesis and in resistance to apoptosis. Selumetinib is a highly selective allosteric inhibitor of MEK1/2, suppressing pERK levels in melanoma independent of BRAF and NRAS mutation status. In melanoma cells, docetaxel induces mitochondrial dependent apoptosis by activation of Bax. Activation of ERK1/2 results in degradation of the BH3-only protein Bim and phosphorylation of Bad, inhibiting apoptosis. Selumetinib and docetaxel have demonstrated synergy in a variety of xenograft models, including melanoma. Methods: DOC-MEK (NCT01256359) is a randomised, double-blind, placebocontrolled multi-centre study in patients with wild-type BRAF advanced melanoma. Patients were randomised (1:1) to docetaxel with placebo or selumetinib, with stratification for M stage and performance status. Docetaxel was administered intravenously every 3 weeks at a dose of 75mg/m2 for a maximum 6 cycles. Placebo or selumetinib 75mg was given orally twice per day until disease progression or unacceptable toxicity. Results: Between October 2010 and April 2012 eighty three patients were randomised at 18 sites from 257 patients screened. Progression free survival (PFS) favored combination therapy (HR 0.753, p⫽0.13), as did response rate (32 vs 14%, p⫽0.059) and 6 month PFS (40 vs 26%, p⫽0.19). Patients on docetaxel with selumetinib experienced more rash, diarrhea, febrile neutropenia and edema, but less neuropathy. Overall survival data and outcomes according to tumor NRAS mutation status will be presented. Conclusions: Although PFS and response rates favored docetaxel with selumetinib further interest in the regimen will be dependent on overall survival outcomes and/or the identification of a subpopulation that benefit most from this approach. Clinical trial information: NCT01256359.

9070


Italian cohort of ipilimumab expanded access programme (EAP): Efficacy, safety, and correlation with mutation status in metastatic melanoma patients. Presenting Author: Paola Queirolo, Department of Medical Oncology A, National Institute for Cancer Research, Genoa, Italy Background: Ipilimumab was the first agent approved for the treatment of unresectable or metastatic melanoma to show a survival benefit in randomised phase III trials. Efficacy and safety of ipilimumab treatment outside of clinical trials and the correlation with BRAF and NRAS mutation status were evaluated. Methods: Ipilimumab was available upon physician request for patients (pts) aged ⱖ16 years with unresectable stage III/stage IV melanoma who had either failed systemic therapy or were intolerant to ⱖ1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for 4 doses. Tumour assessments were conducted at baseline and after completion of induction therapy using immune-related response criteria. BRAF and NRAS mutation status was retrospectively collected for all available pts. Patients were monitored for adverse events, including immune-related AEs, using Common Terminology Criteria for Adverse Events v.3.0. Results: In total, 855 Italian pts participated in the EAP from June 2010 to January 2012 across 55 centres. With a median follow-up of 6.5 months (range 0.5-30), the disease control rate among 833 pts evaluable for response was 34.3%: 28 pts (3.4%) with complete response, 83 (10.0%) with partial response and 175 (20.9%) with stable disease. As of December 2012, median progression-free survival and overall survival were 3.3 months and 7.2 months respectively, with 1-year survival rate of 36%. The Table shows mutation status for available patients. Disease control rates were comparable among pts with BRAF positive tumors and BRAF wild-type (37.5% vs 39.5%) and among pts with NRAS positive tumors and NRAS wild-type (57.1% vs 49.3%). Survival curves were also comparable between groups. 399 pts (46.7%) had a AEs of any grade, with 286 (33.5%) considered IrAEs. IrAEs were reversible with protocol specific guidelines. Conclusions: Based on EAP data, ipilimumab is an effective and safe treatment for pretreated pts with metastatic melanoma regardless BRAF and NRAS mutation status. BRAF NRAS

Mutated

Wild-type

Total

173 (36.9%) 14 (17.1%)

296 (63.1%) 68 (82.9%)

469 82

9069


Personal melanoma risk awareness versus intrinsic risk. Presenting Author: Caroline Robert, Institut Gustave Roussy, Villejuif, France Background: Intrinsic risk factors for melanoma include personal and family history of the condition, a high number of naevi and a light skin phototype (I or II). The objective of this study was to evaluate the correlation between personal awareness of melanoma risk and objective risk factors and to analyze the elements associated with under-or over-evaluation of the actual risk. Methods: EDIFICE melanoma, a nationwide French observational survey, was conducted through phone interviews on a representative sample of 1502 subjects aged ⱖ 18 using typical quotas. The survey took place from 28th Sept 2011 to 20th Oct 2011. Results: 393 subjects (26%) had at least one melanoma risk factor: personal: 1%; family history: 11%; high number of naevi: 8% and phototype I-II: 11%. 1109 (74%) had no risk factor. 1029 (73%) had a correct perception of their risk level, 135 (10%) overestimated their risk and 241 (17%) underestimated it. Compared to the control group (correct perception), the population overestimating the melanoma risk is characterised by a higher percentage of individuals living alone (32% vs. 24%, p⬍0.05), socio-professional category ⫹ (38% vs. 28%, p⬍0.01) and greater alcohol consumption (45% vs. 34%, p⬍0.02). They are also more likely to expose themselves to the sun (89% vs. 78%, p⬍0.004) and less likely to use sunscreen protection (58% vs. 44%, p⬍0.003). A greater proportion of them participates in melanoma screening programmes (21% vs. 14%, p⬍0.04). The population that underestimates the risk is characterised by lower educational attainment (11% vs. 7%, p⬍0.05), greater use of high SPF sunscreen (41% vs. 29%, p⬍0.0004) and a more frequent use of UV sunbeds (9% vs. 6%, p⬍0.06). Conclusions: Overall, the French have a fair perception of their personal likelihood of developing melanoma. Interestingly, subjects overestimating their intrinsic risk do not behave appropriately with respect to sun protection measures (more sun exposure and less sunscreen protection). On the other hand, subjects underestimating their risk use UV sunbeds more extensively.

9071


Upstream MAPK pathway inhibition: MEK inhibitor followed by a BRAF inhibitor in advanced melanoma patients. Presenting Author: Simone M. Goldinger, University Hospital Zurich, Dermatology, Zurich, Switzerland Background: The presence of activating BRAF mutations in about 60% of all metastatic melanomas (mM) has led to the development of inhibitors (i) targeting the RAF and MEK kinases. MEK is the downstream effector of BRAF. However, the blockage of the MAPK pathway is limited due to the development of resistance mechanisms. MEK resistance can confer crossresistance to BRAF inhibition, whereas BRAF resistance is independent from the MAPK pathway. Hence, it seems reasonable to start a MAPK pathway inhibition by a BRAFi. An upstream inhibition beginning the treatment reversed with a MEKi followed by a BRAFi has not yet been clinically explored. Methods: Patients at the Dermatology Department of the University Hospital of Zurich with mM harboring a BRAF mutation formed the study cohort. Patients were divided into a group who was treated initially with a BRAFi (vemurafenib or LGX818) followed by a MEKi (AZD6244, trametinib, or MEK 162), and a group who first received a MEKi and was later treated with a BRAFi. Duration of disease control (DDC) was measured in time from the initiation of the treatment to discontinuation due to disease progression or toxicity. Results: A total of 16 patients (7 females, 9 males, age 30-73 years) with BRAF mutated mM were evaluated. The median DDC (mDDC) was similar in both groups. When patients were treated first with a BRAFi (n⫽7), the mDDC for BRAFi was 7.6 and for MEKi 1.7 months, respectively. In contrast, when the treatment sequence was inversed (n⫽9), the mDDC for MEKi was 3.9 and for BRAFi 4.7 months. We observed some benefit (partial response, stable disease) using chemotherapy after BRAFi/MEKi progression. Conclusions: This analysis indicates that the sequential MEK-RAF inhibition of the MAPK pathway is acceptable in BRAF mutant mM patients. The sum of the DDC of both groups (9.3 and 8.6 months) is comparable to the promising BRAFi/MEKi combination therapy (median PFS 9.4 months). Besides the sequenced administration analyzed here, an intermittent administration should be further studied.


566s 9072


Thrombocytopenia associated with ipilimumab therapy of advanced melanoma at a single institution. Presenting Author: Monique Z. Sajjad, University of South Florida, Morsani College of Medicine, Tampa, FL Background: Ipilimumab (IPi) is a monoclonal IgG1␬ antibody targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) that was approved for the treatment of metastatic melanoma (MM). IPi therapy is associated with immune-related adverse events (irAEs) (Weber et al. J Clin Oncol2012 Jul 20;30(21):2691-7). Hematologic toxicity has rarely been reported. Methods: We analyzed 172 pts with MM treated adjuvantly or for metastatic disease with IPi on 2 clinical studies and an expanded access program (protocols MCC15283, MCC15722 and MCC15977). Clinical characteristics and hematologic parameters related to therapy were recorded. Medications, infections, comorbidities, prior therapies, and pathology reports from bone marrow (BM) biopsies were reviewed. Results: Of 172 subjects, 10 (5.8%) pts with normal platelet counts prior to therapy, developed thrombocytopenia (TCP) following IPi. Median number of doses was 8.5 (range 1-19). Median age at development of TCP was 64 years (range 21-93). Median time to development of TCP was 16.5 months (range 0.25 – 39). Of ten pts, three developed grade (gr) 1 or 2 TCP, three developed gr 3 and four pts developed gr 4 thrombocytopenia. BM analysis in pts with gr 4 TCP showed normal hematopoiesis and no evidence of melanoma. Six of 10 (60%) pts required therapy and were initiated on prednisone, but were deemed steroid refractory. No sustained responses to subsequent treatments with IVIG, rituximab, danazol, and/or splenectomy were observed. Three pts with grade 4 TCP were treated with eltrombopag. One of them achieved a sustained complete response lasting ⬎ 20 months. The other 2 pts who received eltrombopag discontinued treatment due to vascular events. Three out of 10 (30%) pts with any gr of TCP experienced mild bleeding episodes in the form of epistaxis. One pt with gr 4 thrombocytopenia experienced severe gastrointestinal bleeding requiring hospitalization. No deaths related to bleeding occurred. Conclusions: This is the first case series of hematologic irAEs in pts treated with IPi on clinical trials, suggesting that steroid refractory TCP may occur with IPi treatment . The timing and severity of IPi associated TCP is highly variable so careful hematologic monitoring should be considered.

9074


9073


Gender differences in survival from cutaneous melanoma: Analysis of United States SEER data, 1992 to 2009. Presenting Author: Roxana Stefania Dronca, Mayo Clinic, Department of Medical Oncology, Rochester, MN Background: An accumulating body of evidence suggests that the outcome of early-stage melanoma is influenced by endocrine and menopausal status. However, it remains controversial as to whether the superior female melanoma-specific survival (MSS) is restricted to early stage disease or if it also pertains to patients with metastatic melanoma (MM). Methods: We analyzed data from the 13 registries that participate in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program. We identified all cases of primary invasive melanoma diagnosed between 1992 and 2009; none of the patients had a prior history of another cancer. MSS was compared between males and females, stratified by stage of disease. Age groups were defined as 18-45y, 46-54y, 55-64y, 65⫹y as a proxy of female menopausal status. Results: The study population included 87,165primary invasive melanoma cases (unstaged n⫽2834). MSS was significantly poorer for males compared to females for localized (n⫽72,456) and regional (n⫽8,945) disease for all age groups (Hazard ratio (HR) ranging from 1.21 to 2.09, all p⬍0.001). MSS was not significantly different between males and females for patients with distant disease at diagnosis (n⫽ 2930; HR 0.99, 0.92, 1.11, 1.07 for each age group) and remained non-significant after adjusting for Breslow thickness, histologic subtype, anatomic site, and age group (adjusted HR 1.04 males vs. females; 95% CI 0.95-1.14; p⫽0.41). Conclusions: While our results were consistent with earlier reports that women have higher MSS rates compared to men for early (stage I-III) melanoma, the intriguing finding of this study was that the female survival advantage does not vary with age or menopausal status as compared to men, which is contrary to previously published reports. Furthermore, we found that the difference in survival was no longer significant for patients with MM, suggesting that sex may influence local and regional, but not distant cancer progression.

9075


Relevance of MIA and S-100 to monitor BRAF inhibitor (iBRAF) therapy in metastatic melanoma patients. Presenting Author: Miguel F. Sanmamed, Department of Oncology, University of Navarra, Pamplona, Spain

High-dose interleukin-2 (HD IL-2) in the treatment of advanced melanoma: The University of Pittsburgh experience. Presenting Author: Diwakar Davar, University of Pittsburgh, Pittsburgh, PA

Background: MIA and S-100 have been proposed as tumor markers for patients with melanoma, but they are not widely accepted. BRAF V600E mutation has been reported in more than 50% of melanomas. Recently, selective BRAF inhibitors have proved to be more active than DTIC in first line treatment of BRAF V600E melanoma patients. The aim of the present work is to evaluate the utility of MIA and S-100 during iBRAF treatment. Methods: BRAF V600E mutation was analyzed in 77 patients with metastatic melanoma by automated direct sequencing in tumor DNA. Tumor markers (MIA, S-100 and LDH) were studied in serum from all patients. Sixteen of these patients received iBRAF therapy (11 Vemurafenib, 5 Dabrafenib) and tumor markers were analyzed sequentially: baseline, best response and progression. MIA and S-100 were determined by immunometric methods and LDH by a spectrophotometric assay. The cut-off points were MIA⫽9 ug/L, S-100⫽0.1 ug/L, and LDH⫽290 U/L. Non-parametric statistical analysis was performed. Results: Forty-three patients had BRAF V600E mutation and 34 were wild type (WT). The percentage of cases with MIA above the cut-off in patients with V600E mutation was significantly higher than in the WT group (76.3% vs. 52.9%; p⬍0.05), while the frequency of elevated S-100 and LDH was similar. Among patients treated with iBRAF, the response rate was 87.5% (5 CR, 9PR). In responding patients, MIA and S100 levels decreased dramatically, but not LDH (Table). At the time of this report, thirteen patients have progressed. Upon progression, MIA and S-100 increased significantly above levels achieved at best response (Table). Conclusions: Serum MIA and S-100 are potentially useful markers in the clinical and follow-up management of patients receiving iBRAF therapy. Validation in a larger series is needed.

Background: IL-2 is a T-cell growth factor tested in a variety of regimens for advanced melanoma (MEL) and renal cell carcinoma (RCC). High-dose IL-2 (600,000-720,000 IU/kg administered intravenously every 8 hours for up to 14 consecutive doses) was approved by FDA for advanced MEL and RCC in 1998 based upon the durability of responses observed. Early studies of HD IL-2 reported overall (OR) and complete response (CR) rates of 16% and 8% respectively. Severe toxicity limited use to specialized centers with standardized protocols, either intensive care (ICU) or oncology specialty settings. The U Pittsburgh has treated 1022 patients with IL-2 at any dosage and we here present outcomes of 550 MEL pts treated with HD IL-2 in an oncology specialty non-ICU setting. Methods: Clinical and radiological data were collected on all pts treated with IL-2 using the UPCI Cancer Registry and Medical Archival System (MARS). Pharmacy records were reviewed for dosing details. The influence of baseline characteristics on treatment outcomes was assessed using Cox proportional hazards analysis. Results: A total of 848 pts received HD IL-2, of which 298 pts had RCC while 550 had MEL. Detailed pharmacy dosing records were reviewed from 176 pts treated over the past 12 years (2000-2012) who received a total of 3738 cycles. Of 165 pts evaluable for response, OR was documented in 24 pts (14.8%) and CR in 5 pts (3.0%). Median overall survival (OS) was 10.0 mos for all patients and 21.5 mos for responders (CR⫹PR). Median number of doses per cycle was 7. Toxicity was consistent with prior reports. HD IL-2 required ICU transfers in 5% and 1 death was attributed to HD IL-2. Pts with higher baseline lactate dehydrogenase (LDH) had poorer OS (p ⬍ 0.05). Conclusions: In this large and uniformly treated series of recent patients treated with IL-2 OR/CR rates with HD IL-2 are 14.8% and 3.0% respectively. Higher LDH is associated with poorer outcome. Biomarkers of response are currently being evaluated in banked clinical specimens collected from patients under the SPORE in Skin Cancer (P50 CA121973).

MIA, S-100 and LDH values at baseline, best response, and progression. Baseline M (Q1-Q3)

Best response M (Q1-Q3)

B vs BR p

Progression M (Q1-Q3)

BR vs P p

17 (13-44) 9.4 (7.6-11.3) ⬍0.01 13 (10.3-17) ⬍0.01 MIA (␮g/L) S-100 (␮g/L) 0.43 (0.13-6) 0.07 (0.06-0.15) ⬍0.01 0.2 (0.05-1.1) ⬍0.05 LDH (U/L) 258 (221-768) 213 (183-235) NS 213 (192-529) NS M: Median. NS: no significant.




9077


A phase I study of the combination of sorafenib (Sor) and bortezomib (Bor) in patients (pts) with metastatic melanoma (MM). Presenting Author: Ryan J. Sullivan, Massachusetts General Hospital Cancer Center, Boston, MA

Trends and variations in the use of adjuvant immunotherapy for stage III melanoma in the U.S. population. Presenting Author: Teresa J. Nasabzadeh, Medstar Washington Hospital Center, Washington, DC

Background: Sor is a small molecule tyrosine kinase inhibitor that has many targets and previously was developed for the treatment of MM. Bor is a proteasome inhibitor widely used to treat multiple myeloma and other malignancies. In preclinical studies, the combination of Sor and Bor has been shown to modulate expression of BCL-family members and augment cytotoxicity in MM cell lines. Methods: Pts with MM were enrolled in cohorts of 3 during dose escalation to determine the maximum tolerated dose (MTD) of Sor twice daily (BID) in combination with Bor given days 1, 8, 15 of a 28 day cycle. The MTD was defined as the highest dose level at which less than 33% of pts exhibited a dose limiting toxicity (DLT). Efficacy, as measured by 6-month progression free survival (PFS) and response rate (RR) per RECIST, was documented. Results: Eleven pts were enrolled in 3 dose levels. DLTs (fatigue and rash respectively) were seen in 2 of 3 patients enrolled at the highest dose level (Sor 400 mg and Bor 1.3 mg/m2). The next lowest dose level (Sor 400 BID and Bor 1.0) enrolled 5 pts and none had DLTs. Thus, this dose level was defined as the MTD. Toxicities seen in ⬎20% of pts included hypertension, pruritus, hand-foot syndrome, mucositis, nausea, vomiting, rash, constipation, abdominal pain, anorexia and fatigue. Of 9 response evaluable pts, none had radiographic evidence of tumor response. Two of 11 (18%) pts remained progression free for greater than 6 months. Conclusions: The combination of Sor and Bor is safe, but minimally active in pts with MM. In the absence of tumor response at or above the MTD, the study was closed with only 5 pts treated at the provisional MTD and enrollment to a planned dose expansion cohort will not occur. Clinical trial information: NCT01078961.

Background: High dose Interferon alfa-2b (IFN), an adjuvant immunotherapy for patients (pts) with stage III melanoma, was the only approved treatment option in the US from 1995-2011. There is limited information on how high dose IFN has been disseminated to eligible pts in general clinical practice, and whether variations exist in its adoption according to non-clinical factors. Methods: We obtained data on 34,208 pts diagnosed between 1998-2010 with stage III melanoma from the National Cancer Data Base (NCDB). IFN treatment was abstracted as immunotherapy. We investigated the use of immunotherapy according to pt demographic, socioeconomic, and clinical variables. We conducted multiple logistic regression analysis to examine the effect of these variables on the receipt of immunotherapy. Results: 62% of pts in our study population were male, 88% were Caucasian and 31% were over age 65. Overall, 27% of the pts received immunotherapy. There was no significant trend in its adoption between year 1998 and 2010. After adjustment for clinical variables, age at diagnosis, facility type, and geographic region are predictors strongly associated with use of immunotherapy. Only 16% of pts aged 65-74 and 3% over 75 received immunotherapy compared to 42% of those ages less than 45 (adjusted ORs 0.44 [0.32-0.59], 0.05 [0.04-0.14), respectively). Also 24% of pts treated at a comprehensive community cancer program received immunotherapy compared to 30% of those treated at an academic/ research program (OR, 0.71 [0.51-0.99]). The frequency of immunotherapy was 25% in the Atlantic region and 17% in the Western region compared to 33% in Northeast (ORs 0.42 [0.18-0.99], 0.31 [0.13-0.74], respectively). Median household income, insurance type and comorbidity were not associated with adoption of immunotherapy after adjustment for all other variables. Conclusions: Less than one-third of all eligible patients received adjuvant immunotherapy in US general practice over the past decade. There is significant variation in its adoption according to nonclinical factors. Further exploration of the reasons for these variations and whether they are linked to important patient outcomes is needed.

9078

9079



Dissection of anti-CTLA4-induced cytotoxic T-cell responses in melanoma. Presenting Author: John B. A. G. Haanen, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands

A phase IB study of ipilimumab with peginterferon alfa-2b in patients with unresectable melanoma. Presenting Author: Ragini Reiney Kudchadkar, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL

Background: There is strong evidence that melanoma-reactive T cells induced by immunotherapeutic interventions such as anti-CTLA4 therapy can exert clinically effects. However, there is very little information on how these therapies influence tumor-specific T cell responses. Furthermore, as the number of potential melanoma-associated antigens to which these responses can be directed is very high, classical strategies to map cytotoxic T cell reactivity do not suffice. Knowledge of such reactivities would be useful to design targeted strategies, selectively aiming to induce immune reactivity against these antigens. Methods: We have addressed these issues by designing MHC class I molecules occupied with UV-sensitive ‘conditional’ ligands, thereby allowing the production of very large collections of pMHC complexes for T cell detection. Secondly, we have developed a ‘combinatorial coding’ strategy that allows parallel detection of dozens of different T cell populations within a single sample. The combined use of MHC ligand exchange and combinatorial coding allows the high-throughput dissection of disease- and therapy-induced CTL immunity. We have used this platform to monitor immune reactivity against a panel of 145 melanoma-associated epitopes in patients receiving Ipilimumab treatment. Results: Comparison of PBMC samples from 32 melanoma patients preand post-therapy indicated a significant increase in the number of detectable melanoma-associated T cell responses (p⫽0.004). Furthermore, kinetic data on T cell responses during therapy suggests that this broadening generally occurs within weeks after start of therapy. The magnitude of melanoma-specific T cell responses that was detectable prior to start of therapy was not significantly altered (p⫽0.8). Conclusions: These results establish the pattern of melanoma-specific T-cell reactivity induced by anti-CTLA4 treatment and form a benchmark for evaluation of other immunotherapeutic interventions, like anti-PD1 treatment, that are currently undergoing clinical evaluation. Furthermore, our data suggests that the clinical activity of Ipilimumab may be mostly due to epitope spreading, rather than through enhancement of pre-existing immune activity.

Background: Peginterferon alfa-2b (Sylatron) as adjuvant therapy has been shown to benefit patients with high-risk resected melanoma and some interferon studies have shown that the induction of autoantibodies may correlate with benefit. Ipilimumab (IPI, Yervoy) is a fully human antiCTLA-4 antibody that induces autoimmune toxicity that in some cases appears to correlate with clinical benefit. This study was performed to assess whether ipilimumab can be safely administered with peginterferon alfa-2b. Methods: This study combined IPI at 3mg/kg every 3 weeks for 4 doses along with concurrent peginterferon alfa-2b at 3 mcg/kg weekly for up to 156 weeks or until disease progression, unacceptable toxicity or patient decision to discontinue. The study was designed to obtain toxicity, tolerability and autoimmune antibody data and to define a well-tolerated dose of the combination. Results: Median age was 61 with 9 female and 8 male subjects. There were 3 patients (pts) with partial responses, 1 stable disease, and 6 with progressive disease in 10 pts evaluable for response thus far. Six pts have not yet completed cycle 1 and therefore are not evaluable for response at the time of this publication but will be presented. One pt withdrew consent prior to finishing cycle 1. Toxicities from peginterferon alfa-2b 3mcg/kg were dose-limiting with 7 pts requiring dose reduction in peginterferon alfa-2b secondary to toxicity. The Grade 3 events leading to dose reductions were nausea and vomiting, leucopenia, dehydration, and hyponatremia. peginterferon alfa-2b was dose reduced to 2 mcg/kg weekly in future pts after these toxicities were noted. No Grade 3 or 4 toxicities attributable to ipilimumab have occurred thus far. No Grade 3 or 4 events have been noted to date in the10 pts initiated at 2 mcg/kg of peginterferon alfa-2b. There was no significant change in the presence autoantibodies (ANA, anti-double stranded DNA, antithyroglobulin, antimicrosomal antibodies, and anticardiolipin antibodies) between responders and non-responders in the evaluable pts. Conclusions: Peginterferon alfa-2b added to IPI results in an excellent response rate in this small population. Peginterferon alpha-2b at 2 mcg/kg weekly with IPI at 3 mg/kg every 3 weeks appears well-tolerated and the combination warrants further exploration. Clinical trial information: NCT01496807.


568s 9080


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Blood mRNA signature to predict survival in patients with metastatic melanoma treated with tremelimumab. Presenting Author: Yvonne M. Saenger, Mount Sinai School of Medicine, New York, NY

Response rate to vemurafenib in BRAF-positive melanoma brain metastases. Presenting Author: Marcin Radoslaw Dzienis, Princess Alexandra Hospital, Woolloongabba, Australia

Background: Tremelimumab (Ticilimumumab, Pfizer), a monoclonal antibody targeting CTLA-4, a T cell inhibitory molecule, has shown activity in metastatic melanoma. Ipilimumab (Yervoy, BMS), another antibody targettingCTLA-4, improves survival relative to a peptide vaccine and is now FDA approved. A minority of patients will achieve durable tumor control with CTLA-4 blockade and biomarkers are urgently needed to identify those patients. Methods: 170 inflammatory, melanoma-specific and CTLA4pathway related mRNA transcripts were measured using RT-PCR in pre-treatment peripheral blood samples from 218 patients with refractory melanoma receiving tremelimumab in a multi-center phase II study. A 2-class latent model yielded a risk score based on 4-genes that was highly predictive of survival (p⬍0.001), and was used to categorize patients into low, medium and high-risk groups. An independent cohort of 260 treatment naïve melanoma patients receiving tremelimumab as part of a multi-center phase III study was then used to validate the risk score as well as the 3 risk groups defined using the pre-specified cut-points. Results: There was no significant difference between the two cohorts in terms of age, gender, stage of disease or ECOG status. Median time of follow up was 297 days for the training cohort and 386 days for the validation cohort. 67% of patients in the training cohort and 70% of patients in the validation died during time of follow-up. Collectively, the ability of the 170 genes to predict survival exhibited a high degree of consistency across the cohorts (p ⬍ 0.001). A 4-gene model including cathepsin D (CTSD), Phopholipase A2 group VII (PLA2G7), Thioredoxin reductase 1 (TXNRD-1) and Interleukin 1 receptor associated kinase 3 (IRAK3) predicted survival in the validation cohort (p⫽0.001 by log rank test). Multivariable cox analysis showed that the 4-gene model added to the predictive value of clinical predictors (p⬍0.0001). Conclusions: Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral blood are predictive of survival in melanoma patients treated with ticilimumab (␣CTLA-4). Blood mRNA signatures should be further explored to define patient subsets likely to benefit from immunotherapy.

Background: Brain is a common site for melanoma metastases. Responses to dabrafenib have already been reported in over 50% of patients. We aimed at assessing response rate (RR) to vemurafenib (Vem). Methods: Patients with BRAF positive melanoma and asymptomatic brain metastases at initiation of Vem were eligible. Records were analysed retrospectively to calculate RR (at least 30% decrease in the sum of diameters of target lesions), duration of response and time to CNS progression (TTP). Results: 18 patients with CNS metastasis received Vem (M/F⫽8/10; median age 50); 9 received no prior therapy to the brain (group A), 6 had previous surgery and/or radiotherapy with residual disease (group B; n⫽6), 3 patients had prior ⬙brain therapy⬙ but with evidence of progression in CNS before the start of Vem and were added to group A (n⫽9⫹3⫽12). 50% RR was observed in group A; 5 had no prior therapy, 1 relapsed after resection/WBRT. Duration of response was: 8, 8, 8, 16, 32 weeks and 1 not reached yet. Similarly, 50% RR was observed in group B; however contribution of Vem to CNS control in this group was more difficult to assess. Duration of responses: 4, 26, 33 weeks. All except 2 patients progressed in CNS before, or at the time of, systemic progression. Median TTP in group A was: 21 weeks (16-41) in responding patients and 12 weeks (4-22) in those without a response (includes SD). Median TTP in group B ⫽ 44 weeks (16-60) in responders, 8 weeks (3-16) in non-responders. Conclusions: Vemurafenib resulted in 50% CNS response rate. Prospective comparison to dabrafenib may be warranted.

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Updated interim analysis of UCI 09-53: A phase II, single arm study of pazopanib and paclitaxel as first-line treatment for subjects with unresectable advanced melanoma. Presenting Author: Shlomit Y. Ein-Gal, University of California, Irvine, Orange, CA Background: Metastatic melanoma lacks effective therapy. Pazopanib is an inhibitor of VEGFR-1,2,3, PDGFR-B and c-KIT that has antiangiogenic activity in renal cell cancer as well as inhibition of melanoma tumor xenografts. We designed a phase II single arm, open label clinical trial evaluating pazopanib in combination with metronomic paclitaxel as first line therapy for subjects with unresectable stage III and stage IV melanoma. Methods: This protocol utilizes a Simon 2-stage Minimax design, with a planned interim analysis to confirm ⬎3 responders to move to the second stage. To date, 31 patients are evaluable for response. All subjects were treatment naïve and received paclitaxel at 80mg/m2 weekly for three weeks in a 4 week cycle and pazopanib 800mg continuous daily oral dose. The primary endpoint is 6 month progression free survival. Exploratory endpoints include biomarker analysis that may be associated with treatment outcomes (serum VEGF, soluble VEGFR-2, serum HIF, serum TSP1 and BRAF mutation status). An additional exploratory endpoint includes the in vitro activity of pazopanib and paclitaxel on patient biopsy material co-cultured with vascular endothelial cells. RECIST 1.1 criteria were used to define treatment response (SD criteria was a minimum interval of 8 weeks). Results: For the 31 evaluable patients treated to date the following results were seen: 1 CR, 9 PR’s, 13 SD’s and 8 PD’s. The overall RR (CR⫹PR) was 32%. Total disease control rate was 74% (CR⫹PR⫹SD). The most common AEs/lab abnormalities were diarrhea (66%) nausea (60%), hypertension (63%), fatigue (63%) and vomiting (29%). Grade 3-4 AEs included hypertension (26%), transaminitis (23%) and neutropenia (17%).One patient discontinued for grade 4 transaminitis which subsequently resolved completely. Dose reductions were required for pazopanib in 15 patients and for paclitaxel in 4 patients. Conclusions: Updated interim analysis of this phase II study demonstrated that pazopanib in combination with paclitaxel was well tolerated and resulted in a 32% response rate, indicating that this combination is of further interest. Accrual will continue to reach a goal of 60 patients. Clinical trial information: NCT01107665.


Treatment patterns in patients with early and advanced malignant melanoma. Presenting Author: Victor M. Gastanaga, Amgen, Inc., Thousand Oaks, CA Background: We seek to characterize tx patterns for patients (pts) with early stage (ES) and advanced stage (AS) malignant melanoma (MM). MarketScan is a large insurance claims database with complete diagnosis (dx) and tx information. Methods: Using MarketScan data, pts were identified between Jan 2001 and Jun 2011 using ⱖ1 inpatient or ⱖ2 outpatient MM ICD9 codes ⱖ6 weeks apart. Pts with a history of other malignancies or lacking records at least 1 year prior to diagnosis were excluded. Pts were considered AS if they received chemotherapy, interferon, ⱖ2 days of MM surgery, or a code of secondary metastases. All other pts were classified as ES. Radiotherapy, immunotherapy, chemotherapy, and surgery type were identified with HCPCS, CPT, and ICD9 procedure codes. Pts were categorized by type of progression (ToP): AS at time of dx (AS-D), ES at dx with progression to AS during follow-up (ES-P), and ES at dx with no progression during follow up (ES-NP). Results: Of 30,678 eligible pts, 55% were male, median age was 59 yrs, and median follow-up was 31 months. Initial disease locations were head and neck (21%), torso (27%), upper extremities (17%), and lower extremities (14%). Twenty-five percent (7607 pts) were identified as having AS MM during follow-up. Of these, 2,445 (8%) were AS-D, while 5162 (17%) were ES-P. The remaining 23,071 pts (75%) were ES-NP. Frequency of most extensive surgery type after diagnosis date are shown by ToP (table). No ES-NP pts received systemic tx during follow-up, but 21% of ES-P and 64% of AS-D pts received either chemotherapy, immunotherapy, or both. Agents most commonly prescribed in AS pts were interferon and temozolomide. Conclusions: The tx burden in MM pts is extensive and appears to increase with disease severity. Claims data can be a valuable tool in elucidating MM tx patterns by disease stage. Extent of surgery by disease type (%). None Biopsy Wide local excision Sentinel node biopsy Lymph node dissection

ES-NP

ES-P

AS-D

37 5 37 18 3

9 1 58 25 7

30 2 8 21 39




9085

569s General Poster Session (Board #50D), Sat, 8:00 AM-11:45 AM

Changes in the quality of life of advanced melanoma patients after 12 weeks of treatment with ipilimumab compared to gp100 in a phase III clinical trial. Presenting Author: Becca Harvey, BresMed, Sheffield, United Kingdom

Use of tumor exome analysis to reveal neo-antigen-specific T-cell reactivity in ipilimumab-responsive melanoma. Presenting Author: Nienke van Rooij, The Netherlands Cancer Institute-Antoni Van Leeuwenhoek Hospital, Amsterdam, Netherlands

Background: This study analyses health-related quality of life (HRQL) outcomes for ipilimumab (ipi) with and without gp100 and gp100 alone during the 12 week treatment (T) induction period compared to baseline. The aim of this study was to express the HRQL as proportions of patients experiencing changes during the induction period, when most of the immune-related adverse events (ir-AE) on ipi occur. Methods: Data from the MDX010-20 trial, including 676 previously treated patients (pts) with unresectable stage III or IV melanoma, was analysed. Differences between ipi with/without gp100 and gp100 alone in terms of HRQL 12 weeks after randomisation according to the EORTC QLQ-C30 were searched for. The sample consisted of 388 pts (ipi: 83; ipi ⫹ gp100: 227; gp100: 78) completing both baseline and week (W)12 questionnaires. Ordinal regression was performed for these pts to determine a T effect on W12 scores (in ordered categories) whilst adjusting for key covariates. Fisher’s Exact Test was used to detect differences between Ts for each EORTC domain when considering mean change in scores, categorised as “clinically worse” (ⱕ-10 on functional domains, ⱖ10 on symptoms), “stable” (⬎-10 to ⬍10) and “clinically improved” (ⱖ10 on functional domains, ⱕ-10 on symptoms). Results: There were no significant differences for any domain score between the 3 T arms at W12. The odds of attaining high HRQL scores at W12 were heavily dependent on the baseline scores; baseline scores explained most of the variability as per regression analysis. There was no significant difference between the 3 T arms in terms of pts showing a clinically significant reduction or improvement in HRQL. HRQL remained globally stable from baseline to W12, in ⬎ 50% of pts for most domains. Conclusions: Ipi with/without gp100 does not have a significant negative HRQL impact in stage III-IV melanoma during the T induction phase relative to gp100 alone after adjustment for differences in baseline scores. The lower rate of pts showing HQRL reduction and the absence of difference with gp100 suggest that ir-AE have little impact on HRQL. Further HRQL studies are needed, as efficacy benefits of ipi continue after W12.

Background: Evidence for T cell mediated regression of human cancer in particular melanoma following immunotherapy is strong. Anti-CTLA4 treatment has been approved for treatment of metastatic melanoma and blockade of PD-1 has shown encouraging results. However, it is unknown which T cell reactivities are involved in cancer regression. Reactivity against non-mutated tumor self-antigens has been analyzed in patients treated with Ipilimumab or with autologous TILs, but the size of these responses are modest. Therefore, T cell recognition of patient-specific mutant epitopes may be a potentially important component. Animal model data recently suggested that analysis of T cell reactivity against patientspecific neo-antigens may be feasible through exploitation of cancer genome data. However, human data have thus far been lacking. Methods: To address this we have used MHC class I peptide exchange technology allowing production of very large collections of pMHC complexes, together with a pMHC ⬙combinatorial coding⬙ strategy for parallel detection of dozens of different T cell populations within a single sample. Results: From a melanoma patient responding to ipilimumab treatment, we identified tumor specific mutations via exome sequencing of tumor material. The exome contained 1,075 non-synonymous mutations. Possible MHC epitopes covering these mutations were predicted based on; 1) predicted to bind the patient’s MHC; 2) predicted to be cleaved by the proteasome; 3) genes of which the mutated peptides arose had evidence of RNA expression. The analysis yielded 1,952 epitopes restricted to the HLA-A and HLA-B. To screen for T cell reactivity against these epitopes we used the pMHC combinatorial coding approach. We found T cell reactivity against 2 neo-antigens, including a dominant T cell response against a mutant epitope of the ATR gene product. Analysis of PBMC samples collected before and during Ipilimumab therapy showed that this particular response increased strongly after treatment from 0.06% to 0.28% of CD8 T cells after being stable in magnitude for 10 months. Conclusions: These data provide the first demonstration of cancer exome-guided analysis to dissect the effects of melanoma immunotherapy.

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Graded prognostic assessment index for melanoma with brain metastases (MBM). Presenting Author: Kwabena Osei-Boateng, Cleveland Clinic Foundation, Cleveland, OH

A phase I study of high-dose calcitriol in combination with temozolomide for patients (Pts) with metastatic melanoma (MM). Presenting Author: Erin Pettijohn, Northwestern University, Chicago, IL

Background: The Graded Prognostic Assessment (GPA) is a commonly used prognostic index in patients with brain metastases (BM). GPA for melanoma consists of Karnofsky Performance Scale (KPS) and the number of BM present. The purpose of this study was to evaluate the utility of GPA index in a contemporary cohort of patients (pts) with MBM at a single institution to predict Overall Survival (OS). Methods: With IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify pts with MBM treated between 2000-2012. The primary endpoint was OS from diagnosis of MBM. Cox proportional hazards models were used for data analysis. Stepwise variable selection was used to identify independent prognostic factors. Results: 90 MBM (51 females) median age 57 years (range 24-87) were included for analysis. The median number of BM was 2 (range, 1-11). KPS was 90-100(52%), 70-80 (43%) and ⬍70 (6%). Extracranial metastases was present in 75 patients (83%). Initial treatment included Stereotactic Radiosurgery (SRS) (49%), Whole Brain Radiotherapy (WBRT) (8%), WBRT ⫹ SRS (22%), WBRT ⫹ Surgery (S)(14%) and SRS ⫹ (S) (7%). Median OS was 7.8 months (95% C.I. 6.8-10.1). GPA was prognostic for OS ( p⫽0.01), however this was because pts with scores of 4 had worse outcomes (median 5.1months) than the other 3 groups, which had similar OS (median 9.0-12.8 months). In addition, number of BM was not associated with OS (p⫽0.19). In contrast, KPS (p⫽0.02), Liver (p⫽0.04) and hemorrhagic metastasis (p⫽0.02) were independently prognostic for OS. These factors can be used to derive a new prognostic index with 3 groups: Unfavorable, Intermediate and Favorable (see Table). Conclusions: GPA was prognostic for OS in pts with MBM, however separation of the groups was not clear. A new prognostic index consisting of KPS, liver and hemorrhagic metastases is proposed for MBM.

Background: Temozolomide (Tem) has demonstrated efficacy as an oral alternative for pts with MM on traditional and extended dosing schedules. Calcitriol has known antiproliferative properties in vitro, and has shown synergistic effects with chemotherapy. Additionally, vitamin D receptor (VDR) polymorphisms are associated with alterations in melanoma susceptibility and disease progression. Specifically, the VDR genotype tt/ff (Taq1 and Fok1 polymorphisms) has been associated with tumors ⬎3.5mm, though no studies have focused on survival. Methods: Tem 150mg/m2was administered on days 2-8 and 16-22 every 28 days until progression or significant toxicity. Calcitriol was given on days 1 and 15 every 28 days with 3 pts at a dose of 0.2mcg/kg, 3 pts at 0.3mcg/kg, 3 pts at 0.5mcg/kg, and an additional 11 pts at a maximum dose of 0.5mcg/kg. VDR gene analysis was completed on 17/20 pts using PCR-RFLP based assays. Tolerability was the primary objective with secondary objectives of time to progression (PFS) and overall survival (OS), both as a whole and by VDR genotype. Results: Twenty pts (males⫽15) with MM treated with at least one prior systemic therapy or who were not candidates for interleukin-2 (conducted pre BRAF and anti CTLA agents), were accrued. Median age was 58. The regimen was well-tolerated with leukopenia, lymphopenia, thrombocytopenia, anemia, and thrombosis as the most common grade 3 or 4 toxicities at 10% incidence each, less than observed in prior studies (Patel et al Eur J Ca 2011). Obj RR was 10%. Median PFS was 1.8 mo with a mean of 2.7 cycles given. Pts with low-risk VDR genotype non-tt or ff (n⫽ 11) had a median OS of 7.4 mo compared to 3.8 mo for tt or ff or both (n⫽6)(median ratio⫽1.95) from time of enrollment, although not statistically significant given small sample sizes. Conclusions: The extended dosing of Tem with calcitriol is a well-tolerated oral regimen in MM. The trend toward improved OS in non-tt/ff VDR genotypes is consistent with prior studies associating the tt/ff genotype with biologic aggressiveness. Whether this represents a benefit of the inclusion of calcitriol should be studied further. Clinical trial information: NCT00301067.

New prognostic index. Prognostic group No. of points Unfavorable Intermediate Favorable

0-1 2 3

N

Median survival (months)

P

18 (22%) 38 (46%) 27 (33%)

4.4 8.4 12.8

⬍0.0001


570s 9088


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Gamma knife stereotactic radio-surgery and BRAF inhibition in metastatic melanoma. Presenting Author: Melissa Wilson, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA

Melanoma recurrence risk stratification using Bayesian systems biology modeling. Presenting Author: Edda Lind Styrmisdottir, DecisionQ Corporation, Washington, DC

Background: Gamma knife radio-surgery (GK) is an effective approach to treating brain metastases in patients with metastatic melanoma. BRAF inhibition with vemurafenib produces a median progression free survival (PFS) of 7 months, but low central spinal fluid penetration may limit its effectiveness in patients who develop brain metastases. We report long term follow-up of patients with BRAF mutant melanoma treated with vemurafenib and GK. Methods: Demographics and clinical outcomes were characterized for 18 BRAF mutant melanoma patients with brain metastases treated between 2007 and 2012 with GK and with vemurafenib (vem) for ⬎1 month. Results: The median age at starting vem was 51 yrs (range 34-76). 61% of the patients were women. Patients were treated with a median of 1 prior therapy (range 0-3). 7/18 patients (39%) had brain involvement prior to starting vem. 16/18 patients (89%) had stage M1c disease at the time of starting vem. Patients were treated with vem for a median of 8.4 months (range 2.1 to 27 months), had a median survival of 15.7 months after starting vem (range 4.2-29.4), and a median survival after GK of 7.8 months (range 1.2-21.1). Patients underwent GK to a median of 3 lesions (range 1-6). In total, 8/18 patients (44%) were treated with WBRT. 7/18 patients underwent craniotomies, 2 of which were for progression in lesions treated with GK, and 4 of which were also among the patients treated with WBRT. In 7/18 patients treated with GK for new brain progression after starting vem, vem was continued after GK for a median duration of 4.1 months (range 1.3 to 15.8). In these 7 patients that had vem and GK and continued vem, the median overall survival after starting vem was 19.9 months (range 6.7 to 29.3). Of these 7 patients, 4 required whole brain radiation therapy (WBRT); 3 have not required any additional brain directed therapy, including 2 patients who continue on vemurafenib at the time of analysis. 5/18 patients were treated with more than 1 round of GK, 3 of which were subsequently treated with WBRT. Conclusions: Despite the brain being a common site of progression on vemurafenib therapy, long term survival can be achieved in some cases by continuing vem after GK therapy.

Background: Estimating the risk of recurrence in patients with melanoma is extremely challenging. Standard of care is AJCC staging system, but the accuracy and robustness of this method is still under development. We conducted a proof of concept study exploring the use of machine-learned Bayesian Belief Networks (ml-BBNs) using a miRNA profiled cohort of melanoma patients with extended follow up to create Bayesian Biological Systems Models (BBSMs). We sought to determine if ml-BBNs could describe the biological system and if we could use the model to identify new cases with higher risk of recurrence. Methods: Our study cohort consisted of 89 patients (42 of which recurred) with a median follow up time of 118 months, that were examined for 869 miRNAs. Prior to modeling we segmented the data into training data (72 cases/80%) and testing data (17 cases/20%) at random. We recursively trained ml-BBNs on the training set, using all miRNAs. We used the directed graph structure of the ml-BBNs to identify miRNAs that consistently had more connectivity and goodness of fit as determined by Bayesian Information Criteria (BIC) scoring. MiRNAs that were in the top 50 BIC-scoring nodes across all models were selected for use to train the recurrence BBSMs. To compensate for a small number, bootstrapping was used to increase the sample to 100 records. We then compared our test set cases to our recurrence model, and used a similarity scoring algorithm to evaluate the similarity of values in each test instance to our biological models. For comparison we also trained an ml-BBN using clinical data from the same cohort. We then evaluated the scores against known recurrence outcome using Receiver Operating Characteristic (ROC) curve analysis. Results: BIC-scoring analysis selected 35 miRNAs for use in BBSM modeling. Area Under the Curve (AUC) for detection of recurrence is 0.76 in the training set and 0.62 in the testing set, while the clinical data yielded an AUC of 0.5 in this cohort. Conclusions: Our data suggest that ml-BBNs can be used to describe a biological model of melanoma recurrence. Additional data and refinement need to be made using independent datasets to be of a level that is clinically useful.

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Cetuximab with or without chemotherapy for recurrent, unresectable squamous cell carcinoma of the skin (SCCS). Presenting Author: Kalyan Nadiminti, University of Iowa Hospitals and Clinics, Iowa city, IA

Targeting BET proteins in melanoma: A novel treatment approach. Presenting Author: Luca Paoluzzi, NYU Cancer Institute, NYU Langone Medical Center, New York, NY

Background: With an increasing aging population and a growing number of people with organ transplant on immune suppression, patients presenting with locally advanced, unresectable and metastatic SCCS are on the rise. Options of therapy are limited to platinum or taxane doublets but the tolerability of these regimens is poor. Data regarding use of cetuximab in advanced SCCS is scarce and consists of a few case series and one phase II trial. The purpose of this study is to evaluate the use of cetuximab alone or in combination with chemotherapy in patients with SCCS treated at the University of Iowa Hospitals (UIHC). Methods: Patient data was compiled through medical record review of all patients diagnosed with locally recurrent, unresectable or metastatic SCCS seen at UIHC and treated with cetuximab alone or in combination with chemotherapy. Pathology was centrally reviewed. Results: A total of nine patients with SCCS received cetuximab as part of a definitive or palliative therapy with a loading dose of 400 mg/m2 followed by weekly 250mg /m2.Median age of patients is 64. Four patients had locally recurrent or unresectable disease, and five had distant metastases. Three patients had prior history of organ transplant. Chemotherapy included carboplatin AUC 5 with 5 fluorouracil 1000mg/m2/ day for four days in two patients and weekly paclitaxel 80mg/m2 in four patients. One patient received concurrent definitive radiation with 6600 cGy. In total, six patients completed at least 6 weeks of cetuximab. All these patients showed clinical improvement in pain, tumor ulcer and bleeding as compared to pretreatment. Median time to disease progression after stopping treatment was 3 months. Three patients could not complete 6 weeks of cetuximab due to disease progression. The most common side effect was skin rash and hypomagnesemia. Conclusions: Cetuximab alone or in combination with chemotherapy is well tolerated and does show promise in treatment of patients with unresectable or metastatic SCCS. Most common side effect was skin rash. A larger trial with longer follow up is warranted to establish the role of cetuximab and an optimal combination therapy in improving quality of life in this patient population.

Background: Manipulation of key epigenetic regulators in melanoma proliferation is emerging as a new therapeutic strategy. Bromodomaincontaining proteins such as the extraterminal domain (BET) family are components of transcription factor complexes and determinants of epigenetic memory. We investigated the expression of BRD4, a BET family member in melanoma cell lines and tissues, and the effects of its inhibition with the small molecule compounds MS436 and MS417 in in vitro and in vivo models of melanoma. Methods: BRD2 and BRD4 expression were analyzed by immunohistochemistry. We tested the effects of pharmacological or RNAi-mediated inhibition of BRD4 in melanoma cells using crystal violet-based assays for proliferation/colony formation and flow-cytometry for cell cycle analysis. The molecular effects of BRD4 suppression were examined using RNA sequencing, Real-Time quantitative PCR and western blots for p27, p21, MYC, ERK1 and SKP2. In the in vivo xenograft experiments NOD/SCID/IL2␥R-/-mice were injected with melanoma cells and treated with MS417. Statistical significance was determined by unpaired t-test (GraphPad). Results: BRD4 was found significantly upregulated in primary and metastatic melanoma tissues compared to melanocytes and nevi (p⬍0.001). Treatment with BET inhibitors impaired melanoma cell proliferation in vitro and tumor growth and metastatic behavior in vivo, effects that were mostly recapitulated by individual silencing of BRD4. Rapidly after BET displacement, key cell cycle genes (SKP2, ERK1 and c-MYC) were downregulated concomitantly with the accumulation of CDK inhibitors (p21, p27), followed by melanoma cell cycle arrest. BET inhibitor efficacy was not influenced by BRAF or NRAS mutational status. Conclusions: Our results demonstrate for the first time a role for BRD4 in melanoma maintenance and support the role of BET proteins as novel targets in melanoma. Further investigation in the clinical setting is warranted.




9093

571s General Poster Session (Board #52C), Sat, 8:00 AM-11:45 AM

Frequency of BRAF V600E variant in circulating free DNA compared with the single melanoma biopsy. Presenting Author: Lorenza Di Guardo, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Metastatic melanoma patients: Prospective follow-up of pigmented lesions under vemurafenib by digital dermoscopy. Presenting Author: Marie PerierMuzet, Hospices Civils de Lyon, Pierre-Bénite, France

Background: To select melanoma patients for treatment with BRAF inhibitors, the BRAF mutational status is determined in the most recent tumor biopsy. However, tumor specimens are not always available for the analysis, and relying on a single biopsy specimen can potentially exclude from treatment patients with heterogeneity among metastatic tumors due to polyclonality of BRAF mutation, which appears as a rather common condition. As an alternative approach we explored a blood-based mutation detection assay. Methods: We developed a method including enrichment for the BRAV600E variant by selective elimination of the wild type allele by TspRI digestion and BRAFV600E detection by TaqMan Mutation Detection Assay (BRAF_476_mu, Life Technologies). Sensitivity testing showed that BRAFV600E variant was detected starting from 6.25X10-5 ng of DNA, and specificity testing showed that the variant can be detected when diluted in 8X105 copies of wild-type alleles. Results: Mutational analysis performed by Sanger sequencing of exon15 in 114 melanoma biopsies showed that 4 (3%) harbored the c.1798_1799GT⬎AA (V600K) mutation, 1 (1%) the c.1799_1800TG⬎AA mutation (V600E), and 56 (49%) the most common c.1799T⬎A mutation (V600E), while by the novel method the latter mutation was detected in 9 additional specimens (8% increment) and confirmed by sequencing the PCR product after TspRI digestion. Presurgery plasma was available for 50/114 patients at advanced stages, 26/50 (52%) showing a mutated specimen, including 4 with a double nucleotide substitution (V600K and V600E). The matched plasma samples resulted mutated in 25/26 cases with mutated biopsy and in further 14/25 samples with biopsy resulting wild type; in contrast, plasma of 50 healthy controls tested negative. Taken together, these results indicate that V600E circulating variant was detectable in 39/50 (78%) plasma samples and in 22/50 (44%) tumor specimens. Conclusions: Detection of BRAF V600E variant in circulating free DNA may represent a more sensitive approach for patient selection and decision making process during the treatment with BRAF inhibitors.

Background: Vemurafenib is the first approved by the FDA BRAF V600 inhibitor for the treatment of metastatic melanoma. Many cutaneous side-effects such as squamous cell carcinoma, xerosis, photosensitivity are observed. We first reported the occurrence of second primary melanomas (SPM) under BRAF inhibition. These SPM were shown to be wild-type for BRAF. The exact occurrence of these changes is still unknown. We wanted then to explore prospectively the impact of vemurafenib on cutaneous pigmented lesions using sequential digital dermoscopy. Methods: We registered prospectively following inform consent the pigmented lesions of patients under vemurafenib. We examined the total body surface and captured from 9 to 134 pigmented lesions on 24 patients. Each single lesion was followed monthly from vemurafenib initiation to vemurafenib disruption due to disease progression. Dermoscopic modifications of the melanocytic lesions including external diameter, dermoscopical pattern, pigmentation, network thickness, dots distribution and keratosis appearance were analyzed. Results: The median duration of dermoscopic follow up was 6,9 months ( range from 2 to 16 months), 1098 pigmented lesions were included. At least one modification occurred in 56% of the lesions. Most frequent modifications were the occurrence of dark globules (56%), change in the pigmentation coloration (47%), variations in network thickness (32%), increase of the external size (20,1%), onset of black areas (14%), onset of keratosis (4,4%). Up to 5,3% of lesions spontaneously disappeared; 21 excisions were performed due to significant dermoscopic changes and revealed 10 early melanomas in 5/24 patients (20,8%). The 11 remaining lesions were benign. Conclusions: More than fifty percent of the patients under vemurafenib will experiment significant modifications on their pigmented lesions. In our experience 10/21 removed lesions were early melanomas that could not be otherwise diagnosed using naked-eyes examinations only. Digital dermoscopy is one of the tool that can be use to discriminate earlier the modifications. Such careful monitoring will improved the safety when evaluating BRAF inhibitors in adjuvant setting.

9094

9095



Activity of cabozantinib in metastatic uveal melanoma: Updated results from a phase II randomized discontinuation trial (RDT). Presenting Author: Adil Daud, University of California, San Francisco, San Francisco, CA

Identification of functional DNA methylation aberrations associated with outcome in melanoma patients with brain metastasis. Presenting Author: Diego M Marzese, John Wayne Cancer Institute, Santa Monica, CA

Background: MET and VEGF signaling are implicated in angiogenesis, invasion, and metastasis, and upregulation of MET as a consequence of GNAQ/GNA11 mutation has been implicated in uveal melanoma. Historical rates of median overall survival (OS) in patients (pts) with metastatic uveal melanoma range from 6-9 months (mos). A RDT evaluated activity and safety of cabozantinib, a MET and VEGFR2 inhibitor, in 9 tumor types including a metastatic melanoma cohort where 55% and 5% of pts experienced objective tumor regression and confirmed partial response, respectively (J. Clin. Oncol. 30, 2012 (suppl; abstr. 8531)). Here we report on the longer term followup of metastatic uveal melanoma pts enrolled to this cohort. Methods: Eligible pts were required to have progressive measurable disease per RECIST. Pts received cabozantinib at 100 mg po qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ⱖ wk 12 was based on response: pts with PR continued open-label cabozantinib, pts with SD were randomized to cabozantinib vs placebo, and pts with PD discontinued. Pts were followed for overall survival. Results: 23 of 77 pts enrolled in the melanoma cohort had the uveal subtype. Median age was 65 yrs; median prior regimens was 1 (range 0-5). Tumor mutation status was determined for 10/23 pts. 9/10 harbored either a GNAQ or GNA11 mutation, while GNA11 status was unknown for one pt. Pts had substantial tumor burden; median sum of the longest diameter of target lesions was 11.9 cm (range, 2-37.2). Median follow-up was 26.5 mos. (range 21.7-33.8). Median PFS from Study Day 1 was 4.8 mos. The estimate of PFS at month 6 (PFS6) was 41% and median OS was 12.6 mos. Most common Grade 3/4 AEs were HTN (13%), abdominal pain (9%), hypokalaemia (9%), hyperbilirubinaemia (9%) and increased lipase (9%). Conclusions: Cabozantinib is active in pts with metastatic uveal melanoma. Treatment with cabozantinib is associated with encouraging progression-free and overall survival. The safety profile of cabozantinib was comparable to that of other VEGFR TKIs. A randomized Phase 2 study is planned comparing cabozantinib to temozolomide plus dacarbazine in pts with uveal melanoma. Clinical trial information: NCT00940225.

Background: Brain metastasis (MBM) represents one of the most significant causes of death in melanoma patients. Identification of clinically relevant markers is necessary to recognize patients with high risk of MBM development. Alterations in DNA methylation patterns have been recognized as a major epigenetic hallmark of metastasis initiation and progression. Methods: To generate a comprehensive genomic DNA methylation landscape of MBM, we performed genome-wide data integrative analyses examining the DNA methylation (Illumina HumanMethylation 450K), gene expression (Affymetrix HumanExon 1.0), and genotype (Affymetrix SNP 6.0) of specimens related to melanoma progression from normal to MBM (n⫽65). Results: We observed significant genome-wide hypomethylation and CpG island hypermethylation according to melanoma progression to the brain. To identify significant differentially methylated CpG sites between lymph node metastasis and MBM, we applied a strict statistical threshold (␤-value difference ⬎0.3 and FDR-corrected p ⬍0.005). We identified the homeobox D (HOXD) gene family members amongst the most significantly affected genes. The influence on gene expression and the frequency of HOXD hypermethylation were verified using integrative analysis of publicly available data generated from 168 melanoma specimens. In a cohort of clinically annotated melanoma patients (n ⫽ 159), we demonstrated that hypermethylation of a genomic region in the HOXD gene cluster was significantly associated with shorter disease-free survival (p ⫽ 0.004) and overall survival (p ⫽ 0.002).Multivariate analysis confirmed the association with poorer survival (p ⫽ 0.01 and HR ⫽ 2.8; CI95%: 1.3-6.1). Conclusions: The use of genome-wide DNA methylation, gene expression, and genotyping integrative analyses allowed the identification of novel markers with functional and clinical implications for melanoma patients with brain metastasis.


572s 9096

Melanoma/Skin Cancers General Poster Session (Board #53A), Sat, 8:00 AM-11:45 AM

Assessment of absolute lymphocyte count (ALC) as a predictor of progression-free survival (PFS) and overall response rate (ORR) in metastatic melanoma (MM) patients (pts) treated with high-dose interleukin-2 (HD IL-2). Presenting Author: Jeffrey Thomas Yorio, The University of Texas MD Anderson Cancer Center, Houston, TX Background: HD IL-2 is an approved immunotherapy that can achieve durable cures in MM pts. Due to toxicity and low ORR, identification of predictors of clinical benefit would enhance pt selection and outcomes with HD IL-2. Recent research identified a positive correlation for ALC ⱖ 1000 (either at baseline or at dose 3) with OS among MM pts treated with the immunotherapy agent ipilimumab. We tested the hypothesis that ALC (ⱖ 1000) or other hematological parameters correlates with clinical benefit from HD IL2. Methods: Results of hematologic testing in patients (n⫽98) treated with HD IL2 at MD Anderson Cancer Center were collected, including absolute levels of neutrophils (ANC), lymphocytes (ALC), monocytes (AMC), eosinophils (AEC), and platelets (APC) at baseline, after cycle 1 (C1), and after cycle 2 (C2) of HD IL-2; changes in each parameter for each interval were also calculated. Hematologic values were assessed as categorical (for ALC, ⱖ 1000 Yes/No; other parameters, above upper limit of normal [ULN] Yes/No) and continuous variables. Associations between these parameters and PFS and ORR were analyzed. Results: ALC wasⱖ 1000 in 75 pts (76%) at baseline, in 81 (83%) after C1, and in 80 of 86 pts (93%) after completion of C2 of HD IL-2. PFS was not significantly associated with ALC ⱖ 1000 at baseline (HR 0.69, p⫽0.13), after C1 (HR 1.32, p⫽0.33), or after C2 (HR 1.01, p⫽0.98). ALC ⱖ 1000 at each timepoint was not significantly associated with ORR or OS. There was no significant difference in the change in ALC with HD IL2 treatment among responders versus non-responders. Among baseline hematological factors, APC ⬎ ULN was significantly associated with PFS (p⫽0.001), but it was rare (2/98 patients). Exploratory analyses identified significantly shorter PFS for patients with baseline APC ⬎ 300 (11%, HR 2.75, p⫽0.002). Analysis of hematologic factors as continuous values identified significant associations with PFS for AMC (HR 2.42, p⫽0.03) and AEC (HR 1.73, p⫽0.009) after C2. Conclusions: ALC ⱖ 1000 did not correlate with PFS, ORR, or OS with HD IL-2 therapy in this cohort of metastatic melanoma pts.

9098


9097


What is the behavior of Breslow’s thickness? Presenting Author: Gelcio L. Q. Mendes, National Cancer Institute of Brazil - Hospital do Câncer II, Rio de Janeiro, Brazil Background: Localized cutaneous melanomas (CM) have their clinical course predicted by microscopic findings in the tumor specimen, mostly Breslow’s thickness (BTL), ulceration and mitoses. It is not certain whether BTL has a linear relationship with overall survival (OS) or relapse-free survival (RFS). The aim of this study was to evaluate BTL´s linear (LC) and its non-linear component (NLC) with relation to survival. Methods: All consecutive cases of CM treated from 1997 to 2006 at a single institution were identified, individuals with stage I or II tumors, minimum follow up of one month and known BTL were selected, socio-demographic data, clinical and pathological findings, treatment and outcomes were abstracted. Information about ulceration was missing in more that 30% of cases and it was not evaluated, there was no information about mitotic rate. Survival was estimated by the Kaplan-Meier method. Multivariate analyses were performed by the Cox model. BTL was evaluated as a continuous variable, and the LC and NLC by the technique of smoothing, using p-splines. Results: There were 1465 cases of CM, 51 with no follow up, 137 had no information about BTL and 202 had advanced stages. This analysis is based on 1075 cases. In the Cox model, the variables associated OS were age [hazard ratio (HR) 1.02, 95% CI 1.01 to 1.03], sex (HR 1.56, 95% CI 1.2 to 2.04) and BTL (HR⫽1.079, 95% CI 1.065 to 1.094). The variables associated with RFS were age (HR 1.017, 95% CI 1.009 to 1.024), sex (HR 1.372, 95% CI 1.104 to 1.704) and BTL (1.068, 95% CI 1.057 to 1.080). In the analysis of LC and NLC of BTL, it was found that both LC and NLC were statistically significant for OS and RFS. There was an increase in the HR as BTL increased in those lesions thinner than 4mm, then such increase was not as evident and lesions with more than 10mm had a similar OS and RFS (plateau). Conclusions: BTL is one of the most powerful prognostic criteria of patients with stage I and II CM. The risk of death increases linearly for thin lesions up to 4mm, lesions thicker than 10mm behave as a uniform group with no further decrease in OS or RFS as the lesion becomes larger. In conclusion, BTL may not behave as a linear function, it has a LC for thinner lesions, but for thicker lesions, above 10mm, further increase in BTL may add no more risk.

9099


Melanomas of the head-and-neck skin with mutation BRAF-V600K or BRAF-V600R define a melanoma subtype with particular clinical features. Presenting Author: Hans Starz, Klinikum Augsburg, Augsburg, Germany

Analysis of stage of melanoma diagnosis in relation to insurance type and income as indicator of early/late diagnosis. Presenting Author: Peter Makram Lamie, Creighton University, Omaha, NE

Background: “Malignant melanoma” is a melting pot of diverse melanocytic tumor entities, which arise in different organs under varying pathogenetic circumstances. Chronic sun exposure is a major factor for the development of cutaneous melanomas of the head-and-neck (HN) region. Methods: 131 patients with metastatic cutaneous melanomas were included in a monocentric retrospective study. The HN skin was the primary tumor site in 41 patients. The mutational hotspots of BRAF and NRAS were analysed by Sanger sequencing. In BRAF and NRAS wildtype cases, additionally exons 11, 13 and 17 of the KIT gene were investigated. HN patients with the mutations BRAF-V600K or BRAF-V600R were defined as group A (n ⫽ 11), those with other mutations or wildtype as group B (n ⫽ 30). A and B were compared with regard to the emergence of different categories of metastases, using the Kaplan-Meier method and log rank tests. The average follow-up time was 50 months. Results: BRAF-V600K occurred in 10 of the 41 HN patients and in 2 of the 90 non-HN patients (p ⫽ 0.003 by T-test), BRAF-V600R in 1 HN and in 1 non-HN patient. KIT mutations were restricted to 2 HN patients. Inversely, NRAS mutations were rare in the HN (3 of 41) versus the non-HN (26 of 90) cohort (p ⫽ 0.001). Lymphatic metastasis became apparent in each of the 11 group A patients not later than 35 months after the diagnosis of the respective primary melanoma. 5 out of the 8 group A patients, who underwent sentinel node biopsies (SNB), had nodal micrometastases. During follow-up, regional nodal macrometastases emerged earlier and at a higher rate in group A compared to B (p ⫽ 0.044 by log rank test). The same applied even more significantly for satellite/intransit metastases (p ⫽ 0.002), whereas for distant metastasis no significant difference was found. Conclusions: BRAF-V600K/R mutations in HN melanomas define a distinct melanoma subtype with an especially high risk of lymphatic metastasis. Clinical implications may be mutation analyses already for primary HN melanomas, and SNB even for thin melanomas of this subtype. Extra-guidelines should be considered for the monitoring of these patients. Special attention to this subgroup is also necessary in clinical trials.

Background: This study compares the average stage of diagnosis for melanoma by insurance status and household income. This is the largest such study for melanoma to date. Methods: Using the National Cancer Database we examined 299K patients with melanoma between 2000 and 2009 at 1,408 hospitals. The relationship of average stage of diagnosis is compared across insurance types and by income for 293K patients. Results: The VA patients had the lowest average stage of diagnosis 0.8 with the Medicaid population exhibiting the highest 1.8. The VA was lower than Tricare which had an average diagnosis of 1.1, private insurance 1.2, Medicare 1.3, and uninsured 1.7. The lowest rate of stage IV was private insurance 3.3%, Tricare 3.6%, VAH 4.4%, Medicare 5.7%, uninsured 10%, and the highest rate was among Medicaid 14.3%. The highest income category ⱖ$49K had the lowest average stage at diagnosis of 1.1 compared to $39K to $48K 1.2, $33K to $38K 1.3, $28K to $32K 1.4, and ⬍$28K had the highest average stage of diagnosis 1.4. Stage IV rate increased from the highest income 3.6%, $39K to $48K 4.6%, $33K to $38K 5.1%, $28K to $32K 5.8%, and ⬍$28K 6.9%. Data available. Conclusions: VA, higher income and private insurance had earlier stage of melanoma compared to uninsured and Medicaid who had higher frequency of stage IV disease. Insurance type

Veterans affairs Tricare/military Private insurance Medicare Uninsured Medicaid Total

Stage 0

I

II

III

IV

3,758 44.48% 1,017 27.67% 36,952 21.75% 24,312 23.41% 952 12.88% 751 12.69% 67,742 22.64%

3,068 36.32% 1,813 49.33% 89,811 52.86% 42,255 40.68% 3080 41.66% 2,161 36.52% 142,188 47.52%

823 9.74% 401 10.91% 21,346 12.56% 21,025 20.24% 1324 17.91% 946 15.99% 45,865 15.33%

422 5.00% 309 8.41% 16,183 9.52% 10,308 9.92% 1290 17.45% 1,210 20.45% 29,722 9.93%

377 4.46% 135 3.67% 5,623 3.31% 5,965 5.74% 748 10.12% 849 14.35% 13,697 4.58%

Weighted average Stage of diagnosis

P value of average stage of diagnosis

0.89 1.11

⬍0.0001

1.20

⬍0.0001

1.34

⬍0.0001

1.70

⬍0.0001

1.87

⬍0.0001

Totals N

%

8,448 100% 3675 100% 16,9915 100% 103,865 100% 7,394 100% 5,917 100% 299,214 100%

2.82% 1.23% 56.79% 34.71% 2.47% 1.98% 100.00%

P value based on student t-statistic calculated for weighted average stage of diagnosis. VA is the comparison category.




9101


Detection of DDR2 mutations in malignant melanoma: A potentially targetable feature of advanced stage disease. Presenting Author: Yongbao Wang, Quest Diagnostics Nichols Institute, Chantilly, VA

Impact of complete lymphadenectomy in stage I melanoma: SEER analysis, 2004-2009. Presenting Author: Victoria Stager, John Wayne Cancer Institute, Santa Monica, CA

Background: The discoidin domain receptor tyrosine kinase 2 (DDR2) gene is mutated in a subset of non-small cell carcinoma of the lung. In lung cancer, targeting of DDR2 with the inhibitor dasatinib has been shown to inhibit DDR2-mutated cell line growth. Responses to dasatinib in DDR2mutated lung tumors are currently being investigated in clinical trials. We investigated whether somatic DDR2 mutations also occur in melanomas using a set of different clinical subtypes bearing a variety of melanomaassociated molecular alterations. Methods: DNA was extracted from macrodissected FFPE sections of 168 melanomas and subjected to nextgeneration sequencing using a custom-designed 36-amplicon panel including the coding regions of DDR2 and exons 11 and 15 of BRAF. PCR products were prepared by Access Array, sequenced on the Ion Torrent PGM, and analyzed using Sequence Pilot software. All DDR2 mutations were confirmed by bidirectional Sanger sequencing. Relative expression analysis of the DDR2 gene was performed using RT-PCR on RNA extracted from FFPE sections, with levels normalized to ABL1 and GAPDH. Results: Heterozygous DDR2 point mutations were identified in 3.4% of BRAFmutated melanoma (n⫽117) but not in any cases that lacked BRAF mutations (n ⫽ 51). All DDR2-mutated melanomas were advanced stage with lymph node and/or extensive soft tissue involvement and included both BRAF V600K and V600E cases. In contrast to the range of mutation sites reported in lung cancers, DDR2 mutations in melanoma (I488S, F574C, S667F and L701F) were at highly evolutionarily conserved positions in the kinase domain. The mutations are expected to be disruptive and may therefore modulate kinase activity. DDR2 transcripts were expressed in tumor cells in all mutated cases. Conclusions: DDR2 mutations in advanced stage melanoma may provide a targetable genetic feature for tyrosine kinase inhibitors such as dasatinib. The invariant association of DDR2 mutation with activating BRAF mutations suggests synergy in transformation between these distinct signaling pathways.

Background: Stage I melanoma has excellent prognosis, yet it remains a treacherous entity leading to fatal disease progression in a small and ill-defined population of patients. Role of complete lymphadenectomy in early melanoma is not determined. Methods: We used the Surveillance Epidemiology and End Results (SEER) database from 2004 to 2009 to identify patients who underwent wide local excision (WLE) with or without nodal surgery for management of AJCC Stage I primary cutaneous melanoma. Patients with complete data on age, race, sex, and primary tumor histology and anatomic site were categorized by type of surgical treatment into WLE, WLE⫹sentinel node biopsy (SNB), or WLE⫹complete lymphadenectomy (CLND) groups. Five-year disease-specific survival (DSS) was determined by treatment group and by sentinel node status. Specific risk factors were identified using multivariate analysis. Results: During the selected time period, 51,573 patients were diagnosed with AJCC Stage I cutaneous melanoma. Rate of SNB was 22%, and out of this group, 2% of patients had metastases to the regional lymph nodes. Five-year DSS was decreased in the node-positive group compared to the patients who had a negative SNB or WLE only (HR⫽4.95). Rate of CLND was 67%, and it did not improve survival of the patients with positive SNB (5-year DSS 83% vs. 79%, p⫽0.29). Performance of CLND did not correlate with age, histological type, presence of ulceration, or Breslow depth. Conclusions: SEER database suggests that a clinical equipoise regarding the utility of CLND in patients with positive SLN remains. These findings justify ongoing MSLT II.

9102

TPS9103


Relationship of bleeding to pathologic ulceration in a primary melanoma lesion. Presenting Author: Paul T Kang, University of Arizona Cancer Center, Tucson, AZ Background: Lesion bleeding (BL) is a catalyst symptom leading to melanoma (MEL) diagnosis and is associated with adverse outcomes. The pathophysiologic significance of BL has not been elucidated. We hypothesize that BL reflects pathologic ulceration (UL). Methods: This retrospective cohort study was conducted using data from 850 patients seen 2005-2009 at our center. Eligible patients reported the pre-diagnosis BL status of their primary lesion; determination of its UL status was also required. Demographic, clinical, pathologic and outcomes data were abstracted from records. ⌾2 and independent t-tests were used for univariate comparisons. Predictors of UL were analyzed with multiple logistic regression. Survival indices were analyzed by the Kaplan-Meier, log-rank, and Cox proportional hazards. Results: 190 patients with 193 MEL lesions were eligible. Median follow-up was 5.3 yr. 67 lesions bled prior to diagnosis; 68 demonstrated UL. BL and UL were associated with each other and with Breslow depth in univariate analyses; UL was also associated with age at diagnosis. Neither was associated with gender, lesion site, use of BL-associated drugs or Clark’s level. A logistic model was developed using BL, gender, lesion site, use of BL-associated drugs, and age at diagnosis. Only BL and age at diagnosis were associated with UL probability (OR⫽10.6/p⬍0.001 and OR⫽1.04/p⫽0.006, respectively). BL was associated with worsened median relapse-free (RFS) and overall survival (OS) (median 1.16y vs. 1.96y, p⫽0.001 and 3.06 y vs. 3.41y, p⫽0.001), as was ulceration. When status of BL and UL were considered together, only UL predicted outcomes. A Cox model of clinical factors (BL, gender, age at diagnosis, lesion site) confirmed the association of BL with RFS and OS (HR 1.82/p⫽0.006 and HR 2.36/p⫽0.001). Addition of UL to the model abrogated BL’s predictive value. Conclusions: BL of primary MEL lesions is strongly associated with pathologic UL. When clinical parameters are considered, BL significantly predicts RFS and OS, although this value is lost once UL status is known. Our data are consistent with BL’s reflecting the ulceration status of a primary lesion. When UL status is unknown, BL may be able to serve as its surrogate marker.


CA184-240: A single-arm, open-label phase II study of vemurafenib followed by ipilimumab in patients with BRAF V600-mutated advanced melanoma (AM). Presenting Author: F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA Background: Ipilimumab (Ipi), a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4 expressed on T cells, and vemurafenib (Vem), a small molecule inhibitor of BRAF V600-mutated kinase, are both approved treatments for AM. Ipi has shown improved overall survival (OS) in two randomized phase III trials of patients with previously treated (3 mg/kg monotherapy) and previously untreated (10 mg/kg plus dacarbazine) AM. Vem has shown improved OS in a randomized phase III trial of patients that harbor the BRAF V600E mutation. The most common drug-related adverse events (AEs) with Ipi monotherapy were immune-related GI tract and skin toxicities, which were generally manageable using treatment guidelines. The most common AEs with Vem were arthralgia, rash, and fatigue. Vem can induce rapid and substantial responses, and resistance mechanisms are a focus of current investigation. This study will evaluate the safety of Vem lead-in followed by Ipi (prior to resistance) in patients with BRAF V600-mutated AM. Methods: An estimated 45 patients will be enrolled. Eligible patients include those ⱖ18 years old with previously untreated AM, a BRAF V600 mutation, and an ECOG PS of 0 or 1. Major exclusion criteria are primary ocular melanoma, active brain metastases, and autoimmune disease. Patients will initially receive Vem for 6 weeks (960 mg twice daily). After a washout period of 3-10 days (per protocol), patients will be initiated on Ipi at 10 mg/kg (every 3 wk for 4 doses, then once every 12 wk beginning at week 24, until disease progression or unacceptable toxicity). Vem will be restarted at the time of disease progression on Ipi (no minimum time to restart) or unacceptable toxicity on Ipi (restart minimum of 1 mo after the last dose of Ipi). Vem will be restarted at the last dose level tolerated at the end of the lead-in phase. Patients will be followed every 12 weeks for toxicity and/or disease progression, and subsequently will be followed every 12 weeks for survival. The objectives of this study are to estimate the incidence of grade 3-4 drug-related AEs. Exploratory objectives include the evaluation of efficacy (OS). Clinical trial information: NCT01673854.


574s TPS9104

Melanoma/Skin Cancers General Poster Session (Board #54A), Sat, 8:00 AM-11:45 AM

TPS9105^


Open-label, multicenter, single-arm, phase I, dose-dscalation with efficacy tail extension study of vemurafenib in pediatric patients with surgically incurable and unresectable stage IIIc or IV melanoma harboring BRAFV600 mutations (NCT01519323). Presenting Author: Fariba Navid, St. Jude Children’s Research Hospital, Memphis, TN

A phase III open-label study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus investigator’s choice in advanced melanoma patients progressing post anti-CTLA-4 therapy. Presenting Author: Bartosz Chmielowski, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA

Background: Although rare, melanoma is the most common form of skin cancer in children and the incidence is rising in the adolescent population. Similar to adults, the outcome for pediatric patients with advanced or recurrent melanoma is poor. Many adult studies of melanoma exclude patients under the age of 18 years. Approximately 50% of melanomas carry a mutation in the BRAF gene and the oral BRAF inhibitor vemurafenib (VEM) has demonstrated improved rates of overall and progression-free survival in adult melanoma patients who carry this mutation (Chapman et al; NEJM 2011). The current study is designed to determine the maximum tolerated dose (MTD)/recommended dose (RD), pharmacokinetics, safety, tolerability, and efficacy of VEM in pediatric patients with surgically incurable and unresectable stage IIIC/IV melanoma harboring BRAFV600mutations. Methods: Patients aged 12 through 17 years with newly diagnosed or previously treated measurable disease are eligible. Patients with radiographically stable, asymptomatic previously treated central nervous system lesions are also eligible. In the dose-escalation phase, patients will be enrolled sequentially to increasing dose cohorts of VEM following a 3⫹3 design. Dose-limiting toxicity will be assessed during the first cycle (defined as the first 28 days). The initial dose will be 720 mg BID (patients ⱖ45 kg) or 480 mg BID (patients ⬍45 kg). Once the MTD/RD for the extension phase is defined based on the dose-escalation window, all patients will be eligible to receive the MTD/RD. The efficacy tail of the trial will enroll additional pediatric patients at the MTD/RD. Patients will receive VEM until disease progression, death, unacceptable tolerability, discontinuation from the study, or other protocol-specified criteria. The study aims to treat approximately 20 patients at the RD with 3-15 additional patients treated at other dose levels during the dose-escalation phase. This study is currently open at 18 sites in the USA, UK, Germany, Italy, and Australia. As of January 24, 2013, one patient has been enrolled. Clinical trial information: NCT01519323.

Background: Despite the recent approval of ipilimumab and vemurafenib for advanced melanoma, there is still a large unmet need for patients (pts) who have progressed on anti-CTLA-4 therapy and a BRAF inhibitor (depending on BRAF status). Programmed death-1 (PD-1) is a co-stimulation inhibitory receptor that negatively regulates T-cell activation and is upregulated in tumor-infiltrating lymphocytes. Upregulation of PD-1 is also associated with advanced disease in melanoma. Nivolumab, an anti-PD-1 receptor blocking monoclonal antibody, demonstrated durable antitumor activity in a phase 1 study in 106 pts with advanced melanoma with objective responses (OR) observed in 31% and stable disease ⱖ24 weeks in 6% with a manageable safety profile (Topalian SL et al; ESMO 2012 [Abstr 453P]). Here we describe a phase III study designed to compare the clinical benefit of nivolumab to chemotherapy of investigator’s choice in previously treated pts with unresectable or metastatic melanoma. Methods: In this two arm open-label study, approximately 390 pts will be randomized 2:1 to receive either nivolumab 3 mg/kg IV every two weeks (Arm A) or either dacarbazine 1000 mg/m2 IV or carboplatin AUC6/paclitaxel 175 mg/m2 IV every 3 weeks (Arm B) until disease progression or treatment discontinuation. Pts included are those with ⱕ2 regimens for advanced melanoma who have progressed on anti-CTLA-4 therapy as well as a BRAF inhibitor if BRAF V600-mutation positive. Pts without active brain metastases are eligible. All pts require baseline fresh biopsy to determine PD-L1 expression. Pts will be stratified by tumor PD-L1 expression, BRAF status, and prior anti-CTLA-4 best response. Tumor response per RECIST 1.1 will be assessed 9 weeks following randomization and every 6 weeks thereafter for the first year. After the first year, response will be assessed every 12 weeks until disease progression or treatment discontinuation. The co-primary endpoints are overall survival (OS) and OR rate. Secondary endpoints include progression-free survival, correlation of PD-L1 expression with clinical outcome, and health-related quality of life. Clinical trial information: NCT01721746.

TPS9106

TPS9107^



A phase III, randomized, double-blind study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus dacarbazine in patients (pts) with previously untreated, unresectable, or metastatic melanoma (MEL). Presenting Author: Caroline Robert, Institut Gustave Roussy, Villejuif, France

An open-label, randomized, phase II study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) given sequentially with ipilimumab in patients (pts) with advanced or metastatic melanoma (MEL). Presenting Author: F. Stephen Hodi, Dana-Farber Cancer Institute, Boston, MA

Background: The 5-year survival rate for late-stage MEL is currently only 15%. Despite recent advances with ipilimumab and vemurafenib, a considerable unmet need remains for pts with previously untreated, unresectable or metastatic BRAF wild-type MEL. Objective response rate (ORR) with first-line dacarbazine, a widely used chemotherapy in MEL, is 13%, with median overall survival (OS) ranging from 5.6 to 11 months. Programmed death-1 (PD-1) is an immune checkpoint receptor that negatively regulates T-cell activation through interaction with its ligand, PD-L1. This ligand is overexpressed by multiple tumor types, including advanced MEL. The PD-1 receptor blocking antibody nivolumab demonstrated clinical activity at 0.1-10 mg/kg in a phase I study in pts with advanced MEL (n ⫽ 106), with OR in 33 pts and stable disease ⱖ24 weeks in 6 pts. We describe a double-blind, randomized phase III study designed to compare the clinical benefit of nivolumab vs dacarbazine in pts with advanced MEL. Methods: Approximately 410 pts with untreated, unresectable stage III or stage IV MEL will be randomized 1:1 to receive either nivolumab 3 mg/kg IV every two weeks or dacarbazine 1000 mg/m2 IV every three weeks until disease progression or unacceptable toxicity. All pts must be BRAF wild-type as per V600 mutational testing. Pts will be stratified by PD-L1 status (positive vs negative/indeterminate) and metastatic (M) stage (M0/M1a/M1b vs M1c). PD-L1 positivity will be defined as ⱖ5% total membrane staining in tumor cells. Tumor response (per RECIST 1.1) will be assessed 9 weeks following randomization and every 6 weeks thereafter for the first year. After the first year, response will be assessed every 12 weeks until disease progression or treatment discontinuation. Treatment may continue beyond initial progression at the investigator’s discretion for pts showing clinical benefit and tolerating therapy. The primary endpoint is OS. Secondary endpoints include progression-free survival, ORR, whether PD-L1 expression is a predictive biomarker for OS, and health-related quality of life. Clinical trial information: NCT01721772.

Background: Programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) are immune checkpoint receptors that attenuate T-cell responses and contribute to immune evasion by tumor cells. Nivolumab is a PD-1 receptor blocking monoclonal antibody that has shown clinical activity in phase 1 trials with various tumor types including MEL. Ipilimumab is an anti-CTLA-4 monoclonal antibody approved for advanced or metastatic MEL. Preclinical data suggest that combined PD-1 and CTLA-4 receptor blockade may improve antitumor activity in MEL, with PD-1 blockade upregulating CTLA-4 expression and CTLA-4 blockade upregulating PD-1 expression on tumor-infiltrating T cells. We describe a phase II study evaluating nivolumab administered sequentially with ipilimumab in pts with advanced (unresectable stage III) or metastatic (stage IV) MEL. Methods: This open-label, phase II study will enroll approximately 80 pts. During the induction period, pts will be randomized 1:1 to either nivolumab (3 mg/kg, q2w) from Weeks (Wk) 1-13 followed by ipilimumab (3 mg/kg, q3w) from Wks 14-25, or ipilimumab followed by nivolumab at the same doses and schedules. All pts will then receive nivolumab (3 mg/kg, q2wk) during the continuation period until disease progression or unacceptable toxicity, for ⱕ2 years from initial study treatment. Pts may be treatment-naive or have disease recurrence or progression after one prior systemic therapy, excluding prior anti-PD-1, anti-CTLA-4, or a BRAF inhibitor. The primary endpoint is the incidence of treatment-related Grade 3–5 adverse events (AEs) during the induction period. Secondary endpoints are response rate at Wk 25 and progression rates at Wks 13 and 25. Exploratory endpoints include safety and tolerability; overall survival; pt-level time course of treatment-related grade 3–5 AEs, response, progression, treatment discontinuation, and death; the association of changes in pharmacodynamic immune markers from baseline to Wk 13 and Wk 25 and clinical response; the association between baseline immunological parameters and clinical response; and immune-related single nucleotide polymorphisms. Clinical trial information: NCT01783938.


Patient and Survivor Care 9500


Magnetic resonance guided focused ultrasound surgery for palliation of painful bone metastasis: Results of a multicenter phase III trial. Presenting Author: Mark Hurwitz, Thomas Jefferson University and Hospitals, Philadelphia, PA Background: Pain due to bone metastases is a common cause of cancerrelated morbidity. Magnetic resonance guided focused ultrasound surgery (MRgFUS) is a non-invasive approach to thermal tissue ablation. This multi-center phase III trial assessed efficacy of MRgFUS compared with sham treatment to alleviate pain due to bone metastases. Methods: Subjects with a painful bone metastasis amenable to MRgFUS treatment for whom radiation therapy was ineffective or contraindicated were randomized 3:1 to MRgFUS or sham treatment in a single blind design. Unblinding of sham subjects who did not experience significant pain relief within 2 weeks was permitted with crossover allowed to salvage MRgFUS treatment. Pain response and impact on quality of life (QOL) were assessed using the numerical rating scale (NRS) and Brief Pain Inventory-Quality of Life (BPI-QOL). Safety was also assessed. Results: 142 randomized subjects were included in an intent-to-treat analysis. 67% (95%CI: 57.5-76.0%) of 107 subjects in the MRgFUS arm experienced clinically significant pain relief, equating with an anchor descriptor of “much improved” or better at 3 months compared to 20% of 35 sham arm subjects (p⬍0.0001). Median baseline and 3 month NRS scores were 7.0 and 2.0 for the MRgFUS arm vs. 7.0 and 6.0 for the sham arm. A clinically significant improvement at 3 months in BPI-QOL score for MRgFUS but not sham treatment was noted [average change: 2.4 vs. 0.2 respectively, (p⬍0.0001)]. MRgFUS treatment was well tolerated. Conclusions: MRgFUS, as demonstrated by this phase III trial, results in excellent rates of pain relief and improvement in QOL for patients with oncologic related bone pain who are not candidates for radiation therapy. Given these excellent results coupled with a favorable side effect profile, MRgFUS should be considered a primary choice for this patient population. Clinical trial information: NCT00656305.

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Outcomes and toxicity for hypofractionated and single-fraction imageguided stereotactic radiosurgery for sarcoma metastatic to the spine. Presenting Author: Michael Ryan Folkert, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Conventional radiation treatment (20-40 Gy total dose, 5-20 fractions, 2-5 Gy per fraction) for sarcoma metastatic to the spine provides subtherapeutic doses and results in poor local control (58-77% at 1 year). Hypofractionated (HF) and/or single-fraction (SF) image-guided stereotactic radiosurgery (IG-SRS) may provide a more effective means of control and salvage for these lesions. Methods: Patients with pathologically-proven high-grade sarcoma metastatic to the spine treated with HF and SF IG-SRS were included. Local control (LC) and overall survival (OS) were analyzed using Kaplan-Meier statistics; univariate/multivariate analyses were performed using Cox regression. Toxicities were assessed according to CTCAE v4.0 criteria. Results: From 5/2005 and 11/2012, 88 patients with 120 discrete metastases were treated with HF (3-6 fractions, median dose 28.5 Gy; n⫽52, 43.3%) or SF IG-SRS (median dose 24 Gy, n⫽68, 56.7%). Median followup was 12.3 months. LC at 12 months was 87.9% (95% CI 81.3-94.5%). OS at 12 months was 60.6% (95% CI 49.6-71.6%) with a median survival of 16.9 months. SF IG-SRS demonstrated superior LC to HF IG-SRS (P⫽.007) (Table). SF IG-SRS retained its significance in terms of improved LC on multivariate analysis, HR 0.304 (95% CI: 0.1170.790); variables tested included prior radiation therapy, histology, IG-SRS fractionation, surgery, and chemotherapy. Treatment was well-tolerated with 1% acute Grade 3 toxicity and 4.5% chronic Grade 3 toxicity observed; there were no ⬎ Grade 3 toxicities. Conclusions: In the largest series of metastatic sarcoma to the spine to date, image-guided stereotactic radiosurgery provides excellent local control in the setting of an aggressive disease with low radiation sensitivity and poor prognosis. Single-fraction image-guided stereotactic radiosurgery demonstrates the highest rates of local control with minimal toxicity. Oncologic outcomes with IG-SRS. LC All patients HF SF OS All patients

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12 months

24 months

% (95% CI) 87.9% (81.3-94.5%) 84.1% (72.9-95.3%) 90.8% (83-98.6%)

% (95% CI) 77.4% (67.4-87.4%) 65.7% (46.7-84.7%) 85.2% (74.6-95.8%)

60.6% (49.6-71.6%)

39% (27.6-50.4%)


A randomized trial of single versus multiple fractions (Fx) for re-irradiation (RE-RT) of painful bone metastases (PBM): NCIC CTG SC.20. Presenting Author: Edward Chow, Odette Cancer Centre, Sunnybrook Health Sciences Centre; University of Toronto, Toronto, ON, Canada

A multicenter, randomized, double-blinded, placebo-controlled trial of modafinil for lung cancer-related fatigue: Dose response and patient satisfaction data. Presenting Author: Kate Fife, NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom

Background: The optimal RE-RT dose and fractionation schedule for PBM is uncertain. Methods: Patients (pts) with PBM after previous radiation (RT) to the same site were stratified by previous Fx schedule and pain response and randomized to 8 Gy in 1 Fx or 20 Gy in 5 Fx (8 Fx if previous RT was to spine/whole pelvis in multiple Fx). The primary endpoint was overall response rate (RR) at 2 months using the International Consensus schema (Chow 2002) which combines Brief Pain Inventory worst pain score and opioid analgesic use. We tested if 8Gy was non-inferior (NI), analyzed by intention to treat (ITT) and a per-protocol (PP) sensitivity analysis excluding those who were ineligible, inevaluable or received non-allocated therapy. Sample size was calculated using an expected RR of 70% with 20Gy and a NI margin of 10% (i.e. upper boundary of 1-sided 95% CI for the RR difference). Pts reported adverse events (AEs) by questionnaire on Day 14. Quality of life (QoL) was assessed using the EORTC QLQ C30. Results: Between 01/2004 and 06/2012, we enrolled 850 pts from 9 countries. Most common cancers were prostate (27%), breast (26%) and lung (22%). Before the 2 month assessment, 98 (11%) pts died. By ITT, the 2-month RR was available in 66% (557/850) and was 119/425 (28%) with 8Gy and 136/425 (32%) with 20Gy (P⫽0.2); the upper boundary of the 95% CI for RR difference ⫽ 9.2% and is less than the pre-specified NI margin. By PP analysis, 2-month RR was available in 521 and was 117/258 (45.3%) with 8Gy and 135/263 (51.3%) with 20Gy (P⫽0.17); the upper boundary of the 95% CI for RR difference ⫽ 13.2%, which exceeds 10% non-inferiority boundary. Day 14 AEs differing by treatment were: lack of appetite (P⫽0.01), vomiting (P⫽ 0.001), diarrhea (P⫽0.02) and skin reddening (P⫽0.002); all were worse with 20Gy. There were 30 vs 20 pathological fractures and 7 vs 2 spinal cord compressions with 8Gy and 20Gy, respectively (P⫽NS). No difference in QoL existed between arms. Conclusions: In pts with PBM receiving RE-RT, the 2-month RR obtained with 8Gy is non-inferior to 20 Gy when assessed by ITT but findings were not robust to a PP sensitivity analysis. When choosing between options tested, trade-offs exist between pain response and acute toxicity. Clinical trial information: NCT00080912.

Background: Fatigue is a very common, disabling symptom in cancer, and particularly severe in lung cancer. Modafinil is a novel central nervous system stimulant, which, along with methylphenidate, is cautiously recommended by the 2013 National Comprehensive Cancer Network Guidelines for fatigue. In this phase IV randomized placebo-controlled trial, we assessed the efficacy of modafinil for managing fatigue in lung cancer. Methods: Adults with locally advanced or metastatic non small cell lung cancer (stages III and IV), ECOG performance status (PS) 0-2 and suffering from fatigue (score 5/10 or greater) were randomised 1:1 to modafinil or matched placebo, 100mg daily for 14 days and 200mg daily for a further 14 days. The primary outcome measure was change in the Functional Assessment of Chronic Illness Therapy fatigue subscale (FACIT-fatigue) at 28 days. The trial was powered to detect a 5-point difference with 80% power and 5% significance allowing for 25% attrition. Dose-response, patient satisfaction and safety were also evaluated. Results: 208 patients were recruited from 24 UK centres. Baseline characteristics were wellbalanced. 160 patients completed both baseline and 28 day questionnaires and were included in the modified-ITT analysis. FACIT-fatigue mean change from baseline was modafinil⫽5.28, placebo⫽5.11, difference⫽0.17, (95%CI -4.17, 3.82). Adjustment for baseline fatigue and PS had no impact on outcome. No dose response was seen; the majority of improvement on all scales was seen at 14 days and sustained to 28 days. 47% of the modafinil group and 23% of the placebo group stated the study treatment was not helpful (p⫽0.132). Adverse events were equal. Conclusions: Both modafinil and placebo led to a clinically significant 5-point improvement in FACIT-fatigue score, but there was no significant difference between the two groups. This well-powered study suggests that there is a large placebo effect and NCCN guidelines should be reviewed. Clinical trial information: NCT00829322. FACIT-F score Baseline Day 14 Day 28

Modafinil (mean, [SD] N)

Placebo (mean, [SD] N)

24.64 [10.58] 104 30.58 [12.17] 88 31.28 [13.66] 75

24.98 [10.83] 103 29.43 [11.57] 90 30.66 [13.85] 85


576s 9504

Patient and Survivor Care Oral Abstract Session, Sun, 8:00 AM-11:00 AM

Losing sleep over cancer: Relationships with negative affect, blood pressure, and disease-free interval among women with metastatic breast cancer. Presenting Author: Arianna Aldridge Gerry, Stanford University, School of Medicine, Stanford, CA

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Phase II double-blind placebo-controlled study of armodafinil for brain radiation induced fatigue. Presenting Author: Edward G. Shaw, Wake Forest University, School of Medicine, Winston Salem, NC

Background: Few studies have examined how polysomnographic (PSG) measured sleep disturbance is associated with negative affect and markers of health status among women with metastatic breast cancer (MBC). Methods: 91 women with MBC (aged 57.9 ⫾ 7.3 yrs) and Karnofsky ratings of at least 70 were recruited. We used latent profile analysis to identify distinct patterns of in-lab sleep disturbance. These profiles were used to predict affect (measured by PANAS), blood pressure, and disease progression (disease free months before metastases). Results: Two classes of women emerged and were distinguished as “severely disturbed sleepers” (n ⫽ 24) or “mildly disturbed sleepers” (n ⫽ 67). Severely disturbed sleepers had worse quality of sleep (e.g., sleep efficiency⫽54% vs. 69%) and spent significantly and less time in slow wave and REM sleep. One-way ANOVA revealed that severely disturbed sleepers reported significantly more negative affect (p ⬍ .05). Specifically, they reported greater negative affect in the afternoon (2-3pm) and evening (6:30-7pm) prior to lab-sleep, and the morning (9:30-10:30am) and afternoon (12:30pm and 2pm) following lab-sleep. In addition, severely disturbed sleepers had higher systolic blood pressure (M⫽140 vs. M⫽124, p ⫽ .001) measured the afternoon prior to lab-sleep. Strikingly, women with severely disturbed sleep had significantly shorter disease free intervals (49 months vs. 80 months, p ⬍ .05), and worse Karnofsky ratings (p ⬍ .05) indicating worse medical prognosis than mildly disturbed sleepers. Conclusions: Women with MBC and severely disturbed sleep experienced more negative affect prior to and following a poor night’s sleep. In addition, they exhibited hypertension and accelerated cancer progression relative to women with mild sleep disruption. These detrimental changes may be an indication of the effects of chronic sleep disruption. Understanding the role of daily negative affect in conjunction with physiological markers of disease progression may inform better treatment methods for women with MBC experiencing severe sleep disruption.

Background: Armodafinil (ARM), the R-enantiomer of modafinil, is FDA approved for narcolepsy, shift work disorder, and treated sleep-apnea, and has also been shown to reduce fatigue/improve cognitive function in cancer patients. This phase II study estimated the efficacy and toxicity of ARM in primary brain tumor (PBT) patients receiving brain radiation therapy (RT) to determine whether a larger phase III study would be warranted. Methods: Eligibility criteria – adult, PBT, total RT dose ⬎45Gy, KPS⬎60, no severe headaches, and concurrent chemotherapy allowed. Patients were assessed at baseline, end of RT, then 4 weeks after end RT with the Brief Fatigue Inventory (BFI), Epworth Sleep Scale (ESS), FACT, and FACT brain and FACIT fatigue subscales. Patients were randomized to receive ARM 150mg/day during RT and for 4 weeks after RT or placebo (PLAC). Results: 54 patients enrolled between 9/10-12/12; 26 to ARM, 28 to placebo PLAC. Median age 59; 59% female; 95% White; 41% KPS 90-100, 59% KPS 60-80; 74% malignant glioma, 26% low-grade glioma/benign histology. 83% patients had concurrent chemotherapy. For all randomized patients, there were no statistically significant differences in outcome between ARM and PLAC groups at end-RT vs. baseline or 4 weeks post RT vs. baseline. For patients who had more baseline fatigue (fatigue subscale score ⬍median), ARM-treated patients had significantly/suggestively better outcomes at end-RT vs. baseline compared to PLAC-treated patients: less fatigue (BFI p⫽0.056, fatigue subscale p⫽0.0295), less sleepiness (ESS p⫽0.1034), and better QOL (FACT p⫽0.0001). Incidence of grade 2/3 toxicities was the same between the two treatment groups: 7% anxiety, 7% nausea, 18% headaches, and 20% insomnia. There were no grade 4 or 5 toxicities. Conclusions: In irradiated PBT patients, fatigue, sleepiness, and reduced QOL occurring at the end of brain RT was less with ARM in those patients who were more fatigued at baseline. Toxicity was minimal. These data support conducting a larger phase III study. Analysis of cognitive function data is ongoing. Support - NIH/NCI grant 2U10 CA 81851 and Teva Pharmaceuticals. Clinical trial information: 95709.

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Association of pro-inflammatory biomarkers and post-chemotherapy cognitive changes in Asian breast cancer patients: A prospective cohort study. Presenting Author: Yin Ting Cheung, National University of Singapore, Singapore, Singapore

The course of depression, inflammation in the serum and tumor microenvironment, and survival in the context of advanced cancer. Presenting Author: Jennifer Lynne Steel, University of Pittsburgh School of Medicine, Pittsburgh, PA

Background: Although existing evidence suggests that cytokines play an intermediary role in the development of post-chemotherapy cognitive changes, specific cytokines associated with this neurotoxic sequela of chemotherapy are still unknown. This study was designed to identify pro-inflammatory biomarkers that are associated with memory and attention impairment in Asian patients receiving chemotherapy. Methods: This is a prospective, cohort study conducted at the National Cancer Centre Singapore. Early-stage Asian breast cancer patients (Stage I to III), who received anthracycline and/or taxane-based chemotherapy were recruited. Computerized neuropsychological assessments (Headminder) were administered to evaluate patients’ memory and attention performances and a panel of pro-inflammatory plasma cytokines (IL-1␤, IL-2, IL-4, IL-6, IL-8, IL-10, GM-CSF, IFN-␥ and TNF-␣) was evaluated using multiplex immunoassay at three time points: prior to chemotherapy (T1), at midpoint (T2), and end of chemotherapy (T3). Memory and attention impairment were defined as a ⬎2.5 reduction of the Zscore from baseline, as calculated by the reliable change index for repeated cognitive measurements. Results: Thirty-six patients were included (mean age 49.7⫾9.0 years; 80.6% Chinese). Comparing to T1, 50.0% and 36.1% of the patients suffered memory and attention impairment at T3, respectively. Comparing patients with intact memory to those who suffered impairment from T2 to T3, they had higher levels of circulating IL-1␤ [median (IQR): 0.44 (0.1-0.5) vs 0.56 (0.4-0.7) pg/ml, p⫽0.069], IL-4 [0.41 (0.0-0.8) vs 0.85 (0.2-1.5) pg/ml, p⫽0.067) and TNF-␣ [1.78 (1.3-2.2) vs 3.01 (1.3-3.5) pg/ml, p⫽0.069]. At T3, reduction of attention scores were associated with higher levels of IL-1␤ (rs⫽ -0.37, p⫽0.023) and IL-6 (rs⫽ -0.33, p⫽0.045). No significant associations were identified with IL-2, IL-8, IL-10, GM-CSF and IFN-␥. Conclusions: These findings suggest that an increase in the postchemotherapy levels of TNF-␣, IL-1␤, IL-4 and IL-6 may have an association with the manifestations of memory and attention impairment in Asian breast cancer patients.

Background: The aims of the present study were to study the course of depression in patients diagnosed with cancer and the link with biomarkers of inflammation in the serum or tumor microenvironment and survival. Methods: A total of 474 patients diagnosed with advanced cancer were administered the Center for Epidemiological Studies-Depression (CES-D) scale every 2-months and blood samples were drawn to assess biomarkers of inflammation in the serum and tumor microenvironment. The course of depression was estimated using a semi-parametric trajectory analyses and cross-lagged panel analyses were performed to assess the link between depression and biomarkers of inflammation. Cox regression analysis was use to test the link between depression and survival while adjusting for demographic and disease specific factors. Results: A three-class solution was chosen based on Bayesian information criterion and theory. The first class, “not depressed,” with a mean CES-D score of 6.7 at baseline contained 32% of patients and no significant change in depression scores across time. The second class, “mildly depressed” (53% of sample) had a significant increase in the mean CES-D from 14.5 at baseline to 18.0 at 12 months and 20.0 at 16 months [B ⫽ .35, z ⫽ 3.12, p ⫽ .002]. The third class, “severely depressed,” with a mean of 31.5 at baseline (15% of patients) and no significant change win depression over 24 months. Depression predicted serum levels of Tumor Necrosis Factor (TNF)-alpha and Interleukin-1alpha at subsequent time points and was associated with High Mobility Group Box 1 in the tumor microenvironment. Trajectory group assignment significantly predicted survival after demographic and disease specific factors were adjusted (p⫽0.04). The non-depressed trajectory group had a median survival of 13 months (95%CI⫽8.9-17.1), the mildly depressed group median survival was 10 months (95% CI 7.1-12.9) and the severely depressed group median survival was 6 months (95% CI⫽7.6-12.4). Conclusions: These findings may facilitate the targeting of psychosocial and biological interventions to reduce depression symptoms, improve quality of life, and potentially slow disease progression.




Biomarker prediction of chemotherapy-related amenorrhea. Presenting Author: Kathryn Jean Ruddy, Dana-Farber Cancer Institute, Boston, MA Background: Chemotherapy-related amenorrhea (CRA) is associated with infertility and may impact treatment decision-making. We investigated whether anti-mullerian hormone (AMH) levels before chemotherapy predict likelihood of CRA. Methods: 591 patients enrolled on the quality of life substudy of ECOG5103, which randomized breast cancer patients to doxorubicin-cyclophosphamide followed by paclitaxel: 1) alone; 2) with concurrent bevacizumab; or 3) with prolonged bevacizumab. 144 of the 195 women who reported a period ⬍12 months before enrollment consented to serum collection prior to chemotherapy. AMH was measured in 143 with available serum. Participants self-reported menstrual frequency at 12 and 18 months after enrollment. 12-month CRA was defined as no menses for 6 months before the 12-month survey, and 18-month CRA as no menses for 6 months before the 18-month survey. Fisher’s exact test was used to identify associations with CRA. Results: Of the 143, 16 were excluded due to bilateral oophorectomy or initiation of ovarian function suppression within 12 months, and 2 due to missing data at 12 months. In the remaining 125, median age at enrollment was 45 (range 25-55). 103 (82%) had CRA at 12 months, including 68% of patients ⬍/⫽ 45 (43/63) and 97% of patients ⬎45 (60/62). Median pre-chemotherapy AMH was 0.11 (range 0.01-8.63). 12-month CRA was more likely in women who received bevacizumab (p⬍0.01), were ⬎45 (p⬍0.01), and had AMH ⬍/⫽0.11 (p⬍0.01) pre-treatment. Hormonal tx was not associated with 12-month CRA (p⫽0.63). 100 patients were eligible for 18-month CRA analysis: 81 (81%) had CRA, including 63% of patients ⬍/⫽ 45 (33/52) and 100% (48/48) of patients ⬎45. 18-month CRA was more likely in women ⬎45 (p⬍0.01) and with AMH ⬍/⫽0.11 (p⬍0.01) pre-treatment. Bevacizumab (p⫽0.15) and hormonal tx (p⫽0.07) were not statistically significant predictors of 18-month CRA. Conclusions: Pre-chemotherapy AMH predicts risk of CRA at 12 and 18 months, and is a promising biomarker of ovarian reserve in young breast cancer survivors. Longer studies will be needed to ascertain whether lower pre-treatment AMH is associated with increased risk of later infertility. Clinical trial information: NCT00433511.

9510


Baseline cognitive functions among elderly patients with localized breast cancer. Presenting Author: Florence Joly, GINECO/Centre François Baclesse, Caen, France Background: Cognitive deficits (CD) were reported among patients receiving chemotherapy (CT) for cancer, but could also be observed before treatment. Elderly patients were poorly studied although they are more prone to present age-related CD and CD onset or enhancement during CT. This study assessed baseline cognitive functions among elderly localized breast cancer (LBC) patients before adjuvant treatment therapy. Methods: Episodic memory, working memory, executive functions and information processing speed were assessed with neuropsychological tests. Validated questionnaires were used to assess subjective CD, anxiety, depression and fatigue before adjuvant treatment. Geriatric assessment was also realized. Objective CD were defined as a score less than 1.5 standard deviation (SD) of normative data on ⬎2 tests, or less than two SDs on ⬎1 test. Significant subjective CD (evaluated by the FACT-Cog) were defined when the 4 subscales below the first tercile distribution. Results: Results concern 123 elderly LBC (71⫾4 years): planned treatment included CT and radiotherapy (RT) for 61 patients and RT only for 62 patients. Characteristics are as follows: mastectomy (28%), stage (I: 60%, II: 27%, III: 13%), positive hormonal receptor (88%) and positive Her2 (17%). Before any adjuvant treatment, objective CD were observed in 40% of patients (46% in CT group, episodic memory mainly impaired and 37% in RT group, executive functions and information processing speed mainly impaired). No relation was observed between cancer stage, geriatric frailty and objective CD. Twenty nine percents of patients presented fatigue, 6% anxiety and 10% depression. These variables were not related to objective CD but they were related to subjective CD. Conclusions: More than 40% of elderly LBC patients presented objective CD before any adjuvant therapy that is higher than observed among younger patients. It is important to take account in the decision making of adjuvant treatment in elderly patients. Clinical trial information: NCT01333735.

9509

577s Clinical Science Symposium, Mon, 1:15 PM-2:45 PM

Do elderly patients benefit from enrollment in phase I clinical trials? Presenting Author: Wai Meng David Tai, National Cancer Center Singapore, Singapore, Singapore Background: Despite the significant burden of cancer in the older population, their outcomes in the context of phase I studies have been poorly studied. We evaluated the clinical characteristics and outcomes of elderly pts enrolled in phase 1 clinical trials in our centre and evaluate the performance of Royal Marsden Hospital (RMH) prognostic score (albumin, LDH, no of met sites) in this pt population. Methods: 296 consecutive pts who were treated in 20 phase 1 trials from 2005-2012 in our unit were analysed. Clinical characteristics and outcomes between young pts (⬍65, n⫽202) and older pts (ⱖ65, n⫽94) were compared. Results: The median age of the older pts was 69 (65-84), 71% were males. 51% of the pts received chemotherapy based treatment with or w/out biological agents. 61% of the pts had lung cancers and 32% had gastrointestinal cancers. 52% of pts had ⱖ2 co-morbidities. After median follow up of 7.5 mths (0.36-50.6 mths), the median progression free survival (PFS) and overall survival (OS) were 5.8 and 8.8 mths respectively. Although elderly pts had more co-morbidities and lower albumin levels at baseline, there was no significant difference in survival (8.8 vs 9.9 mths), p⫽0.68) compared to younger pts. The prognostic factors for OS identified in multivariate analysis were prior lines of chemotherapy (0-2 vs ⱖ3), baseline sodium levels (ⱖ135 vs ⬍135mmol/L) and platelet levels (ⱕ400 vs ⬎400⫻10⁹). We developed a risk nomogram based on the factors identified prognostic of OS with concordance(c)-index of 0.65. RMH score (2-3 vs 0-1) predicted for OS with hazard ratio of 2.1, p⫽0.03 and c- index of 0.63. 26% of elderly pts experienced grade 3/4 toxicities in the first cycle of treatment. Common grade 3/4 toxicities were dermatological (25%), haematological (17%) and gastrointestinal (13%). Both age of pts (p⫽0.70) and dose levels (p⫽0.18) did not have any bearing on occurrence of grade 3/4 toxicities. Conclusions: Elderly pts (ⱖ65) enrolled into phase 1 clinical trials had similar survival outcomes and toxicity profiles compared to younger pts. Risk scoring models to aid patient selection need further clarification in this population.

9511


Predictive factors for chemotherapy feasibility in elderly patients with solid tumor: Results of GERCOR old prospective multicenter study. Presenting Author: Elisabeth Carola, Groupe Hospitalier Public Sud Oise, Senlis, France Background: One quarter of patients with cancer are 75 year old and over. Previous studies suggested that geriatric parameters improved survival in elderly patients with solid advanced cancer and chemotherapy severe toxicity. A simplified scale would be helpful for oncologist to predict chemotherapy feasibility. The aim was to identify geriatric predictors of chemotherapy feasibility in chemo-naïve elderly patients. Methods: We conducted a prospective multicenter cohort study (NCT00664911). Inclusion criteria were: ⱖ 75 years, solid tumor, able to receive at least 2/3 of the standard dose at the first course of treatment. Ten geriatric parameters were recorded at baseline by the oncologist: 1-three words test, 2-date and address for cognitive function, 3-Instrumental Activities of Daily Living (IADL), 4- monopodal stand-up test, 5-hospitalization during the previous year, 6-number of medicines taken for comorbidities, 7-creatinine clearance, 8-albumin serum level, 9-self-rated depressive mood question and 10-presence of a caregiver. The main outcome was chemotherapy feasibility defined by the ability to receive at least 3 months of the planned therapy. Multivariate logistic regression was used. Results: 576 patients were included in 49 centers from 2008 to 2012, 516 (89.6%) were eligible for analysis. Mean age was 81 years, 50.6% had colorectal cancer, 69.5% advanced stage and 83.6% had performance status 0-1. Chemotherapy feasibility was observed in 298 (57.8%) patients. Grade 3-4 toxicity was observed in 26.2% of patients. In multivariate analysis albuminemia ⬍ 30g/l (adjusted OR ⫽2.34 CI95% [1.43-3.83]) and depressive mood (adjusted OR⫽1.55 CI95% [1.02-2.35]) were significantly associated with chemotherapy unfeasibility whereas others geriatrics parameters were not. Conclusions: Albuminemia and self rated depressive mood status were independently predictive for chemotherapy feasibility in elderly patients with solid tumor. Unexpectedly others geriatrics parameters were not independent predictors. Clinical trial information: NCT00664911.


578s 9512

Patient and Survivor Care Poster Discussion Session (Board #1), Sat, 1:15 PM-5:15 PM and 4:45 PM-5:45 PM

Efficacy of NEPA, a novel combination of netupitant (NETU) and palonosetron (PALO), for prevention of chemotherapy-induced nausea and vomiting (CINV) following highly emetogenic chemotherapy (HEC). Presenting Author: Paul Joseph Hesketh, Lahey Hospital & Medical Center, Burlington, MA Background: Further progress in preventing CINV will require the introduction of novel agents providing maximal convenience and with efficacy for nausea as well as vomiting. NEPA is a single dose combination of NETU, a novel NK1 receptor antagonist (RA) and PALO, a pharmacologically distinct 5-HT3RA. This study was designed to determine the proper dose of NETU to combine with PALO. Methods: This was a randomized, double-blind, parallel group study in chemotherapy-naïve patients (pts) undergoing cisplatin-based HEC. Four study arms compared 3 oral doses of NEPA (NETU 100, 200, 300mg ⫹ PALO 0.50 mg) with oral PALO 0.50 mg, all given on day 1. All pts received oral dexamethasone (DEX) days 1-4. An exploratory aprepitant (APREP) ⫹ ondansetron/DEX arm was included. The primary endpoint was complete response (CR: no emesis, no rescue) in the overall (0-120h) phase. Results: 694 pts were enrolled with comparable characteristics across groups: males (57%), median age 55. Common cancers: lung (27%), head and neck (21%). Median cisplatin dose: 75 mg/m2. All NEPA groups showed superior CR rates compared with PALO during the overall and delayed phases, with NEPA300also superior to PALO during the acute phase. NEPA300was also superior to PALO during all phases for no emesis, no significant nausea and complete protection with incremental benefits over lower NEPA doses. AEs were comparable across groups with no dose-response. The % of pts developing ECG changes was comparable across groups. Conclusions: Each NEPA dose resulted in superior CR rates compared with PALO. NEPA300was the best dose studied, with an advantage over lower doses for all efficacy endpoints (including nausea). NEPA doses were well tolerated with similar safety profiles to PALO and APREP. NEPA combined with DEX is superior to PALO plus DEX in prevention of CINV following HEC. CR rates (% pts) PALO NEPA100 NEPA200 NEPA300 p value* (Nⴝ136) (Nⴝ135) (Nⴝ137) (Nⴝ135) Overall (0-120h)

76.5

Acute (0-24h)

89.7

Delayed (25-120h)

80.1

87.4 0.018 93.3 0.278 90.4 0.018

87.6 0.017 92.7 0.383 91.2 0.010

89.6 0.004 98.5 0.007 90.4 0.018

* p value: logistic regression adjusted for gender.

LBA9514


Phase III study of NEPA, a fixed-dose combination of netupitant (NETU) and palonosetron (PALO), versus PALO for prevention of chemotherapyinduced nausea and vomiting (CINV) following moderately emetogenic chemotherapy (MEC). Presenting Author: Matti S. Aapro, Clinique de Genolier, Genolier, Switzerland


9513


Does gabapentin prevent delayed chemotherapy-induced nausea and vomiting (N/V)? Results of a randomized placebo controlled trial, NCCTG N08C3 (Alliance). Presenting Author: Debra L. Barton, Mayo Clinic, Rochester, MN Background: The need for more research in N/V control is exemplified by agents that are costly, interfere with cytochrome P450 metabolism, and inadequately address delayed N/V. Based on pilot data, there was justification for evaluating whether gabapentin could improve the prevention of delayed N/V from highly emetogenic chemotherapy (HEC). Methods: Patients (pts) about to receive HEC were randomized to prophylactic treatment with 20 mg of dexamethasone (dex) and a 5HT3 receptor antagonist (RA) on the day of chemotherapy, followed by either gabapentin (gaba) 300 mg BID and dex or placebo (plac) and dex. Gaba/plac was started the evening of the day of chemotherapy and continued through day 5 of the first chemotherapy cycle. Dex was given at 8 mg BID days 2-3, then 4 mg BID for day 4, in both arms. The primary endpoint was complete response (CR), defined as no emesis and no rescue medications day 2-6, using a nausea and vomiting diary. The percent of CR were compared in each group by Fisher’s exact test. Secondary outcomes included the Functional Living Index-Emesis (FLIE), satisfaction, and a side effect questionnaire. Results: 430 pts were enrolled in this study between 5/2009 and 2/2011. 47% of pts in the gaba arm and 41% in the plac arm had a CR (p⫽.23). At some time during days 2-6, 30% in the gaba and plac arms experienced emesis, and 45% and 53% in the gaba and plac arms, respectively, took rescue medication. Mean diary nausea scores over days 2-6 ranged from 0.9 – 1.2 (gaba arm) and 1.0-1.3 (plac arm)(7 ⫽ the worst); mean number of diary emetic episodes ranged from 0.1 -0.3 (gaba arm) and 0.1-0.2 (plac arm). The FLIE was not significantly different between arms. Mean vomiting satisfaction was 9.1 in both arms and for nausea was 8.3 for gaba, 8.1 for plac (10⫽ totally satisfied). There were no significant differences in toxicities by CTCAE provider grading or by self-report. Conclusions: In this study, gaba did not improve delayed N/V. Overall, there was little emesis and nausea severity was low. Patients were satisfied with the control of their N/V, irrespective of arm. The use of standard prophylactic guidelines that include a 5HT3RA and dex provided good control of N/V for most patients. Clinical trial information: NCT00880191.

9515


Effect of renal function (RF) on outcomes in the adjuvant treatment of older women with breast cancer (>65 years): CALGB/CTSU 49907 (CC) ancillary data study. Presenting Author: Stuart M. Lichtman, Memorial SloanKettering Cancer Center, New York, NY Background: CC 49907 showed superiority of standard therapy (cyclophosphamide/doxorubicin [AC] or cyclophosphamide/methotrexate/5-fluorouracil [CMF]) over capecitabine[C]. Dose adjustments made for renal insufficiency (RI) for methotrexate and C; ideal body weight used. Purpose was to analyze the relationship between RF at baseline and 5 endpoints: toxicity, dose modification, therapy completion, relapse-free survival [RFS] and overall survival [OS]. Methods: Pre-treatment RF was calculated (Cockcroft-Gault). Endpoints assessed by regimen. RF was tested as a dichotomous and continuous variable of stages 1,2 vs. 3,4 kidney disease (National Kidney Foundation). Logistic regression modeled the relationship between renal stage and the first three endpoints of toxicity, dose modification and therapy completion. Toxicity divided by hematologic or not. The relationship of RFS and OS with RF was assessed with the logrank test and as a continuous variable with Wald chi square. Results: 619 patients; incidence of stage 3/4 RI(⬍60 ml/min) was: CMF⫽72%; AC⫽64%; C⫽75%. With AC the incidence of toxicity differed by renal function. 31% of patients with poorer function ⬎grade 3 non-hematologic toxicity vs. 14% with better function(p⫽0.011). There was a suggestion of effect of RF on OS and RFS for C-treated patients. RF was not associated with dose modification, premature therapy termination, RFS or OS for the CMF-treated patients. Conclusions: 1) AC: declining RF was associated with increased non-hematologic toxicity. 2)Patients with RI who received dose modifications were not at increased risk for complications in comparison to those who did not have renal insufficiency and received full dose. 3)Declining RF did not affect therapy completion. 4)C: suggestion that worse RF was related to poorer RFS or OS. 5)Exclusion of patients from clinical trials with RI based on concern of excessive hematologic toxicity may not be justified with appropriate modification. 6)Results should be considered in the design of clinical trials for older patients.




9517


Predicting fitness for chemotherapy in older cancer patients. Presenting Author: Damien B. Thomson, Princess Alexandra Hospital, Woolloongabba, Australia

The role of age on dose-limiting toxicities (DLTs) in phase I dose-escalation trials. Presenting Author: Anita Schwandt, Case Western Reserve University School of Medicine, Cleveland, OH

Background: The Vulnerable Elders Survey-13 (VES-13) is increasingly used to screen for older patients who can proceed to intensive chemotherapy without further comprehensive assessment. This study compared the VES-13 determination of fitness for treatment with the oncologist’s assessments of fitness. Methods: Sample: Consecutive series of solid tumour patients ⱖ65 years (n⫽175; M⫽72; range⫽65-86) from an Australian cancer centre. Patients were screened with the VES-13 before proceeding to usual treatment. Blinded to screening, oncologists concurrently predicted patient fitness for chemotherapy. A sample of 175 can detect, with 90% power, kappa coefficients of agreement between VES-13 & oncologists’ assessments ⬎0.90 (⬙almost perfect agreement⬙). Separate backward stepwise logistic regression analyses assessed potential predictors of VES-13 & oncologists’ ratings of fitness. Results: Kappa coefficient for agreement between VES-13 & oncologists’ ratings of fitness was 0.41 (p⬍0.001). VES-13 & oncologists’ assessments agreed in 71% of ratings. VES-13 sensitivity ⫽ 83.3%; specificity ⫽ 57%; positive predictive value ⫽ 69%; negative predictive value ⫽ 75%. Logistic regression modelling indicated that the odds of being vulnerable to chemotherapy (VES-13) increased with increasing depression (OR⫽1.42; 95% CI: 1.18, 1.71) & decreased with increased functional independence assessed on the Bartel Index (OR⫽0.82; CI: 0.74, 0.92) & Lawton instrumental activities of daily living (OR⫽0.44; CI: 0.30, 0.65); RSquare⫽.65. Similarly, the odds of a patient being vulnerable to chemotherapy, when assessed by physicians, increased with increasing age (OR⫽1.15; CI: 1.07, 1.23) & depression (OR⫽1.23; CI: 1.06, 1.43), & decreased with increasing functional independence (OR⫽0.91; CI: 0.85, 0.98); RSquare⫽.32. Conclusions: Our data indicate moderate agreement between VES-13 & clinician assessments of patients’ fitness for chemotherapy. Current ‘one-step’ screening processes to determine fitness have limits. Nonetheless, screening tools do have the potential for modification & enhanced predictive properties in cancer care by adding relevant items, thus enabling fit patients to be immediately referred for chemotherapy.

Background: Elderly oncology patients are not enrolled on phase I trials in proportion to the prevalence of cancer in the age-matched population. They are excluded from these trials based on the perception that these patients will have an increased number of and more severe toxicities, per dose level, than younger patients. We hypothesize that if other patient characteristics are accounted for, then age will not be an independent predictor of dose limiting toxicities (DLTs). Methods: We retrospectively reviewed data from 162 single- agent dose-escalation phase I clinical trials performed at the Cancer Therapy Evaluation Program/National Cancer Institute. Several baseline patient characteristics, including age, were collected. Patient dose levels were described as %MTD and an analysis of age, dose and DLTs was performed. Results: Data was obtained from 5,401 patients who were divided into five age groups, with 556 pts ⬍ 40 years old, 2,438 between 40-59, 1,481 between 60-69, 836 between 70-79 and 90 pts ⬎ 79. Proportion of DLT occurring in each age group and %MTD are described in the Table. Conclusions: This analysis of DLTs occurring in nearly 1000 patients over 70 years of age on phase I dose-escalation trials is the largest reported. A logistic regression model will be performed to determine if age, by itself, predicts for DLTs and what concurrent patient characteristics contribute to their occurrence.

9518


Proportion of patients with DLT in each dose level of %MTD in each age group. Dose level as % MTD 100% Total n

9519

Age79 prop (n)

DLT proportion per dose level

Total pts

.045 (44) .024 (85) .062 (306) .066 (121) 556

.026 (265) .053 (356) .061(1254) .122 (563) 2,438

.013 (153) .053 (225) .079 (793) .017 (310) 1,481

.024 (82) .067 (135) .076 (423) .122 (196) 836

.011 (8) 0 (11) .1 (51) .011 (20) 90

.1 .15 .52 .23 -

552 812 2,827 1,210 5,401


Intensity of palliative care and its impact on the aggressiveness of end-of-life care in patients with advanced pancreatic cancer. Presenting Author: Raymond Woo-Jun Jang, University of Toronto, Princess Margaret Hospital, Toronto, ON, Canada

Outcomes of prognostic disclosure: Effects on advanced cancer patients’ prognostic understanding, mental health, and relationship with their oncologist. Presenting Author: Andrea Catherine Enzinger, Dana-Farber Cancer Institute, Boston, MA

Background: Quality indicators have been developed to avoid overly aggressive care in patients with advanced cancer. Specialized palliative care (PC) may reduce overly aggressive care in patients with advanced pancreatic cancer. Our objective was to examine the impact of the intensity of specialized PC (defined as a physician consultation focusing on PC needs, lasting at least 40 minutes) on (a) use of chemotherapy within 14 days of death; (b) more than one emergency department (ED) visit; (c) more than one hospitalization; and (d) at least one intensive care unit (ICU) admission, all within 30 days of death. Methods: A retrospective population-based cohort study using linked administrative databases in Ontario, Canada was conducted with patients diagnosed with advanced pancreatic cancer from Jan 1 2005 to Dec 31 2010. Multivariable logistic regression analyses were performed with the above quality indicators as the outcomes of interest and the intensity of PC visits as the exposure, adjusting for other variables (age, sex, comorbidity, rurality, and health region). Intensity of PC was defined in both absolute numbers (ie 0, 1, 2, 3⫹ visits) and rate of visits per month. Results: Of 6076 patients with advanced pancreatic cancer, 5381 had died at last followup. 2816 (52%) received a PC consultation, 218 (4%) received chemotherapy near death, 234 (4%) patients went to the ICU near death, 993 (18%) had multiple ED visits near death, and 447 (8%) had multiple hospitalizations near death. 2565 (48%) had 0 PC visits, 513 (10%) had 1, 555 (10%) had 2, and 1748 (32%) had 3 or more. In multivariable analyses, having had one PC consultation was associated with a lower odds of ICU admission near death (odds ratio (OR) 0.25; 95% CI 0.13-0.46), multiple ED visits near death (OR 0.44; 95% CI 0.33-0.58), and multiple hospitalizations near death (OR 0.47; 95% CI 0.33-0.69). Two PC visits were associated with a lower OR for chemotherapy near death (OR 0.26; 95% CI 0.14-0.51). Using the monthly PC visit rate, a higher rate was associated with less aggressive care for each outcome. Conclusions: In patients with advanced pancreatic cancer, more intensive PC involvement is associated with less frequent overly aggressive care.

Background: Many oncologists are reluctant to discuss life expectancy with advanced cancer patients. We examined the frequency of prognostic disclosure and its impact on patients’ prognostic understanding, the patient-doctor relationship, and psychological distress. Methods: Coping with Cancer was an NCI-funded, multi-site prospective cohort of 726 patients with advanced incurable cancer, enrolled 2002-2008. At baseline, patients were asked if their oncologist had ever discussed prognosis, and if so what estimate was communicated. Patients also estimated their prognosis. The therapeutic alliance scale measured patient-doctor relationship, and the McGill QOL instrument assessed symptoms of depression and anxiety. Multivariable analyses (MVA) assessed relationships between prognostic disclosure and psychological symptoms, controlling for confounds. Results: Among this cohort of terminally ill patients (median survival 4mos), most (72%) wanted to be told their life expectancy. Only 19.8% (104/525) of patients had received a prognostic estimate from their oncologist (median estimate 6mos; IQR 6-15mos). When queried about factors informing their prognostic understanding, 85.9% of patients cited personal or religious beliefs; only 11.7% cited a physician’s estimate. Of the 299 patients willing to estimate their life expectancy, patients who had been previously informed of their prognosis were substantially more realistic in their own estimate (median 12mos v 48mos, Wilcoxon test p⬍0.001). Moreover, patients’ and oncologists’ prognostic estimates were significantly correlated (␳⫽0.49, p⬍0.001). Prognostic disclosure was not associated with poor patient-doctor relationship rating (Fisher’s Exact, p⫽0.625), nor was it associated with depressive symptoms (␤ 0.06, p⫽0.242) or anxiety (␤ 0.06, p⫽0.234) in MVA. Conclusions: Few advanced cancer patients are informed of their life expectancy, although most want this information. Prognostic disclosure is associated with substantial improvement in patients’ prognostic understanding, without compromising the patient-doctor relationship or increasing psychological distress.


580s 9520


Prognostic information (PI), psychological well-being, and quality of life for advanced cancer patients (ACP) in phase I trials and their spousal caregivers (SC). Presenting Author: Fay J. Hlubocky, The University of Chicago Medicine, Chicago, IL Background: The impact of the physician’s (MD) disclosure of PI on the psychological well-being and quality of life (QoL) of clinical trial subjects with terminal disease on Phase I trials has not been formally evaluated. Methods: A prospective cohort of ACP enrolling in phase I trials was assessed at baseline (T1) and one month (T2) utilizing various measures including: state-trait anxiety (STAI-S/T), depression (CES-D), quality of life/QoL (FACIT-Pal), and global health (SF-36). Semi-structured interviews of ACPs also evaluated MD-Pt communication re prognosis and worry about ACP death. Results: 100 subjects (50 Phase I ACPs and 50 SC) were separately interviewed at T1 and T2. For the population as a whole: median age 62 (28-78y); 51% male; 100% married; 88% Ca; 68% ⬎ HS educ; 56% GI dx; 54% income ⬍$65,000 yr. At T1, 45% of ACPs acknowledged having a discussion re life expectancy with MD; 35% stated the MD gave a prognostic timeframe; and 41% reported worry re death. For SC at T1, 62% recalled a prognosis discussion with the MD; 50% stated MD gave a timeframe; 53% reported PI disclosure was initiated by the MD; 66% reported worry re ACP death. At T2, rates remained consistent for both ACP and SC with the exception of increased reported worry re ACP death at 55% and 70% respectively. At T2, ACP who denied a prognosis was given by the MD had higher STAI-S (35 ⫾ 10 v 29 ⫾ 9, p⫽0.03) and CES-D scores (16 ⫾ 12 v 7 ⫾ 4, p⫽0.01); and lower FACT-Pal scores (128 ⫾ 18 v 153 ⫾ 24, p⫽0.01). SC with acknowledgement of a prognostic timeframe given by the MD had higher STAI-S anxiety (39 ⫾ 16 v 35 ⫾ 14, p⫽0.04) at T2. Regression analyses revealed that ACP with acknowledgement of a prognostic timeframe given by the MD had poorer FACIT-Pal QoL over time. Also, SC with acknowledgement of a prognostic timeframe at T2 was negatively associated with SF-36 scores. ACP and SC qualitative responses re PI disclosure revealed salient themes: hope for a positive outcome or prolonged survival; stabilization of disease; emotional distress; ambivalence/ fear; acceptance. Conclusions: Physician disclosure of a prognostic timeframe is negatively associated with QoL among clinical trial subjects and SC in phase I trials.

9522


9521


Patients’ perceptions of caregivers’ preference for comfort care at the EOL: Impact on DNR completion. Presenting Author: Kalen Michele Fletcher, Dana-Farber Cancer Institute, Boston, MA Background: Research has shown that informal caregivers provide substantial psychosocial and material support to advanced cancer patients. Few studies have examined how family caregivers influence patients’ advance care planning. Here we test whether patients’ perceptions of their caregivers’ preference for comfort (vs. life-extending) end-of-life (EOL) care is associated with DNR order completion. We also evaluated whether caregivers’ actual agreement with patients on preference for comfort EOL care was associated with their rates of DNR order completion. Methods: Coping with Cancer II is an NCI –funded, multi-site, prospective cohort study of patients with advanced cancer and their informal family caregivers. Patients are interviewed after receiving restaging scan results and asked if they would prefer a plan of EOL care focused on life-extension or one focused on relieving pain. Patients are also asked what type of EOL care they think their family caregivers would prefer for them and whether or not a DNR order has been completed for them. Caregivers are interviewed separately after patients receive restaging scan results and asked what type of EOL care they would want for the patient. Results: Based on patient data alone (N⫽72), patients who preferred comfort care at the EOL and who believe that their family caregiver agrees with them on this were significantly more likely than others to report DNR order completion (OR⫽3.67, p⫽0.013). Based on data from both patients and caregivers, patients’ perception of agreement with their caregivers on desire for comfort EOL care was more strongly associated with patients’ reports of DNR completion (rs⫽0.51, p⫽0.004) than was actual agreement with their caregivers on desire for comfort EOL care (rs⫽0.36, p⫽0.045). Conclusions: Patients who prefer comfort care to life-extending care at the EOL, and who think that their caregivers also want them to pursue comfort care, are more likely to have a DNR order completed. Interestingly, patients’ perception of this agreement had a stronger influence on DNR completion than the caregivers’ actual agreement with patients’ preference for comfort EOL care. DNR completion is influenced by patients’ perceptions of family support.

9523


Caregivers’ perception of advanced cancer patients’ quality of death: Impact on caregiver suicidal ideation in bereavement. Presenting Author: Caroline H Abbott, Dana-Farber Cancer Institute, Boston, MA

End-of-life care for Medicare beneficiaries with ovarian cancer: Evaluation of intensity and rate of hospitalizations. Presenting Author: Alexi A. Wright, Dana-Farber Cancer Institute, Boston, MA

Background: Evidence suggests that patients’ quality of life (QOL) at the end of life (EOL), i.e., patients’ quality of death, may affect the health and well-being of informal family caregivers. Here we examine the relationship between family caregivers’ perception of patients’ QOL at the EOL and caregiver suicidal ideation in bereavement. Methods: Our analysis was based on data from a sub-sample of family caregivers (N⫽112) from the Coping with Cancer Study, an NCI-funded multicenter prospective cohort investigation of advanced cancer patients and their caregivers enrolled September 2002 – February 2008. Caregiver baseline suicidal ideation was assessed using the Yale Evaluation of Suicidality (YES) Scale a median of 4.1 months pre-loss; caregivers’ perception of patients’ overall distress in the last week of life was assessed a median of 1.9 months post-loss; and caregiver suicidal ideation in bereavement was assessed using the YES a median of 6.5 months post-loss. Suicidal ideation was defined as a positive screen on the YES. Multiple logistic regression analysis examined the effect of caregivers’ perception of patients’ quality of death on bereaved caregiver suicidal ideation, adjusting for caregivers’ baseline suicidal ideation and potential demographic confounds. Results: Caregivers’ perception of patients’ overall distress at the EOL was significantly related to caregivers’ suicidal ideation post-loss (AOR⫽1.26, p⫽0.022) adjusting for caregivers’ baseline suicidal ideation, relationship to patient, and years of education. Conclusions: The more caregivers’ perceive their loved ones’ quality of death to be poor, the more they are at risk for suicidal ideation in bereavement. Improving QOL at the EOL will not only benefit patients but also protect caregivers from suicidal ideation.

Background: Patients with advanced cancer are receiving increasingly aggressive medical care at the end-of-life (EOL). Population-based studies have not examined the medical care that ovarian cancer patients receive near death. Methods: We identified a national cohort of 6,956 Medicare beneficiaries who were living in Surveillance, Epidemiology, and End Results (SEER) areas, were diagnosed with epithelial ovarian cancer between 1996 and 2007, and died from ovarian cancer by December 2007. Using multivariable models, we examined rates of aggressive medical care within 30 days of death over time and examined indications for hospitalizations near death. Results: Adjusted rates of intensive care unit (ICU) admissions and emergency department (ED) visits increased significantly between 1996 and 2007 (ICU: 6.4% to 16.6%, p⬍0.0001 and ⱖ2 ED visits: 19.7% to 32.1%, p⬍0.0001). In contrast, late (within 7 days death) or absent hospice referrals decreased (63.1% to 47.8%, p⬍0.001) and chemotherapy use within 30 days of death decreased slightly (8.1% vs. 7.1%; p⫽0.04). Although terminal hospitalizations decreased (28.0% to 19.1%, p⫽0.001), rates of hospitalizations near death increased over time (41.4% vs. 45.3%, p⫽0.01). The most common indications for hospitalization included: bowel obstructions (20.0%), infections (10.4%), fluid or electrolyte abnormalities (9.2%), and malignant effusions (8.1%). Conclusions: Despite significant increases in the use of hospice near death, utilization of ICUs, EDs, and acute inpatient care at the EOL rose significantly between 1997 and 2007 for older ovarian cancer patients. Future studies should examine whether this high-intensity health care is avoidable given evidence that high-intensity care is associated with lower patient quality-of-life near death and increased complications in bereaved caregivers.




Prospective study of vaginal dilator use adherence and efficacy following pelvic and intravaginal radiotherapy. Presenting Author: Ethel B Law, Memorial Sloan-Kettering Cancer Center, New York, NY

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Preliminary results of RTOG 0831, a randomized, double-blinded, placebocontrolled trial of tadalafil in the prevention of erectile dysfunction in patients treated with radiotherapy for prostate cancer. Presenting Author: Deborah Bruner, Nell Hodgson Woodruff School of Nursing, Emory University, Atlanta, GA

Background: Vaginal stenosis (VS) as a late effect of pelvic radiotherapy (RT) and intravaginal brachytherapy (IVB) can impair long-term quality of life. The best care guideline for post-treatment 3x/week vaginal dilator (VD) use is based on limited research. This prospective study aimed to determine adherence and efficacy of VD use as measured by ability to return to pre-RT VD size at 12 months (mos). Methods: From 2009-2011, women with rectal (n⫽28), anal (n⫽35), endometrial (n⫽ 45) and cervical (n⫽1) cancers were followed for one-year post-radiation therapy (RT). Clinicians provided structured teaching to use dilators 3x/week, regardless of frequency of sexual intercourse. For 12 mos, patients self-reported dilator size and vaginal symptoms in monthly diaries. At pre-RT, 1, 6 and 12 mos post-RT, clinicians graded VS using CTCAE v3. Adherence was measured as the percentage of times patients used the dilator out of the number of times they were instructed (3x/week X 52 weeks⫽156). Fisher’s exact and Kruskal-Wallis tests were used to assess differences among groups. Results: Among 109 participants, aged 28-81 years (median ⫽ 58), mean adherence with VD use over a 12 mos period was 42% (sd 34%, 95% Cl:36%- 49%). Adherence was highest in the first quarter (58%), but fell to 25% by the fourth quarter. Disease type, treatment sequence and chemotherapy were predictors of adherence (all p⬍0.05). Rectal cancer patients were less likely to adhere to dilator use than anal and endometrial patients. 82% of all patients returned to pre-RT size at 12 mos; of the 49% who reported a decrease in dilator size from pre-RT to 1 month post-RT, 71% were able to return to pre-RT size at 12 mos. Anal cancer patients were most likely to report a decrease in VD size at 1 mo post-RT (77%), but 68% of these patients were able to return to baseline at 12 mos. Disease type and greater adherence to VD use at 6 months were associated with returning to pre-RT size at 12mos (both p ⬍0.05). Conclusions: Based on this prospective study, VD use is an effective strategy in minimizing VS, but adherence at 12 mos was poor. Future studies are needed to evaluate methods of improving adherence with VD use and to determine the optimal frequency and duration of VD use.

Background: Determine if prophylactic tadalafil maintains spontaneous (off-drug) erectile function (EF) compared to placebo in patients (pts) treated with radiotherapy (RT) for prostate cancer. Methods: Double-blind 1:1 randomization to tadalafil 5mg daily for 6 mos vs placebo starting with RT. Primary outcomes measured by International Index of Erectile Function (IIEF). Eligibility included pre-RT IIEF Question [Q] 1 response “sometimes/ most times/always” able to get an erection. Ps treated with hormones were excluded. Primary outcome was response to IIEF Q1 at 30 wks (6 wks off drug). Pts were stratified by RT modality (external vs. brachytherapy) and age (ⱕ65 vs. ⬎65 years). 182 pts were needed in an intent-to-treat analysis to show a difference from 20% responders with placebo to 40% with tadalafil based on a 2-sided Fishers exact test with ␣⫽0.05 and 80% power. Results: We report on 155/222 analyzable/eligible pts. Median age was 63 years, white (73%), and external RT (63%). Mean total dose for external RT was 77.23 Gy and 136.74 Gy for brachytherapy with penile bulb D50 of 24.46 Gy and 31.24 Gy respectively. Most pts completed treatment per protocol (84% tadalafil, 70% placebo). Spontaneous EF at 30 wks from drug start was not different (p⫽0.99) between arms based on IIEF Q1 response, total IIEF score (52.5 drug vs 52.8 placebo), or score change from baseline (-8.0 drug vs -8.8 placebo). No difference in these outcomes was noted at 1 year. Non-responders at 30 wks were likely to be older (ageⱖ65; p⫽0.432), but there were no significant predictors at 1 year. About 80% of pts maintained spontaneous EF in both arms. Conclusions: Low-dose daily tadalafil did not preserve EF within the first year of RT for prostate cancer. If tadalafil positively influences delayed RT-induced vasogenic injury, additional time may be needed to observe a benefit to tadalafil as a preventive agent. Alternatively, tadalafil dose modification or altered dosing schedules may be needed to demonstrate a protective effect of this agent when used with RT. Clinical trial information: NCT00951184.

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Psychosocial outcomes among bereaved and non-bereaved parents of children with cancer. Presenting Author: Abby R. Rosenberg, Department of Pediatrics, Seattle Childrens Hospital, University of Washington, Seattle, WA

Screening for depression in community-based radiation oncology settings: Results from RTOG 0841. Presenting Author: Lynne I. Wagner, The Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL

Background: Psychosocial outcomes among parents of children with cancer are not well characterized and may affect the well-being of cancer-survivors and other children in the home. In order to examine adverse psychosocial outcomes among bereaved (BR) and non-bereaved (NBR) parents, we conducted a cross-sectional, survey-based study. Methods: Enrolled parents completed the “Resilience in Pediatric Cancer Assessment” (RPCA) at least 6 months after their child completed therapy or died from cancer. The RPCA is comprised of validated instruments to assess resilience, emotional distress, social function, health-related quality of life, and financial hardship. Descriptive statistics were used to characterize groups. Differences between groups were assessed with t or Fisher’s exact tests. Differences between the combined sample and population norms were assessed with one-sample t or binomial tests. Results: 120 (78%) of invited parents completed the RPCA (24 BR; 96 NBR). Compared to the general population, parents had lower levels of self-perceived resilience and higher levels of psychological distress. They were more likely to meet criteria for serious, debilitating psychological distress, or Post-Traumatic Stress Disorder (PTSD). All parents (100%) endorsed at least some PTSD symptoms. Parents also reported less marital satisfaction and family cohesion, and more sleep disturbance and binge drinking than population norms. Conversely, enrolled parents reported higher levels of social support and family adaptability, and were less likely to smoke cigarettes (all p⬍0.05). Compared to parents of survivors, BR parents were less likely to report appreciation for life, an ability to cope, or deal with stress. They had higher levels of psychological distress, more sleep difficulties, and greater financial hardship (all p⬍0.05). There were no differences between BR and NBR parents with respect to marital satisfaction, family function, or perceived general health. Conclusions: Parents of children with cancer are at high risk for poor psychosocial outcomes. Compared to parents of survivors, bereaved parents are at additional risk. Interventions aimed at improving resilience and other psychosocial outcomes are needed.

Background: Depression screening is recommended in routine cancer care. Brief tools are needed to identify depressed patients in radiation oncology treatment settings. Methods: Patients starting radiotherapy for first diagnosis of any tumor were eligible. Screening measures administered prior to or within the first 2 weeks of radiation therapy included: Hopkins Symptom Checklist (HSCL-25), Patient Health Questionnaire (PHQ-9; PHQ-2), and the National Comprehensive Cancer Network-Distress Thermometer (NCCNDT). Patients exceeding validated cutoff scores on the HSCL-25, PHQ-9 or PHQ-2, and a systematic sample of patients who screened negative, completed telephone-based administration of the Structured Clinical Interview for DSM-IV (SCID) Mood Disorder modules. Results: 463 patients from 35 community-based and 2 academic radiation oncology sites were accrued. The majority were women (n⫽298, 66%). Participants had breast (45%), GI (11%), lung (10%), gynecologic (6%), or other (27%) cancers. All 454 eligible patients completed the screening questionnaires and 100% of questionnaire items were completed. 75 (16%) screened positive for depressive symptoms. A total of 70 SCID interviews were administered to 37 patients who screened positive and 33 who screened negative. Among those who screened positive, 14 (20%) met SCID criteria for major depression. One participant who screened negative met depression criteria (1.4%). Results indicate the prevalence of depression is 3%. The PHQ-2 demonstrated good psychometric properties for identifying current major depressive episode, using a cut-off score ⬎ 3 (ROC area under the curve⫽0.839). The PHQ-9 ⬎ 9 was comparable (AUC⫽0.837). The NCCN-DT ⬎ 4 did not adequately detect depression (AUC⫽0.64). Conclusions: The prevalence of depression was low (3%) among this communitybased sample of adults receiving radiotherapy. The PHQ-2 demonstrated excellent psychometric properties to detect depression, which were equivalent to the PHQ-9 and superior to the NCCN-DT. Our findings support using the PHQ-2 to identify patients in need of further assessment and treatment for depression, a low prevalence but clinically significant comorbidity.


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Perceived versus measured functional vaginal capacity in cancer patients with sexual function concerns. Presenting Author: Vanessa Kennedy, Department of Obstetrics and Gynecology, University of California Davis Medical Center, Sacramento, CA Background: Actual and perceived loss of vaginal capacity can be a source of distress among female cancer survivors. The objective of this study was to assess perceived (PC) versus measured (MC) functional vaginal capacity in patients presenting with sexual function concerns. Methods: This was a cross-sectional registry-based study of women seen at the Program in Integrative Sexual Medicine for Women and Girls with Cancer (PRISM) Clinic. During the visit, patients were presented with graduated vaginal dilators and asked to select the largest dilator they perceived could be inserted without pain (PC) and the dilator representing their desired functional capacity (DC) (for patients with a male partner, this was the size closest to the partner’s erect penis). Two models of dilators were offered. Dilators were numbered 1-24 in order of increasing volume. If the patient could accommodate the dilator chosen as PC without pain, she was examined with dilators of gradually increasing size until the patient reported discomfort. The largest dilator tolerated without pain was MC. Differences between PC and MC, and between DC and MC were calculated. The association between penetrative sexual activity in the prior 4 weeks and accuracy of PC was assessed using the Mann-Whitney U test. Results: Mean patient age was 46 years (range 21-80, N⫽69). Most patients had breast (60%) or a gynecologic cancer (23%). Nearly half reported two or more sexual concerns; painful intercourse (81%), vaginal complaints (21%), and loss of libido (19%) were most common. Mean PC was 16.9 (SD 5.2, range 3-24), mean MC was 20.8 (SD 3.4, range 10-24), and mean DC was 21.8 (SD 3.4, range 6-24). PC equaled MC in 22%. PC was less than MC in 75% and less than DC in 81% of patients. Of patients with PC less than DC, 41% had MC equal to or larger than DC. PC was closer to MC in patients reporting penetrative sexual activity in the prior 4 weeks (p⫽0.03). Conclusions: In this single-site study, many cancer survivors seeking care for sexual concerns underestimate their functional vaginal capacity. Further study is needed to determine whether correcting patient perception of capacity lessens distress and improves function.

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Prevalence and predictors of suicidal ideation in long-term prostate cancer survivors. Presenting Author: Christopher J Recklitis, Dana-Farber Cancer Institute, Boston, MA Background: Prostate cancer (PC) is associated with an increased risk of suicide, even a decade after diagnosis. Prior research has relied largely on registry data collected at diagnosis, so little is known about the role of post-treatment functioning on the development of suicidal ideation (SI) in long-term prostate cancer survivors (PCS). To address this, our study examined the prevalence of SI, and the association with cancer therapy and post-treatment physical and emotional health in a cohort of long-term PCS. Methods: 695 PCS (5-10 years post-diagnosis) completed a mailed survey on physical and psychological functioning, including the SF-12, EPIC-26, a depression rating scale and 8 items about SI in the prior year. Results: 12% endorsed having SI and 2% reported serious SI, plans or urges. Serious SI was more common in PCS compared to age and gender-adjusted normative data. SI was not associated with demographic variables (age, ethnicity, marital status, education, income). SI was not associated with prostate cancer stage, treatments or progression. In univariate analyses, SI was significantly associated with prostate-specific symptoms, poor physical and emotional function, a higher frequency of significant pain, and clinically significant depression (p⬍.01). In an adjusted logistic model, depression and frequent pain remained associated with SI. Of note, 61% of PCS with SI denied a prior depression diagnosis, and 47% denied elevated current depressive symptoms. The majority of PCS with SI (97%) had a recent physician visit, and reported significant interest in receiving mental health information. Conclusions: A significant proportion of PCS report recent SI, which is associated with physical and psychological dysfunction, but not PC treatments. Depression and frequent pain, rather than PCspecific symptoms, are most important in the development of SI. While depression is strongly associated with SI, many PCS with SI have no prior or current depression, underscoring the need to evaluate SI independently. PCS with SI reported receiving regular medical care and interest in information about mental health. This emphasizes the critical role that physicians can play in identifying PCS at high risk for suicide.

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Long-term symptom burden and orodental health of oropharyngeal cancer (OPC) survivors following treatment with chemoradiotherapy (CRT) or sequential therapy (ST). Presenting Author: Sewanti Atul Limaye, DanaFarber Cancer Institute/Harvard Medical School, Boston, MA

Effect of YOCAS yoga on insomnia and sleep medication usage among breast cancer patients receiving hormone therapy: A URCC CCOP randomized, controlled clinical trial. Presenting Author: Luke Joseph Peppone, University of Rochester Medical Center, Rochester, NY

Background: OPC treatment is associated with significant long-term toxicity. Very little is known about the long-term symptom burden and orodental health in OPC survivors ⬎2 yrs from treatment. Methods: Survivors treated for OPC with CRT/ST (involving definitive RT) at Dana Farber Cancer Institute between 2002-2011 and ⬎2 yrs from treatment completion, were identified by chart review and asked to complete the Vanderbilt Head and Neck Symptom Survey version 2 (VHNSS v2), National Health And Nutrition Examination Survey for Oral Health Questionnaire, health care availability survey. Results: 200 survivors were contacted, 127 responded (RR: 64%). Median age at diagnosis was 54 yrs; 85% males; 85% stage IVA/B, 13% stage III; 56% CRT, 43% ST. HPV status: 47% (⫹), 10% (-), 43% unknown. Median time from treatment completion: 50 mths (24-135 mths). Residual moderate to severe toxicities reported in VHNSS v2: 71% dry mouth; 59% difficulty chewing/swallowing food; 53% feeling of food becoming stuck in the throat; 53% prolonged time to eat; 31% thick mucus, 6% had difficulty sleeping secondary to this; 16% trouble speaking, 27% trouble hearing;30% limitation of neck/shoulder movement; altered taste/smell - 45%/23%; sensitivity to spicy food and dryness-57%/ 62%; 30% decreased desire to eat, 11% had moderate weight loss. Orodental health assessment: 13% thermal sensitivity, 21% teeth cracking and chipping, 20% loose teeth, 33% had treatment for gum disease, 42% had lost bone around teeth. 98% survivors had health insurance; only 66% had dental insurance. No statistically significant difference was noted with respect to symptoms between CRT or ST. ST did not affect long-term toxicity compared to CRT alone. Conclusions: OPC is known to correlate with HPV positivity, early age at diagnosis and high rates of long-term survival after appropriate therapy. Our study documents that the OPC survivors have substantial residual long-term head and neck and orodental symptoms directly related to the treatment that significantly impacts their quality of life. A substantial number of patients lack dental health coverage, which likely further impacts symptom burden and QOL.

Background: Insomnia (INS) is a highly prevalent side effect of hormonal therapy for breast cancer. Patients often turn to Rx sleep meds, which may lead to negative interactions with cancer therapeutics, dependency, rebound impairment, and do not cure INS. We conducted a secondary data analysis of a multi-site, phase III RCT examining the efficacy of yoga for improving INS and decreasing sleep medication usage among breast cancer patients currently receiving hormone therapy through the University of Rochester Cancer Center Community Clinical Oncology Program (CCOP). Methods: The original RCT randomized patients with any type of nonmetastatic cancer without previous yoga participation into 2 arms: 1) standard care monitoring [controls] or 2) 4-week yoga intervention (2x/wk; 75 min/session) plus standard care. The yoga intervention utilized the UR Yoga for Cancer Survivors (YOCAS) program consisting of breathing exercises, 18 Hatha and Restorative yoga postures, and meditation. Only breast cancer patients currently receiving aromatase inhibitors (N ⫽ 95) or tamoxifen (N ⫽ 72) were included in this analysis. Changes in INS and sleep meds between the groups were assessed using ANCOVA with baseline values as covariates. Results: Despite using Rx sleep meds at baseline, INS, assessed by the Insomnia Severity Index, was worse for those women compared to women not taking any Rx sleep meds (Rx ⫽ 15.3 vs No Rx ⫽ 13.1; p⬍0.01). Yoga participants demonstrated greater improvements in INS compared to controls (CS⫽change score; Yoga CS ⫽ ⫺3.3 vs Control CS ⫽ ⫺0.5; p⬍0.01). In addition to improved INS, yoga participants significantly decreased Rx sleep med usage compared to controls (Yoga ⫽ ⫺17.6% vs Control ⫽ ⫺3.3%; p⫽0.04). There was also a trend toward lower combined Rx/Non-Rx sleep med use for the yoga group compared to controls (Yoga ⫽ ⫺14.5% vs Control ⫽ ⫺3.1%; p⫽0.09). Conclusions: YOCAS yoga is a safe intervention that significantly improves INS while concurrently reducing Rx sleep medication usage among breast cancer patients receiving hormone therapy. Funding: MRSG-13-001-01-CCE, NCI U10CA37420, K07CA120025 and OCCAM supplement. Clinical trial information: NCT00397930.




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Actigraphy measured sleep disruption as a predictor of survival in advanced breast cancer. Presenting Author: Oxana Palesh, Stanford University, School of Medicine, Stanford, CA

The impact of positive spousal support on trauma symptoms and sleep disturbance among prostate cancer survivors. Presenting Author: Charles Stewart Kamen, University of Rochester Medical Center, Rochester, NY

Background: Sleep disruption, prevalent in cancer patients and survivors, is associated with disrupted hormonal circadian rhythms and poor quality of life. Previous studies in cancer patients and survivors have pointed out the association between poor sleep and faster disease progression. However, until now these studies have been limited by their retrospective or correlational design, providing little resolution of the question of whether sleep disruption accelerates disease progression or whether disease progression dysregulates sleep, or whether a third factor might underlie the association between sleep dysregulation and disease progression. This study aimed to clarify this relationship by using a longitudinal research design to examine whether sleep disruption assessed at baseline predicts survival in women with metastatic breast cancer. Methods: We examined sleep quality and duration in 97 women diagnosed with metastatic breast cancer (mean age⫽54.6, SD⫽9.8) via wrist-worn actigraphy for 3 days and sleep diaries. Sleep quality was operationalized as poor sleep efficiency (the ratio of total asleep time to total time in bed * 100%). Results: As hypothesized, poor sleep efficiency was found to predict shorter survival (Hazard Ratio (HR), 0.96, 95% CI, 0.93 to 0.98, p⬍0.001) over 6 years. This relationship remained significant (HR, 0.94, CI, 0.91 to 0.97, p⬍.001) even after controlling for other known prognostic factors (age, ER status, cancer treatment, metastatic spread, cortisol levels, and depression). Conclusions: Our findings show that sleep dysregulation is a clear and significant independent prognostic factor for disease progression in metastatic breast cancer. Further research is needed to determine whether treating sleep disruption with cognitive behavioral therapy or medication can improve survival in metastatic breast cancer. Funded by P01AG018784, R01CA118867, K07CA132916.

Background: Receiving a diagnosis of cancer can lead to psychological effects including symptoms of traumatic stress. Trauma symptoms can dysregulate sleep and sleep disturbance has been linked with negative health outcomes. Cancer-related trauma symptoms and sleep disturbance can affect the spouse of the cancer patient and the couple’s relationship; conversely, a supportive relationship can improve cancer survivors’ mental health. The impact of spousal support on trauma and sleep disturbance among prostate cancer survivors has not yet been examined. Methods: 315 prostate cancer survivors (mean age 66, 89% Caucasian), of whom 265 were married and 50 were unmarried (single, widowed, separated or divorced) completed the Impact of Events Scale (IES), Stanford Sleep Questionnaire, and a measure of positive spousal support. Data are self-report. Rates of trauma symptoms and sleep disturbance by marital status were compared using t-tests, and the contribution of marital status and spousal support to variance in these outcomes was evaluated using linear regression. Results: 13.4% of survivors reported significant (i.e., ⬎27 point IES cutoff) symptoms of traumatic stress and 23.2% reported moderate or higher rates of sleep disturbance. Trauma symptoms (t⫽ -2.16, p⬍.01) and sleep disturbance (t⫽ -3.14, p⬍.01) were significantly lower in married than unmarried survivors. Spousal support was negatively associated with trauma symptoms (r⫽ -.18, p⬍.01) and sleep disturbance (r⫽ -.20, p⬍.05), and inclusion of spousal support as a covariate rendered the linear relationship between marital status and both trauma symptoms and sleep disturbance non-significant (p⬎.05). Conclusions: Spousal support is associated with reductions in trauma and sleep disturbance, over and above dichotomous marital status. This area needs further study, given high rates of trauma symptoms and difficulty disclosing health-related concerns among men with prostate cancer. Future research needs to explore mechanisms by which spousal support leads to improvement in trauma symptoms and sleep outcomes. Interventions bolstering spousal support could improve mental health in prostate cancer survivors.

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Risk perceptions in localized breast cancer (BC). Presenting Author: Pallavi Kumar, Massachusetts General Hospital, Boston, MA Background: Risk perceptions (RP) play an important role in decision making in localized BC. Little is known about RP in the context of adjuvant (adj) therapy decisions. We examined the accuracy of estimate of absolute benefit of adj therapy among patients (pts) with localized BC and sought to identify determinants of accurate RP. Methods: A cross-sectional survey was conducted in localized (Stage I-III) BC pts within 3 months after surgery at 4 U.S. cancer centers. Pts completed the Decision Quality Instrument, which includes items on BC knowledge, numerical estimates of benefit of adj therapy, and communication with providers. We analyzed pts with Stage I/II and calculated objective estimates of benefit of adj therapy using Adjuvant! Online. Based on published data, an estimate that was ⫹/- 5% of the calculated risk was considered correct. We used multivariable (MV) regression to identify determinants of accuracy including tumor stage, age, adj treatment, education, total knowledge score, and decision involvement. Results: 192/249 (77.1%) pts completed the survey; analyses were limited to 166 pts stage I/II with complete risk estimate data. Mean age was 56.4 years (SD 12.1), 83% of respondents were white, and 58.5% were college graduates. 56.3% had stage I and 43.7% had stage II disease. Most (95.6%) had some type of adj therapy, either endocrine therapy only (43.2%), chemotherapy only (15.3%), or both (32%). On average, pts estimated the absolute benefit of adj therapy to be 31.8% (SD24.9), and this varied by stage (28.4 and 35.9 for stage I and II, p⫽0.06). The overall estimate for this sample from Adjuvant! Online was 11.8% (SD 7.67) and this varied by stage (8.6/16.0 for stage I/II respectively, p⬍0.001). Few pts (18.1%) had accurate estimates and the majority (68.3%) overestimated the benefit. In MV logistic regression analysis, only BC knowledge score was associated with accurate estimate of benefit (OR 1.36 95%CI 1.04, 1.8). No other factors were significantly associated with accuracy. Conclusions: Pts with localized BC overestimated the absolute benefit of adj therapy by an average of 20 percentage points. Some pts may be taking on risks of adj therapy without accurate knowledge of the benefits, calling into question whether these decisions are truly informed.


From Bayesian modeling to genomic mapping: Biologic validity of predictive single nucleotide polymorphism networks for chemotherapy-related side effects. Presenting Author: Stephen T. Sonis, Inform Genomics, Inc., Boston, MA Background: Using proprietary Bayesian network (BN) algorithms, we discovered interacting single nucleotide polymorphism (SNP)-BNs predicting patient-risk for 6 chemotherapy (CT)-induced side effects (SEs): oral mucositis (OM), diarrhea (D), CT-induced nausea and vomiting (CINV), fatigue, cognitive dysfunction (CD) and peripheral neuropathy (PN). To assess biologic validity, SNP-BNs mapped each SE to its gene loci, exploring biologic pathways for those genes. Roles of genes and pathways found in similar phenotypic diseases (e.g., Inflammatory Bowel Disease [IBD] for D, Alzheimer disease [AD] for CD, chronic fatigue syndrome [CFS] for F) were explored. Methods: Via an FDA-cleared DNA extraction kit, saliva was collected from 78 women with breast cancer (dose-dense AC⫹T) and 57 patients with colon cancer (FOLFOX ⫹/- bevacizumab). We assessed 2.5M SNPs/patient (Illumina OmniQuad bead chip assays). SEs were measured via a validated tool (Patient Care Monitor). Analyzed SNP arrays and SEs discovered SNP-BNs. Final SNP-BNs per SE included gene name, symbol, and loci. Pathways and networks were analyzed for gene function and related genes, querying 6 databases (NLM, NextBio, Weizmann Institute, SPRING, Gene Ontology, AmiGO). Results: Mucosal injuryimplicated networks and genes were identified, including oxidative stress, NF-␬B, pro-inflammatory cytokines IL-1, IL-6, and TNF, MMPs and fibronectin breakdown (SPOCK3). D networks and genes overlapped with IBD (ERG, IER2, CASK). SNP-BNs for CINV overlapped in both CT regimens with genes for neurotransmitters (serotonin, dopamine, substance P) and nerve impulse transmission. B3GAT1, involved with opioidinduced CINV, was identified. F networks involving genes and pathways for cytokines and skeletal muscle overlapped to CFS. CD networks involve genes in AD. PN networks mapped genes involving myelination, demyelination, inflammation, and toxic neuropathy. Conclusions: SNP-BNs predicting CT-induced SEs mapped to genes associated with known biology of each SE, sharing central traits with other diseases, and are targets for drug discovery in cancer-related SEs and unmet needs, including AD.


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The role of social exposure to smoking on smoking cessation in adult cancer survivors. Presenting Author: Lawson Eng, Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada Background: We previously described a strong inverse relationship between social smoking exposures (at home, spousal and with peers) and smoking cessation in lung cancer, with adjusted odds ratios (aOR) of 3-8 (Eng et al, ASCO 2012, abst 9032). In the current analysis, we evaluated whether these associations hold true in adult cancers in general, particularly cancers not traditionally known to have smoking as a risk factor. Methods: 616 cancer survivors across multiple cancer sites were surveyed on their smoking, alcohol, and physical activity habits before and at various times after cancer diagnosis. Social smoking exposures were documented. Multivariate logistic regression models evaluated the association of each variable with change in each habit after diagnosis adjusted for significant socio-demographic and clinico-pathological covariates. Results: Median follow-up after diagnosis was 26 months. 15% had breast cancers; 15% gastrointestinal; 20% genitourinary-gynecological; 24% haematological; 36% other. Among current smokers at diagnosis, 56% quit after diagnosis; no ex- or never-smoker restarted. Patients without secondary home smoking exposure were significantly more likely to quit smoking than those with home exposures (aOR⫽9.5, 95% CI [2.4-37.8]). Similar results were seen in patients with non-smoking spouses versus smoking spouses (aOR⫽3.7 [1.0-13.4]), and with lack of peer smoke exposure (aOR⫽3.7 [1.3-10.7]). 63% patients who quit did so in the 1 year period surrounding the diagnosis date (6-months pre or post diagnosis). In comparison, first and secondhand smoking exposures did not affect other modifiable behaviours such as alcohol or physical activity. Patient awareness of quality of life and survival benefits of smoking cessation and receiving smoking cessation counselling were not associated with improved smoking cessation. Conclusions: Secondary smoking exposures are associated with lack of smoking cessation in adult cancer survivors, even in cancers not traditionally linked to smoking. Being diagnosed with cancer may be an important ⬘teachable moment⬘ to help patients quit, but results are strongly influenced by the surrounding social exposure to smoking. PS and GL contributed equally.

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Opportunities for improved end-of-life (EOL) care for adult patients with advanced cancer: Results of a longitudinal assessment of care provided by Quality Oncology Practice Initiative (QOPI) participants. Presenting Author: David W. Dougherty, University of Rochester Medical Center, Rochester, NY Background: End of life care of patients with advanced cancer has received recent attention because of evidence of widespread variation in utilization of aggressive therapies and interventions and possible suboptimal use of palliative care and hospice services. QOPI, the ASCO sponsored quality assessment program, has been available to all United States physician members since January 2006 and has assessed EOL care since its inception. The current analysis explores whether the increased national focus on EOL and increased availability of palliative care and hospice services has resulted in improvements in EOL care as reported by QOPI participants. Methods: Data was aggregated across all EOL care quality measures for 9 sequential semi-annual QOPI collection periods from 2008 through 2012. Trends were analyzed among rates of eligible patients related to hospice enrollment and timing of enrollment, palliative care referrals, discussions about hospice and palliative care, and chemotherapy administration at the end of life. The Cochran-Armitage trend test was performed to determine the significance of trends and differences in measure performance over time. Results: From Fall 2008 to Fall 2012, the rate of hospice enrollment for appropriate patients improved by 7.4% [51.8% to 59.2%; p⬍0.0001] and the rate of hospice enrollment or palliative care referral improved by 5.6% [63.3% to 68.9%; p⬍0.0001]. Modest improvements were seen in the rates of hospice enrollment more than 3 and 7 days before death [2.8%, 2.6%], discussion of hospice or palliative care with patients not referred for these services within the last 2 months of life [2.7% increase; 19% to 21.7%], and chemotherapy administration within the last 2 weeks of life [2.4% improvement from 13.7% to 11.3%]. Conclusions: Despite modest increases in the rate of hospice enrollment and palliative care referrals over time, EOL care for adult patients with cancer associated with QOPI practices remains suboptimal. Opportunities exist to increase more meaningful participation in hospice and palliative care and to reduce exposure to chemotherapy near death.

9539


Factors related to end-of-life (EOL) chemotherapy in solid tumor (ST) patients. Presenting Author: Maria Alma Rodriguez, The University of Texas MD Anderson Cancer Center, Houston, TX

Pattern of chemotherapy use at end-of-life (EOL) in patients with solid tumors (ST). Presenting Author: Thomas W. Burke, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: Oncologists will be required to report quality measures for cancer care, including use of chemotherapy in the last two-weeks of life. In this study, we evaluated how use of chemotherapy in ST patients (pts) within 14 days of EOL may be influenced by clinical factors. Methods: Adult pts (ⱖ18 years) treated for ST at our institution, deceased December 01, 2010 through May 31, 2012, were retrospectively studied. Data on demographics, chemotherapy (excluded: hormones) within 14 days EOL, comorbidities, and cancer diagnoses were from tumor registry and administrative databases. Logistic regression analysis was performed for association of EOL chemotherapy with age, gender, ethnicity, comorbidities , cancer types, and metastatic status. Results: 5,607 pts met study criteria: median age 64 years; 48% female; 76% metastatic disease. EOL chemotherapy frequency was 3.9% overall, 4.6% in metastatic disease versus 1.7% in non-metastatic disease (p⬍0.01). In 23 patients with nonmetastatic disease who received chemotherapy, the diagnoses were: brain/other nerve system (34.8%, 8/23) and lung/bronchus (21.7%, 5/23).The top 10 frequencies in chemotherapy use by tumour sites were: melanoma (6.7%), female breast (5.5%), lung & bronchus (4.9%), pancreas (4.2%), brain/other never system (3.9%), head & neck (3.8%), female genital system, excluding ovary (3.4%), ovary (3.2%), liver/ intrahepatic bile duct (3.0%), colon & rectum (2.6%). By regression analysis, the factor statistically significantly associated with receiving chemotherapy was metastatic disease (odds ratio [OR], 3.29; 95% CI,1.96-5.54), while factors associated with significantly less treatment were age ⱖ 65 (OR, 0.66; 95% CI, 0.49-0.90); and any co-morbid conditions (ⱖ1 versus 0) (OR, 0.58; 95% CI, 0.38-0.89). Conclusions: A small portion of ST patients who died received EOL chemotherapy (3.9%). However, metastatic disease and diagnosis category influenced treatment. Melanoma and breast cancer patients had higher frequency of EOL treatment. Older age and comorbidities were associated with less treatment. Variation in EOL treatment of ST patients is thus influenced by several clinical factors, but did not seem influenced by gender or ethnicity factors.

Background: Quality performance measures for cancer care, including use of chemotherapy in the last two-weeks of life, will be required for reporting. In this study, we evaluated the pattern and frequency of chemotherapy use for ST patients in the last two-weeks of life, and whether such treatment included standard or investigational drugs. Methods: We conducted a retrospective study of 5,607 adult cancer patients (ⱖ18 years) who received their care at The University of Texas MD Anderson Cancer Center and died between December 01, 2010 through May 31, 2012. Data on patients’ demographics, and chemotherapy agents dispensed (excluded: hormones) were obtained from the institution’s administrative databases. Type of treatment (research versus standard) was obtained from our chemotherapy dispensed database. Chi-square test and Fisher’s exact test were used to determine the association between categorical variables.All statistically significant levels were determined with P values ⬍ 0.05. Results: Only 3.9% (216/5,607) of ST patients who died had received chemotherapy within 14 days EOL. For those 216 patients who received chemothapy: median age 64 years; 48% female; 89% metastatic disease. The distribution by chemotherapy treatment route: intravenous (IV) 85%; IV plus oral 6%; oral 6%; other 3%. The distribution of patients by number of chemotherapy agents: one 56%; two 31%, and three or more 13%. Among those who received chemotherapy, 98.6% (213/216) of the chemotherapy administered were standard agents. There were no differences in frequency distribution for chemotherapy treatment route (p⬎0.05), number of chemotherapy agents (p⬎0.05) between patients with metastatic and non-metastatic disease, or between men and women (p⬎0.05). Conclusions: Our results indicate EOL chemotherapy use was infrequent in our patients with STs, and most of those treated received standard chemotherapy, with simple one or two drug regimens. We need more research to determine factors that influence chemotherapy use at EOL, and if it palliates physical symptoms and/or emotional distress in advanced stages of disease.




9541

585s General Poster Session (Board #26B), Mon, 1:15 PM-5:00 PM

End-of-life experience of patients with rare cancers and their caregivers. Presenting Author: Elizabeth Trice Loggers, Group Health Research Institute and Fred Hutchinson Cancer Research Center, Seattle, WA

Palliative sedation (PS) given to patients treated at the Fundación Santa Fe de Bogotá. Presenting Author: Milton Alberto Lombana Quinonez, Oncologos Asociados de Imbanaco, Cali, Colombia

Background: Cancers are defined as rare if fewer than 35,000 cases are diagnosed per year. Rare cancers represented 23% of incident cancer cases and 33% of cancer deaths in 2008. However, little is known about the end-of-life (EOL) experience of patients with rare cancers or their caregivers. Methods: From September 2002 to August 2008, 618 advanced cancer patients (195 with rare and 423 with common stage IV cancers following failure of first line chemotherapy) and their caregivers participated in a U.S. multi-site, prospective, interview-based cohort study (Coping with Cancer). Patients were interviewed about EOL preferences, planning, and care at study entry. Interviews with caregivers at baseline assessed caregiver mental and physical health, while post-mortem surveys assessed EOL patient care. Descriptive statistics (t-test, chi-square) were used to characterize the study sample; logistic regression tested the association between cancer type and care received, controlling for confounders. Results: Rare cancer participants were more likely to be younger (57.7 vs 60.7 years, p⫽.01), Hispanic (19% vs 9%, p⫽.002) and have fewer co-morbidities (Charlson comorbidity index, mean 5.9 vs 6.5, p⫽.004), than their common-cancer counterparts. Rare cancers patients were four times more likely to be receiving both radiation and chemotherapy at study entry than common cancer patients (10.3% versus 3.3%, OR 4.31, p⫽0.003), but equally as likely to acknowledge their illness was terminal, have EOL discussions, and participate in advance care planning as common cancer patients. Caregivers of patients with rare cancers were more likely than common cancer caregivers to report declining health during the prior year of care-giving (22.1% versus 15.7%, p⫽0.05) and marginally more likely to prefer the patient choose treatment focusing on extending life rather than pain relief (22.3% vs 16.5%, p⫽0.08). Conclusions: Patients with advanced-stage, rare cancers may be treated more aggressively following failure of first line chemotherapy than individuals with common cancers. Future research should investigate patterns and quality of care for terminally ill patients with rare cancers and caregiver burden.

Background: Around 50% of advanced-stage cancer patients have inadequate control of symptoms during the final period of life; palliative sedation (PS) would seem to be appropriate in such scenario. Methods: A retrospective cohort analytical study was carried out for determining the effectiveness of PS, evaluating the non-reduction of the number of final days of life in patients suffering advanced-stage cancer. PS therapy consisted of using a continuous infusion of benzodiazepines, opioids, antipsychotics and/or anaesthetics. Results: The study included 145 patients recorded between July 2008 and October 2012. Median age was 68 years (24% of the patients being aged over 80). The main motives for considering PS were dyspnoea (30%), uncontrolled pain (25%), delirium (26%) and presenting more than one of these symptoms (19%). The drugs used were opioids (in 87% of the patients), benzodiazepines (54%) and anaesthetics (2%). Using PS led to symptoms becoming controlled in 79% of the cases compared to 53% without it; symptoms became controlled in 85% of the cases in less than 24 hours when PS was used compared to 15% when it was not used (p⬍0.001). Mean overall survival (OS) was 6.8 days for those who received PS and 7.2 for those who did not (RR 0.94, 0.97-1.33 95%CI; p⫽0.72) and final days of life after starting PS was 2.2 days (⬍1-16 days). Multivariate analysis showed that using PS (HR 1.49, 1.08-2.07 95%CI; p⫽2.04) and the presence of oedema (RR 0.79, 0.61-1.0 95%CI; p⫽0.01) modified the course of controlling symptoms. Conclusions: PS improved the time to controlled cancer symptoms in patients suffering terminal illness, and their presentation profile without modifying the OS.

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9543


Comparison of toxicity experienced by elderly (E) and younger (Y) patients in breast cancer (BC) clinical trials. Presenting Author: Caroline Joy Mariano, British Columbia Cancer Agency, Vancouver, BC, Canada Background: E patients (pts), age 65 and older, form a large percent of BC pts, but are under-represented in trials, due to actual/perceived frail health, or actual/perceived greater potential toxicity from therapy (rx). With ethics approval, we examined whether E pts had more toxicity than Y pts (⬍ 65 years) in clinical trials. Methods: All BC phase II and III drug trials open from 1999 to 2012 at British Columbia Cancer Agency Vancouver Center were reviewed, excluding trials with only premenopausal pts. Adverse events (AE) were captured from case report forms and charts. The primary endpoint was meaningful toxicity (MTOX), defined as any grade 3 or 4 AE; any AE with dose delay or reduction; or premature discontinuation of rx. Frequencies of MTOX were compared using chi-square tests, means were compared with T-tests. Results: Among 46 trials enrolling 799 pts, rx types were chemotherapy ([CT], 18% of pts), hormone ([HT] 40%), skeletal ([ST] 14%), targeted ([T] 14%]) and CT ⫹ T (14%). Pts were 19% E (age range 65-84) and 81% Y (age range 25-64). E pts were more likely to enroll in HT and ST trials; Y pts were evenly distributed among all rx types. Toxicity data (Table) was available for 778 pts (97%). Conclusions: In non CT trials, E and Y pts had similar frequency and number of MTOX. Few E (5%) enrolled in CT trials, but with no more MTOX than Y pts. Discontinuation of rx was equal in E and Y, considering all rx types. Appropriate selection of E pts by eligibility criteria, self selection, and/or clinician assessment allows safe participation of E pts in BC trials. Fear of increased MTOX should not exclude fit E pts from trial participation. Toxicity by age cohort. All trials N (%) Pts with MTOX (%) Average number MTOX per pt Pts with AE leading to change in rx (%) Pts discontinuing rx due to AE (%) Pts discontinuing rx for non AE reason (%) CT and CT ⴙ T trials N Pts with MTOX (%) Average number MTOX per pt HT, ST, T trials N Pts with MTOX (%) Average number MTOX per pt

All

Y

E

P value

778 (100) 408 (52) 1.0 341 (44) 122 (16) 30 (3.9)

631 (81) 337 (53) 1.0 288 (46) 96 (15) 22 (3.5)

147 (19) 71 (48) 0.78 53 (36) 26 (18) 8 (5.4)

0.26 0.01 0.035 0.46 0.27

245 189 (77) 1.7

232 178 (76) 1.7

13 11 (85) 2.5

0.51 0.13

533 219 (41) 0.65

399 159 (40) 0.65

134 60 (45) 0.62

0.32 0.70


Health behaviors (HB) and geriatric assessment (GA) in older women with breast cancer (BC). Presenting Author: Trevor Augustus Jolly, The University of North Carolina at Chapel Hill, Chapel Hill, NC Background: Physical inactivity (PI), alcohol (A) and tobacco (T) abuse are associated with poor health outcomes in older adults, however, little is known about the prevalence of these HB and their associations with GA domains in older cancer patients (pts). This study explores the relationship between HB and GA in older BC pts. Methods: Between 03/2010-01/2013, 111 pts ⱖ65 yrs completed a predominantly self-administered GA (Hurria et al. Cancer 2005) comprising measures of comorbidity, polypharmacy, cognitive, functional, psychosocial and nutritional status as well as a nine-item HB questionnaire based on the 2006/7 National Health Interview Survey (www.cdc.gov/nchs/nhis.htm) assessing PI, A and T use. Fisher’s Exact and Wilcoxon Rank sum test were used to evaluate associations with GA measures. Results: Median age was 72 (range 65-94). Most pts were white (89%), married (61%), retired (86%) and at least high school graduates (96%). 51% never smoked while 45% were former and 4% current smokers. Former/current smokers were more likely than never smokers to have slower gait speeds (Timed “up and go” ⬎14 second; 32 vs 14%; p⫽.04) and took more daily prescription medications (mean 5 vs. 4; p⫽.04). 52% of pts consumed at least one alcoholic drink per week (median 3.5). Modest alcohol consumption was associated with less activity of daily living (ADL) impairment (p⫽.03), lower mean BMI (29 vs. 26 kg/m2 p⫽.03) and greater non-prescription medication use (p⫽.04). 48% never performed vigorous activity and these pts were more likely than those exercising to have one or more functionally impairing comorbidities (p⫽.03); mainly arthritis. PI correlated with more impairment in both ADL (p⬍.0001) and instrumental ADL (p⫽.004). HB were not associated with demographic factors, treatment phase, weight loss, falls, sensory impairment, social activity, anxiety or depression in this dataset. Conclusions: PI, T and A use were common in this cohort of older BC pts and were associated with significant impairments in several GA domains. These findings reinforce the need for interventions to improve HB in older BC pts. Support: Breast Cancer Research Foundation, New York, NY and Lineberger Comprehensive Cancer Center, Chapel Hill, NC.


586s 9544

Patient and Survivor Care General Poster Session (Board #27B), Mon, 1:15 PM-5:00 PM

Outcomes of patients > 65 yrs with advanced cancer treated on phase I clinical trials. Presenting Author: Ishwaria Mohan Subbiah, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX Background: Older patients with cancer are underrepresented in clinical trials; their disease biology and comorbidities may impact the decision to consider a clinical trial. Here we systematically analyze outcomes of elderly pts treated on phase I clinical trials. Methods: The characteristics, toxicity, survival, and response of pts with advanced cancer treated on phase I clinical trials from 1/04 – 12/09 were studied. Results: Overall,347 of 1,182 pts (29%) were ⬎65 yrs old. The Table lists pt characteristics by treatment regimen. 251 pts received a targeted agent, of which 241 (96%) received an investigational, non-FDA approved drug. Of 347 pts, 3 (1%) had a CR, 15 (4%) a PR, 127 (37%) SD, of which 43 (12%) had SD ⱖ 6mos. Of 347 pts, 194 (56%) had ⬎1 drug-related toxicity, of which 89 (26%) had a Grade 3-4 toxicity, most often hematologic; 72% of toxicities on targeted therapies were Grade 1-2. Six pts had a DLT; there was one death (⬍0.01%) “possibly” attributed to the study drug. Median OS from 1st phase I Clinic visit was 8.8mos (95% CI, 7.8-10.6). Median TTF on 1st phase I trial was 1.9mos (95% CI, 1.8-2.1). Multivariate analyses demonstrated that ECOG PS 2-3 (vs. 01) (p ⬍0.001) and liver mets (vs. no liver mets) (p ⬍0.01) were independent factors predicting shorter TTF and OS. Conclusions: Our results suggest that phase I clinical trials are well tolerated and offer a reasonable therapeutic option for pts ⬎ 65 yrs. Patient characteristics and outcomes by treatment regimen. N Age, median, yrs Age, range, yrs Gender: M:F ECOG 0 1 2 3 Presence of liver mets: Y:N # prior therapies, median (range) Median PFS on phase I therapy, mos Median OS on phase I therapy, mos # pts with therapy-related toxicity (%) # of SAEs # of grade 1/2 events (%) # of grade 3/4 events (%)

Cytotoxic

Targeted

Cytotoxic ⴙ targeted

HAI or IP

22 74 65 - 84 10:12

251 70 65 - 88 150:101

55 69 65 – 81 31:24

19 69 65 - 76 8:19

5 14 3 0 8:14 4 (0 - 12) 2.4 8.9 10 (45%) 22 9 (41%) 13 (59%)

69 165 16 1 111:140 3 (0 - 16) 1.8 7.8 130 (52%) 301 216 (72%) 87 (28%)

18 32 5 0 16:39 4 (0 - 10) 2.3 12.7 41 (75%) 95 59 (62%) 36 (38%)

8 10 1 0 17:02 4 (1 - 7) 3.1 9.9 13 (68%) 45 40 (89%) 5 (11%)

9545


Measures of polypharmacy and chemotherapy toxicity in older adults with cancer. Presenting Author: Ronald John Maggiore, University of Chicago Medical Center, Chicago, IL Background: Polypharmacy is common and associated with adverse clinical outcomes in older adults. Potentially inappropriate medication (PIM) use serves as an adjunctive assessment of polypharmacy. The goals of this study in an outpatient population of older adults with cancer (CA) were: 1) to estimate the prevalence of polypharmacy using multiple measures; and 2) to determine the relationship between polypharmacy and chemotherapy (chemo) toxicity. Methods: Medication use was evaluated in 500 patients (pts) age ⱖ65 years with invasive CA who were starting a new chemo regimen. Polypharmacy was defined by number of daily medications (meds), including non-prescription meds. PIM use was defined by 4 indices: Beers (2003 and 2012 update), Zhan, and HEDIS Drugs to Avoid in the Elderly (DAE) criteria. Prevalence of polypharmacy, PIM, and their association with grade 3-5 chemo toxicity [NCI Common Toxicity Criteria (v. 3.0)] were analyzed using chi square test and unconditional logistic regression. Results: All 500 pts were evaluable [mean age, 73 years (range 65-91); 56% female; 61% stage IV]. The mean number of daily meds was 5 (range 0-23); 38% used ⱕ3 daily meds, 51% used 4-9 meds, and 11% using ⱖ10 meds. Using 0-3 daily meds as the referent group, no association was found between daily meds and chemo tox: 4-9 meds, OR 1.34 (95% CI: 0.92-1.97); ⱖ10, OR 0.82 (95% CI: 0.45-1.49). PIM use was identified in 87 (17%), 147 (29%), 54 (11%), and 69 (13%) patients utilizing the 2003 Beers, 2012 Beers, Zhan, and HEDIS DAE criteria, respectively. There was no association between each PIM use index and chemo toxicity (p⬎0.10 for all). Conclusions: Polypharmacy and PIM use were common in the geriatric oncology population. Although polypharmacy did not increase the risk of chemotherapy toxicity in this sample, further studies of polypharmacy’s impact on additional outcomes, including non-chemotherapy adverse drug events, in older persons with cancer are warranted.

HAI, hepatic arterial infusion; IP, intraperitoneal; OS, overall survival; PFS, progression-free survival.

9546


9547


Differences in patterns of care and outcomes of elderly versus younger metastatic pancreatic cancer (mPC) patients. Presenting Author: Namrata Vijayvergia, Fox Chase Cancer Center, Philadelphia, PA

Population-based patterns of palliative systemic therapy use in elderly patients with metastatic colorectal cancer (mCRC). Presenting Author: Matthew Chan, British Columbia Cancer Agency, Vancouver, BC, Canada

Background: Despite a median age at diagnosis of 72, elderly pancreatic cancer patients (pts) are poorly represented in clinical trials. We thus compared patterns of care and outcomes of mPC pts ⱕ and ⬎ 65 yrs of age. Methods: We retrospectively analyzed medical charts of 277 mPC pts treated at an academic center between 2000 and 2009. Age groups ⱕ 65 yrs and ⬎65 yrs were compared with respect to gender, comorbidities, performance status (PS), tobacco/alcohol use, primary site, stage, histological grade, metastatic sites, treatment modalities, type and number of chemotherapeutic agents received, and survival after diagnosis of mPC (OS). Log-rank tests and Cox proportional hazards models were used to analyze survival endpoints and Fisher’s exact test to compare categorical variables. Results: 155 pts ⱕ65 yrs with median age of 58 and 122 pts ⬎65 yrs with median age of 73.5 were evaluated. The groups were well balanced with respect to sex (majority male), PS (majority ⱕ1), stage (majority 3, 4), and primary site (majority head). Cardiovascular (CV) disease was more prevalent among older pts (OR 1.7, p⫽0.04). Older pts were less likely to receive any chemotherapy for mPC (79% vs 92%; OR 0.33, p⬍ 0.001) and if treated were less likely to receive more than one agent (34% vs 52%; OR 0.48, p⫽0.003). Median OS was shorter in older pts (5m vs 6m, p⫽0.01). OS was longer with higher number of agents received (RR: 0.57 for young, 0.51 for old; p⬍ 0.001). CV and renal disease negatively impacted OS only in younger pts. The presence of lung metastases was associated with longer survival (10m vs 6m (p⫽0.01)) and liver metastases with decreased survival (5m vs 8m (p⬍0.01)) only among younger pts. Conclusions: Elderly mPC pts have shorter OS, are less likely to receive chemotherapy, and if treated receive fewer agents compared to younger pts. These differences cannot be explained solely by PS or disease characteristics and warrant further study.

Background: Elderly cancer patients are consistently under-represented in clinical trials, which may lead to under-treatment. Our aims were to 1) determine the impact of advanced age on use of palliative systemic therapy in mCRC, 2) examine the reasons for treatment choices and 3) compare adverse events and treatment discontinuations in elderly vs young patients. Methods: All patients diagnosed with mCRC from 2006 to 2007 and referred to any 1 of 5 regional cancer centers in British Columbia, Canada were reviewed. Summary statistics were used to describe treatment patterns between elderly patients (EP; ⬎/⫽70 years) and young patients (YP; ⬍70 years). Cox regression models that adjusted for age and confounders were used to determine the effect of systemic therapy on overall survival (OS). Results: We identified 1,013 patients: median age was 67 years (range 23-93); 42% were elderly and 58% were young; 57% were men; and 66% had ECOG 0/1. Compared to YP, fewer EP were offered systemic therapy (46 vs 76%, p⬍0.001). Among those treated, EP were less likely than YP to be given combination chemotherapy (47 vs 81%, p⬍0.001) and bevacizumab (19 vs 47%, p⬍0.001). Most common reasons for no treatment were similar in EP and YP: patient choice (32% for both), poor ECOG (18% of EP and 16% of YP), and significant comorbidities (11% for both). Advanced age alone was also cited as a reason among EP (7%) for not receiving therapy. In the subset that was treated, risk of adverse events (24 vs 14%, p⫽0.24) and early treatment discontinuations (14 vs 13%, p⫽0.88) were comparable between EP and YP, respectively. Receipt of systemic therapy was associated with improved OS in both the elderly (HR for death 0.45, 95% CI 0.37-0.56, p⬍0.001) and the young (HR for death 0.43, 95% CI 0.35-0.53, p⬍0.001), regardless of age (p interaction of age and treatment ⬎0.05). Conclusions: In this populationbased cohort of mCRC, EP were more likely to receive no treatment, monotherapy rather than combination therapy, or a regimen without bevacizumab. In carefully selected EP, however, it appears that rate of adverse events, frequency of early treatment discontinuations, and magnitude of survival benefit from systemic therapy were comparable to YP.




9549

587s General Poster Session (Board #29A), Mon, 1:15 PM-5:00 PM

Efficacy and safety data from elderly patients with pretreated advanced melanoma in the Italian cohort of ipilimumab expanded access programme (EAP). Presenting Author: Vanna Chiarion-Sileni, Department of Medical Oncology, Veneto Oncology Institute (IOV)-IRCCS, Padova, Italy

Impact of bladder cancer (BC) on health-related quality of life (HRQL) in 1,476 older Americans. Presenting Author: Chunkit Fung, James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, Rochester, NY

Background: Ipilimumab was the first agent approved for the treatment of unresectable or metastatic melanoma that showed an overall survival benefit in randomised phase III trials. Here we evaluate the safety and efficacy of ipilimumab treatment outside of clinical trials in elderly (⬎70 years old) patients (pts) enrolled in the EAP in Italy. Methods: Ipilimumab was available upon physician request for pts aged ⱖ16 years with unresectable stage III/IV melanoma who had either failed systemic therapy or were intolerant to ⱖ1 systemic treatment and for whom no other therapeutic option was available. Ipilimumab 3 mg/kg was administered intravenously every 3 weeks for 4 doses. Disease evaluation was performed at baseline and after completion of induction therapy using immunerelated response criteria. Patients were monitored for adverse events (AEs), including immune-related AEs, using Common Terminology Criteria for Adverse Events v.3.0. Results: Out of 855 Italian pts participating in the EAP from June 2010 to January 2012 across 55 centres, 193 (22.6%) were over 70 years old (median 75; 70-88). Of these, 132 pts (68.4%) received all 4 doses of ipilimumab, 24 (12.4%) 3 doses, 17 (8.8%) 2 doses and 20 pts (10.4%) received 1 dose. With a median follow-up of 7.6 months (range 1-26), the disease control rate among 188 pts evaluable for response was 38.3%, including 4 pts (2.1%) with a complete response, 24 (12.8%) with a partial response and 44 (23.4%) with stable disease. As of December 2012, median progression-free survival and overall survival were 3.7 months and 8.9 months respectively, with 1-year survival rate of 38%. In total, 96 pts (49.7%) reported an AE of any grade, which were considered treatment-related in 69 pts (35.7%), with a safety profile comparable to the general population. Grade 3/4 AEs were reported by 19 pts (9.8%) and drug-related in 11 pts (5.7%). AEs were generally reversible with treatment as per protocol-specific guidelines with a median time to resolution of 2.0 weeks. Conclusions: Based on the data from EAP, ipilimumab is a feasible treatment in the elderly population; efficacy and safety results were similar to those observed in the general population.

Background: The impact of BC on HRQL is poorly understood. To our knowledge, this is the first and largest cross-sectional study that compares HRQL of patients before and after BC diagnosis (DX). Methods: Our sample included 1,476 BC patients (ⱖ age 65) within the SEER-Medicare Health Outcomes Survey linkage database (1998-2007). We assessed differences in HRQL as measured by SF-36 physical (PCS) and mental (MCS) summary scores in patients who had a survey ⬎1 yr before BC DX (n⫽620) and those who had a survey after BC DX (n⫽856). We compared groups by year from BC DX using regression analyses and results were adjusted for cancer stage, race, gender, age at BC DX, marital status, education, income, smoking status, activity of daily living (ADLs), and non-cancer comorbidities. Results: Patients who had a survey after BC DX were diagnosed with BC at an older age than those with a survey before BC DX (55.9% at age ⱖ75 yr vs. 36.8%; P⬍0.01). Other baseline demographic and socioeconomic characteristics were similar. Baseline HRQL were poor in patients before DX (PCS mean⫽40.1; MCS mean⫽51.1) with 50.6% and 31.9% of them having comorbidity score ⱖ2 and impairment of ⱖ1 ADLs, respectively. After BC DX, significant decreases in PCS (-2.7; 95% CI -3.8,-1.7) and MCS (-1.4; 95% CI -2.6, -0.3) were observed, with HRQL being lowest in those who had BC DX within 1 yr (PCS mean⫽ 36.6; MCS mean⫽49.7). Declines in PCS during the ⬍1, 1-3, 3-5, 5-10, and 10⫹ yr periods after BC DX compared to before BC DX were -3.8 (P⬍0.01), -2.5 (P⬍0.01), -2.2 (P⫽0.01), -1.1 (P⫽0.19) and -0.8 (P⫽0.57) whereas decreases in MCS were -2.0 (P⫽0.01), -2.2 (P⬍0.01), -1.2 (P⫽0.21), -0.1 (P⫽0.92), -0.8 (P⫽0.62) respectively. More advanced BC, lower educational level, higher comorbidity score, and impaired ADLs were significantly associated with both worse PCS and MCS after BC DX (P⬍0.05). Lower income and older age at BC DX showed significant association with low PCS (P⬍0.05). Conclusions: Older BC patients are a vulnerable population with poor baseline HRQL. HRQL of patients after BC DX is significantly worse than HRQL of patients before DX, possibly due to therapy and/or disease progression. Future research that evaluates interventions to improve HRQL in older patients with BC is critical.

9550

9551



Local tumor control and survival outcomes of percutaneous radiofrequency ablation plus post-ablation chemotherapy for lung tumors in nonsurgical patients: A meta-analysis. Presenting Author: Peter Andrew, Department of Internal Medicine, The Ottawa Hospitals, Ottawa, ON, Canada

Comparing elderly and non-elderly adult cancer survivors: Differences in modifiable behaviours of smoking and alcohol cessation and physical activity. Presenting Author: Chongya Niu, Princess Margaret Hospital, Toronto, ON, Canada

Background: Local recurrence is a frequent outcome post radiofrequency ablation (RFA) for local control of lung tumors. We sought to examine local tumor control and survival benefits of RFA plus post-ablation chemotherapy versus RFA alone for management of lung tumors in non-surgical patients. Methods: Search strategy: MEDLINE, the Cochrane Library, and EMBASE databases from January 2000 to December 2012. Inclusion criteria: RFA ⫹/- post-ablation chemotherapy in non-surgical patients with solid lung tumors. Exclusion criteria: Post-RFA radiation therapy, biologics, brachytherapy, or other ablation modalities. Outcomes: Local tumor progression (LTP), overall survival (OS), and disease-free survival (DFS) at 12 month follow-up. Statistical analysis: Fixed effect analyses, bias assessment, and sensitivity analyses (BioStat Inc., NJ, USA). Results: RFA plus postablation chemotherapy group: 11 clinical studies, 684 patients (mean age 64 years [range 50 to 74]; 434 men, ECOG ⱕ2), ablation of 1,314 lung tumors, with a 4:1 ratio being ⬍3cm versus ⱖ3cm in diameter, and a 1:4 ratio being primary versus metastatic. RFA alone group: 38 clinical studies, 1,874 patients (mean age 65 years [range 49 to 75]; 1,041 men, ECOG ⱕ2), ablation of 2,604 lung tumors, with a 2.1:1 ratio being ⬍3cm versus ⱖ3cm in diameter, and a 1:1 ratio being primary versus metastatic. RFA plus post-ablation chemotherapy versus RFA alone: LTP of 15% over median follow-up of 31 months [range 12 to 59]) versus 19% over median follow-up of 21 months [range 12 to 29]); OR 0.73 (95% CI: 0.61-0.86, p⬍0.05) at 12 month follow-up. OS was 89% versus 78%, respectively, at 12 month follow-up; OR 1.52 (95% CI: 1.16-2.00, p⫽0.003). DFS was 90% versus 82%, respectively, at 12 month follow-up; OR 3.18 (95% CI: 2.04-4.96, p⬍0.05). Sensitivity analyses were robust, publication bias relatively narrow, and heterogeneity within acceptable limits; Q statistic⬍21; p⬎0.13 for all outcomes. Conclusions: This meta-analysis reveals that RFA plus post-ablation chemotherapy of lung tumors yields improved outcomes in terms of LTP, OS, and DFS compared with RFA alone.

Background: In developing a cancer survivorship program at Princess Margaret Cancer Centre (Canada), cancer survivors were surveyed on modifiable behaviours: smoking/alcohol intake and physical activity. We evaluated whether special considerations should be given to elderly cancer survivors (age 65 years or higher), where few data currently exists. Methods: 616 adult cancer survivors of all disease sites were asked about their smoking, alcohol, and physical activity habits, and their attitudes and knowledge about effects of these habits on cancer outcomes. Univariate and multivariate logistic regression models evaluated the effect of age on these factors. Results: 23% were elderly; 53% female; 15% breast, 20% gastrointestinal/gynecologic, 24% hematologic, 19% thoracic/head and neck, and 13% genitourinary cancers. Median follow up was 24 months. Elderly survivors were more likely to be ever smokers (OR⫽1.69, 95% CI [1.12-2.53]) and ex-smokers than current (OR⫽4.11 [2.02-8.33]), but less likely to know how smoking could affect cancer treatment (OR⫽1.72 [1.09-2.69]) or outcome (OR⫽1.66 [1.07-2.60]). Elderly patients were less likely to binge drink (OR⫽2.07 [1.34-3.19]), but more likely to perceive alcohol as improving quality of life (OR⫽1.98 [1.11-3.56]) and overall survival (OR⫽2.32 [1.22-4.41]) in their own situation. Elderly survivors were less likely to receive information about alcohol use (OR⫽2.89 [1.29-6.49]). Meeting exercise guidelines at diagnosis (OR⫽1.76 [1.162.67]) and improving/maintaining them after treatment (OR⫽2.02 [1.122.93]) was substantially lower in elderly survivors, but perceived benefits/ harms of exercise did not differ with age. Conclusions: Elderly patients know less about the impact of smoking on their overall health, despite having higher rates of cumulative exposure. A lower proportion received information on alcohol use. Elderly patients are less able to achieve the same exercise goals as younger patients. Survivorship programs may need to tailor counselling on modifiable behaviours by age group. CN, LE, SMHA, and GL contributed equally.


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Patient and Survivor Care General Poster Session (Board #29D), Mon, 1:15 PM-5:00 PM

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Identification of comprehensive geriatric assessment based risk factors for malnutrition in elderly Asian patients with cancer. Presenting Author: Tira Jing Ying Tan, Department of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore

Gender differences in comprehensive geriatric assessment (CGA): Results from the IN-GHO registry. Presenting Author: Friedemann Honecker, Department of Oncology and Hematology, Hubertus Wald Tumorzentrum, University Cancer Center, Hamburg, Germany

Background: Elderly patients with cancer are at increased risk for poor nutrition. Malnutrition is associated with increased morbidity and mortality. There is limited information on the clinical risk factors for malnutrition in elderly Asian cancer patients. We aim to identify comprehensive geriatrics assessment (CGA) based clinical factors in elderly Asian cancer patients associated with an increase in malnutrition risk. Methods: CGA data was collected from 249 Asian patients aged 70 years or older who attended the outpatient oncology clinics at the National Cancer Centre Singapore. Nutritional status, one of the seven domains of CGA, was assessed based on the DETERMINE nutritional risk index. Univariate and multivariate logistic regression analyses were applied to assess the association between patient clinical factors together with domains within the CGA and moderate to high nutritional risk. Goodness of fit was assessed using Hosmer-Lemeshow test and discrimination ability assessed based on the area under the receiver operating characteristics curve (AUC). Internal validation was performed using simulated datasets via bootstrapping. Results: Among the 249 patients, 184 (74%) had moderate to high nutritional risk. Multivariate logistic regression analysis identified stage 3– 4 disease (Odds Ratio [OR] 2.54; 95% CI, 1.14-5.69), ECOG performance status of 2-4 (OR 3.04; 95% CI, 1.57–5.88), presence of depression as measured by geriatric depression scale (OR 5.99; 95% CI, 1.99-18.02) and haemoglobin levels ⬍12 g/dL (OR 3; 95% CI 1.54-5.84) as significant independent factors associated with moderate to high nutritional risk. The model achieved good calibration (Hosmer-Lemeshow test’s p ⫽ 0.17) and discrimination (AUC ⫽ 0.80). It retained good calibration and discrimination (bias-corrected AUC ⫽ 0.79) under internal validation. Conclusions: Having advanced stage of cancer, poor performance status, depression and anaemia were found to be independent predictors of moderate to high nutritional risk. Early identification of patients with these risk factors will allow for nutritional interventions which may improve treatment tolerance, quality of life and survival outcomes.

Background: Elderly cancer patients (pts) are a heterogeneous population. As chronological age does not provide sufficient information on individual limitations and resources, a CGA helps to describe the heterogeneity in a structured way. Assessment instruments might be sensitive to gender differences. We therefore analyzed the IN-GHO registry for gender associated differences in results of CGA. Methods: The internet based IN-GHO registry prospectively collects data of elderly cancer pts from ⬎ 100 centres in Germany and Austria. Data from 1,580 pts aged 70⫹ years were analyzed comparing results between female (n⫽883) and male (n⫽697) pts by Chi-square or Mann-Whitney U test. Analyses included results from CGA, physicians´ rating (fit vs. compromised vs. frail) and pts´ self rating of fitness for treatment (Likert scale 1 ⫽ very fit to 6 ⫽ very unfit), type (combination vs. monotherapy vs. no), and dosage (full vs. adapted) of treatment. Results: Mean age was 76.7 years (range 70-97), 71.5% had a solid tumor, and 28.5% a hematological malignancy. Mean age was slightly but significantly higher in women than in men (76.9 vs. 76.4; p⫽0.02), reflected in a higher number of pts. aged 80⫹ (26.5% vs. 21.1%; p⫽0.013). No gender differences were observed in physicians´ rating and pts´ self rating of fitness for therapy, or in type or dosage of treatment. Furthermore, no gender associated differences were noted in KarnofskyPerformance-Scale, comorbidity (Charlson-Comorbidity-Score), polypharmacy, and cognition (Mini-Mental-Status-Examination). Gender associated differences, however, were noted in body mass index (more women in categories ⬍19 and ⬎35), mean ADL (91.7 vs. 93.4, p⫽0.03), mean IADL (6.9 vs. 6.7 (p⫽0.049), and timed-up-and-go test (⬍ 10 seconds 36.1% vs. 43.6%, p⫽0.005). The main differences between women and men in ADL and IADL scores were noted in the item bathing (ADL) and food preparation, housekeeping, and laundry (IADL). Conclusions: The internet based registry is a valuable tool to gain data on prognostic factors, treatment, and outcome in old cancer pts. In several items of CGA, significant differences exist between women and men.

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The prognostic value of rapid screening tests (RST) in geriatric assessment of patients with cancer over 70. Presenting Author: Antonio Bononi, ULSS 18, Rovigo, Italy

A prospective study examining PROs and other geriatric outcomes in older adults with prostate cancer undergoing chemotherapy. Presenting Author: Tharsika Manokumar, University Health Network, Toronto, ON, Canada

Background: Comprehensive Geriatric Assessment (CGA) may help to evaluate the functional status of elderly patients, but, because timeconsuming, RST have been proposed. However, whether these instruments may predict survival is still unclear. The aim of this study was to correlate overall survival (OS) with the results of 3 rapid tests: G8 (1), VES-13 (2, aCGA (3) in patients over 70. Methods: From April 2009 to April 2012, 530 unelected outpatients over 70, 263 males and 267 females, were evaluated. During the first oncologic visit, they were homogeneously assessed by a trained oncogeriatric team using a dedicated, expressly developed web-based software (www: oncoger.ro.it) including all of the 3 rapid tests. Survival curves were drawn using Kaplan-Meier method and compared with log rank test; multivariate analysis was performed according to Cox regression method. Results: The tests identified frail patients as follows: VES-13 69%, aCGA 50%, G8 68.5%. Frailty was significantly associated with poor OS, with different hazard ratios (HR) for each test. HRs for death of frail vs non-frail pts were for aCGA 1.45 (95%CI 1.09-1.89, p⫽0.008), for VES-13 1.55 (95%CI 1.12-2.00, p⫽0.005) and for G8 2.57 (95%CI 1.66-2.93, p⬍0.0001). In the multivariate analysis including the 8 items of the G8 test, appetite loss (HR 1.44, p⫽0.002), weight loss (HR 1.28, p⫽0.003), and personal perception of poor health (HR 1.58, p⫽0.002) were significantly associated with a higher risk of death. Conclusions: i) Frailty, as identified by RST (VES-13, aCGA, G8), is statistically associated with poor OS; ii) G8 presents the most meaningful HR for OS; iii) appetite loss, weight loss and personal perception of poor health are significantly associated with lower OS.Our data show that RST and in particular G8 represent a useful prognostic tool for the assessment of geriatric patients with cancer.

Background: Treatment of metastatic castration-resistant prostate cancer (mCRPC) with chemotherapy improves disease control and survival in older men (age 65⫹) based on large clinical trials. Its effects, though, on more frail elderly men are not well understood and chemotherapy may negatively impact frailty, daily function, physical performance, and quality of life (QOL), particularly outside the clinical trial setting. Methods: Men aged 65⫹ with mCRPC starting first-line chemotherapy were enrolled in this prospective observational pilot study. Physical function was assessed with the timed up and go (TUG) test, timed chair stands, and grip strength. Frailty was evaluated using the Vulnerable Elders Survey (VES-13) questionnaire in addition to functional status (OARS-IADL), social activities limitations and social support (MOS measures). Patients completed the FACT-P and FACT-G to measure prostate-specific QOL and general QOL, respectively. Assessments were completed before each cycle of chemotherapy. Pre-post within-group comparisons were done using student’s T-tests and linear regression. Results: 25 patients (mean age 75) receiving Docetaxel ⫹ Prednisone were enrolled, 3 of whom died and 2 dropped out. Both general and prostate-specific QOL improved over a median of 6 cycles. Patients’ instrumental activities of daily living (IADL) scores remained stable. On average, grip strength was stable and lower extremity function improved on both the TUG and Timed Chair Stands. At baseline, 13 of 25 patients (52%) were frail (VES score 3⫹). Of the patients that completed chemotherapy, 40% were frail. Conclusions: Contrary to our hypotheses, QOL did not decline in this frail elderly cohort, IADL function remained stable, and physical function remained stable or improved during first-line chemotherapy. Frailty also did not increase at the end of treatment as hypothesized. Older men with mCRPC appear to tolerate first-line chemotherapy fairly well in terms of QOL and geriatric domains.




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Safety and tolerability in patients over age 75 included in phase I: The Institut Gustave Roussy experience. Presenting Author: Carole Helissey, Institut Gustave Roussy, Villejuif, France

Comparison of preoperative screening tools predicting postoperative complications in oncogeriatric surgical patients. Presenting Author: Monique Huisman, University Medical Center Groningen, Groningen, Netherlands

Background: Safety and tolerability of anti-cancer therapy in elderly people (⬎⫽75 years, EP) is of major interest since they represent 31% of US patients diagnosed with cancer. However proportion of EP recruited is only 9% in clinical trials and probably less in phase I trials, which aim to determine the recommended phase II dose. Our objective was to evaluate the safety of phase I trials in EP. Methods: Patients treated from 2007 to 2012 at Institut Gustave Roussy in phase I trials, in which patients aged over 75 years had been included. Population was divided into two groups: EP or patients aged ⬍ 75 years (YP). Time to occurrence of first high toxicity (any grade 3-4 adverse event (AE) or dose-limiting toxicity DLT) and overall survival were estimated using Kaplan-Meier method. Conditional Cox proportional hazards model was used to compare occurrence of AE in a sub population of patients aged ⬎⫽ 75 years matched with patients aged ⬍75 years of same Royal Marsden Hospital (RMH) score (Albumin, LDH, Number of metastatic site) and protocol. Results: In the 33 EP and the 161 YP, 20(60%) and 100(62%) grade 3-4 AEs and 1(3%) and 18(11%) DLTs occurred. The median time to occurrence of high toxicity were 2 months (95%CI⫽1-4) and 2 months (95%CI⫽1-2). The median overall survival were 22 months (95%CI⫽11-non estimable) (EP) and 13 months (95%CI ⫽10-16) (YP). Twenty-seven patients aged ⬎⫽75 years could be matched: age over 75 years was not associated with higher risk of neither high toxicity (HR⫽0.85, 95%CI⫽[0.45 ; 1.61], p⫽.62) nor death (HR⫽1.03, 95%CI⫽[0.47;2.24], p⫽.94). Conclusions: No impact of age over 75 years on occurrence of neither high toxicity nor death was identified. Patients above 75 years are good candidates for phase I trials.

Background: In the onco-geriatric surgical population it is important to identify patients at increased risk of adverse post-operative outcome in order to effectively implement preventive measures and to improve outcome in this population. There is need for a time saving and efficient screening tool. Our aim was to determine the predictive ability of the Mini Mental State Examination (MMSE), Brief Fatigue Inventory (BFI) and Timed “Up & Go” (TUG) concerning the occurrence of a major postoperative complication in a series of elderly patients undergoing elective surgery for solid tumors. Methods: In an international cohort, 329 patients ⱖ70years undergoing elective surgery for solid tumors were prospectively included. Primary endpoint was the incidence of a major complication during the first 30 days after surgery. Pre-operatively the MMSE, BFI and TUG were scored. TUG depicts the time needed to stand up from a chair, walk 3 meters, turn around, walk back and sit down. Data were analyzed using multivariable logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (95%-CI). Results: The majority of patients underwent major surgery (n⫽219; 66.6%). A total of 71 (22.1%) patients experienced major complications. TUG, MMSE and BFI, adjusted for center, gender and minor or major surgery, were independent predictors of the occurrence of major post-operative complications (see Table). Conclusions: Screening tools are able to predict major post-operative complications in onco-geriatric surgical patients. TUG is most specific in identifying patients at risk and could be considered to allocate preventive measures effectively. TUG BFI MMSE

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Outcomes of severe sepsis in very elderly (age >80 years) patients with metastatic cancer. Presenting Author: Zahra Touqir, Massachusetts General Hospital, Boston, MA Background: With better treatment and prolonged life expectancy of cancer patients, more elderly patients with metastatic cancer are being treated aggressively for sepsis. There has been philosophical debate about how aggressive the treatment should be for very elderly patients with metastatic disease admitted to intensive care unit with severe sepsis. The data with regards to the outcome of severe sepsis in those above 80 years with metastatic disease is very limited. Methods: Using the Healthcare Cost and Utilization Project - Nationwide Inpatient Sample 2007-2008, patients older than 80 years, discharged with severe sepsis were identified using ICD-9-CM codes. Those with metastatic disease were identified using ICD-9-CM codes 196-199. The outcomes studied were mortality and discharge disposition. We also examined the rates of invasive mechanical ventilation, blood transfusion, use of central venous catheter, tracheostomy and dialysis. The outcomes were compared to those who did not have cancer. Chi square test was used to compare the variables. Significance was defined as p value ⬍0.05. Results: There were 458,443 discharges with severe sepsis in patients aged ⱖ80 years. Of these 3.3% had metastatic disease. The in-hospital mortality was significantly higher in those with metastatic disease (43.7% vs. 33.3%, p⬍0.001). The discharge disposition of the very elderly is shown in the Table. The rates of invasive mechanical ventilation, tracheostomy, use of central venous lines and dialysis were similar in both the groups. Blood transfusions were observed to be higher in metastatic group. Conclusions: Resource utilization in elderly with severe sepsis is similar regardless of the presence of metastatic disease. However, the mortality is significantly higher in those with metastatic disease. Of the survivors, only a fraction reaches home with independent functioning. Involvement of palliative care services at an early stage and addressing code status promptly during the beginning of each hospitalization may help relieve resource and financial burden to health care providers. Disposition (%) Home Home health care* Nursing home* Hospice* Others * p⬍0.05

No cancer

Metastatic disease

12 13.9 57.7 12.2 4.2

12.5 21.6 34.1 27.6 4.2

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OR (95% CI; p value)

Major complications in patients with good test results

Major complications in patients with poor test results

4.25 (1.69-10.68; 0.002) 2.03 (1.04-3.95; 0.04) 2.56 (1.30-5.04; 0.006)

15.3% 15.5% 15.2%

47.1% 30.7% 32.3%


The influence of autologous stem cell transplant (ASCT) on survival in older adults with multiple myeloma (MM). Presenting Author: Tanya Marya Wildes, Washington University School of Medicine in St. Louis, St. Louis, MO Background: In randomized trials, ASCT improves survival in MM patients (pts) ⬍ age 65. The impact of ASCT on survival in older adults with MM is unknown. Methods: In a retrospective cohort study, all pts ⱖ age 65 with MM diagnosed between 2000 and 2010 were identified from the BarnesJewish Hospital Oncology Data Services Registry (N⫽199), including demographic, comorbidity (ACE-27 index) and survival data. Medical records were reviewed for stage, ECOG Performance Status (PS) and treatment. Pts ⬎ age 77 or who received only steroids/supportive care were excluded (N⫽53). The primary endpoint was overall survival (OS), defined as time from diagnosis to death, censored at last follow-up. Univariate analyses for factors associated with undergoing ASCT were performed using Fisher’s exact test or nonparametric rank-sum test; multivariate logistic regression was used to create propensity scores for ASCT. The association between ASCT and OS was assessed using a multivariate Cox proportional hazard model with propensity scores adjustment; missing values in predictors were imputed using multiple imputations. Results: Of 146 pts included, the median age was 68 (range 65-77); 53% were male, 81% Caucasian; 43% underwent ASCT. Comorbidities were common (43.9% mild, 21.6% moderate and 9.3% severe). Durie-Salmon Stages were I – 9.5%, II-18.1%, III-72.4%. PS at diagnosis was 0 - 18.3%, 1 - 51.0%, 2 21.2% and 3 - 9.6%. Most received novel agents (thalidomide, lenalidomide or bortezomib) in their initial treatment (25.2% alkylators only, 58.6% novel single agents ⫾ steroids, 16.2% novel combination regimens). Age (p⬍0.0001) and insurance/payer (p⫽0.02) were associated with ASCT. On univariate analysis, ASCT [Hazard Ratio (HR) 0.54 (95% confidence intervals (CI) 0.35-0.82)] and PS [PS 1: HR 2.3 (CI 1.0-4.9), PS2: HR 3.3 (1.4-7.9); PS 3: HR 3.5 (CI 1.3-9.3)] were associated with mortality. On multivariate analysis controlling for PS, comorbidity, stage and propensity to undergo ASCT, ASCT was associated with reduced mortality [HR 0.52 (CI 0.30-0.92), p⫽0.02]. Conclusions: In pts over age 65 with MM, ASCT is associated with better OS after adjusting for propensity to undergo ASCT.


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Best supportive care (BSC) in published clinical trials. Presenting Author: Amy Pickar Abernethy, Duke University Medical Center, Durham, NC Background: BSC as a control arm in clinical trials is poorly defined. A systematic review was conducted to evaluate clinical trial concordance with published, consensus-based framework for BSC delivery in trials. Methods: A consensus-based Delphi panel previously identified 4 key domains of BSC delivery in trials: multidisciplinary care; supportive care documentation; symptom assessment at least as often as the intervention arm; and guideline-based symptom management. A systematic review of trials including BSC control arms assessed BSC concordance to the consensusbased domains. Databases were searched from 2002-2012 using search strings: “cancer”; “best supportive care”; “randomized” or “random allocation”; and “supportive” or “palliative.” Exclusion criteria were: no BSC arm, non-human trial, not randomized, not English, not advanced cancer, or not including anticancer therapy. Data were independently extracted by 2 reviewers and scored by 4 reviewers for conformance with consensus-based BSC framework. Results: 373 articles were retrieved, 17 retained after applying exclusion criteria. Overall, trials conformed to ⬍18% of the consensus-based BSC standards. 35% of articles offered a detailed description of BSC. 65% reported baseline and regular symptom assessment, and 47% reported using validated symptom assessment measures. 35% reported symptom assessment at identical intervals in both experimental and BSC arms. None listed an evidence-based guideline for symptom management. None of the multicenter trials reported standardization of BSC across sites. No studies reported educating patients on symptom management or goals of anti-cancer therapy. No studies reported offering access to palliative care specialists, social workers, financial or spiritual counseling. Conclusions: Reporting of BSC in trials is incomplete, resulting in uncertain internal and external validity. Such poorly defined interventions and variation between sites is unacceptable for other aspects of a clinical trial. Unless it is truly best supportive care, such studies may risk systematically over-estimating the clinical effect of the comparator arms. Standardization of a BSC delivery framework is needed to improve trial design and data generalization.

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Cancer patients with ECOG-PS higher than 1: Who are those who benefit of palliative chemotherapy? Presenting Author: Rafael Caires-Lima, Instituto do Câncer do Estado de São Paulo, Universidade de São Paulo, São Paulo, Brazil Background: Palliative chemotherapy (PC) is a treatment option in pts with metastatic cancer. Although pts with ECOG-PS ⬎ 1 are underrepresented in clinical trials, they are often treated with PC in daily practice. We aimed to identify factors associated with poorer survival and lack of benefit of PC in this subset of pts. Methods: We conducted a case-control retrospective analysis of 301 consecutive pts with solid tumors and ECOG-PS ⬎ 1 when initiated PC, selected from 2514 pts who died between Aug/2011 and Jul/2012 in a tertiary cancer care institution or its hospice. Cases were defined as those pts who survived ⬍ 90d after the first cycle of first line PC, and controls were those who had a longer survival. Frequencies were compared by chi-square test or Fisher exact test. Risks were estimated by odds ratios (OR) and logistic regression analysis. Overall survival (OS) was calculated by Kaplan-Meier method and curves was compared using log-rank test. Results: 142 cases/159 controls were included: median age 58/63 y.o. (p⫽0.09; t-test) and 49%/50% female (p⫽0.941; chi-square). Gastrointestinal and lung cancers were the most frequent primaries (31 and 17%, respectively). Factors associated with poorer OS were age ⬎ 60 y.o. (OR 1.7; 95%CI 1.0 –2.6), ECOG-PS ⬎ 2 (1.9; 1.2–3.1), weight loss ⬎ 10% (1.8; 1.1-2.8), hemoglobin ⬍ 10 g/dL (2.6; 1.6-4.2), albumin ⬍ 3 g/dL (2.7; 1.5-5.1), serum creatinine (sCr) ⬎ 1 mg/dL (2.8; 1.6-5.0), C-reactive protein ⱖ 5 mg/L (8.6; 1.0-72.9), altered mental status (4.2; 1.4-13.2) and in-hospital PC (3.2; 1.9-5.2). Cases were more likely to experience grade ⱖ 3 toxicity (43 vs. 28%; p⫽0.005), die of toxicity (16 vs. 6%; p ⫽ 0.0007) and not be offered palliative care only (47 vs. 71%; p⬍0.0001). mOS was 204 and 34d among controls and cases, respectively (HR 0.177; 95%CI 0.015-0.033, p⬍0.0001). Median time to death was 39.5d (0-1103). Logistic regression analysis identified ECOG-PS ⬎ 2 (OR 2.3, p⫽0.044) and sCr ⬎ 1 mg/dL (OR 11.2, p⫽0.0002) as independent predictors of 3-mo fatality. Conclusions: ECOG-PS ⬎ 2 and elevated sCr were identified as independent predictors of poor OS in these pts. PC needs to be prescribed with caution in ECOG-PS ⬎ 1 pts, since it seems to offer no benefit in OS and could lead to abbreviation of life.

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Variation in health-related quality of life (HRQoL) during chemotherapy for advanced non-small cell lung cancer. Presenting Author: Bjørn Henning Grønberg, European Palliative Care Research Centre, Trondheim, Norway

Long-term use of fentanyl pectin nasal spray in patients with breakthrough pain in cancer. Presenting Author: Donald Taylor, Georgia Center for Cancer Pain Management and Palliative Medicine, Marietta, GA

Background: Physicians might overestimate benefits and underestimate toxicity of cancer therapy. Thus, patient reported HRQoL is an important part of evaluating treatment effect and assessing side effects. HRQoL is commonly reported once per chemotherapy cycle and just prior to administration of the next course (day 0). Several studies have not detected differences in HRQoL despite differences in physician-observed toxicity. We hypothesized that HRQoL varies during chemotherapy cycles; that side effects are most pronounced the first week after chemotherapy administration; and that repeated assessments improve the ability to detect differences in HRQoL. Methods: Patients were randomized to receive 3 courses of either vinorelbine/carboplatin (VC) or gemcitabine/carboplatin (GC) every 3 weeks. They reported HRQoL on the EORTC QLQ C30 ⫹ LC13 on day 0, 3, 8, 11, 15 and 22 of each cycle. A difference in mean scores of ⬎ 5 points is considered clinically detectable. Results: 52 pts (VC: 25, GC: 27); median age 65; 56 % men; 85 % stage IV; 93 % performance status 0-1; 75 % completed 3 cycles; 32 % response-rate; 71 % grade 3-4 toxicity. Baseline characteristics; treatment administered and outcomes of therapy were similar between treatment arms. Completion rates of QLQs were 96-64 %. There were significant variations in mean scores during cycles for several domains (mean scores during cycle 1 for some domains are listed in the table). For several domains, there were differences of ⬎ 5 points between the treatments arms at day 3-15 that were not detectable on day 22 (day 0 of next cycle). In general, treatment related symptoms were most pronounced on day 3 in every cycle. Conclusions: Our results suggest that timing and number of assessments influence the likelihood of detecting differences in HRQoL during chemotherapy. Day 3 was the best time point for assessing reduced function and side effects of the regimens administered in our trial.

Background: Given that patients with cancer are living longer, there is a need to ensure that treatments used for palliative care are well tolerated and effective during long-term use. The objective of this study was to investigate the use of fentanyl pectin nasal spray (FPNS) for the treatment of breakthrough pain in cancer (BTPc) in patients taking regular opioid therapy. Methods: A total of 401 adult patients, taking at least 60 mg/day oral morphine or equivalent, with an average of 1 to 4 episodes of BTPc per day, who were either newly enrolled or had completed a randomized controlled trial with FPNS, entered into an open-label assessment study (NCT00458510). Of these, 171 patients, continued into an extension period. Up to 4 episodes of BTPc per day were treated with FPNS at titrated doses between 100 ␮g and 800 ␮g. Patients returned to the clinic at 4-week intervals for assessment and reporting of any adverse events (AEs). Results: There were 163 patients with documented FPNS use. The mean duration of use was 325 days; 46 patients used FPNS for more than 1 year, while the maximum duration was 3 years and 8 months. In total, 2% of patients withdrew from the study due to lack of efficacy. Seventy-four percent of patients did not change their FPNS dose. The most common AEs, aside from disease progression, were: insomnia, 9.9%; nausea, 9.4%; vomiting, 9.4%; and peripheral edema, 9.4%. The overall incidence of treatment-related AEs was 11.1%, the most common being constipation (4.1%), with no apparent dose relationship. Ten patients (5.8%) experienced treatment-related nasal AEs, which, with the exception of 1 severe event, were all mild or moderate. Conclusions: FPNS appeared to provide a sustained benefit and was well tolerated during the long-term treatment of BTPc. Clinical trial information: NCT00458510.

Mean scores - All patients - Cycle 1 Functional scales (a high score ⴝ better function) Symptom scales (a high score ⴝ more symptoms)

Day

0

3

8

11

15

22

Global quality of life

54

49

53

55

55

57

Physical function Fatigue

63 44

57 52

61 45

61 42

62 47

64 40

Nausea - vomiting Constipation

6 25

16 34

15 34

9 33

9 29

6 25




Epoetin biosimilars in the management of anemia secondary to chemotherapy in patients with solid tumors, lymphomas, and myelomas: The ORHEO study. Presenting Author: Elisabeth Luporsi-Gely, Centre Alexis Vautrin, Nancy, France Background: Chemotherapy may induce anemia with potentially severe consequences. The ORHEO (place of biOsimilaRs in the therapeutic management of anaemia secondary to chemotherapy in HaEmatology and Oncology) study examined the efficacy and safety of epoetin alfa biosimilars (EABs) for the treatment of chemotherapy-induced anemia (CIA) in the clinical setting. Methods: ORHEO was a multicenter, observational, prospective, post-marketing study conducted in France. Patients with CIA (Hb ⬍110g/L) ⬎18 years old, with solid tumors, lymphomas or myelomas and eligible for epoetin alfa treatment were included in the study; they received EAB as prescribed by their physician. Baseline patient characteristics and anemia-related data including baseline and target Hb level epoetin treatment, adverse events and any other concomitant treatments prescribed were recorded. The primary endpoint was the rate of responders (defined as an increase in Hb levels to 100 g/L or at least 10 g/L since inclusion visit, or reaching target Hb set at start of study, without any blood transfusions in the 3 weeks prior to measurement) at ⫹3 months (M3). Other endpoints included rate of responders at ⫹6 months (M6) and safety endpoints. Results: 2310 patients (51.43 % male, 48.57 % female) from 232 centers were included in this study. At baseline 79.6% had solid tumors, 13.0% lymphomas and 7.4% myelomas. Median age was 68 y (range: 18 –93). Mean baseline Hb level was 96 g/L with a target Hb level of ⬎⫽ 120 g/L for 52.7% of patients. Almost all (99.9%) received the biosimilar epoetin zeta (median dose 30,000 IU/week) with 26.6% receiving additional iron supplementation. A total of 2056 and 1664 patients had at least one Hb level value at M3 and M6 respectively. The rate of response was 81.6% and 86.5% at M3 and M6, respectively. In total, 17.0% of treated patients reported clinically relevant adverse events (all grades), the most common being infections (5.0%) and thromboembolic events (3.5%). Transfusion rates were reported as 9.4% and 5.8% at M3 and M6, respectively. No EAB-related deaths were reported. Conclusions: EAB was effective and well-tolerated in the management of CIA. Clinical trial information: NCT01626547.

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Safety and quality assurance of MR-guided focused ultrasound (MRgFUS) in palliation of painful bone metastases. Presenting Author: Joshua E. Meyer, Fox Chase Cancer Center, Philadelphia, PA Background: Palliation of bone metastases is typically performed with radiation therapy (RT). However, a significant minority of patients cannot obtain durable relief from RT. MRgFUS combines non-invasive focused ultrasound with MR guidance. Preliminary phase III results comparing MRgFUS to sham treatment have demonstrated efficacy. This study examines the safety of this procedure in a large prospective, multi-center study. Methods: Patients with a painful bone metastasis were randomized (3:1) to either MRgFUS or sham treatment for the single most painful lesion. Sham patients were given the opportunity to cross over after 2 weeks. Each adverse event (AE) was recorded prospectively and scored for severity and relation to treatment. Results: Thirty-seven patients were enrolled to receive sham treatment and 115 to receive MRgFUS. Sites of treatment were: 102 pelvis, 28 thorax, 7 lower extremity and 2 upper extremity. Seventy-seven target lesions were osteolytic, 29 were osteoblastic and 33 were mixed. Treatment was discontinued prior to completion in 8 treatments. Of these, 7 were pelvic targets and 6 lesions were osteolytic. The most common reasons for discontinuation were pain (4) and patient movement (2). Forty-seven percent of treatment patients and 2.7% of sham patients reported at least one AE. Of 76 AEs, 67 were considered non-significant and anticipated, 57 being intra-procedure pain. Four significant events included 2 possibly related fractures at treated lytic lesion sites, 1 grade 3 skin burn and 1 patient with neuropathy. Four patients experienced events unrelated to study treatment and 1 patient experienced temporary apnea from anesthesia described as incidental. Conclusions: MRgFUS is a safe treatment for palliation of painful bone metastases. Ninety-three percent of MRgFUS treatments were carried out to completion. Three percent of patients experienced significant AEs, including 2 fractures of treated lytic tumors. These safety data reinforce and confirm previous experience with this technology and encourage its use for patients not suitable for RT. Clinical trial information: NCT00656305.

9567


Integrated oncopalliative care versus standard care for patients with metastatic lung cancer: A single institution retrospective review. Presenting Author: Jonathan Douglas King, University of Wisconsin Hospitals and Clinics, Madison, WI

Patient-reported outcomes for determining prognostic groups in veterans with stage IV solid tumors starting systemic therapy. Presenting Author: Victor T Chang, VA New Jersey Health Care System/ University of Medicine and Dentistry of New Jersey, East Orange, NJ

Background: Patients with metastatic non-small cell lung cancer (NSCLC) receiving early palliative care (PC) demonstrated improved anxiety, quality of life, and survival compared to standard oncology care (SOC). ASCO clinical practice guidelines recommend concurrent PC and SC be offered to patients with metastatic NSCLC. Our lung cancer clinic is partially integrated with PC. We performed retrospective chart review comparing patients seen in our integrated clinic with SOC patients for survival, trial participation, chemotherapy and hospice utilization. Methods: Charts of all patients with advanced lung cancer from July 2007-June 2011 were reviewed. Eligible patients were those who received any care at our center. Demographic, treatment details, survival, and hospice utilization data were obtained. Overall survival and length of hospice enrollment were calculated for patients treated with PC compared to SOC. Results: Of 207 patients, 82 received PC. Overall survival favored PC (11.9 months vs. 10.1 months, p⫽0.032). Hospice length of stay (LOS) favored PC (38.5 days vs. 24 days in SOC, p⫽0.047). There was not a significant difference in lines of chemotherapy, chemotherapy in the last 30 days of life, or trial participation. Conclusions: Our chart review provides confirmatory evidence that early integrated PC in lung cancer patients increases survival and hospice LOS without affecting chemotherapy utilization or trial participation.

Background: A Recursive Partitioning Analysis (RPA) algorithm predicted four groups with distinct median survivals in patients with advanced cancer entering palliative care (ASCO 2010, Abst 9040). We investigated whether this algorithm could apply to cancer patients starting systemic therapy. Methods: The RPA algorithm is based upon Karnofsky performance status (KPS), Functional Assessment of Cancer Therapy (FACT) physical wellbeing (PWB) subscale, and Memorial Symptom Assessment Scale Short Form (MSAS-SF) physical symptom distress (PHYS) subscale. Starting in 2007, a convenience sample of Veterans who were prescribed systemic treatment for their cancer was enrolled in an IRB approved protocol, and completed quality of life (FACT- G) and symptom (MSAS SF) questionnaires prior to starting the first cycle of treatment. We analyzed records of patients with stage IV metastatic solid tumors enrolled through August 2011, and determined survival as of December 1, 2012. Analyses were performed with STATA 11.0. Results: There were 72 patients (pts). The median age was 63 yrs, (range 46-86). Men comprised 71 (98%) pts. First line systemic therapy was given to 59 (82%) pts. The most common primary sites were lung cancer (25 pts, 35%), prostate 9 pts(12%) and colon 7 pts (10%). Median KPS was 90% (range 40-100%), PWB median 23 (range 6-28), and MSAS SF median PHYS 0.73 (range 0-2.93). Overall median survival was 269 days (range 6-1762) and 57 pts (79%) had died. There was 1 pt in group 1, 45 pts in group 2, 8 pts in group 3, and 18 pts in group 4. Median survival (days) by RPA group was 155 for group 1, 177 for group 2, 292 for group 3, and 610 for group 4 (p⫽.011). Conclusions: These preliminary findings suggest that this algorithm is capable of dividing patients with metastatic solid tumor who are starting chemotherapy into prognostic groups. It may have applications in clinical trials. Further development is indicated.

Concurrent oncology and PC (nⴝ82)

Age LOS in hospice (days) ECOG PS 0 1 2 >3 Lines of chemotherapy 0 1 2 >3 Chemotherapy last 30 days of life N Y Clinical trial participation N Y OS (months)

Standard care (nⴝ125)

Median

Range

Median

Range

P value

62 38.5 N 17 39 12 9

41-95 0 – 378 % 22 51 16 12

64 24 N 50 34 25 6

29-85 0 - 387 % 43 30 22 5

0.978 0.047* P value 0.002*

11 31 27 12

14 38 33 15

21 38 35 28

17 31 29 23

0.374

65 8

89 11

99 20

83 17

0.265

55 23

71 29

97 23

81 19

0.0929

11.9

0.6 – 35.8

10.1

0.7 – 44.6

0.113† 0.032‡*

RPA group 1 2 3 4

Definition

N (solid tumor)

Median survival (d)

KPS ⬍ 50% KPS ⬎50%, PWB⬍25 KPS ⬎50%, PWB⬎25, PHYS⬎0.6 KPS ⬎50%, PWB ⬎25, PHYS ⬍0.6

1 45 8 18

155 177 292 610


592s 9568


Breaking bad news: Comparison of perspectives of Middle Eastern cancer patients and their relatives. Presenting Author: Jamal M Zekri, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia Background: It is believed in some Middle Eastern (ME) cultures that disclosure of bad news to cancer patients may cause loss of hope. On many occasions the relatives’ and patients’ wishes are opposed regarding this matter. This study investigates cancer patients’ and their relatives’ perspectives regarding communication of cancer-related bad news in a ME population. Methods: Nine close-ended questions were designed in a questionnaire format to obtain cancer patients’ (cohort I) and their relatives’ (cohort II) perspectives regarding communication of cancer related bad news from diagnosis to end-of-life. The questionnaire was answered by patients and relatives during out-patient visits. Chi-square test was used to test differences in responses between the two cohorts. Results: 203 participants (100 patients and 103 relatives) completed the questionnaire. In cohorts I and II, 28% and 58% of participants were males respectively (p⬍0.001). In contrast to relatives’ views, majority of patients preferred to be informed of diagnosis and possible adverse outcome of their illness, as detailed in the Table. Conclusions: Our study indicates that there is significant discordance between the preferences of ME cancer patients and their relatives regarding disclosure of cancer related bad news to the patient. As opposed to relatives’ beliefs, most patients would prefer to know bad news throughout the course of their illness. Unless a patient indicates otherwise, physicians should strive to keep cancer patients informed of their health related events. Percentage of “yes” answers by patients and relatives. Should the patient be informed of: Diagnosis of cancer? Any poor outcome? Failure of treatment? Every change in their condition and outcome? Serious health-related news? Unavailability of treatment options? Do you agree that doctors should not hold information from the patient at the request of family members? Should the patient be involved in end of life discussion? Bad news should be disclosed first to: The patient A family member Both at the same time

9570

Patients

Relatives

P value

87% 90% 85% 92% 98% 90% 80%

68% 57% 39% 71% 85% 61% 56%

0.001 ⬍0.001 ⬍0.001 ⬍0.001 0.001 ⬍0.001 ⬍0.001

56% _ 43% 16% 40%

30% _ 9% 61% 30%

⬍0.001 ⬍0.001


The Minneapolis-Manchester Quality of Life Instrument (MMQL): Reliability and validity of the Adult Form (AF). Presenting Author: Alysia Bosworth, City of Hope, Duarte, CA Background: Cancer survivors are at risk for deficits in health-related quality of life (HRQL). Youth (8-12y) and adolescent (13-20y) versions of the MMQL have been developed to address survivor-specific issues and are currently in use; the MMQL-AF has now been developed to assess HRQL in cancer survivors aged 21-55y, enabling cross-sectional and longitudinal assessment of childhood cancer survivors as they age. Methods: The MMQL-AF was administered to 499 adults: 65 patients undergoing cancer therapy, 107 off therapy, 327 healthy controls (matched on sex, age, education). Factor analysis was performed; items with factor loadings ⱖ0.40 were retained. The following psychometric properties were evaluated: internal consistency reliability (Cronbach’s alpha), construct validity (concurrent administration of SF-36), known-groups validity (score comparisons across the 3 groups), and stability (intraclass correlations from patients completing MMQL-AF twice, 2 weeks apart). Results: Among patients, 46% had hematological malignancies, 33% were males, 64% were non-Hispanic whites; median age was 40y. Factor analysis resulted in retention of 44 items across 6 scales: social functioning (n⫽9), physical functioning (n⫽12), cognitive functioning (n⫽7), outlook on life (n⫽4), body image (n⫽5), and psychological functioning (n⫽7).Internal consistency was 0.8-0.9 for scales and 0.95 overall.The MMQL-AF distinguished between known groups; healthy controls scored significantly higher (better HRQL) than patients on 4 of 6 scales. Off-therapy patients scored higher than on-therapy patients on physical functioning.The MMQL-AF scales correlated highly with SF-36 scales hypothesized to tap similar domains (all P values ⬍0.001), demonstrating construct validity.Intraclass correlations were 0.82-0.95 for scales and 0.98 overall (all P values ⬍0.001), indicating high stability. Conclusions: MMQL-AF is a reliable and valid self-report instrument for measuring multi-dimensional HRQL in cancer survivors aged 21-55y. Development of this instrument ensures availability of a tool that can assess HRQL from 8-55y, thus addressing needs of childhood cancer survivors as they age.

9569


Practical assessment of psychosocial concerns associated with genetic testing in ovarian cancer patients using the MICRA questionnaire. Presenting Author: Merete Bjørnslett, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway Background: Ten to 15% of ovarian cancer patients are BRCA mutation carriers. By offering genetic testing, families at risk and healthy female mutation carriers will be identified and offered clinical follow-up. The MICRA questionnaire was developed as a brief, practical, and targeted assessment of concerns and psychosocial issues associated with genetic testing. This study evaluates the practical and psychometric properties of the MICRA (Norwegian translation) in tested ovarian cancer patient. Methods: Since 2002, ovarian cancer patients at Oslo University Hospital, Norwegian Radium Hospital are offered genetic counseling and testing. By the end of 2009, 1,032 were included. The 530 (51%) patients still alive, were mailed the MICRA and three other instruments relevant for mental distress. 354 (67%) patients responded. Among them 9% were BRCA mutation carriers, 7% had a personal history of breast cancer, 29% had a family history of breast and/or ovarian cancer, and 55% had no such family history. Results: In the BRCA mutation carrier group, the total MICRA score and its subscale scores of distress, uncertainty, and positive experiences were all significantly higher than in the other groups. Confirmatory factor analyses of the three subscales of MICRA showed inadequate fit indices, while a four factors solution including the new factor of Support from family (items #18 and #19), showed adequate fit. The Positive Experiences subscale showed a maximum of 4% explained variance in relation to the Hospital Anxiety and Depression Scale total score, the Impact of Event Avoidance and Intrusion scores, and the Eysenck’s Neuroticism score. The subscales of Distress and Uncertainty showed maximum 12% and 41% explained variance, respectively, while the total MICRA score showed 22% explained variance. Conclusions: Our study supports the feasibility of the MICRA in ovarian cancer patients. Frail women may be identified for closer follow-up by using MICRA. Discrimant, content and construct validities of the MICRA were supported, while the factor structure still is open to further investigation.

9571


Taking control of cancer: Why women are choosing mastectomy. Presenting Author: Andrea Marie Covelli, University of Toronto, Toronto, ON, Canada Background: Rates of both unilateral (UM) and bilateral mastectomy (BM) for early stage breast cancer (ESBC) have been increasing since 2003. Studies suggest that this is due to women playing a more active role in their decision making, however they do not describe why women are choosing this option. Methods: We conducted a qualitative study using grounded theory to identify factors influential in women’s choice for mastectomy. Purposive sampling was used to identify women across the Greater Toronto Area (Ontario, Canada), who were suitable candidates for breast conserving surgery (BCS) but underwent UM or BM. Data were collected through semi-structured interviews. Constant comparative analysis identified key ideas and themes. Results: Data saturation was achieved after 29 in-person interviews. 12 interviewees were treated at academic cancer centres, 6 at an academic non-cancer centre and 11 at community centres. 15 women underwent UM; 14 underwent BM. Median age was 55. ‘Taking control of cancer’ was the dominant theme that emerged. There were 7 subthemes: 1.the Diagnosis of cancer was received with shock and fear; 2.during Surgical Discussion both BCS and UM were discussed; BM was discouraged by the surgeon 3.women Misperceived Risk, misunderstanding recurrence and survival rates 4.Women’s choice for UM was due to fear of recurrence and/ or radiation 5.Women’s choice for BM was due to fear of recurrence, ‘never wanting to do this again’ and/or need for cosmetic balance 6.Sources of Information varied in importance, previous cancer experience had the greatest impact 7.women were actively Controlling Outcomes, more surgery was seen as greater control. Conclusions: Women seeking UM and BM for treatment of their early stage breast cancer manage their fear of recurrence and ‘never wanting to go through this again’ by undergoing more extensive surgery. The patient’s effort to control the cancer outcome is the driving factor behind women choosing mastectomy.




Use of modafinil to moderate the relationship between cancer-related fatigue and depression in 541 patients receiving chemotherapy: A URCC CCOP study. Presenting Author: Claire Conley, The Ohio State University, Columbus, OH

9573


Spiritual/religious struggle in hematopoietic cell transplant survivors. Presenting Author: Stephen Duane Watkins King, Seattle Cancer Care Alliance, Seattle, WA

Background: Over 50% patients with cancer report symptoms of depression; 15% meet diagnostic criteria for Major Depressive Disorder. Depression is associated with increased insomnia, fatigue and reduced quality of life. We previously found that modafinil is effective for reducing high levels of fatigue among patients undergoing chemotherapy. This study aims to test whether modafinil can alleviate symptoms of depression by reducing fatigue. Methods: This study is a secondary analysis of 541 cancer patients receiving chemotherapy and experiencing fatigue (Brief Fatigue Inventory (BFI) ⬎⫽3) that were randomized to receive either 200 mg of modafinil (N⫽260) or placebo (N⫽281) daily from baseline (Cycle 2) until post-test (Cycle 4). Depression was measured by the Center for Epidemiologic Studies Depression Scale (CES-D) at baseline and post-test. The CES-D total score and its subscales (Positive Affect, Negative Affect, Somatic Symptoms, and Interpersonal Symptoms) were analyzed. A linear model with CES-D post (outcome) and BFI baseline, Arm, and BFI*Arm interaction term (independent variables) was used to address the hypothesis; p⬍0.05 indicates significance. Results: We found no overall effect of modafinil on depression; however, the model demonstrated a significant moderating effect of modafinil on the relationship between baseline fatigue and CES-D total scores (p ⫽ 0.04). For subjects with severe fatigue (BFI ⱖ 7), the drug reduced CES-D scores by 3-4. Modafinil also significantly moderated the relationship between baseline fatigue and Positive Affect subscale scores (p ⫽ 0.003), but not the relationship between baseline fatigue and Somatic, Negative Affect, or Interpersonal subscales. Conclusions: Modafinil differentially impacts depression based on a patient’s level of fatigue; reduced depressive symptoms occurred in those with extreme fatigue. This effect is driven by increases in positive affective symptoms. These results have significant implications for intervention; in patients with high levels of fatigue, modafinil might also reduce depression. Future RCTs are needed to confirm these results. Funding: U10CA37420, K07CA120025, K07CA132916.

Background: Spiritual/religious (SR) struggle (e.g., feeling abandoned or punished by God) has been associated with poorer coping and quality of life (QOL), greater depression and pain, and health declines in general cancer populations. Few studies have been conducted among survivors of hematopoietic cell transplantation (HCT). This study examined the prevalence and predictors of SR struggle in HCT survivors. Methods: Data were collected as part of an annual questionnaire of adult (age ⬎18 years) survivors of HCT at Fred Hutchinson Cancer Research Center in Seattle, WA. The 2011 survey included a SR module that incorporated the following items: Negative Religious Coping subscale of Brief RCOPE, subscales from the McGill QOL Questionnaire and the SF-36, Patient Health Questionnaire-8, disease information and socio-demographics. SR struggle was defined as any non-zero response on the Negative Religious Coping subscale of the Brief RCOPE. A multi-variable logistic regression model was used to determine factors associated with SR struggle. Results: Of 2113 returned surveys (52% response rate), 83% returned the SR module (n⫽1745) and of those 1586 were included in this analysis. Subjects were 49% female; 67% Christian and 20% Agnostic/Atheist/No preference; and 91% white. Mean age was 55 years; survivors ranged from 6 months to 40 years posttransplant. Primary indications for transplant were leukemia (49%), lymphoma (20%), and multiple myeloma (15%). Twenty-eight percent indicated SR struggle. In a multi-variable model, SR struggle showed statistically significant associations with age ⬎⫽65 years (odds ratio [OR] .57, p⫽.02); patient report of being religious only (OR 3.5, p⬍.001) or spiritual only (OR 1.8, p⬍.001) compared to being both religious and spiritual; depression (OR 1.1, p⬍.001); and better social support (OR 0.77, p⬍.001). Time since HCT, religious affiliation and race/ethnicity did not show statistically significant associations with SR struggle. Conclusions: SR struggle is common among HCT survivors, even years after HCT.Further study is needed to determine causal relations, longitudinal trajectory, impact of struggle intensity, and effects of SR struggle on health, mood and social roles for HCT survivors.

9574

9575


Validation of the supplementary quality of life questionnaire for mouth/ throat and hand/foot soreness. Presenting Author: Jennifer L Beaumont, Feinberg School of Medicine, Northwestern University, Chicago, IL Background: PISCES is a randomized crossover trial evaluating patient preference of pazopanib versus sunitinib in advanced/ metastatic renal cell carcinoma. The Supplementary Quality of Life Questionnaire (SQLQ) was developed for this trial to assess hand/foot soreness and mouth/throat soreness (MTS). The objective of this project is to validate the SQLQ. Methods: SQLQ was administered at baseline and every two weeks thereafter. EQ-5D was administered at baseline, during the washout period, and end of second treatment period. Treatment arms were collapsed for validation. SQLQ assesses severity of MTS (1 item), limitations due to MTS (5 items), severity of hand soreness (1 item), severity of foot soreness (1 item), limitations due to foot soreness (5 items) and ability to work (1 item). Cronbach’s coefficient alpha was used to evaluate the internal consistency reliability of the multi-item subscales.T-tests compared scores between groups defined by performance status (0 versus 1) and number of metastatic sites (0/1 versus 2⫹) at baseline. Effect sizes (ES ⫽ mean difference / pooled standard deviation) were calculated. Results: Of 169 patients randomized, data was available on 168. Over 80% of on-study patients completed the SQLQ at each assessment. Cronbach’s coefficient alpha was ⱖ 0.80 for both limitations subscales at all assessments except baseline (limitations due to MTS). Both scores differentiated between performance status groups at baseline with ES ⬎ 0.40 (p⬍0.05). Scores significantly differed by severity of soreness with large ES of 0.9-2.1. Moderate correlations with EQ-5D were observed for limitations scores; correlations were smaller for soreness ratings. MTS and limitations due to MTS worsened after baseline with moderate – large ES; moderate ES was observed for changes in other scores. Limitation change scores were minimal in groups with no change in soreness rating; patients with worsened soreness reported similarly worsened limitations due to soreness with moderate – large ES. Conclusions: SQLQ is a valid and responsive measure of MTS, hand/foot soreness, and limitations due to soreness. Use of the SQLQ in future clinical trials will provide further external validation.


A feasibility study using a touchscreen tool in the AYA population. Presenting Author: Jonathan R. Espenschied, City of Hope, Duarte, CA Background: Adolescent and young adults (AYA) 15 to 39 years present unique health care needs; however, barriers to communication of treatmentrelated and psychosocial difficulties exist. We hypothesized that a tailored AYA Touchscreen Tool (AYATT) in cancer patients/survivors would facilitate patient-provider communication, toward the larger goal of timely intervention. As a first step, we evaluated the feasibility of such a tool, operationally defined as an 80% acceptance and completion rate. Methods: Eligible City of Hope AYA patients receiving treatment and follow up care for oncologic or hematologic disease were systematically approached for study participation. Target accrual to assess feasibility was set at 50 participants. Consented patients completed a concise AYATT battery, mostly standardized measures, assessing access to care (CHIS), needs, neurocognitive function (BRIEF-A, CogState), and other quality of life (PedsQL) issues. Patients and clinical/support staff completed satisfaction and ease-of-use surveys to further evaluate feasibility. Results: 54 participants were accrued over 8 weeks, with a 96% completion rate exceeding our primary feasibility criteria. At the time of participation: Mean age⫽26.2 years; Range 15.3 to 38.9 years. Acceptability was high with positive responses throughout the survey. Based on patient responses, the AYATT helped 52% remember issues they had, or have, with their care or treatment; 39% were encouraged to discuss medical issues with their care team that they might not have discussed; 92% found it a useful way to communicate with their health care team; and 98% would recommend that other patients use AYATT. A separate survey from 31/36 clinical/support staff reported AYATT had minimal negative impact in clinic or patient care, increased communication, and was useful in maintaining/improving care. Conclusions: The aggregate findings from this feasibility study support utilizing a tailored touchscreen device in the AYA oncology population. Predictably, high levels of computer knowledge in our AYA cohort may account for the success and acceptance of using such a tool. These results provide evidence for further exploration and continued use in the AYA clinic and patient care setting.


594s 9576


Attitudes regarding privacy of genomic information in personalized cancer therapy. Presenting Author: Deevakar Rogith, The University of Texas, School of Biomedical Informatics, Houston, TX Background: Cancer therapy is increasingly personalized to the molecular characteristics of a particular patient and his/her tumor. Patients and providers express interest in personalized therapy yet concerns regarding the privacy of genomic data have been raised, particularly in the context of research. We evaluated patients’ attitudes regarding privacy of genomic data. Methods: Newly registered female breast cancer patients at MD Anderson Cancer Center were invited to participate. Of 308 consecutive patients approached, 100 completed a survey assessing attitudes regarding association of personal identifying information with genomic data, risks for potential insurance and employment discrimination based on genomic information, and willingness to share genomic data (32% response rate). Results: Most patients (83%) indicated that genomic data should be protected. However, only 13% endorsed concern regarding genomic data privacy, measured using a composite scale (␣⫽ 0.92). Patients expressed more concern about insurance discrimination than employment discrimination (43% vs. 28%, p⬍0.001), and these two variables were highly correlated (␹2⫽32.7, p⬍0.001). Patients expressed greater trust in research institutions like MD Anderson to protect the security of their molecular data compared with government agencies or drug companies (80% vs. 63% vs. 56%; p ⬍ 0.001). Most did not endorse concern regarding association of their genomic data with their name and identities (51%), billing and insurance (56%), or clinical data (73%). Patients were more willing to share de-identified data than identified data with researchers other than their treating physicians (p⬍0.001). 36% of patients were willing to share identified data with any MD Anderson researcher and 14% with any cancer researcher. Conclusions: Patients generally expressed low levels of concern regarding privacy of genomic data. Cancer patients may recognize the clinical and research value of genomic testing and a significant proportion are willing to share their genomic data with researchers.

9578


9577


Correlations of patient-reported measures (PRM) for health, quality of life (QOL), functional status, and social supports with survival in early-stage colon cancer. Presenting Author: Annie Chen, University of British Columbia, Vancouver, BC, Canada Background: PRM can enhance our understanding of patients’ needs and facilitate cancer treatment decision making. Few studies have explored the relationships between brief PRM and outcomes in early stage colon cancer. Our aims were 1) to determine the effects of prospectively collected PRM on cancer-specific (CSS) and overall survival (OS) and 2) to examine if this association is modified in the elderly. Methods: Patients diagnosed with stage 1 to 3 colon cancer in 2008, evaluated at 1 of 5 regional cancer centers in British Columbia, and provided baseline PRM were included. PRM consisting of a series of short, self-administered scales that described patient-reported health, QOL, functional status and social supports were collected at baseline and correlated with CSS and OS using regression models that controlled for known prognostic factors such as tumor and nodal stage. We subsequently assessed for effect modification by age, stratifying the cohort into younger (YP; ⬍70 years) and elderly patients (EP; ⬎/⫽70 years). Results: In total, 223 patients were included: 94 (42%) were EP, 111 (49%) were women, and 152 (68%) were white. Compared to YP, EP were more frequently widowed (27 vs 9%, p⫽0.0005) and reported having children (92 vs 81%, p⫽0.03), but they were less likely to receive chemotherapy (57 vs 90%, p⬍0.0001). There were no significant differences in PRM based on age, with the majority indicating they had regular contact with family and friends (92%) and many describing good overall health, QOL, and functional status (48, 61, and 69%, respectively). However, a significant proportion wished for more emotional support (54%). In regression models, self-reported poor functional status was associated with worse OS (HR 2.69, 95%CI 1.09-6.65), but not CSS (HR 1.74, 95%CI 0.61-4.94). This did not differ significantly between YP and EP (p interaction ⬎0.05). No other PRM correlated with OS or CSS (all p⬎0.05). Conclusions: For early stage colon cancer, self-reported functional status was independently associated with OS. Additional PRM failed to enhance prognostication, suggesting that more comprehensive tools may be required to improve patient assessments.

9579


Provider-patient communication about cost of care: Results from a national patient education program. Presenting Author: Ivy A. Ahmed, Cancer Support Comunity, Research and Training Institute, Washington, DC

Role of religiosity in medical decision making among patients with colorectal cancer. Presenting Author: Mosmi Surati, University of Michigan, Ann Arbor, MI

Background: A 2010 NIH study indicates direct cancer care expenditures will reach $158 billion in the U.S. by 2020, impacting millions of Americans. The cost of insurance for a family of 4 has increased from $6000 (2000) to over $16,000 (2011). Medical debt is a significant cause of personal bankruptcy, even if insured. The financial realities posed by costs associated with cancer care greatly complicate a cancer diagnosis. The most recent American College of Physicians Ethics Manual recommends all parties must interact honestly, openly, and fairly. (Snyder L, et al. Ann Int Med 2012, p86) This analysis explores the occurrence and value of patient-provider communication surrounding costs associated with care in a national survey of those affected by cancer. Methods: From 2011-12, 505 individuals attending Frankly Speaking About Cancer: Coping with the Cost of Care workshops completed a survey assessing experiences about the costs of cancer care. This is a Cancer Support Community national evidence-based educational program. All attendees (n⫽708) were eligible to complete survey. Results: Most attendees (71.3%) responded. The majority (62.4%) were people with cancer/survivors; the remainder included spouses/partners, family members, and 8.7% were health care professionals. Most (80.8%) were Caucasian, and averaged 57.2 years. Of those with cancer, 89.9% were insured at diagnosis. 59.4% reported no one on their health care team initiated a discussion about the financial aspects of their care. Included in this figure, 22.7% actively sought information from health care team, and 36.7% received no information about cost. When topic was initiated, it was by social workers (16.2%), physicians (12.3%), nurses (6.3%) or financial specialists (8.2%). When information was provided, 72.1% found it somewhat or very useful. Also, regardless of provider discussion, respondents independently sought resources for managing costs, such as other patients (44.2%), the Internet (41.5%), and patient support organizations (38.1%). Conclusions: Patients want financial information but do not receive it. These data highlight the need and value of providers initiating a dialogue about the cost of cancer care with patients.

Background: Physician-based medical decision making (DM) has declined in favor of more patient-centered approaches. Most studies indicate that patients want to be involved; however, the level of desired involvement varies between patients wanting to make their own decisions and those preferring to leave decisions to physicians. Little is known of the factors associated with DM preferences. Given data demonstrating the influence of religion among cancer patients, we explored religiosity and decision making preferences in colorectal cancer (CRC) patients. Methods: We surveyed a population-based cohort of Stage III CRC patients from the Detroit and Georgia SEER registries. Patients were queried about desired level of involvement in DM, trust in physicians, religiosity, receipt of adjuvant chemotherapy, and demographics. Religiosity was assessed using the Holland System of Belief Inventory. Physician trust was assessed using the Wake Forest Physician Trust scale. Responses were collected along a Likert scale and results were dichotomized. Surveys were analyzed using univariate and bivariate methods. Results: Thus far, 430 CRC patients have responded (56% response rate). The median participant age is 61 years, 45% are female, and 19% are black. 54% indicated a preference for shared DM, 35% prefer “doctors to make [their] decisions”, and 11% prefer to “make [their] own decisions”. The distribution did not differ by age, gender, race, income, or level of education. Higher religiosity was associated with higher trust in the surgeon (p⫽0.007) but not the oncologist (p⫽0.3). Patients with higher religiosity scores and higher physician trust were more likely to prefer that their doctors make the decisions (p⫽ 0.023, p⬍0.001). Preference for physician DM was associated with higher receipt of adjuvant chemotherapy (p⫽0.002). Conclusions: Patients who were more religious preferred to leave medical DM to physicians. Those who relied on physician DM were more likely to receive chemotherapy. This association may be mediated through higher trust. Understanding the influence of religiosity may be a tool to help providers get their patients appropriate cancer care.




Impact of functional outcomes on long-term quality of life after open retropubic radical prostectomy. Presenting Author: Bjoern Loeppenberg, Department of Urology; Ruhr-University Bochum, Marienhospital Herne, Herne, Germany Background: Patients who underwent open retropubic radical prostatectomy (ORRP) for prostate-cancer (PCA) have excellent long-term survival. Besides oncologic safety, recovery of continence and erectile function are highly important, as adverse functional outcomes may have a detrimental effect on health-related quality of life (HRQOL). We report the long-term HRQOL of PCA survivors after ORRP using standardized tools. Methods: Men treated between August 2003 and December 2007 with ORRP for localized PCA at a single academic hospital received validated questionnaires (International consultation on incontinence questionnaire (ICIQ), International index of erectile function (IIEF-5), Erection hardness score (EHS), EORTC QLQ-C30) to assess functional outcomes and HRQOL. Results were correlated with the global-health score (GHS) of the EORTC QLQ-C30 to assess the impact of ORRP on HRQOL. Results: In the study period 1936 men underwent ORRP of whom 1156 (59.7%) received a nerve-sparing (NS) procedure. Questionnaire return-rate was 59% (n⫽1141) comprising the final study cohort. Median follow-up (FU) was 62 months. Mean age at surgery and FU was 63.7⫾6.2 and 69.2⫾6.2 years, respectively. Biochemical recurrence (BCR) occurred in 17.5% (n⫽200/ 1141) and 2% (n⫽40/1936) deceased. Mean GHS in the study population was 71.5⫾20.8. In the ICIQ 28% (n⫽320) scored 0 indicating complete continence and 9.9% (n⫽113) scored ⱖ11 indicating severe incontinence. The corresponding GHS was 78.1⫾19.5 and 55.4⫾21.8, respectively. 68.5% (n⫽782) of patients used no pads and 17.9% (n⫽204) ⱖ2 pads. Corresponding GHS scores were 74.9⫾19.8 and 58.9⫾20.7. Using the IIEF-5 in men who received NS, 24.1% (n⫽154) had no erectile dysfunction versus 50% (n⫽318) using the EHS. Corresponding GHS scores were 82.2⫾16.3 and 74.7⫾19.8, respectively. Patients with BCR had a GHS of 66.8⫾21.8 versus 72.5⫾20.5 for patients without. Men who achieved the Trifecta and Pentafecta criteria had a GHS of 83.1⫾15.1 and 83.3⫾15, respectively. Conclusions: Incontinence severely impacts the HRQOL of long-term survivors after ORRP while erectile dysfunction and BCR have a lesser effect. Every effort should be undertaken to maintain functional integrity.

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ALGA: A cancer patient profiling tool to improve physician-patient communication—An analysis in breast cancer patients. Presenting Author: Gabriella Pravettoni, University of Milan, Milan, Italy Background: Considerable improvement of communication between physicians and patients (pts) will need to occur as personalised medicine becomes the norm. An accurate profile of the pt’s cognitive and psychological status should help the physician shape his language and his messages to maximise the pt’s understanding of her management options. To this aim a computerized tool (ALGA questionnaire) has been created and validated. Methods: The validation process produced a questionnaire with 4 main factors: Health State Perception, Psychological, Psychosocial and Cognitive aspects. To test its ability to discriminate between healthy people and pts, ALGA has been administered to 50 newly diagnosed primary Breast Cancer (BC) pts prior to their first visit with the oncologist to discuss their adjuvant treatment, and to 50 healthy women (age range:20-60), using an iPad. Results: A multivariate analysis showed a significant difference between BC pts and healthy women relatively to the four aforementioned broad areas: Psychosocial (F(1,56)⫽13.42, p⬍.001), Cognitive (F(1,56)⫽6.53, p⬍.01), and Psychological Aspect (F(1,56)⫽2.77, p⫽.05). ALGA detected pts with higher levels of anxiety and depression. Pts tended to ruminate more than healthy subjects. Finally, pts showed higher level of positive Health State Perception, suggesting a dissociation between cancer illness and general health. Cognitive and Psychological aspects and Health State Perception interacted with participants’ level of education (respectively: F(1,56)⫽12.23, p⬍.001; F(1,56)⫽4.58, p⬍.05; F(1,56)⫽7.9, p⬍.05). Starting from this results a personal profile for each pt was created. Conclusions: The ALGA confirmed ability to discriminate between healthy people and BC pts, and is a good tool to create a personal pt’s profile with which physicians can empower patient with tailored knowledge. Starting from ALGA questionnaire, a smart environment is being implemented as a decision support infrastructure to help communication, interaction and information delivery process from doctor to patient, influencing patient’s quality of life and satisfaction.

9581


Differences in psychosocial factors among diverse women enrolled in a phase III cooperative group metastatic breast cancer trial (CALGB 40502/ Alliance). Presenting Author: Blase N. Polite, The University of Chicago, Chicago, IL Background: Previous metastatic breast cancer trials have shown lower overall survival among African American (AA) women. Studies have also shown links between higher comorbidities and lower levels of social support and survival. Whether these factors differ by race and ethnicity is not known. Methods: Breast cancer patients enrolling in a phase III cooperative group metastatic breast cancer trial completed a self-administered survey measuring psychosocial and socio-demographic factors and comorbidities. Results were analyzed by self-identified race/ethnicity and evaluated by other measured variables. Results: 703 out of 799 patients completed the survey (88%). Questions were answered by greater than 95% of participants. The table shows differences broken down by Race/Ethnicity. AA and Hispanic (H) patients were more likely to have trouble paying for medications and have incomes less than 15K per year. AA were less likely to be married, and had lower levels of social support. Differences in income did not mediate these social support differences. Marital status did not mediate lower social support for AA (p⫽0.79) but did so for whites (p⬍0.001) Conclusions: Compliance with the questionnaire was quite high. Differences in social support by race were apparent and were mediated by different factors according to race. Future efforts will analyze the impact of these factors on survival and as mediators for potential racial and ethnic differences in survival. Variable Age (median) Committed relationship Trouble paying for meds (at least some of time ) Income: 5 years

TSs %

17

51

20* 15

60* 46

16* 31 19 20

50* 68 54 61

14* 21 17 15

43* 57 54 48

9609


Psychosocial health in survivors of adult versus childhood cancer. Presenting Author: Charles A Phillips, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN Background: The growing population of cancer survivors is characterized by two subgroups, those diagnosed as children and those diagnosed as adults. While psychosocial challenges are recognized in these survivors, little data exists comparing the psychosocial health between these two subgroups. Our objective is to compare adult and childhood cancer survivors for symptoms of depression, anxiety, somatic complaints, and post traumatic stress disorder (PTSD). Methods: At entry to the Vanderbilt Cancer Survivorship program, survivors of childhood and adult onset cancer, ages 15 – 55 years old, completed the Achenbach System of Empirically Based Assessment and the revised Impact of Event Scale. Using normalized T scores, independent sample t tests,and ␹2 analyses, responses were compared to normative data for each group and responses of the two survivor groups were compared to one another. Results: There were 172 survivors of childhood cancer (M⫽ 9 years old at diagnosis) and 125 survivors of adult cancer (M⫽ 41 years old at diagnosis). Childhood cancer diagnoses included hematologic cancer (56%), sarcoma (17%), brain tumor (8%), and other (19%). Adult cancer diagnoses included breast cancer (45%), colon cancer (8%), hematologic cancer (14%), sarcoma (4%), and other (29%). After adjusting for age-related population norms, adult survivors were significantly more likely to have symptoms of depression (p⫽.011), anxiety (p⫽.029), somatic problems (p⫽.043), and PTSD (p⫽.004) compared to their childhood counterparts. Compared to age-expected norms, significantly more adult, but not child, survivors scored in the clinical range for depression (29%, p⬍.001; vs. 18% n.s) and somatic problems (23%, p⫽.013; vs. 12%; n.s.). Time elapsed from cancer diagnosis to completion of the questionnaires was not significantly correlated with any of the measures. Conclusions: Survivors of adult onset cancer face a significantly higher amount of psychologic distress, particularly depressive and somatic symptoms, compared to their childhood counterparts and age-expected norms. Analyses are ongoing to evaluate other demographic, disease, and treatment related risk factors that may contribute to this age-related phenomenon in order to develop interventions.

*p⬍.001

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Use of intravaginal 17-␤ estradiol to improve sexual function and menopausal symptoms in postmenopausal women with breast cancer on aromatase inhibitors. Presenting Author: Shari Beth Goldfarb, Memorial SloanKettering Cancer Center, New York, NY

High-flow oxygen (HFO) and bilevel positive airway pressure (BiPAP) for refractory dyspnea in patients with advanced cancer: A randomized controlled trial. Presenting Author: David Hui, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: The majority of women with early stage breast cancer (BC) will become long-term survivors, living with the sequelae of treatment. Attention to symptoms and quality of life (QoL) are therefore of increasing importance both during treatment and survivorship. Aromatase inhibitors (AIs) are used to treat postmenopausal women with hormone-receptor positive (HR⫹) BC and can lead to profound urogenital atrophy. Atrophic vaginitis in BC survivors is prevalent, its management is complex and it negatively impacts QoL. Methods: A prospective longitudinal IRB-approved study was performed at MSKCC in26 postmenopausal women with stage I-III HR⫹ BC on adjuvant letrozole or anastrozole for at least 3 months and had urogenital atrophy. All women were initiated on 10␮g intravaginal 17-␤ estradiol. Patients completed the Female Sexual Function Index (FSFI) and Menopausal Symptom Checklist (MSCL) at baseline and wks 12 & 24. Increase in FSFI score means better sexual function and a decrease in MSCL score means improved symptoms. We used the Wilcoxon Signed Rank Sum test to compare QoL measures at baseline to wks 12 and 24. The primary endpoint was change in systemic estradiol level from baseline to wk 12. Serial estradiol/FSH levels were measured at baseline and wks 2, 7, 12, 18 & 24; we used a highly sensitive estradiol radioimmunoassay, ESTR-USCT, from Cisbio US, Inc. Herein we report the results from the QoL secondary endpoints. Results: During treatment with intravaginal 17-␤ estradiol 10mcg, improvement in sexual function as measured by the FSFI was seen from a median of 12.4 at baseline to 21.2 at wk 12 (p⫽.0091) and 21.8 at wk 24 (p⫽.0271). Improvement was seen from baseline to wk 12 in lubrication (p⫽.0091), desire (p⫽.0303), satisfaction (p⫽.0331) and pain (p⫽.0005) and from baseline to wk 24 in lubrication (p⫽.0210), desire (p⫽.0309) and orgasm (p⫽.0369). A reduction in menopausal symptoms was also seen from 30.0 at baseline to 23.6 at wk 12 (p⫽.01) and 22.5 at wk 24 (p⫽.003). Conclusions: Intravaginal 10␮g 17-␤ estradiol provided relief from menopausal symptoms and improvement in sexual dysfunction in the domains of lubrication, desire, satisfaction, orgasm, and pain.

Background: Dyspnea is one of the most common and distressing symptoms in cancer patients. Few treatments are evidence based because research in this area is difficult. The role of HFO and BiPAP in the palliation of severe refractory dyspnea has not been well characterized.We examined the changes in dyspnea, physiologic parameters and adverse effects in patients receiving HFO and BiPAP. Methods: In this phase II “pick the winner” randomized trial, we assigned hospitalized advanced cancer patients with refractory dyspnea to either HFO or BiPAP for 2 hours. We assessed dyspnea with the numeric rating scale (NRS) and modified Borg scale (MBS) before and after intervention. We also documented the vital signs, transcutaneous carbon dioxide and adverse effects. We used the sign rank test to compare before and after each intervention, and the Wilcoxon rank sum test to compare between arms with intention-to-treat analysis. Results: Thirty patients were enrolled (1:1 ratio) and 23 (77%) completed the assigned intervention. The median baseline dyspnea NRS was 7/10 (Q1-Q3 5-8), despite being on supplemental oxygen and opioids. Both HFO and BiPAP were associated with significant improvement in dyspnea after 2 h, with no differences detected between arms (Table). We observed prolonged dyspnea relief in 6 patients 1 h after completion of the study intervention. HFO improved oxygen saturation. No adverse effects were observed. Conclusions: HFO and BiPAP alleviated dyspnea, improved physiologic parameters and were safe. Our results justify larger randomized controlled trials to confirm these findings. Clinical trial information: NCT01518140. Improvement in dyspnea and physiologic parameters with HFO and BiPAP. Variables

Mean change with HFO (95% CI)

P value

Mean change with BiPAP (95% CI)

P value

BiPAP vs. HFO P value

Dyspnea NRS Dyspnea MBS Heart rate Respiratory rate Oxygen saturation (%) Carbon dioxide (mmHg)

-1.9 (-3.4, -0.4) -2.1 (-3.5, -0.6) -3.6 (7.8) -3.0 (5.2) 5.3 (5.2) -0.9 (5.5)

0.02 0.007 0.42 0.11 0.003 0.06

-3.2 (-5.1, -1.3) -1.5 (-3.2, 0.3) -5.0 (5.1) -2.0 (4.0) 3.3 (5.3) 1.9 (2.7)

0.004 0.13 0.02 0.11 0.11 0.04

0.32 0.29 0.43 0.97 0.62 0.02




Aprepitant, granisetrone, and dexamethasone for prevention of CINV after high-dose melphalan in autologous transplantation: Results of a randomized, placebo-controlled phase III trial. Presenting Author: Thomas Schmitt, Department of Hematology, Oncology, and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany Background: Aprepitant (A) is a NK1-antagonist approved for prevention of chemotherapy-induced nausea and vomiting (CINV). Though melphalan (M) is regarded only moderately emetogenic, CINV after high-dose M conditioning in autologous TPX can severely interfere with patients’ (pts) quality of life. Here we present the results of our monocentric, randomized (1:1), placebo-controlled, double-blind phase IIIb trial of A, granisetrone (G) and dexamethasone (D) in this setting. Methods: Pts were treated with A 125 mg po day 1, A 80 mg po days 2-4, G 2 mg po days 1-4 and D 4 mg po day 1, D 2 mg po days 2-3 (arm A) or placebo (P) days 1-4, G 2 mg po days 1-4 and D 8 mg day 1, D 4 mg days 2-3 (arm B). Melphalan 100 mg/m² iv was administered days 1-2. Episodes of emesis, modified functional living index – emesis questionnaire (FLIE) and intensity of nausea by visual analogue scale (VAS) were recorded between days 1-6. Primary endpoint was defined as no episode of vomiting and no additional antiemetic therapy within 120h of M administration. Results: Between 07/05 and 01/12 a total of 362 pts were randomized. 361 subjects (arm A⫽180; arm B⫽181; male n⫽229; female n⫽132; median age arm A⫽59.5 years; median age arm B⫽58 years) were available for the efficacy analysis. There were no significant differences in gender distribution and previous experience of CINV. Significantly less pts receiving A failed the primary endpoint (42% vs. 59%, OR⫽0.53 [0.34; 0.82], p⫽.0046). This effect was stressed in women (57% vs. 82%, OR⫽0.30) and patients with previous CINV (48% vs. 71%, OR⫽0.38). Emesis within 120h occurred in 22% of pts receiving A and 35% receiving P (OR⫽0.5 [0.31; 0.80], p⫽.0036). Though differences in overall nausea (16% vs. 22%, OR⫽0.65 [0.83; 1.10], p⫽.11) did not reach statistical significance, major nausea (VAS ⬎25mm) was reduced (6% vs. 12%, OR⫽0.42 [0.19; 0.92], p⫽.026). Difference in FLIE score was -8.2 (p⫽.0007). Study medication was well tolerated. PK analyses showed no interaction between M and A. Conclusions: The combination therapy with A resulted in significantly less CINV compared to placebo. This effect was pronounced in women and pts with previous CINV. Clinical trial information: NCT00571168.

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Aprepitant (AP) versus dexamethasone (D) for preventing delayed emesis induced by anthracyclines plus cyclophosphamide (AⴙC) chemotherapy (CT) in breast cancer patients (pts): A double-blind, multicenter, randomized study. Presenting Author: Fausto Roila, Medical Oncology, Terni, Italy Background: A combination of AP ⫹ a 5-HT3 receptor antagonist ⫹ D and AP alone is recommended, respectively, for the prophylaxis of acute and delayed emesis induced by A⫹C CT in breast cancer pts. In the registrative study the role of AP in delayed emesis was not defined because prophylaxis of acute emesis was different between the two arms, and the superiority of AP on delayed emesis could be the consequence of a dependent effect on the different results achieved in acute phase. Aim of this study was to compare the efficacy of AP versus D in preventing delayed emesis in pts receiving the same prophylaxis of acute emesis. Methods: A randomized double-blind study comparing AP versus D was completed in naive breast cancer pts treated with A⫹C. Before CT, all pts were treated with intravenous palonosetron 0.25 mg and D 8 mg, and oral AP 125 mg. On days 2 and 3 pts randomly received D 4 mg bid or AP 80 mg qd. Primary endpoint was rate of complete response (no vomiting, no rescue treatment) from days 2 - 5 after CT. Results: From September 2009 to July 2012, 580 pts were enrolled; 551 were fully evaluated, 273 in arm D and 278 in arm AP. Day 1 complete response rates were similar: 239/273 (87.6%) in D arm and 236/278 (84.9%) in AP arm. From day 2-5, complete response was the same with both antiemetic prophylaxes (79.5%), and all secondary endpoints (complete protection, total control, no vomiting, no nausea, score of FLIE) assumed similar values. During the delayed phase, incidence of insomnia (2.9% vs. 0.4%) and heartburn (8.1% vs. 3.6%) was significantly superior in D arm. Conclusions: In breast cancer pts submitted to A⫹C CT and receiving the same antiemetic prophylaxis for acute emesis, D and AP present similar efficacy and toxicity. Clinical trial information: NCT 00869973.

9613


Complementary and alternative medicine (CAM) use in lung cancer: The impact of control. Presenting Author: Joshua Bauml, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA Background: Lung cancer (LC) remains the leading cause of cancer death for both men and women in the U.S., and is associated with significant symptom burden. The diagnosis and treatment of LC can make patients feel a loss of control, and desire for control has been associated with CAM use. While interest in CAM has surged recently, scant literature exists on its use in LC. This study aimed to quantify the prevalence of and identify the factors associated with CAM use in patients (pts) with LC with a specific focus on perceived control. Methods: We performed a cross sectional survey in pts with LC treated at the oncology clinic of an academic medical center. Self-reported CAM use was the primary outcome. Demographic and clinical variables were collected by chart abstraction. Pts’ perception of their degree of control was measured using the Cancer Locus of Control scale. Multivariate logistic regression was performed to determine which factors were independently associated with CAM use. Results: 296 pts were surveyed (77.5% response rate) with a mean age of 63.1 (28-84). 45.6% were male, 83.5% were Caucasian, 21% had never smoked, and 52.4% had Stage IV disease. 50.9% of pts used ⱖ1 form of CAM, most commonly vitamins (31.5%), herbs (19.3%), relaxation techniques (16%) and special diets (15.7%). In multivariate analysis, CAM use was associated with ageⱕ65 (AOR 1.64, 95% CI 1.01-2.67), college level or greater education (AOR 2.17, 95% CI 1.29-3.64), never having smoked tobacco (AOR 2.39, 95% CI 1.25-4.54), and having a greater feeling of control over the cause of cancer (AOR 2.27, 95% CI 1.35-3.80). Gender and perceived control over treatment outcome were not associated with CAM use. Conclusions: In the largest study evaluating CAM in LC, half of pts surveyed used CAM. CAM use was associated with younger age, increased education, never having smoked tobacco and a greater feeling of control over the cause of cancer. In contrast to prior research, we did not find an association with CAM usage and gender or perceived control over treatment outcome. Since CAM use is common, future research is needed to evaluate how to integrate CAM into clinical care to help patients with LC regain a sense of control and improve their quality of life.

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Pain sensitivity and aromatase inhibitor (AI)-associated arthralgias (AIAA). Presenting Author: Norah Lynn Henry, University of Michigan Medical Center, Ann Arbor, MI Background: AIAA affect up to half of AI-treated women with early stage breast cancer, and can lead to treatment discontinuation in 20-30%. The etiology is thought to be related to estrogen deprivation although the mechanism is unknown. In premenopausal women, lower estrogen levels have been associated with increased pain. Impaired descending pain inhibitory pathways, which may be a risk factor for developing chronic pain, have also been associated with lower estrogen levels. We prospectively tested whether AI-induced estrogen deprivation alters pain sensitivity, thereby increasing the risk of developing AIAA. Methods: Fifty postmenopausal women with early stage breast cancer initiating AI therapy were enrolled to the study. Subjects underwent experimental pressure pain testing and conditioned pain modulation (CPM) assessment and completed symptom questionnaires prior to AI initiation and after 3 months. Positive CPM values (⬎0) signify impaired descending pain inhibition. Serum estradiol concentrations were determined using an ultrasensitive assay. T-tests, Fisher’s exact test, and linear regression models were used to assess associations among baseline (BL) experimental pain measures, patient-reported pain, and clinical factors. P values ⬍0.05 were considered statistically significant. Results: All subjects had decreased serum estradiol concentrations with AI therapy. No statistically significant change in pressure pain threshold or CPM with AI therapy was detected. In addition, no association between change in patient-reported pain with AI therapy and change in pain threshold or CPM was identified. Patients demonstrated impaired CPM at baseline (mean 8.0, SD 14.9), and this impairment was greater in patients previously treated with chemotherapy 14.4 vs 2.0, p⫽0.006), with non-significant trends towards this being more pronounced in those with more severe pain. Conclusions: AI therapy did not impact pressure pain threshold or CPM, suggesting that AIAA is not likely due to pain amplification from estrogen depletion. Studies examining chemotherapy-induced changes in pain processing are needed to better understand how these alterations might contribute to the pain that these patients often develop.


604s 9616


Determination of evidence-based diagnostic thresholds for upper limb lymphedema secondary to treatment for cancer. Presenting Author: Elizabeth S Dylke, University of Sydney, Lidcombe, Australia Background: Diagnosis of upper limb lymphedema (LE) secondary to treatment for cancer has been complicated by the range of diagnostic thresholds used. Traditional thresholds were arbitrarily chosen but recently normative-based cut-offs have been established. However, the diagnostic power of these thresholds has not been compared to changes identified with lymphoscintigraphy, the gold standard for diagnosis of LE. The aim of this study was to determine thresholds for commonly used clinical diagnostic tools based on lymphatic imaging outcomes. Methods: Women previously diagnosed with LE secondary to treatment for cancer (n⫽67), and women without LE (n⫽20) participated. Lymphoscintigraphy was completed and the presence and severity of dermal back flow qualitatively scored as none to mild or moderate to severe by an experienced nuclear medicine physician. On the same day, circumference measurements and segmental bioimpedance spectroscopy (BIS) for 10 cm intervals from the ulnar styloid to 40 cm proximal were recorded. The BIS inter-limb ratio for each segment and the inter-limb circumference differences were compared to diagnostic thresholds based on 2 and 3 standard deviations (SD) above the mean from normative data. Results: The number of BIS segments and circumferences measurements above a 3SD threshold correlated significantly with the dermal backflow score (Rs⫽ 0.710 and 0.824 respectively).The number of abnormal BIS segments detected did not differ significantly between a 2SD and 3SD threshold (␹2⫽0.23 p⫽0.63). Of the 20 new abnormal segments detected, 7 were from participants with no or mild evidence of dermal backflow on lymphoscintigraphy including 3 from control participants. In contrast, 46 new abnormal inter-limb circumference differences, all from those with a LE diagnosis, were detected using a 2SD threshold (␹2⫽ 31.785, p⬍0.001) Conclusions: The need for a standardized, evidenced-based approach for identification of LE is essential. We recommend diagnostic thresholds for segmental BIS be set at 3SD above the mean to minimize false positive diagnoses whereas a lower threshold of 2SD is necessary for the less sensitive inter-limb circumference difference measurements.

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Effect of abiraterone acetate (AA) on patient-reported pain in metastatic castration-resistant prostate cancer (mCRPC) post-docetaxel: Results of longitudinal sensitivity analyses. Presenting Author: Yanni Hao, Janssen Global Services, Raritan, NJ Background: The COU-AA-301 phase 3 trial showed that AA ⫹ prednisone (P) improved overall survival in mCRPC patients (pts) post-docetaxel. Compared with P alone, AA ⫹ P also had significant benefits on patientreported pain. Here we describe post hoc sensitivity analyses of pain data from that trial, using different methods to compensate for the potential impact of missing data. Methods: Pts with mCRPC progressing after docetaxel-based chemotherapy were randomized 2:1 to AA ⫹ P or placebo ⫹ P. Pain intensity and interference of pain with daily activities were assessed with the Brief Pain Inventory-Short Form (BPI-SF) questionnaire at baseline, Day 15 of Cycle 1, and Day 1 of each 28-day treatment cycle thereafter until treatment discontinuation. The effect of treatment on BPI-SF scores was analyzed using repeated measure mixed-effects (RMM) models, piecewise linear mixed-effects (PWLME) models, and joint mixedeffects and log time-to-dropout (JMEL) models. RMM and PWMLE models assumed missing data (due to death, study dropout, or administrative issues) to be missing at random, the JMEL model to be missing not at random. Model results were compared between treatment arms. Results: 797 pts were randomized to AA ⫹ P, and 398 to P only. RMM model estimates suggested statistically significant (p ⬍ 0.05) differences in change from baseline for pain intensity and pain interference scores in favor of AA ⫹ P at the majority of study visits through cycle 11. PWLME models yielded significantly smaller areas under the curve (AUCs) for AA ⫹ P vs P for pain intensity (p ⫽ 0.0031) and pain interference (p ⫽ 0.0006); smaller AUCs reflect better pain outcomes. Results using JMEL models were nearly identical to those with PWLME models, with AUCs for AA ⫹ P significantly smaller than for P alone for pain intensity (p ⫽ 0.0031) and pain interference (p ⫽ 0.0007). Conclusions: Using various modeling methods that assess the impact of missing data, AA ⫹ P showed superior patterns of pain outcomes over time compared with P only in mCRPC pts refractory to docetaxel. These results support the previously reported pain benefits of AA ⫹ P over P alone from the same trial. Clinical trial information: NCT00638690.

9617


Is there an additional health-related quality of life (HRQL) benefit with abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC) beyond that mediated by clinical endpoints? Presenting Author: David Cella, Department of Medical Social Sciences, Northwestern University, Chicago, IL Background: HRQL was evaluated as part of COU-AA-301, a randomized phase 3 trial of AA ⫹ prednisone (P) vs placebo ⫹ P in mCRPC patients (pts) post-docetaxel, where AA ⫹ P demonstrated significant benefits over P in numerous HRQL measures. Here we report post hoc analyses investigating the role of disease progression (px) in mediating the HRQL benefits of AA. Methods: Intensity of pain and fatigue and their interference with daily activities were assessed with the BPI-SF and BFI questionnaires and multiple domains of HRQL with the FACT-P questionnaire. Mediation analyses were conducted using a series of 3 models (Baron & Kenny J Pers Soc Psychol 1986), to assess whether presence and timing of disease px mediated treatment effects of AA ⫹ P vs P on HRQL changes: in Model 1, HRQL (i.e. the outcome variable) is predicted by treatment, in Model 2, px (i.e. the mediator variable) is predicted by treatment, and in Model 3, HRQL is predicted by both treatment and px. Three different disease px indicators (ie, PSA px, radiographic px, and a composite px variable) were used. Results: Treatment predicted the change in FACT-P total score from baseline (Model 1; p ⫽ 0.011). Treatment (as sole predictor) was significantly (p ⱕ 0.001) predictive of both PSA px and radiographic px (Model 2). Some of the treatment benefit of AA ⫹ P on the FACT-P total score was not explained as the result of the effect of treatment on PSA and radiographic px (Model 3; p ⫽ 0.030). In Model 3, pts with late (⬎ 250 d post-randomization) or no px had better FACT-P scores than those with early px for PSA px (p ⫽ 0.019, no px; p ⫽ 0.008, late px) and radiographic px (p ⫽ 0.054, no px; p ⫽ 0.017, late px). Models evaluating the mediating role of the composite px variable showed the same pattern of results. Identical sets of mediation analyses conducted for the BPI and BFI also exhibited very similar outcomes. Conclusions: In post-docetaxel mCRPC pts, the benefits of AA to HRQL appear to be related to both treatment assignment and the mediating effects of disease px. HRQL end points expand understanding of treatment benefit beyond clinical disease px end points. Clinical trial information: NCT00638690.

9619


Real-world symptom burden and early treatment discontinuation in firstline metastatic breast cancer (MBC). Presenting Author: Mark S. Walker, ACORN Research, Memphis, TN Background: Treatment options in 1st line metastatic breast cancer (MBC) vary and may include chemotherapy, targeted, and hormone therapy. Some patients (pts) do not complete therapy as planned, perhaps due to treatment related toxicities. The current study examined the association of symptom burden with early treatment discontinuation (ETD) of 1st line therapy of MBC in real-world settings. Methods: Data were abstracted from medical records of pts at 9 community oncology practices. Eligible pts had stage IV breast cancer with start of 1st line therapy on 1/2004 to 6/2012, were ⱖ 18 years, and had ⱖ 1 Patient Care Monitor (PCM) survey during 1st line. The PCM is an 86-item survey of cancer-related symptoms collected as part of routine clinical care. Age, race, HER2 status, hormone status, oral and infused agents, dates of diagnosis, treatment, progression, and death were recorded. ETD was defined by direct indication of early stopping in the medical record, or by treatment duration ⱕ 6 weeks without evidence of disease progression. Cox regression of ETD with time varying covariates was used to examine the impact of 23 separate symptoms as well as an overall composite symptom burden score based on pt responses on each symptom. Results: 797 pts were included, with mean age of 58.4 years, 62.1% White; with 340 on Chemotherapy (CT), 349 on CT ⫹ Targeted therapy (T) and 108 on Hormone therapy only (H). Overall, ETD occurred in 95 (11.9%) pts, with rates highest among CT (15.3%), followed by T (10.0%) and H (7.4%). Cox regression showed that 21 of 23 symptoms each increased the risk of ETD. In the composite symptom burden score (median 7.1; range 0 - 21) analysis, overall symptom burden was found to be significant (HR ⫽ 1.124, p ⬍ 0.0001), indicating a 12.4% increased risk of ETD with each additional symptom. Pts with 10⫹ symptom score had a significantly increased risk of ETD (HR ⫽ 3.09, p ⬍ 0.0001) compared to pts with ⬍ 5 symptom score. Pts with 15⫹ symptom score had the highest risk of ETD (HR ⫽ 5.75, p ⬍ 0.0001). Conclusions: Pts treated with CT for 1st line MBC had the highest rate of ETD. The likelihood of ETD increased as the number of symptoms increased. Future research is needed to evaluate ETD on pt outcomes, including overall survival.




Randomized double-blind placebo-controlled trial of celecoxib for radiationinduced oral mucositis. Presenting Author: Rajesh V. Lalla, University of Connecticut Health Center, Farmington, CT Background: Oral mucositis (OM) is a painful complication of radiation therapy (RT) for head and neck (H&N) cancer. OM can compromise nutrition, require opioid analgesics and hospitalization for pain control, and lead to treatment interruptions. Due to the role of inflammatory pathways in the pathogenesis of OM, this study investigated the effect of inhibition of cyclooxygenase-2 (COX-2) on severity and morbidity of OM. Methods: In this randomized double-blind placebo-controlled trial,40 H&N cancer patients were randomized to daily use of 200 mg celecoxib or matched placebo, for the duration of RT. Eligibility criteria included planned RT dose of ⱖ 5000 cGy to 2⫹ areas of the mouth and no contraindication for celecoxib use. The planned sample size of 20 per arm provided 80% power to detect a 1 point difference in mean Oral Mucositis Assessment Scale (OMAS) score (range 0-5) at 5000 cGy RT (primary endpoint), applying a two-tailed, two-sample t-test at the 5% level of significance. Clinical OM, normalcy of diet, pain scores and analgesic use were assessed 2-3 times a week by blinded investigators during the 6-7 week period of RT, using validated scales. Results: Twenty subjects were randomized to each arm, which were similar with respect to tumor location, radiation dose, and concomitant chemotherapy. In both arms, mucositis and pain scores increased over the course of RT. Intent-to-treat analyses demonstrated no significant difference in mean (SD) OMAS scores at 5000 cGy [celecoxib 1.32 (0.71), placebo 1.27 (0.86), p ⫽ 0.83, two sample t-test]. There was also no difference between the celecoxib and placebo arms respectively, in mean OMAS scores over the period of RT (SD) [0.98(0.77) & 0.97 (0.86), p ⫽ 0.84], mean worst pain scores [3.38 (3.07) & 3.31 (3.32), p ⫽ 0.83], mean normalcy of diet scores [5.43 (3.86) & 5.11(3.94), p ⫽ 0.65], or mean daily opioid medication use in IV morphine equivalents [19.08 (16.57) & 20.48 (19.07), p ⫽ 0.48], all by linear mixed model fixed effects regression analysis. There were no SAEs attributed to celecoxib use. Conclusions: Daily use of a selective COX-2 inhibitor, during the period of RT for H&N cancer, did not reduce the severity of clinical OM, pain, dietary compromise or use of opioid analgesics. Clinical trial information: NCT00698204.

9622


Differential effects of bevacizumab on the risk of hand-foot syndrome associated with cytotoxic chemotherapy: An updated meta-analysis. Presenting Author: Arun Gopal, Stony Brook University Hospital, Stony Brook, NY Background: Hand-foot syndrome (HFS) is a dose-limiting toxicity of many chemotherapeutic agents. In a prior meta-analysis of published randomizedcontrolled clinical trials (RCTs) we showed that the risk of HFS increased significantly with the use of bevacizumab, an angiogenesis inhibitor that is widely used for the treatment of many cancers. In this study, we have included more recent trials and updated our findings. Methods: Databases from PUBMED, Cochrane Database, and abstracts presented at the American Society of Clinical Oncology until December, 2012 were searched for the identification of relevant studies. Eligible studies included prospective RCTs in which the addition of bevacizumab to chemotherapy was compared directly to chemotherapy alone in cancer patients. Relative risk (RR), and 95% confidence interval (CI) were calculated using a fixed- or random-effects model based on the heterogeneity of the studies. Results: A total of eight RCTs including 8,150 patients (bevacizumab 4211, control 3939) with a variety of tumors were analyzed. The summary incidence of HFS was 14.3% (95% CI: 4.8-36.0%). The addition of bevacizumab to chemotherapy did not significantly increase the risk of developing all-grade (RR: 1.17, 95% CI: 0.90-1.51, P⫽0.240) and high-grade HFS (RR: 1.50, 95% CI: 0.92-2.47, P⫽0.11) as opposed to chemotherapy alone. The risk of HFS did not vary significantly with tumor types (P⫽0.21) and bevacizumab dose (P⫽0.28). However, the risk of HFS varied significantly with concurrent chemotherapeutic agents (P⫽0.004). Bevacizumab significantly increased the risk for 5-FU based agents (RR 1.2, 95% CI 1.08-1.33, P⫽0.001) but decreased the risk for non-5-FU based agents (RR 0.63, 95% CI: 0.41-0.96, P⫽0.03). Conclusions: Bevacizumab may enhance or reduce the risk of HFS depending on particular chemotherapeutic agents used in cancer patients. These findings are of importance to direct supportive care efforts.

9621


Palonosetron (PALO) versus granisetron (GRA) in the triplet regimen with dexamethasone (DEX) and aprepitant (APR) for preventing chemotherapyinduced nausea and vomiting (CINV) in patients (pts) receiving highly emetogenic chemotherapy (HEC) with cisplatin (CDDP): A randomized, double-blind, phase III trial. Presenting Author: Hironobu Hashimoto, National Cancer Center Hospital, Tokyo, Japan Background: Standard antiemetic care for preventing CINV due to HEC is a combination of 5-HT3 receptor antagonist (RA), DEX, and APR. This study compared the efficacy of two 5-HT3drugs, PALO and GRA, in the triplet regimen. Methods: Pts with a malignant solid tumor who were receiving HEC containing 50 mg/m2or more CDDP were enrolled. They were randomly assigned to either Arm A (PALO 0.75 mg, i.v.) or Arm B (GRA 1 mg, i.v.), 30 min before chemotherapy on day 1, both arms with DEX (9.9 mg on day 1 and 6.6 mg on day 2-4, i.v.) and APR (125 mg on day 1 and 80 mg on day 2–3, p.o.). Primary endpoint was complete response (CR; defined as no emetic episodes and no rescue medications) at the overall (0-120 hours) phase. Secondary endpoints included CR at the acute (0-24 h) and delayed (24-120 h) phases, and total control (TC; no emetic episodes, no rescue medications, and no nausea) at the overall, acute, and delayed phases. The planned sample size of 840 provided 90% power to detect a 10% improvement in the CR at 0-120 h with two-sided alpha of 0.05. Primary analysis was conducted with exact Cochran-Mantel-Haenszel (CMH) test. Results: Between July 2011 and June 2012, 842 pts were enrolled and 827 were evaluable. The median CDDP dose was 76.1 mg/m2 in Arm A and 75.7 mg/m2in Arm B. Baseline factors were well-balanced. Efficacy results are summarized in the Table. Conclusions: The present study did not meet its primary endpoint. However, it has shown that the clinical utility of PALO exceeds that of GRA. PALO is a more preferable 5-HT3RA in the triplet regimen than GRA in the prevention of CINV due to HEC. Clinical trial information: 000004863. CR % TC %

9623

Overall Acute Delayed Overall Acute Delayed

Arm A, Nⴝ414

Arm B, Nⴝ413

Odds ratio (95%CI)

P

66% 92% 67% 48% 81% 49%

59% 92% 59% 41% 81% 41%

1.35 (0.99, 1.82) 1.00 (0.58, 1.71) 1.45 (1.07, 1.96) 1.36 (1.01, 1.82) 1.00 (0.69, 1.45) 1.36 (1.02, 1.83)

0.0539 1.0000 0.0142 0.0369 1.0000 0.0369


A randomized multicenter phase II trial on efficacy of a hydrocolloid dressing containing ceramide with a low-friction external surface for hand-foot skin reaction caused by sorafenib in patients with renal cell carcinoma. Presenting Author: Nobuo Shinohara, Department of Urology, Hokkaido University Graduate School of Medicine, Sapporo, Japan Background: Hand-foot skin reaction (HFSR) is the most clinically significant and dose-limiting dermatologic toxicity in metastatic renal cell carcinoma (mRCC) patients who receive sorafenib (SOR). At present, evidence-based management strategy is not completely established. Since HFSR may be attributed to keratinous disorders of the skin and tends to develop in areas on the soles of the feet subject to strong pressure, a hydrocolloid dressing containing ceramide (a protective dressing against pressure ulcer) may prevent the development and worsening of HFSR. The purpose of the study is to investigate the usefulness of this material for HFSR on the soles of the feet in mRCC patients treated with SOR. Methods: Patients with grade 1 HFSR on the soles of the feet were randomly assigned 1:1 to receive a hydrocolloid dressing containing ceramide (Arm A) or 10% urea cream (Arm B). The detailed protocol of this study was presented in ASCO 2011 (Trial in Progress; TPS 233). A hydrocolloid dressing containing ceramide was applied to affected sites on the soles of the feet, but not to the hands. The primary endpoint was the incidence of Grade 2 or 3 HFSR on the soles of the feet in the first 4 weeks. Results: Thirty-three patients were evaluated; 17 patients in Arm A and 16 patients in Arm B. There were no significant differences in baseline characteristics between two arms. Over the 4 weeks period of this study, the incidence of Grade 2 or 3 HFSR on the soles of the feet was significantly lower in Arm A than Arm B; 5 (29%) patients in Arm A versus 11 (69%) in Arm B, p⫽0.03. On the other hand, the incidence of HFSR on the hands was similar between two arms. The median time to Grade 2 or 3 HFSR on the soles of the feet was significant longer in Arm A compared with Arm B; not reach (95%CI 13-28⫹) in Arm A versus 22 days (95%CI 15-27), p⫽0.03. Regarding the pain levels on the soles, Arm A was superior to Arm B (p⫽0.05). Conclusions: These results indicate that a hydrocolloid dressing containing ceramide with a low-friction external surface is effective in preventing the worsening of HFSR caused by SOR in mRCC patients. Clinical trial information: UMIN000002016.


606s

Patient and Survivor Care

9624


9625


Risk of arterial (ATE) and venous thromboembolism (VTE) in a populationbased cohort of bevacizumab-treated metastatic colorectal cancer (mCRC) patients. Presenting Author: Irene S. Yu, British Columbia Cancer Agency, Vancouver, BC, Canada

Population-based patterns of granulocyte colony stimulating factor (GCSF) use in breast cancer (BrCa) patients receiving myelosuppressive chemotherapy. Presenting Author: Michelle Lehmkuhl, British Columbia Cancer Agency, Vancouver, BC, Canada

Background: Bevacizumab potentiates the risk of ATE and VTE in cancer patients who are in a prothrombotic state. Whether there are specific factors that add to this risk and how bevacizumab-related thromboembolisms are best managed remain unclear. Our objectives were to 1) characterize the incidence of ATE and VTE in a population-based cohort of mCRC patients, 2) describe patient and treatment factors associated with thromboembolisms, and 3) examine how ATE and VTE are managed in routine practice. Methods: All patients diagnosed with mCRC from 2006 to 2008, evaluated at 1 of 5 regional cancer centers in British Columbia, and offered bevacizumab were included. Multivariate regression models were constructed to explore the associations between clinical factors and thromboembolisms. Results: A total of 541 mCRC patients were identified: 27 never started bevacizumab and 14 were lost to follow-up. Of the 500 remaining patients: median age was 61 years (IQR 53-67), 297 (59%) were men, 309 (62%) had ECOG 0/1, and 39 (8%) reported prior ATE or VTE. Median number of bevacizumab cycles was 11 (IQR 7-15). After receiving bevacizumab, 91 (18%) patients developed 12 ATE and 88 VTE, with 8 patients experiencing ⬎1 event. Baseline characteristics, such as median age (61 vs 61 years), gender distribution (61 vs 58% men), and ECOG 0/1 (66 vs 58%) were similar between patients with and without thromboembolisms, respectively (all p⬎0.05). In regression models, individuals who experienced ATE or VTE were more likely to have a prior history (14 vs 6%, p⫽0.02), reported greater pre-existing cardiac comorbidities (42 vs 32%, p⫽0.05), and received a higher median number of bevacizumab cycles (13 vs 9, p⬍0.01), suggesting a potential dose-related effect. Following the development of ATE or VTE, management varied: bevacizumab was discontinued in 46%, held temporarily in 14%, and continued in 40% of patients. Conclusions: In this population-based cohort, the thromboembolism risk is high, especially in patients with pre-existing risk factors and those heavily treated with bevacizumab. Management of bevacizumab-related ATE and VTE appears variable, underscoring the need for guidelines.

Background: Prophylaxis with GCSF can reduce hospitalization due to neutropenic fever, but early studies show that use of GCSF is frequently suboptimal. Our aims were to 1) characterize patterns of GCSF use in a population-based cohort of BrCa patients, 2) determine the rate of neutropenia and neutropenic fever in those who received and did not receive GCSF, and 3) identify patient and physician factors associated with appropriate GCSF prophylaxis. Methods: Patients diagnosed with BrCa from January to December 2008, seen at any 1 of 5 regional cancer centers in British Columbia, Canada and treated with chemotherapy protocols that posed ⬎20% risk of neutropenic fever were reviewed. Using regression models that adjusted for confounders, the relationship between GCSF use and 1) various patient and physician characteristics and 2) treatment outcomes, such as neutropenic fever, were analyzed. Results: A total of 525 women were included: median age was 51 years (IQR 45 to 59 years), 38% reported smoking, 50% used alcohol regularly, 62% were ECOG 0, and 26% had private health insurance. In the entire cohort, 203 (38%) patients were given GCSF. Among those treated with GCSF, 80 (39%) and 123 (61%) individuals received GCSF as primary and secondary prophylaxis, respectively. Overall, neutropenia was noted in 292 (56%) cases while neutropenic fever was experienced by 117 (22%) patients. When compared to those who did not use GCSF, patients who used GCSF experienced a lower rate of neutropenia (15 vs 49%, p⬍0.01) and a decreased incidence of neutropenic fever (7 vs 13%, p⬍0.01). In regression models, patients lacking extended medical coverage (35 vs 49%, p⫽0.02), poor performance status (31 vs 53%, p⫽0.03), and those who were evaluated at non-teaching institutions (24 vs 68% p⬍0.01) were less likely to receive GCSF. Patients seen at non-teaching institutions were also given primary GCSF prophylaxis less frequently (15 vs 57%, p⬍0.01) than those at teaching centers. Conclusions: GCSF prophylaxis was associated improved neutropenia-related outcomes. However, use of GCSF was low in this population-based cohort of BrCa patients, especially in specific marginalized subgroups.

9626

9627


Sustainability of antiemetic responses with APF530 (sustained-release granisetron) during multiple cycles of moderately (MEC) and highly (HEC) emetogenic chemotherapy regimens: Results of a randomized phase III trial. Presenting Author: Ralph V. Boccia, Center for Cancer and Blood Disorders, Bethesda, MD Background: Patients receiving MEC or HEC were administered subcutaneous (SC) APF530 500 mg, a sustained delivery formulation of granisetron (10 mg). The complete antiemetic response rates (CR; no emetic episodes and no rescue medication) were non-inferior to those of palonosetron in preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV) (Grous et al. ASCO 2009, #9627). We report on sustainability of CR with APF530 (10 mg) during multiple chemotherapy cycles in this study. Methods: 1428 patients scheduled to receive single doses of MEC or HEC were randomized to APF530 SC (5 or 10 mg granisetron) or 0.25 mg palonosetron intravenously (IV) prior to cycle 1 (C1). In C2-4, patients who received palonosetron in C1 were randomized to APF530 5 or 10 mg; those who received APF530 continued with their C1 APF530 dose. Treatment cycles were separated by 7-28 days. CR rates were compared between cycles using McNemar’s test. Results: No significant differences in withincycle CR occurred between APF530 doses during acute and delayed phases in C2-4 for MEC and HEC, but a trend toward higher CR rates was seen in successive cycles. For the 2 doses, CR was sustained across all 4 cycles in 56.5-62.6% and 68.4-71.7% in acute phase, and 41.8-42.4% and 57.5-57.9% in delayed phase with MEC and HEC, respectively. Examination of CR rates in C2, C3, or C4 compared with the rate in C1 showed that CR rates were sustained and that the proportion of patients with no CR in C1 but CR in later cycles was consistently higher than that of patients with CR in C1 but no CR later. For illustration, the table shows C4 CR and C1 CR for patients who received APF530 10 mg in C1 and C4. Conclusions: CR rates achieved with APF530 during acute and delayed phases of CINV in MEC and HEC were maintained over multiple cycles. Clinical trial information: NCT00343460.


Antibiotic prescribing in primary care for end-of-life cancer patients. Presenting Author: Wei Gao, Cicely Saunders Institute, King’s College London, London, United Kingdom Background: There is ongoing debate on whether it is appropriate to administer anti-infection medications to patients approaching end of life. Population-based epidemiologic data on current antibiotic prescribing status is needed to shed lights on this issue. Methods: A population-based retrospective cohort study, based on data extracted from the General Practice Research Database (GPRD). Patients (N⫽29,810) with one of five major cancers (lung, colorectal, breast, prostate, head and neck), and who died in 2000-2008 were included for this analysis. Prescriptions of antibiotics(BNF codes: 5.1.1-5.1.13) for individual patients in the last 3 months of life were reviewed and analysed. The outcome was with (1) or without (0) antibiotic prescriptions. A Generalized Estimating Equation (GEE) logistic regression model was used to assess for the associations between outcome and explanatory variables. Results: Overall, 26.8% of patients(95%CI: 26.3-27.3%) had been prescribed antibiotics. There was an increasing trend in antibiotic prescribing for end-of-life cancer patients, rising from 23.2%(21.5-24.9%) in 2000 to 29.5%(28.0-31.0%) in 2008 (p⬍0.001). Patients with the following characteristics were more likely to be prescribed antibiotics(p⬍0.001): being younger(⬍70:ORs 1.14-1.27) vs 80⫹, male gender(OR: 1.10; 1.03-1.18), lung & head & neck cancer(ORs:1.50-2.00) vs colorectal cancer, higher co-morbidity score(ORs vs 0-3:1.02-1.19), smoking(OR vs non-smoking 1.17;1.07-1.27), living in Northern Ireland(OR:1.43; 1.17-1.75) and Scotland(ORs: 1.23; 1.03 to 1.47) vs London. No difference by whether they drank alcohol or social economic status. Conclusions: Antibiotic prescribing at the end of life was common and increasing over the years. Further studies need to investigate clinical conditions associated with antibiotic prescribing to inform clinical practices and end of life care policy.

AFP530 (10 mg) CR in C4/CR in C1, n4/n1 (%)

MEC HEC

Phase

CR4/CR1

CR4/No CR1

No CR4/CR1

No CR4/No CR1

Acute Delayed Acute Delayed*

59/67 (88.1) 45/57 (78.9) 70/77 (90.9) 62/67 (92.5)

16/25 (64.0) 15/35 (42.9) 9/14 (64.3) 15/24 (62.5)

8/67 (11.9) 12/57(21.1) 7/77 (9.1) 5/67 (7.5)

9/25 (36.0) 20/35 (57.1) 5/14 (35.7) 9/24 (37.5)

*p ⫽ 0.0414




9629


Hypocalcemia in patients with metastatic bone disease receiving denosumab. Presenting Author: Jean-Jacques Body, Centre Hospitalier Universitaire Brugmann, Université Libre de Bruxelles, Brussels, Belgium

Impact of fosaprepitant use on dermal and vascular adverse events in anthracycline-based regimens administered through peripheral lines. Presenting Author: Takeo Fujii, St. Luke’s International Hospital, Tokyo, Japan

Background: Patients (pts) with metastatic bone disease (MBD) are at risk of skeletal-related events (SREs). Potent antiresorptives reduce the risk of SREs, by inhibiting cancer-induced bone destruction, which also reduces release of skeletal calcium (Ca) into the bloodstream. Hypocalcemia (hypoCa) may occur if Ca and vit D intake is inadequate while taking antiresorptive agents. A combined analysis of 3 phase III trials in pts with MBD showed denosumab (DMAb) was superior to zoledronic acid (ZA) in preventing SREs. The overall safety profiles were similar; hypoCa was more common with DMAb (9.6%) than ZA (5.0%). Characteristics of hypoCa events in DMAb pts in these clinical trials and from post marketing adverse event (AE) reports are presented. Methods: Pts with solid tumors or multiple myeloma and MBD were randomized (1:1) to DMAb 120 mg SC or ZA 4 mg IV (adjusted for renal function) every 4 weeks (Q4W). Pts were advised to take daily Ca (ⱖ 500 mg) and vit D (ⱖ 400 IU); intake was collected by pt report. Albumin-corrected serum Ca was measured Q4W by central lab. HypoCa events were collected as decreases in serum Ca per central lab and investigator-reported AEs. Post marketing data from spontaneous reports of hypoCa to the sponsor’s global safety department (AGS) were reviewed. Results: In the 3 trials, 2841 pts received DMAb and 2836 pts received ZA. The median Ca levels for both treatment groups were similar over time. Among DMAb pts, hypoCa was most common within 6 months of starting treatment and was more common in pts who did not report use of Ca and vit D vs those who did (15.8% vs 8.7%). Grade 3 or 4 (⬍ 7 mg/dL; ⬍ 1.75 mmol/L) decreases in serum Ca were reported in 3.1% of DMAb pts and 1.3% of ZA pts. No fatal cases of hypoCa were reported in the trials. From May to Nov 2012, 37 cases of severe symptomatic hypoCa (seizures, tetany, prolonged QTc, altered mental state) were reported to AGS; fatal outcomes were reported for 3 other pts with advanced cancers and various comorbidities. Conclusions: HypoCa is a known risk with antiresorptive therapy, including DMAb 120 mg. HypoCa occurred less often in pts who reported taking Ca and vit D. HypoCa should be corrected prior to starting DMAb and Ca monitored during treatment. Pts should take adequate Ca and vit D while receiving DMAb. Clinical trial information: NCT00321464, NCT00321620, and NCT00330759.

Background: Fosaprepitant is effective in the prevention of chemotherapyinduced nausea and vomiting. In January 2012, we started using fosaprepitant in anthracycline- and cisplatin-based regimens and observed a tendency for an increase in dermal and vascular adverse events (AEs) at local infusion sites, particularly in the anthracycline group. In this study, we tested the hypothesis that fosaprepitant use is associated with dermal and vascular AEs differentially between anthracycline- and cisplatin-based regimens. Methods: We conducted a retrospective cohort study consisting of all patients who were administered anthracycline- or cisplatin- based regimens in 2011 and 2012 at St. Luke’s International Hospital, Tokyo. Aprepitant was used in 2011 and fosaprepitant was used in 2012. All other factors including pre- and post-hydration, premedication, and injection schedule were the same. Dermal and vascular AEs was defined as any grade pain or skin changes at local infusion sites or infusion veins. Factors we considered include fosaprepitant use, chemotherapy regimen, age, number of prior regimens, and body mass index. Interaction analysis using multivariate logistic regression was used to evaluate the association between treatment regimen, fosaprepitant, and risk of AEs. Results: A total of 268 patients (aged 54.3⫾12.3) were included, of which 120 (44.8%) used fosaprepitant. Among fosaprepitant users, 50 patients (41.7%) developed dermal and vascular AEs, whereas only 16 patients (10.8%) experienced AEs among non-users (P⬍ .001). When stratified by regimen, fosaprepitant was associated with a statistically significant increased risk of AEs (OR 12.10; 95% CI 5.45-26.93) in the anthracycline group. In contrast, no association was observed in the cisplatin group (OR 1.04; 95% CI 0.29-3.75). Statistically significant evidence of interaction was found (P⬍ .001) between regimen and fosaprepitant in the risk of AEs. Conclusions: Our results support the finding that using fosaprepitant in anthracycline-based regimens increases dermal and vascular AEs. In response, we discourage the use of fosaprepitant in anthracycline-based regimens through peripheral lines.

9630

9631



A genetic variant of 5-hydroxytryptamine receptor 3C (HTR3C): A novel link to chemotherapy-induced side effects. Presenting Author: Tami Rubinek, Oncology Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

Treatment of depressive symptoms in breast cancer patients undergoing adjuvant therapy. Presenting Author: Rudolph M. Navari, Indiana University School of Medicine South Bend, South Bend, IN

Background: Symptom clusters are defined as three or more concurrent symptoms that are related to each other. Clusters may stem from common physiological mechanisms and may better represent adverse effects to chemotherapy compared to individual symptoms. We aimed to identify association between the experience of symptom clusters and specific genetic alterations. Methods: Study population consisted of 108 breast cancer patients who received over two cycles of adjuvant doxorubicin and cyclophosphamide (AC) treatment at the oncology institute of the Sheba Medical Center. Participants completed the Memorial Symptom Assessment Scale, the Lee Fatigue Scale and the Center for Epidemiological Studies Depression Scale. Hierarchical cluster analysis was used to identify patients’ subgroups based on their symptom experience. For the genetic analyses, DNA was extracted from peripheral blood and single nucleotide polymorphisms (SNPs) of candidate genes were tested using restriction endonuclease assays. Results: Two distinct subgroups were identified based on severity of fatigue, depression, nausea, and change in food tastes: ⬙all high⬙ (n⫽79) and ⬙all low⬙ (n⫽29) level of all symptoms. As patients did not have active cancer, symptoms were attributed solely to chemotherapy. A genetic variant of HTR3C (rs6766410) results in a substitution of asparagine to lysine (N163K) may be associated with nausea and vomiting. We tested the association between this variant and symptom score. 51 of 75 (68%) patients with high symptom score harbored the variant allele, compared to 13 of 28 (46%) of those with low symptom score (p⫽0.038). Conclusions: Analysis of genetic background of clusters, rather than for individual symptoms, represents a novel approach for the study of chemotherapy-induced side effects. This approach enabled the identification of HTR3C variant as a possible mediator of side effects following treatment with AC. Discovering the genetic basis of symptom clusters may lead to the development of novel diagnostic and therapeutic modalities able to improve symptom management. This may translate to improved outcome among chemotherapy-treated cancer patients.

Background: Studies have shown a high prevalence of depression in patients with cancer. Women with breast cancer may have a high risk of depression particularly in a post-menopausal or estrogen deficient state and may develop a high level of depressive symptoms at the time of initial diagnosis. Newly diagnosed early stage breast cancer patients were screened for depressive symptoms prior to the initiation of adjuvant therapy. The oral antidepressant fluoxetine was studied to determine if its use affected depressive symptoms, completion of adjuvant treatment, quality of life, and survival. Methods: Patients with newly diagnosed early stage breast cancer were screened for depressive symptoms prior to the initiation of adjuvant therapy. Patients with depressive symptoms were randomized in a double blind fashion to daily oral fluoxetine (20 mg) or placebo. Patients were then followed for 6 months and evaluated for quality of life, completion of adjuvant treatment, and depressive symptoms. Patients with stage I disease at the time of initial diagnosis were subsequently assessed for disease recurrence and survival at five years. Results: Two hundred three of 357 screened patients with newly diagnosed early stage breast cancer were found to have depressive symptoms prior to the initiation of adjuvant therapy. One hundred ninety-three patients were randomized to fluoxetine or placebo. The use of fluoxetine for 6 months resulted in a significantly (p⬍0.01) higher number of patients with an improvement in quality of life, a higher completion of adjuvant treatment (chemotherapy, hormonal therapy, chemotherapy plus hormonal therapy) and a reduction in depressive symptoms compared to patients who received placebo. At five years, there was a significant (p⬍0.01) improvement in survival for patients with Stage I disease who received fluoxetine, possibly related to a higher completion of adjuvant treatment. Conclusions: An antidepressant should be considered for early stage breast cancer patients with depressive symptoms who are receiving adjuvant treatment.


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Final results of a phase I trial of fasting prior to platinum-based chemotherapy. Presenting Author: David I. Quinn, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA Background: Fasting confers dramatic protection against chemotherapy toxicity in mice (PNAS 2008). We studied safety and feasibility of escalated fasting duration prior to platinum doublet chemotherapy in cancer patients (pts). Insulin, glucose, ketones and insulin-like growth factor (IGF) were measured as potential biomarkers of the fasting state. Methods: 3 fasting cohorts were evaluated: 24, 48 and 72 hours (hr) (48 pre/24 post chemotherapy). Subjects recorded all calories consumed during the fast period. Feasibility was defined as 4/6 subjects in each cohort consuming ⬍ 200 kCal/24 hr without excess fasting toxicity (using CTCAE v4.0). Results: Primary cancer: Urothelial 5, breast 5, ovarian 7, uterine 1, NSCLC 1. Regimens: gemcitabine⫹ cisplatin 6, docetaxel ⫹ carboplatin (C) ⫹ trastuzumab 5, C ⫹ paclitaxel 8. Median age: 61y (31-73). 4/6 pts, 5/7 pts and 4/6 pts in the 24, 48 and 72 hr groups were fasting compliant ⬍200 kCal/24 hr with no significant toxicities. Median weight change was 0 after 1 cycle of fasting (-3.8% to ⫹3.1%); 1 pt failed to regain 25% of lost weight prior to second cycle and per protocol did not fast again. Reasons for failure included forgetting and inability to maintain fast. Worst symptoms during the 48 and 72 hr fast: grade 1 hypoglycemia and hyponatremia; grade 2 headache, fatigue and dizziness; there were no grade 3 or 4 fasting-related toxicities. After fasting, insulin levels fell by medians of 69% in 24hr pts and 60% in 48hr pts (p⫽0.014). Median IGF1 levels ⌬ by -18.3% (p⫽0.012), interestingly 3 pts who fasted 72 hr had further ⌬ -19% to -59% from 48 to 72 hr. Conclusions: Fasting for up to 72 hr around chemotherapy is safe and feasible for cancer pts and resulted in significant decline in insulin and IGF1 levels. The randomized phase II portion of the trial commenced with 72 hr fast, seeking to delineate insulin and IGF1 as potential biomarkers of chemotherapy toxicity reduction. Clinical trial information: NCT00936364.

9634


N-telopeptide of type I collagen (NTX) dynamics over one year of determinations in patients with breast cancer (BC) with bone metastases (BM): Predictive factors of outcome. Presenting Author: Ning Shan, Thar Pharmaceuticals, Tampa, FL Background: The bone resorption marker NTX at baseline is a prognostic marker in BC patients with BM treated with zoledronic acid (ZOL), Coleman RE, JCO 2005. We investigate how the response of urinary NTX levels during ZOL therapy is related to patient outcome and disease characteristics. Methods: Consecutive BC patients with BM were prospectively included if they received monthly intravenous ZOL. Urinary NTX was determined at baseline and at following 1, 3, 6, 9 and 12 months from the initial ZOL treatment. NTX levels were considered elevated if ⬎ 50 nmol/mmol creatinine. The NTX changes were compared with patient and disease characteristics. Relative risks for negative clinical outcomes were estimated with Cox regression models. Results: Seventy-one BC patients with BM, mean aged 61.4 (29-87), were included. Mean survival was 34.1 months (3-131), with 21 patients alive after the last follow up (median 29 months). Thirty-nine patients also had extraskeletal metastases (BM-E⫹). Totally 329 urinary NTX samples were evaluated. At baseline, mean NTX was 153.0 (15.4 – 700.7) and 78.9% had elevated levels. Mean baseline NTX increased with age: 71.2 (⬍40); 139.3 (50-59); 241.8 (70-79). Among patients with normal NTX at 3 months, 89.5% continued to show normal NTX at 12 months. After ZOL treatments, 46.9%, 54.7%, and 61.0% of patients had normal NTX at 3, 6 and 12 months, respectively. NTX variance (1-12 months) was higher for BM-E⫹ patients compared with BM-only patients, p⬍0.001. Risk factor of death for patients with persistent elevated NTX at 3 months was 1.74 (p⫽0.074). Age and BM-E⫹ were also associated with risk of death. There was a trend to shorter survival in BC-E⫹ patients (p⫽0.056). Majority of patients (88.2%) with longer survival (⬎ 36 months) and younger (age ⬍ 60) received endocrine therapy. Conclusions: Early (3 months) urinary NTX normalization to ZOL correlates with long-term NTX normalization and survival. BC-E⫹ patients have a reduced NTX normalization rate compared to BM-only patients and may deserve further investigation for a more adequate schedule of bone-targeting agents.

9633


A prospective multicenter, single blinded, randomized phase III trial to compare the efficacy of ramosetron, aprepitant and dexamethasone with ondansetron, aprepitant, and dexamethasone for preventing chemotherapyinduced nausea and vomiting: KCSG PC10-21. Presenting Author: Hyo Jung Kim, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang, South Korea Background: Combination of aprepitant, 5-HT3 receptor antagonist and steroid improve complete response (CR) of chemotherapy induced nausea and vomiting (CINV). But until now, there was no information whether ramosetron is as effective as other 5-HT3receptor antagonists for the combination regimen. Therefore, we compared a ramosetron, aprepitant and dexamethasone (RAD) with ondansetron, aprepitant and dexamethasone (OAD) to establish the non-inferiority of RAD in controlling highly emetogenic chemotherapy induced nausea and vomiting. Methods: A total of 334 patients with malignant disease who were scheduled to receive highly emetogenic chemotherapy were randomized to RAD or OAD. Aprepitant (125 mg day 1; 80 mg day 2, 3) and dexamethasone (12 mg day 1; 8 mg day 2-4) were administered to both group. Intravenous ramosetron (0.3mg day 1) or ondansetron (16mg day1) was given to RAD or OAD, respectively. Patients recorded vomiting and nausea (VAS score) on the diary. The primary end point was CR (no vomiting or retching and no rescue medication) rate in the acute period (chemotherapy day 1). The noninferiority margin was defined as -15% differences. Results: 299 patients (RAD 143, OAD 156) were eligible for the efficacy analyses of modified intention-to-treat. Median age and sex were 60 (IQR 52 – 66) and 61 (51.5 – 68, p⫽0.54), 90 Male/66 Female and 114 Male/29 Female (p⬍0.0001) in RAD and OAD, respectively. There were no significant differences between two groups on the other baseline characteristics. The CR rates of RAD vs OAD were 84.6% vs 77.6% (95% C.I. -0.4 – 14.5%) at acute period, 69.5% vs 62.6% (-2.1 – 16.0%) at delayed period (days 2-5), and 66.7% vs 58.1% (-0.6 – 17.8%) at overall period. Median nausea score at acute period were 4 (IQR 2 – 5) and 3 (2-5, p⫽0.14) in RAD and OAD, respectively. There were no grade 3 or 4 toxicities. Conclusions: RAD regimen is as effective and tolerable as OAD antiemetic combination for the prevention of CINV in patients receiving highly emetogenic chemotherapy. Ramosetron could be considered as one of the best partners for aprepitant. Clinical trial information: NCT01536691.

9635


A randomized, double-blind study of “Scrambler” therapy versus sham for painful chemotherapy-induced peripheral neuropathy (CIPN). Presenting Author: Toby Christopher Campbell, University of Wisconsin Carbone Cancer Center, Madison, WI Background: CIPN is a debilitating, dose-limiting toxicity. The MC5A is a non-invasive electro-analgesia device delivering “Scrambler Therapy,” which has shown benefit for painful CIPN in uncontrolled studies. No sham-controlled trials of MC5A have been performed. Methods: Eligible patients included adults with neuropathic pain (NP) for ⬎ 6 months, pain scores ⱖ4/10 numerical rating scale (NRS), and no history of diabetes or other peripheral neuropathies. Patients received up to 10 daily sessions of 50 minutes with either MC5A or a novel active sham device constructed to deliver a just perceptible electrical sensation. Sham output is neither a TENS nor MC5A and is designed to be nontherapeutic. Active and sham treatments were applied to the affected limbs. 14 patients were randomized with no baseline differences. Patients and evaluators were blinded to study arm. Pain was measured before, daily during, after and 3 months post-treatment (verbal NRS). The primary endpoint was change in pain. Secondary endpoints included quantitative neurosensory testing (QST), validated patient-report measures, and cytokines. Results: There were 7 patients in each arm. The table shows changes in pain scores pre- and post-treatment by day and group. There was no difference between arms and no arm x day interaction. There was no significant day or arm effect for the function sub scales. Conclusions: In a small pilot study, MC5A was not significantly different from sham therapy for the primary outcome. The sham is feasible and provides a mechanism for future controlled studies with MC5A. Secondary endpoints, e.g. QST are forthcoming. Clinical trial information: NCT01261780. NRS change by day and treatmen. MC5A (nⴝ7) Day 1 2 3 4 5 6 7 8 9 10 1

N 7 7 7 7 7 7 7 5 5 5

NRS Change -0.14 -0.14 0.00 0.00 -0.43 -0.21 -0.50 -0.40 -0.30 -0.10

SD 0.38 0.94 0.00 0.65 1.27 0.39 0.76 0.55 0.45 0.89

Sham (nⴝ7) P value1 0.99 0.81 0.99 0.75 0.50 0.25 0.50 0.50 0.99

N 7 7 7 7 7 6 5 5 5 5

NRS Change 0.57 0.43 -0.50 0.21 -0.36 -0.42 -0.60 0.10 -0.80 -0.40

SD 0.98 1.27 1.08 0.39 0.48 0.38 0.55 0.55 0.57 0.55

P value1 0.31 0.75 0.34 0.50 0.25 0.12 0.25 0.99 0.12 0.50

P value2 0.10 0.46 0.05 0.52 0.67 0.30 0.65 0.28 0.18 0.57

Within comparison: Wilcoxon Signed Rank Test. 2 Between comparison: Wilcoxon Rank Sum Test.




Patterns of palliative radiation near the end of life: A single-institution retrospective analysis. Presenting Author: Sara R. Alcorn, Johns Hopkins Hospital, Department of Radiation Oncology, Baltimore, MD Background: The care of patients who receive radiation therapy (RT) at the end of life (EOL) is under scrutiny to ensure effectiveness and value, with many patients not completing RT (Gripp, 2010; Toole, 2012). This retrospective analysis seeks to describe patterns of utilization of palliative RT, including rates of completion of RT offered at the EOL and the use of single fraction RT for bone metastases. Methods: Electronic medical records were used to create a database of 3,383 RT plans for brain, bone, lung, and other metastatic sites in patients treated at Johns Hopkins Hospital from 9/1/2007-7/15/2012. RT plans without palliative intent were excluded. T-tests and logistic regression compared patient and treatment characteristics between patients who died ⬎ 1 month versus ⱕ 1 month after their last RT fraction. Results: A total of 983 patients were treated to 1,524 sites, with an average of 1.7 RT sites (SD 1.3) per patient. Of these, 872 (89%) patients had complete records and were included in analysis. At the time of analysis, 85% had died. The mean age of 62.1 years (SD 3.4) did not differ statistically based on time from RT to death. Death ⱕ 1 month after RT was documented in 215 (24.7%) patients. Compared to patients living ⬎ 1 month after RT, patients receiving RT within the last month of life were more likely to be lung (17% versus 9%), less likely to be brain (34% versus 44%), and equally likely to be bone (45% versus 43%) sites. Patients who died ⱕ 1 month after completing RT spent on average 5 days (16.6%) of the last month of life receiving RT, with no significant difference by disease site. Conclusions: Most patients receiving palliative RT finish therapy, with 25% dying ⱕ 1 month after RT. Single fraction bone RT was relatively uncommon, with no significant difference in the rates of single fraction RT based on time from RT to death. These data provide a framework to match treatment patterns with national guidelines. Additionally, they provide context to model risk of death shortly after RT, which can aid in clinical decision-making.

9637


Efficacy of rebamipide-gargle for chemotherapy-induced oral mucositis. Presenting Author: Masato Nakamura, Aizawa Hospital, Matsumoto, Japan Background: Chemotherapy-induced oral mucositis (CIOM) is a severe adverse event resulting from cancer chemotherapy, and causes severe pain which impacts eating, nutrition, infection and overall quality of life. CIOM can result in unplanned treatment interruptions including dose reduction or treatment delay. Toxic free radicals and several pro-inflammatory cytokines produced by anti-cancer drugs have been reported to correlate with CIOM. Rebamipid, an endogenous inducer of prostaglandins, is widely used for gastric ulcers and gastritis in Asia. It has been shown to increase gastric endogenous prostaglandin E2 and I2, to promote gastric epithelial mucin, to behave as an oxygen–free radical scavenger, and to have other anti-inflammatory actions. In this study, we made a rebamipide gargle using rebamipide and ultrahydrogel, which is added for mucosal protection and to sustain the rebamipide on oral mucosa for a long time. Methods: The objective of this study is to evaluate the efficacy of the rebamipide gargle in relieving CIOM. Each 300ml of rebamipide gargle is made by combining rebamipide 600mg, high molecular weight polyethylene oxide 3g, carrageenin 1.2g, pineapple flavor and water. Patients were instructed to use the rebamipide gargle 5-6 times a day. The severity of CIOM was assessed according to the National Cancer Institute Common TerminologyCriteria for Adverse Events (CTCAE version 4.0). Results: From November 2009 to December 2012, 175 patients with CIOM were enrolled in this study (colorectal cancer 95 patients, breast cancer 32, gastric cancer 22, lung cancer 14, and other cancers 12). The patients’ CTCAE grades (3/2/1/0) changed from (n⫽13/64/98/0) to (0/10/103/62) respectively after initiation of rebamipide gargle (p⬍.01; paired t test). A decrease in CTCAE was observed in 142 patients (81.1%) including 62 patients (35.4%) achieving grade 0. The mean duration to best response was 14 days (range: 1-49), and rebamipide gargle was continued 42 days (range: 5-970).There were no unexpected safety events. Conclusions: Rebamipide gargle was well tolerated and demonstrated significant therapeutic response for CIOM.

Results Patterns of care Percent completing RT Number of last 30 days of life spent in RT Single fraction bone RT

9638

Died < 1 month after RT

Died > 1 month after RT

Total

51% 5 days (range 2-15) 6.3%

96% 7.8%

83% 7.4%


9639


Symptom clusters and demographic characteristics in advanced cancer. Presenting Author: Aynur Aktas, Harry R. Horvitz Center for Palliative Medicine and Supportive Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH

Electro-acupuncture for joint pain related to aromatase inhibitors among breast cancer survivors: A randomized placebo-controlled trial. Presenting Author: Jun J Mao, Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA

Background: Little is known about demographic variations in cancer symptom clusters (SC). Our objective was to determine whether SC are associated with age, gender, race, performance status (PS), or primary cancer site. Methods: Symptoms from 1000 advanced cancer patients referred to a palliative medicine program were recorded prospectively. Among 922 patients with complete symptom data, hierarchical cluster analysis identified 7 SC. A SC was considered present if the patient had ⱖ50% of the symptoms in the cluster. Comparisons were made between patients with and without each cluster using the chi-square test (age ⬍65 vs. ⱖ65 years; gender female (F) vs. male (M); race Caucasian (C) vs. African American (AA); 10 primary site groups (PSG), or Wilcoxon rank sum test (ECOG PS 0-4). A p value ⬍0.05 indicated statistical significance. Results: 83% of patients were C, 52% ⱖ65 years, 56% M, and 55% had ECOG PS 3-4 Most common PSG were lung (25%), genitourinary (18%), and gastrointestinal (GI) (11%). Fatigue/anorexia-cachexia cluster was associated with race (58% AA vs. 68% C, p⫽0.032) and PSG (range 47% melanoma to 83% pancreas, p⫽0.012); Neuropsychological cluster was associated with older age (29% ⱖ65 vs. 39% ⬍65, p⬍0.001) and race (22% AA vs. 36% C, p⫽0.001). Upper GI cluster was associated with female gender (16% M vs. 22% F, p⫽0.035) and PSG (range 8% Head & Neck to 32% pancreas, p⫽0.035). Nausea/Vomiting cluster was associated with younger age (35% ⱖ65 vs. 43% ⬍65, p⫽0.010) and female gender (33% M vs. 47% F, p⬍0.001). Aerodigestive cluster was associated with male gender (36% F vs. 44% M, p⫽0.010) and PSG (range 24% pancreas to 58% Head & Neck, p⬍0.001). Debility cluster was associated with race (33% AA vs. 44% C, p⫽0.016) and poor PS (range 17% PS0 to 54% PS4, p⬍0.001). Pain cluster was associated with younger age (88% ⱖ65 vs. 92% ⬍65, p⫽0.028). Conclusions: We identified 7 SC whose prevalence were influenced by age, gender, race, PS, or primary cancer site. This supports the clinical relevance of the cluster concept in palliative and supportive care. Demographic characteristics may warrant different clinical approaches to patient care. Identification of these differences may help develop more effective cancer treatment and management strategies.

Background: Arthralgia is a common and debilitating symptom in a significant proportion of breast cancer patients receiving aromatase inhibitors (AIs). Methods: We conducted a randomized, placebo-controlled trial of electro-acupuncture compared to waitlist control (WLC) and sham acupuncture in postmenopausal women with breast cancer who self-attributed their arthralgia to taking AIs. Acupuncturists delivered ten treatments of tailored acupuncture with 2 Hz electro-stimulation via a TENS unit. Sham acupuncture used non-penetrating Streitberger needles at non-traditional acupuncture points and lacked electro-stimulation. The primary endpoint was pain severity measured by the Brief Pain Inventory (BPI) between electroacupuncture and WLC at Week 8; durability of response at Week 12 and comparison of electro to sham acupuncture were secondary aims. Results: Sixty-seven patients were randomized to the three arms. The mean reduction in BPI pain severity was significantly greater in the electroacupuncture group than WLC group at both Week 8 (-2.2 vs. -0.2 p⫽0.0004) and Week 12 (-2.4 vs. -0.2, p⬍0.0001). The BPI pain-related interference also improved significantly in the electro-acupuncture group compared to WLC group at Weeks 8 (-2.0 vs. ⫹0.2, p⫽0.0006) and 12 (-2.1 vs. -0.1, p⫽0.0034). Sham acupuncture reduced pain severity (-2.3) and pain-related interference (-1.5) at Week 8 similar to electroacupuncture (p⫽ non-significant); however, the effect of sham acupuncture appeared to decrease at Week 12 for pain severity (-1.7) and pain-related inference (-1.3). Conclusions: Electro-acupuncture significantly improved AI-related arthralgia over “usual care” with clinically important and durable changes in symptoms. Treatment effects were similar between the electro and sham groups at Week 8, suggesting that a large component of acupuncture effect is mediated through the process of acupuncture delivery rather than the specificity of needle placement or needle penetration of skin. Research is needed to evaluate the long term effects of electro-acupuncture to improve AI-related arthralgia. Clinical trial information: NCT01013337.


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Incidence of osteonecrosis of the jaw in patients receiving denosumab or zoledronic acid for bone metastases from solid tumors or multiple myeloma: Results from three phase III trials. Presenting Author: Allan Lipton, Penn State Milton S. Hershey Medical Center, Hershey, PA

Differential protein expression profile in skin biopsies from patients with hand-foot syndrome who have benefited from topical heparin treatment. Presenting Author: Analia Rodriguez-Garzotto, Medical Oncology Department. Hospital 12 de Octubre, Madrid, Spain

Background: In patients with metastatic bone disease (MBD), the use of antiresorptive therapies such as denosumab or zoledronic acid (ZA) reduces the risk of skeletal-related events but is associated with a small risk of osteonecrosis of the jaw (ONJ). Two phase 3 clinical trials of denosumab vs ZA in patients with MBD showed overall cumulative ONJ incidences to be 3.8% to 4.7% at approximately 5 years of treatment with denosumab across blinded and open-label extension phases. ONJ associated with ZA was only assessed in the blinded treatment phases, as patients switched to denosumab once superior efficacy was demonstrated. Here we report incidence rates of ONJ by first vs subsequent years of exposure for the blinded treatment phase of all three phase III clinical trials. Methods: Patients (n ⫽ 5,677) with bone metastases from solid tumors or multiple myeloma received either SC denosumab 120 mg and IV placebo or IV ZA 4 mg (adjusted for renal function) and SC placebo Q4W in the double-blinded treatment phase of each trial. Patients who received ⱖ 1 active dose during the blinded treatment phase were included in this analysis for up to 44.5 months of denosumab exposure and 41.3 months of ZA exposure. Oral assessments were conducted at baseline and every 6 months thereafter by the investigator or other qualified examiner. Potential ONJ events were independently adjudicated by a blinded committee of experts. Results: The median (Q1, Q3) time to onset of ONJ was similar in both treatment groups (15.6 [9.5, 20.0] months for denosumab, 15.8 [11.0, 23.6] months for ZA). Cumulative incidence rates of ONJ during the blinded treatment phases for all three trials by patient-years of follow-up are shown below (Table). Conclusions: The incidence of ONJ increased with longer duration of antiresorptive exposure. There were no significant differences between treatment groups in ONJ incidence at year 1 or beyond. Clinical trial information: NCT00321464; NCT00330759; NCT00321620.

Background: Hand-foot syndrome (HFS) is a dose-limiting toxicity of capecitabine (CAP), leading to significant morbidity in patients receiving this agent. Interruption or dose reduction of CAP is the only effective strategy. The purpose of our study is to define the pathophysiology and risk factors predictors of CAP-induced HFS. Previously, we had conducted a clinical trial in patients who developed HFS secondary to CAP. Topical heparin was administered in palms and soles of patients four times/day for three weeks (w), evidencing clinical improvement in 99% of patients. Methods: Paired-skin biopsies of palms at baseline and after 3w from 21 patients were obtained. An iTRAQ (isobaric tags for relative and absolute quantitation) proteomics approach was performed to identify molecular pathways associated with HFS reversion. Results: Comparative analysis between baseline and post-treatment skin samples identified 1876 proteins with high confidence (⬎ 99%). The involvement of the identified proteins in biological networks served to characterize molecular pathways associated with HFS reversion. Conclusions: Several proteins identified in this study have a close relationship with keratinocyte terminal differentiation and keratinocyte intercellular strength. Also, we describe differential expression among proteins involved in inflammatory processes, skin immunity and cell death. In summary, our study not only served to uncover molecular mechanisms associated with HFS reversion, but also to reveal the biomarker role of several proteins in this syndrome.

N, (incidence rate)*

0–1 year

P value

> 1 year

P value

Total

P value

Denosumab (n ⴝ 2,841) Zoledronic acid (n ⴝ 2,836)

22 (1.0) 16 (0.8)

0.37

41 (3.3) 27 (2.2)

0.11

63 (1.9) 44 (1.3)

0.08

Upregulated protein

Downregulated protein

Nicotinamide N-methyltransferase Thy-1 membrane glycoprotein SPARC Serpin H1 Dermcidin Protein S100 Collagen alpha Periostin Cytochrome b-c1 complex subunit 6, mitochondrial Stathmin Caldesmon

Keratinocyte differentiation-associated protein CD9 antigen Keratin, type II cytoskeletal 1 Keratin, type I cytoskeletal 10 Serpin B3 Interleukin-36 gamma Keratin, type II cytoskeletal 2 epidermal Serpin B12 Filaggrin Tenascin-X Plasminogen activator inhibitor 2

* Rate per 100 patient-years of follow-up.

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9643


High-dose Asian ginseng (Panax ginseng) for cancer-related fatigue (CRF): A preliminary report. Presenting Author: Sriram Yennurajalingam, The University of Texas MD Anderson Cancer Center, Houston, TX

The efficacy of subclinical lymphedema detection in high-risk breast cancer survivors. Presenting Author: Atilla Soran, Magee-Womens Hospital of the University of Pittsburgh Medical Center, Pittsburgh, PA

Background: CRF is a common and severe symptom in patients with cancer. There are limited useful treatments available. The objective of this preliminary study was to assess the safety of high-dose Panax ginseng (PG) on CRF. Methods: In this prospective open labeled study, 30 patients with cancer and fatigue ⱖ4/10 (0⫽no fatigue, 10⫽worst possible fatigue) received high dose PG 800mg orally daily for 29 days. Functional Assessment of Cancer Therapy-fatigue (FACIT-F), Edmonton Symptom Assessment System (ESAS) (0⫽best, 10⫽worst), and Hospital Anxiety Depression Scale (HADS) were assessed at baseline and day 29. Results: 24/30 (80%) patients were evaluable. The median age was 58yrs, 50% were females, 84% were white. The most common cancer type was genitourinary cancer (31%). Table shows the changes in fatigue, anxiety, depression scores. ESAS well-being improved from 4.67 (2.04) to 3.50 (2.34) (p⫽0.01374), appetite improved from 4.29 (2.79) to 2.96 (2.46) (p⫽0.0097). 21/24 (87%) patients had an improved FACIT-F fatigue score by day 15. Global Symptom Evaluation score of PG for fatigue was better in 15/24 patients (63%) with median improvement of 5 (1⫽hardly any better, 7⫽ very great deal better). No ⱖ grade 3 adverse events related to the study drug were reported. Conclusions: 1) PG is safe and rapidly improved ESAS fatigue and FACIT-F fatigue scores; 2) Overall quality of life (FACIT-General), appetite, and sleep at night also improved. Randomized controlled trials of PG are justified in CRF. Clinical trial information: NCT01375114.

Background: Lymphedema (LE) is associated with profound functional, psychosocial and medical consequences. Early intervention may decrease morbidity from LE. Bioimpedance spectroscopy (BIS) allows subclinical diagnosis by detecting subtle differences in extracellular fluid volume between the limbs. In our lymphedema program, we prospectively monitor BIS in patients (pts) undergoing axillary lymph node dissection (ALND). The aim of this study is to investigate whether early diagnosis of LE after ALND using BIS can allow early intervention. Methods: BIS in the “Pre-Operative Group,” measurements using L-Dex U400 were obtained pre-operatively (n⫽123) and at 3-6 month intervals thereafter. In the “Follow-up Group⬙ pts who had ALND previously (n⫽89) had baseline measurements and monitoring at the same intervals. Age, BMI, dominant hand use, side of ALND, type of breast surgery, receipt of radiation therapy, and number of LN removed were recorded. L-Dex values ⬎ 10 units or increase ⬎ 10 units above the initial measurement was treated with LE education, an over-the-counter compression sleeve, less intensive physical therapy sessions and daily exercise. Results: The mean age was 58 (27-90). The mean BMI was 28.5 (17.1-65.7)kg/m2. ALND was on the side of the dominant hand in 56% of pts (n⫽119). The mean number of LNs removed was 16 (5-49). The majority of pts underwent mastectomy (59%; n⫽126), 73% (n⫽55) received RT, and 80% (n⫽191) received neo- or adjuvant chemotherapy. 87 pts (41%) were followed for more than 1 year from initial measurement. Since the monitoring began, 18% (n⫽22) in the Preoperative Group and 23% (n⫽20) in the Follow-up group were diagnosed with subclinical LE and received early intervention. 41 pts (97.6%) remain stable with no worsening of LE 1 yr after diagnosis. One pt advanced to stage 2 LE but declined further monitoring at 6 mo. Conclusions: Subclinical detection of LE with BIS and timely intervention reduced the incidence of late-stage LE among women undergoing ALND to ⬍3% compared with historical incidence of ⬎25%. Periodic monitoring of women at high risk for LE can minimize costly and intensive LE treatment such as custom made sleeves, pump and surgery while anticipating elimination of more advanced LE.

Symptom Fatigue (ESAS) Drowsiness (ESAS) Sleep at night (ESAS) Depression (ESAS) Depression (HADS) FACIT-F, fatigue subscale (primary outcome) FACIT-G FACIT-F physical

Baseline, mean (SD)

Day 29, mean (SD)

P value

6.2 (1.82) 3.21 (2.21) 5.38 (2.37) 1.29 (2.22) 6.50 (3.34) 24.58 (8.9)

3.75 (1.62) 2.42 (2.28) 3.54 (2.02) 1.29 (2.03) 6.09 (3.86) 32.90 (11.01)

⬍0.0001 0.0948 0.0012 0.999 0.6088 ⬍0.0001

71.42 (17.54) 17 (5.82)

77.29 (17.79) 19 (4.79)

0.0104 0.002




9645


A pilot intervention addressing sexual dysfunction after risk-reducing oophorectomy. Presenting Author: Sharon Bober, Dana-Farber Cancer Institute, Boston, MA

Hepatotoxicity with chemotherapy in patients infected with hepatitis B virus. Presenting Author: Jean-Luc Szpakowski, The Permanente Medical Group, Fremont, CA

Background: Women at high risk for ovarian cancer due to BRCA1 or BRCA2 mutation or family history are recommended to undergo prophylactic bilateral salpingo-oophorectomy (PBSO) after age 35 or completion of childbearing. This potentially life-saving surgery leads to premature menopause, frequently resulting in profound sexual dysfunction. We developed and piloted the first psychoeducational intervention for managing sexual dysfunction in young women after PBSO. Methods: This single-arm multimodal pilot intervention study included a single half day session with educational modules about sexual health education, relaxation training, and cognitive behavioral therapy (CBT) skills to manage symptoms, followed by tailored telephone counseling. Self-report assessments, including the 19-item Female Sexual Function Index (FSFI) and a 10-item measure of sexual knowledge after PBSO were completed at baseline and two months post-intervention. Eligible women had PBSO for risk-reduction, current age ⱕ 49, and endorsed at least one symptom of sexual dysfunction. Study endpoints include feasibility and effectiveness. Results: 36 women enrolled and completed pre- and post- assessments. Median age was 44 years (range 36-49) and median time since PBSO was 3.2 years (range 0.75-12.3). FSFI scores improved significantly from baseline to post-intervention for the desire (p ⫽ 0.003), arousal (p ⫽ 0.001), and satisfaction (p ⫽ 0.031) domains, as well as on the full scale score (p ⫽ 0.005). In addition, 60% of participants demonstrated improved knowledge scores about managing sexual dysfunction after PBSO following the intervention. Conclusions: The current intervention builds upon recent advances in CBT and sexual health education to address this muchneglected problem after PBSO. Results from this promising pilot intervention provide compelling preliminary data to move toward conducting a randomized clinical trial. Reducing post-PBSO distress, a valuable goal in its own right, may ultimately improve uptake of this potentially life-saving procedure in a high-risk population, as loss of sexual functioning is one of the reasons mutation carriers give for rejecting surgical risk-reduction.

Background: Patients with chronic hepatitis B virus infection (HBV) are at risk for hepatotoxicity (HT) from viral reactivation during chemotherapy courses (TC). This can be minimized with antiviral prophylaxis (AV). Screening for HBV before TC remains controversial. Methods: A retrospective observational data only study was conducted at a Northern California integrated health care delivery system examining patients undergoing TC between 2000 and 2010. Patients were categorized as HBV positive (HBV⫹) if they had a positive HBsAg, HBeAg, or HBV DNA any time before and 1 year post TC. Grade 3 and 4 HT was determined using the National Cancer Institute Common Toxicity Criteria, with adaptation for those who had baseline abnormal liver function tests. We excluded patients with HIV, co-infection with both HBV and hepatitis C, and HBsAb of unclear provenance. Two control groups (CTRL1 and CTRL2) were established that had tested negative for HBV and HCV 1996 through 1 year after the last TC: CTRL1 tested negative for both before TC initiation (index TC); CTRL2 tested negative for one pre and the other post index TC or both at any time after index TC. AV prophylaxis (AVP⫹) was defined as anti-HBV medication given before HT; the remainder were AVP-, including those given AV after HT. Electronic medical record review was conducted on all HBV⫹ patients. Results: We identified 9,279 patients who received 15,960 TC; 57.8% were female with a mean age of 57.8 (⫾14.4) at TC initiation. 464 TC were given to 289 HBV⫹ patients; 22.8% had HT, with 7 deaths from HT, all AVP-. The rate of HT in the controls was 9.9% in CTRL1 (34/343), 12.6% in CTRL 2 (1907/15,153). Conclusions: These findings support the recommendation that all patients planning to receive TC should be screened for HBV. Those found positive should receive AV prophylaxis during therapy.

9646


Chemotherapy-induced peripheral neuropathy in multiple myeloma patients undergoing maintenance therapy. Presenting Author: Qiuling Shi, The University of Texas MD Anderson Cancer Center, Houston, TX Background: After 3-months autologous stem cell transplant (AuSCT), a percentage of multiple myeloma (MM) patients during maintenance therapy continue to experience a complex of symptoms related to peripheral neuropathy. This longitudinal study examined these self-reported neuropathy symptoms and identified circulating inflammatory markers associated with high neuropathy-related symptoms. Methods: MM patients (N⫽51) rated symptom severity on 0-10 scale via the M. D. Anderson symptom Inventory (MDASI) weekly from 3 to 9 months post AuSCT during maintenance therapy. Patient also rated pain on hand or foot in routine clinic visit. A panel of pro- and anti-inflammatory cytokines, receptors, chemokines was evaluated on serum samples by Luminex. Mixed effect analysis was used to describe the changes on cytokines and symptom outcomes across time. Trajectory analysis identified patients that persistently reported higher or lower symptom severity overtime. Results: During the study period, there was no significant reduction on pain in general or on hand/foot, or change in neuropathic symptoms such as numbness/tingling and muscle weakness. Among a third (33%) of patients who was consistently in high pain (mean 5.5), MIP-1a (p⫽.001) and MCP-1 (p⫽.032) showed significant decrease. Approximately 40 % had persistently high numbness/tingling (mean 5.2) across the observation period. Compared to low symptom group patients, this high numbness group had significantly higher IL-6 (p⫽.019) and TNF-alpha (p⫽.006). High muscle weakness (mean 3.1) was for 69% of the sample. This group had significantly higher CRP (p⫽.005) and TNF-alpha (p⫽.001). Conclusions: This is the first longitudinal study that tracked persistent neuropathy-related symptoms for MM patients post AuSCT. Approximately one third reported painful neuropathy, either from induction therapy or ongoing maintenance therapy. High levels of these neuropathy symptoms were associated with higher levels of specific pro-inflammatory markers. This study provided rationale for examining the effectiveness of anti-inflammation as mechanism driven intervention on peripheral neuropathy in this cohort of MM patients.

Rates of HT in all chemotherapy courses and by cancer types. All Excluding cancer of liver or bile ducts Excluding non-Hodgkin lymphoma Non-Hodgkin lymphoma

TPS9647

AVP-

AVPⴙ

CTRL1

CTRL2

AVP- vs AVPⴙ

AVP- vs CTRL1

AVP- vs CTRL2

27.1% 26.4%

14.9% 14.2%

9.9% 7.7%

12.6% 12.2%

p⫽.02 p⫽.02

p⬍.0001 p⬍.0001

p⬍.0001 p⬍.0001

22.6%

15.4%

9.7%

13.3%

p⫽.28

p⬍.0001

p⬍.0001

69%

12%

12.1%

7.6%

p⬍.0001

p⬍.0001

p⬍.0001


Cognitive function in breast cancer and lymphoma patients receiving chemotherapy: An ongoing nationwide University of Rochester Cancer Center (URCC) Community Clinical Oncology Program (CCOP) observational study with 1,200 patients and controls. Presenting Author: Michelle Christine Janelsins, University of Rochester Medical Center, Rochester, NY Background: Chemotherapy-related cognitive impairment (CRCI) is a major concern for up to 75% of cancer patients that can negatively affect quality of life. Studies which have objectively assessed cognitive function (CF) in patients suggest that chemotherapy is associated with declines in multiple domains. A large, prospective longitudinal study with age- and genderpaired healthy controls is needed to confirm and expand these findings, to identify etiological mechanisms of CRCI, and to identify the best assessment methods for detecting CRCI. Methods: We are conducting a nationwide prospective observational study (N⫽1,200), conducted through the URCC CCOP Research Base and 23 CCOPs. The primary aim is to test the hypothesis that breast cancer and lymphoma patients receiving chemotherapy will have greater impairments in CRCI over time than a control comparison group. Breast cancer (stage I-IIIc) and lymphoma patients (intermediate/high grade disease) meet the following eligibility: 1) chemotherapy naïve, 2) ⱖ21 years of age, 3) no CNS disease, 4) scheduled to receive a standard course of chemotherapy, and 5) no concurrent radiation. Healthy control participants meet eligibility criteria 1-3 and are the same gender and age as paired patients. CF is assessed at pre-chemotherapy (Assess. 1), post-chemotherapy (Assess. 2), and 6 months postchemotherapy in patients; their paired controls are assessed at the same time intervals. CF is measured via: 1) Computer-based CANTAB neuropsychological (NP) battery (assessing memory (primary aim), verbal memory, sustained attention, processing speed, and executive function (secondary aims)), 2) paper-based objective NP assessment (secondary aims), 3) phone-based objective NP assessment (tertiary aims), and 4) Single item, patient-reported CF (tertiary aims). Blood is collected at Assess. 1 and 2 to explore inflammatory and genetic mechanisms. 807 participants have been enrolled in 21 months. Funding: U10CA037420-26 Supp. MCJ; U10CA037420, GRM; & URCC/RPCI Grant, MCJ & CBA. Clinical trial information: NCT01382082.


612s TPS9648


TPS9649


Metabolic syndrome and breast cancer: Effects of a 16-week combined exercise intervention. Presenting Author: Christina Marie Dieli-Conwright, University of Southern California, Los Angeles, CA

Phase III clinical trials with anamorelin HCl, a novel oral treatment for NSCLC cachexia. Presenting Author: Amy Pickar Abernethy, Duke University School of Medicine, Durham, NC

Background: Current evidence suggests that breast cancer treatments such as chemotherapy lead to excessive weight gain, fatigue, physical inactivity, and negative alterations in components of metabolic syndrome (MetS). MetS is associated with increased risk of cancer recurrence, cardiovascular diseases and type 2 diabetes, and is defined by visceral adiposity, insulin resistance, hyperglycemia, hyperinsulinemia, low serum high-density lipoprotein cholesterol, and hypertension. MetS is highly prevalent and present in 25% of American and European adults and higher in minorities. Given that chemotherapy for breast cancer induces many of the components of MetS, an effort to offset these consequences of cancer therapy using exercise/lifestyle intervention could improve breast cancer, cardiovascular and endocrine outcomes. Methods: Our study seeks to determine whether a 16-week exercise intervention induces changes in prognostic components of MetS (waist circumference, blood pressure, serum levels of glucose, insulin, lipids, C-reactive protein and HbA1c) among breast cancer survivors if initiated within 3 months of completion of chemotherapy or radiation therapy. We are currently recruiting women diagnosed with Stage I-III breast cancer from the USC Norris Comprehensive Cancer Center and Los Angeles County Hospital, which cares for a high proportion of minority/underserved patients. Participants are randomized to either the Control (usual care) or the Exercise group. The Exercise group participates in aerobic and resistance exercise sessions 3 times a week for 16 weeks supervised by an exercise specialist at the USC Clinical Exercise Research Center. At baseline and following the study period, all participants are tested for MetS components, muscle strength, body composition, bone density, cardiorespiratory fitness, quality of life, fatigue and shoulder function. We will recruit an additional 85 patients (at present time n⫽15) over the next 3 years. It is expected that this intervention will improve components of MetS and physical fitness in breast cancer survivors when compared to the Control group, thus defining intervention and biomarker variables for more definitive trials. Clinical trial information: NCT01140282.

Background: Cancer anorexia/cachexia is a debilitating and life-threatening complication of an underlying malignancy that may develop in up to 80% of terminally ill cancer patients. Cancer cachexia has a multifactorial pathogenesis and is manifested by accelerated losses of skeletal muscle and disproportionate losses of lean body mass (LBM). Anamorelin HCl is a ghrelin receptor agonist that has demonstrated significant increases in LBM, physical strength, and body weight in Phase II trials in patients with cancer cachexia. Through its ghrelin and growth hormone secretagogue activity, it displays both anabolic and appetite stimulating properties – two aspects vital to treating cancer anorexia/cachexia. Methods: HT-ANAM-301 (NCT01387269) and HT-ANAM-302 (NCT01387282), also known as ROMANA 1 and ROMANA 2, are double-blind, placebo-controlled, randomized (2:1 anamorelin HCl vs. placebo) Phase III trials in patients with non-small cell lung cancer (NSCLC) cachexia. Eligible patients must have unresectable Stage III or IV NSCLC and cachexia (weight loss of ⱖ5% body weight within prior 6 months or BMI ⬍20 kg/m2). Patients receive once daily oral doses of anamorelin HCl (100 mg) or placebo for 12 weeks. Co-primary endpoints are the change from baseline in LBM as measured by DXA and in muscle strength as measured by handgrip strength. Secondary endpoints include change in body weight, overall survival, and quality of life (FACIT-F and FAACT questionnaires). For HT-ANAM-301 only, blood samples are collected at Week 6 for population pharmacokinetics. After 12 weeks of treatment, patients may continue in a separate 12-week safety extension study (HT-ANAM-303 [ROMANA 3] NCT01395914). At their last meeting (August 2012), the Independent Data Monitoring Committee suggested no safety issue and allowed the trials to continue as planned. Clinical trial information: NCT01387269, NCT01387282, NCT01395914.

TPS9650

TPS9651



Multimodal therapy for the treatment of fatigue in patients with prostate cancer receiving androgen deprivation therapy and radiation. Presenting Author: Sriram Yennurajalingam, The University of Texas MD Anderson Cancer Center, Houston, TX

Exercise for cancer-related fatigue and putative functional, inflammatory, and metabolic mechanisms in patients receiving chemotherapy: A URCC CCOP research base phase III RCT. Presenting Author: Karen Michelle Mustian, University of Rochester Medical Center, Rochester, NY

Background: Cancer-related fatigue (CRF) is the most frequently reported symptom associated with cancer and its treatment. Unfortunately, there are limited treatment options to alleviate this distressing symptom. Preliminary data suggest that the combination of exercise, cognitive behavioral therapy (CBT), and methylphenidate (that is, multimodality therapy [MMT]) can play an important role in reducing CRF. The project’s objective is to explore the effects and safety of this MMT on CRF in prostate cancer patients scheduled to receive radiotherapy with androgen deprivation therapy. We hypothesizethat the MMT is capable of reducing CRF as measured by the FACIT-F subscale in prostate cancer patients scheduled to receive radiotherapy. Specific Aims:(1) Our primary aim is to obtain preliminary estimates of the effects of various treatments (exercise, CBT, and methylphenidate) and their combinations in reducing CRF in prostate cancer patients receiving radiotherapy, as measured by the change in patients’ FACIT-F subscale scores taken at baseline and on day 57 and the secondary objective is to determine the effects of the treatments and their combinations on anxiety and depressed mood (both measured by the Hospital Anxiety Depression Scale [HADS]); on physical activity and function (measured by an accelerometer and a handgrip dynamometer, respectively); on levels of inflammatory cytokines (IL-1␤, IL-6, TNF-␣, and IL-10) in serum and induced monocytes, before and after treatment Methods: For this study, we will use a randomized factorial design to assess 3 treatments (exercise, CBT, and methylphenidate) and their placebos in 8 replications. A total of 32 patients will receive each primary treatment and 32 will not. Patients will be studied for a 57-day period, during which they are scheduled undergo daily radiation treatments with androgen deprivation therapy. Fatigue, anxiety and depressed mood, and inflammatory cytokines will be determined at baseline and at 3 subsequent postintervention assessments. After successful initiation so far 19/64 patients were enrolled. Accrual continues. Clinical trial information: NCT01410942.

Background: Up to 100% of cancer patients report cancer-related fatigue (CRF) during chemotherapy which co-occurs with impaired cardiopulmonary (CPF) and neuromuscular function (NMF), chronically up-regulated inflammatory responses, and low metabolic energy expenditure. CRF interferes with completion of treatment, increases cancer morbidity and mortality, and impairs quality of life (QOL). Exercise is one of the most promising treatments available for CRF, but no large multicenter phase III RCTs have confirmed these findings and little is known about the mechanisms through which exercise may impact CRF. Methods: We are conducting a nationwide multicenter phase III RCT (N⫽692) through the URCC CCOP Research Base with 23 CCOP affiliates. The primary aim is to determine if exercise will significantly improve CRF, and secondarily, CPF, NMF, inflammation, energy expenditure, and QOL compared to standard care in cancer patients receiving chemotherapy. The exercise intervention is our standardized, individually-tailored, home-based walking and progressive resistance program, “Exercise for Cancer Patients” (EXCAP, 7 days/wk, 6wks). To be eligible, patients must: 1) have a confirmed diagnosis of cancer with no leukemia or metastasis, 2) be chemotherapy naïve and scheduled to start, 3) not be receiving concurrent radiation, 4) have a KPS of ⬎70, 5) be ⱖ21 years of age, 6) have no contraindications to exercise or functional testing, and 7) not be currently exercising. CRF and all secondary outcomes are assessed at baseline (pre-chemotherapy), 3 weeks (mid-intervention), and 6 weeks (post-intervention). Measures include: 1) CRF-Brief Fatigue Inventory, 2) CPF-6-minute walk test, 3) NMF-handgrip dynamometry, 4) inflammation-serum ELISA levels, 5) energy expenditureactigraphy, and 6) quality of life-Functional Assessment of Chronic Illness Therapy. The DSMC reviewed the trial in October of 2012 and suggested it continue as planned. 532 participants have been enrolled in 36 months. Funding: NCI U10CA037420, U10CA37402-28, K07CA120025, K07CA132916, 1R25CA102618, ACS MRSG1300101CCE. Clinical trial information: NCT00924651.


10000

Pediatric Oncology

613s

10001



Treatment of pediatric lymphocyte predominant Hodgkin lymphoma (LPHL): A report from the Children’s Oncology Group. Presenting Author: Burton Appel, Hackensack University Medical Center, Hackensack, NJ

Assessment of end induction minimal residual disease (MRD) in childhood B precursor acute lymphoblastic leukemia (ALL) to eliminate the need for day 14 marrow examination: A Children’s Oncology Group study. Presenting Author: Michael J. Borowitz, The Johns Hopkins Hospital, Baltimore, MD Background: Response to initial therapy is a powerful prognostic factor in pediatric ALL. Traditionally, slow early response (SER) has been defined by marrow morphology 8 or 15 days after start of induction therapy. More recently, MRD has been identified as the most important predictor of adverse outcome. The value of morphologic assessment of response in the setting of MRD has not been established. Methods: In COG studies AALL0331 (for NCI Standard Risk (SR) B ALL patients (pts)) and AALL0232 (High Risk (HR) B ALL pts), SER was defined by morphology as either ⱖ5% blasts in a day 15 marrow, or by flow cytometry as ⱖ0.1% MRD in a d29 marrow (SER MRD). Assignment to treatment arms also depended upon cytogenetic findings and extramedullary disease; each protocol had randomized treatment questions. SER pts were non-randomly assigned to receive augmented BFM therapy (ABFM) with 2 interim maintenance and delayed intensification phases (and CNS radiation for HR SER pts only). All pt treatment groups were combined for these analyses. Rapid early responders (RER) had a better outcome than SER pts (Table). However, pts who were SER only by morphology had a 5y DFS that was not significantly different from that of RER pts, and superior to that of pts who were SER MRD, or SER by both morphology and MRD. In multivariate analysis, SER by morphology was not an adverse prognostic factor after adjusting for risk group and MRD, or separately in SR or HR pts after adjusting for MRD. However, pts with .01-.1% MRD who were SER by morphology had a better 5y DFS than the.01-.1% MRD pts who were RER (90⫾6%, n⫽91 vs 77⫾3%, n⫽592). Only the former group received ABFM, suggesting intensification based on response rescues some poor risk pts. We conclude that a day 15 marrow is not needed to assess response if MRD is measured at end induction, provided that SER MRD is defined using a .01% cutoff, the threshold for intensifying therapy in current COG ALL trials. Clinical trial information: NCT00103285, NCT00075725.

Background: LPHL, an uncommon subtype of HL, typically presents with low stage disease and responds to regimens used for classical HL. Recurrence is uncommon, but second malignant neoplasms (SMN) or development of non-Hodgkin lymphoma (NHL) can occur. Therefore, reducing radiation exposure may be of benefit. We report the results of a prospective trial in which a selected subset of patients had surgery alone and the remainder were treated with limited chemotherapy ⫹/- involvedfield radiation therapy (IFRT). Methods: Patients ages 0-21 years with newly diagnosed, low risk LPHL were eligible for AHOD03P1. Low risk was defined as clinical Stage IA or IIA without bulk disease (mediastinal mass ⬎ 1/3 of the thoracic diameter or nodal aggregate ⬎ 6 cm). Patients with Stage IA LPHL with an unresected node or more than a single involved node or Stage IIA were treated with 3 cycles of AV-PC (doxorubicin/vincristine/ prednisone/cyclophosphamide). Patients with Stage IA LPHL in a single node that was completely resected were initially observed without further therapy; those who recurred after surgery with low risk LPHL received AV-PC x 3. Patients with ⬍ complete response (CR) to AV-PC x 3 received 2100 cGY IFRT. Results: 180 eligible patients with low risk LPHL were enrolled and completed study therapy. 52 patients underwent initial surgery alone; their 3 year EFS ⫽ 81.5%. 137 patients received AV-PC x 3; 128 were treated at diagnosis and 9 upon relapsing after surgery alone. 11 patients receiving AV-PC had ⬍ CR and received IFRT. 12 first events occurred among these 137 patients (11 relapses and 1 SMN, a NHL). One relapse occurred in a patient who received IFRT. The median follow-up among the 125 remaining patients is 39 (range 3 -76) months. Current 4-year EFS estimate is 88.1% (95% CI: 79.5%-93.3%) for these 137 patients. 4 year EFS for the entire cohort of 180 patients ⫽ 86.2%; their overall survival (OS) is 100%. Conclusions: Pediatric LPHL patients have an excellent EFS with chemotherapy that is less intensive than standard regimens; ⬎90% of patients can avoid RT. NHL as a first event may be related to the underlying LPHL and not an effect of treatment. The salvage rate for the few relapses is high, and OS to date is excellent. Clinical trial information: NCT00107198.

RER SER all SER by morphology only SER MRD only SER by morphology and MRD

10002

10003


Effect of dexamethasone (DEX) dose modification on osteonecrosis (ON) risk associated with intensified therapies for standard risk acute lymphoblastic leukemia (SR-ALL): A report from the Children’s Oncology Group (COG) study AALL0331. Presenting Author: Leonard A. Mattano, Bronson Methodist Hospital, Kalamazoo, MI Background: ON is a known toxicity of childhood ALL therapy, particularly in patients (pts) ⬎9 years (y). Intensified use of DEX, methotrexate (MTX), and asparaginase (ASNase) may increase the risk of developing ON among B-precursor NCI SR-ALL pts despite their younger age. Methods: Newly diagnosed SR-ALL pts 1-9y enrolled on AALL0331 between 4/05 and 5/10 were prospectively monitored for symptomatic ON within three treatment cohorts risk-stratified by clinical, cytogenetic, and early response criteria. ON sites were confirmed by imaging. SR-Low (SRL) pts were randomized to standard therapy ⫹/- 4 additional doses of PEG-ASNase. SR-Average (SRA) pts were randomized (2x2) to standard therapy ⫹/- an intensive consolidation (IC) ⫹/- an augmented interim maintenance/delayed intensification (AIM/ADI). SR-High (SRH) pts all received IC and two AIM/ADI phases. After 6/08, alternate week DEX (AWD, days 1-7/15-21) replaced continuous DEX (days 1-21) during DI, and escalating-dose MTX replaced oral MTX during IM. All pts received DEX days 1-28 during induction and 5-day pulses every 4 weeks during maintenance. Results: Overall ON cumulative incidence (CI) at 5y was 2.7% (133/5261), correlating with sex (F 3.7%, M 1.9%, p⬍0.0001), age (1-2y 0.8%, 3-4y 2.0%, 5-6y 3.3%, 7-9y 7.8%, p⬍0.0001), and risk group (SRL 2.6%, SRA 2.9%, SRH 5.7%, p⫽0.0009). Before 6/08, ON CI was higher for SRA pts given intensive vs standard consolidation (5.8% vs 1.9%, p⫽0.002), and trended higher for SRL pts given additional PEG-ASNase (4.0 vs 2.3%, p⫽0.09). Use of AWD significantly reduced ON CI at 3y among SRH pts (7.4% vs 1.5%, p⫽0.003) and further reduced ON events in SRL/SRA pts. Conclusions: Young children receiving intensified therapy for SR-ALL therapy are at risk for ON. Extended exposure to PEG-ASNase is a likely contributing factor, possibly by potentiating DEX exposure during DI. ON risk can be significantly reduced by using AWD during DI, which is now COG standard of care. Clinical trial information: NCT00103285.

Pt group

N

5 y DFS

P value vs RER

6419 1011 339 485 187

89⫾1% 79⫾2% 91⫾3% 72⫾4% 77⫾6%

-⬍.0001 .48 ⬍.0001 ⬍.0001


Bortezomib reinduction therapy to improve response rates in pediatric ALL in first relapse: A Children’s Oncology Group (COG) study (AALL07P1). Presenting Author: Terzah M. Horton, Baylor College of Medicine, Houston, TX Background: Bortezomib (bortez) is a reversible inhibitor of the 26S proteasome. Promising results have been reported adding bortezomib to reinduction chemotherapy in patients (pts) with ALL in 2nd or later relapse (Messinger, Blood 2012). Methods: This was a phase 2 study of bortez with reinduction chemotherapy in 1st relapse pediatric ALL that enrolled pts with pre-B ALL (relapse ⬍36 months (m) from diagnosis). This report summarizes results from 61 evaluable pre-B ALL pts ⱕ21 yrs old, either ⬍18m (stratum 1) or 18-36m (stratum 2) from diagnosis. Therapy consisted of bortez (1.3 mg/m2, days 1, 4, 8, and 11) with reinduction chemotherapy (vincristine, prednisone, PEG-asparaginase, doxorubicin). Complete response (CR2) rates and minimal residual disease (MRD) were determined at the end of the first 5-week therapy block. AALL07P1 utilized a stratified 2-stage design (London 2005) with the primary objective of comparing CR2 rates at the end of block 1 of therapy to historical control CR2 rates (AALL01P2). Block 2 included cyclophosphamide, etoposide, and bortez followed by 5g/m2 methotrexate. Biology studies included assessment of NF-␬B activity. Results: 61 evaluable pre-B ALL pts were assessed. Toxicities were similar to AALL01P2, including 10 Grade 3- 4 hypotension, 4 Grade 4 hypertriglyceridemia, 3 Grade 3-4 typhlitis, and 2 Grade 3-4 enterocolitis. There were 2 deaths due to infection. Although Grade 3-4 infections were not infrequent (13 in block 1 and 7 in block 2) there were no reports of respiratory distress syndrome or Grade 4 peripheral neuropathy. 42 of the 61 patients enrolled (18/28 (64%) in Stratum 1 and 24/33 (73%) in stratum 2) attained CR2 at the end of Induction I. Based on CR2 response rate compared to historical controls, the study met its primary response objective. The number of pts in CR2 with MRD ⬍0.1% also improved from AALL01P2; among pts achieving CR2, MRD was ⬍0.1% in 41% (16/39) in AALL01P2 vs. 71% (25/35) (p⫽ 0.073, Fisher’s exact test). Conclusions: Based on response rates in the very early and early first relapse pre-B ALL, AALL07P1 met its predefined efficacy benchmark. We conclude that bortezomib is worthy of further study in pediatric ALL. Clinical trial information: NCT00873093.


614s 10004

Pediatric Oncology Oral Abstract Session, Sun, 8:00 AM-11:00 AM

10005


Hyaluronidase synthase 3 (HAS3) variant and anthracycline-related cardiomyopathy: A report from the Children’s Oncology Group. Presenting Author: Can-Lan Sun, City of Hope, Duarte, CA

Genetic variations in cytarabine pathway genes as determinants of outcome in acute myeloid leukemia. Presenting Author: Jatinder Kaur Lamba, University of Minnesota, Minneapolis, MN

Background: The strong dose-dependent association between anthracyclines and cardiomyopathy limits the therapeutic potential of this extremely effective class of agents, demanding identification of those at highest risk, such that anthracycline exposure may be tailored. Methods: In a two-stage design, we investigated host susceptibility to anthracyclinerelated cardiomyopathy in cancer survivors by using the ITMAT/Broad/ CARe cardiovascular SNP-array to profile common SNPs in 2100 genes considered most relevant to de novo cardiovascular disease. All cases of cardiomyopathy fulfilled American Heart Association (AHA) criteria for cardiac compromise and were confirmed echocardiographically. Results: Using a matched case-control design (93 cases, 194 controls, all nonHispanic white survivors of childhood cancer) we identified a common SNP rs2232228 in hyaluronan synthase (HAS3) gene that exerts a substantial modifying effect on anthracycline dose-dependent risk of cardiomyopathy. Among individuals with GG genotype, cumulative anthracycline exposure was not associated with cardiomypathy risk at any dose. Individuals with AA genotype, exposed to ⬎250mg/m2 anthracyclines, had an 8.5-fold increased cardiomyopathy risk (95%CI, 2.0-35.6, p⫽0.004). Replication in an independent set of 76 patients (adult-onset and childhood cancer; all races) with anthracycline-related cardiomyopathy revealed the odds of cases with AA genotype in the high-dose anthracycline group to be 4.5-times higher (95%CI, 1.1-18.4, p⫽0.04). Hyaluronan (HA) – produced by HAS3 – is a ubiquitous component of extracellular matrix (ECM). ECM is involved in tissue remodeling; the extent of cardiac remodeling/ repair after anthracycline-induced cardiac injury is possibly modulated by variability in HA production. Conclusions: The significant modifying effect of HAS3 genotype on the dose-dependent association between anthracycline and cardiomyopathy risk suggests that, upon confirmation in prospective studies, genotyping HAS3 may be considered when evaluating risk of anthracycline-related cardiomyopathy.

Background: Cytarabine (ara-C), a key component of AML therapy, is a prodrug that requires activation to ara-CTP, which inhibits DNA/RNA synthesis and triggers leukemic cell death. Thus, cellular pathways involved in ara-CTP metabolism and/or cell death are likely to influence treatment response. Methods: In the present study, we used a pathwaydirected approach to identify the genetic predictors of ara-C response in 187 pediatric patients enrolled in the St. Jude AML02 trial. Patients were randomized to receive the first course of remission induction therapy containing either high- or low-dose ara-C, combined with daunorubicin and etoposide. SNPs in 14 key ara-C pathway genes were genotyped and screened for association with multiple endpoints, such as in vitro ara-C LC50 in diagnostic leukemic cells, minimal residual disease levels (MRD), event-free survival (EFS), overall survival (OS), and rate of relapse. Because AML is a very heterogeneous disease with multiple clinical, cytogenetic, and molecular features that are associated with response, we also evaluated SNPs in ara-C PK genes in the context of prognostic factors of proven clinical utility. Results: Ara-C pathway SNPs were significantly associated with clinical outcome. Known variables such as treatment, core-binding factor leukemia, MRD after one course of therapy, age at diagnosis, 11q23 rearrangements, megakaryoblastic leukemia without t(1;22), and FLT3ITD accounted for 18.7% of variability in EFS. Additional variation in EFS could be explained by individual SNPs or a combination of SNPs within ara-C pathway genes. For instance, our analysis showed that incorporation of a DCTD SNP into existing model could enhance the percent total variation in EFS explained from 18.7% to 22.9%. Inclusion of all DCTD SNPs in the model increased the percent total variation in EFS explained from 18.7% to 29.7% Conclusions: Overall our results indicate that genetic variation in the ara-C pathway genes had a prognostic relevance that was similar to that of well-known factors. Understanding this variation can provide additional insights into the factors influencing treatment response and could lead to the identification of new prognostic markers.

10006

10007



Long-term survival after alternative donor transplantation in children with acute leukemia. Presenting Author: Chelsea Lee Collins, Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI

Cytological and molecular remissions with blinatumomab treatment in second or later bone marrow relapse in pediatric acute lymphoblastic leukemia (ALL). Presenting Author: Lia Gore, University of Colorado Cancer Center, Aurora, CO

Background: Most reports describing long-term survival after allogeneic transplantation are in adults after transplantation of bone marrow (BM) from HLA-matched siblings. This report compares long-term survival after transplantation of unrelated donor BM to that after umbilical cord blood (UCB) in children with acute leukemia. Methods: Included were patients aged less than 18 years with acute myeloid or lymphoblastic leukemia, alive and leukemia-free for at least 1 year after transplantation. Transplants occurred 2000-2009. Patients received BM grafts that were HLA-matched (N ⫽ 205) or mismatched at 1-HLA locus (N ⫽ 112) and UCB grafts that were matched (N ⫽ 55) or mismatched at 1 (N ⫽ 160) or 2 HLA-loci (N ⫽ 134). Multivariate Cox regression models were constructed to explore differences in survival between groups. UCB transplants were treated as a single group as there were no significant differences between HLA-matched and mismatched UCB grafts. Multivariate models held 3 treatment groups: HLA-matched BM, HLA-mismatched BM and UCB grafts. Results: The disease characteristics of the three groups were similar. There were differences in patient and transplant characteristics. Recipients of UCB transplants were younger, more likely non-Caucasian, and more likely to have received a non-irradiation-containing conditioning regimen, in-vivo T-cell depletion and GVHD prophylaxis with cyclosporine and either prednisone or mycophenolate. In multivariate analysis, the risks of longterm mortality were not significantly different after UCB and HLA-matched BM transplants (HR 0.83, p⫽0.41). Mortality risks were significantly higher after HLA-mismatched BM transplants compared to UCB (HR 1.66, p⫽0.03) and HLA-matched BM transplants (HR 2.00, p⫽0.008). In this cohort, surviving disease-free at least 1-year after transplantation, the 8-year probabilities of overall survival after UCB, HLA-matched and HLA-mismatched BM transplants were 78%, 81% and 68%. Conclusions: This is the first report to document long-term durability of UCB grafts. The data continue to support the use of UCB grafts either in the absence of an HLA-matched donor or when transplantation is needed urgently for children with acute leukemia.

Background: Pediatric B-precursor acute lymphoblastic leukemia (ALL) in second or later relapse is an aggressive malignancy that needs therapeutic approaches with new mechanisms of action. Blinatumomab, a bispecific T-cell engaging (BiTE) antibody, has shown a hematological remission rate of 69% in adult patients with relapsed/refractory ALL. In order to establish a recommended dose in pediatric patients, a phase I multicenter trial was initiated. Methods: The primary endpoint is to determine the maximum tolerable dose defined by ⱕ1 of 6 patients experiencing dose limiting toxicity (DLT) within the 1st course of treatment. Up to 6 different dose levels of blinatumomab are being evaluated. Eligible patients must be ⬍18 years old and have B-precursor ALL that is refractory or in second or later bone marrow relapse, or in any marrow relapse after allogeneic hematopoetic stem cell transplantation (HSCT). Blinatumomab is administered by continuous IV infusion over 28 days followed by a 14-day treatment-free interval (up to 5 cycles). To date, 3 dose levels have been explored (Table). Results: Seventeen patients have been treated thus far with a total of 32 cycles. One DLT (gastrointestinal hemorrhage) at dose level 2 (15 ␮g/m²/d) and two DLTs at dose level 3 (30 ␮g/m²/d; both cytokine release syndrome) with 1 death have been observed. One patient had generalized seizures on the 3rd day of the 2nd treatment cycle at the first dose level of 5 ␮g/m2/d, which was completely reversible. The patient successfully underwent an allogeneic HSCT after blinatumomab. Eight (47%) of the 17 patients reached a cytological complete remission in bone marrow and a molecular remission defined as MRD by PCR ⬍10-4. Conclusions: A phase I trial of blinatumomab in patients with relapsed/refractory pediatric ALL has shown hematological and molecular remissions. Dose-limiting cytokine release syndrome has been noted. Alternative dosing regimens are being explored in current cohorts to refine the recommended dose of blinatumomab in this patient population. Clinical trial information: NCT01471782. Cohort

Dose level ␮g/m²/d

1 2 3 Total

5 15 30

Patients treated n

DLTs n

Bone marrow CR/MR (Jan 2013)

5 7 5 17

0 1 2 3

2/2 4/4 2/2 8/8


Pediatric Oncology 10008


Autologous-collected anti-CD19 chimeric antigen receptor T cells (19CARTs) for pediatric acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma (NHL): Clinical activity and cytokine release without graft versus host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Presenting Author: Daniel Warnell Lee, National Cancer Institute, National Institutes of Health, Bethesda, MD Background: Despite intensive chemotherapy and HSCT, outcomes in relapsed/ refractory pediatric B cell ALL and NHL are poor. To treat children with or without prior allogeneic-HSCT and quickly deliver therapy, we developed a Phase I trial of 19CARTs for both HSCT-naive and post-allo-HSCT patients where autologous-collected T cells are manufactured in 11 days. Methods: T cells collected on Day -11 by lymphopheresis were positively selected and activated using anti-CD3/CD28 beads then transduced with the CD19-CAR gene via retrovirus. Cells were infused after 7 additional days of expansion. Patients (Pt) received fludarabine and cyclophosphamide prior to receiving 1e6 19CARTs/kg. Results: A 59-65 fold expansion of 19CARTs with 39-65% transduction efficiency was achieved in Pt 1 and 3 (ALL, NHL). Pt 1 achieved a complete response (CR). Mild cytokine release syndrome was observed (Gr 3 fever, Gr 2 hypotension) correlating with mild elevation in IL6, GM-CSF, INFg and C reactive protein (CRP; Table). No other non-hematologic, CAR-related Gr ⱖ3 toxicities were observed. Pt 2 (ALL) received 2.8% of the targeted cell dose due to lack of cell expansion likely from recent prior chemotherapy but experienced a transient CR with significant 19CART expansion (15% blood, 5% marrow, 6% CSF). Importantly, 19CARTs were well tolerated without evidence of GVHD in these post-allo HSCT patients. Conclusions: Autologous-collected allogeneic derived 19CART cells can be rapidly manufactured and safely administered to children with ALL and NHL. Clinical activity can be achieved without GVHD despite inflammatory cytokine generation. 19CARTs offer a potentially effective strategy to treat post-HSCT relapse warranting further study. Clinical trial information: NCT01593696. Pt 1

Pt 2

Pt 3

IL6 TNFa GM-CSF CRP IL6 TNFa GM- CSF CRP IL6 TNFa GM- CSF CRP Day (pg/mL) (pg/mL) (pg/mL) ( 1 SD above mean 9 (11%) 3 (4%) 4 (6%) 3 (4%) 2 (3%) STAI trait > 1 SD above mean 3 (4%) 2 (3%) 2 (3%) 2 (3%) 2 (3%) # Psychiatry consults 25 8 11 8 4 # Psychiatry diagnoses 11 4 9 6 3 # Patients diagnosed 11 3 4 3 -

10066


10067


Attitudes to the return of incidental and targeted genomic findings obtained in a high-risk pediatric cancer versus an inherited genetic condition research setting. Presenting Author: Conrad Vincent Fernandez, IWK Health Centre, Halifax, NS, Canada

Turkish National Pediatric Cancer Registry 2002-2008 (Turkish Pediatric Oncology Group and Turkish Pediatric Hematology Society). Presenting Author: M. Tezer Kutluk, Hacettepe University Institute of Oncology, Ankara, Turkey

Background: The disclosure of clinically significant, validated incidental and target findings to participants in genomic research is often recommended. There have been no reports on whether attitudes of parents differ if these findings emerge from an acquired pediatric cancer versus an inherited genetic condition setting. Methods: Parents in 3 large-scale projects [Canadian Pediatric Cancer Genome Consortium (CPCGC), the Finding of Rare Genes Canada Consortium (FORGE) and the Orphan Diseases: identifying Genes and Novel Therapeutics to Enhance Treatment Project (IGNITE)] were surveyed using a mailed, validated 29-item questionnaire. Two reminders were sent. Analysis was by descriptive and Chi-square statistics. Results: Response rate: 64% (n⫽307/480). 40% were ⬎ 50 yrs age; more than half had a grade 12 education. 86 were parents of poor risk pediatric cancer patients and 221 were parents or individuals with rare inherited conditions. Most stated a very strong or strong right to genomic research results, irrespective if from the target condition (97%) or incidental (86%). 70% wish genetic counselling pre- and post-research testing; an additional 20% were uncertain what this entails. Almost all indicated that genomic research for childhood onset conditions should occur, regardless of whether therapy existed (99%) or not (91%). A few indicated that they would not want incidental results showing an untreatable fatal condition (17%). Most want results, even if these suggest susceptibility to multiple conditions (87%) or are of uncertain health impact (84%). Most felt a right to genomic research that showed a serious condition in siblings, whether treatable (94%) or not (89%). 74% strongly support that results discovered after death of the proband be shared with family. Conclusions: Parents of children in both cancer and inherited rare conditions genomic research do not differ in indicating a strong right and desire to receive research results, even if they are of uncertain impact, of childhood onset, or after death of the proband. Clear delineation of what will or will not be offered from genomic research should be established at the time of consent.

Background: In childhood cancers cure rates increased up to 80% in the developed countries. On the other hand cure rates goes down 10-20% percent in countries with low resource settings. Reliable pediatric cancer data is essential for all countries. We established a nationwide pediatric cancer registry. Methods: Turkish Pediatric Oncology & Pediatric Hematology Society established a web-based database for the registry of all pediatric cancers. 11898 cases were registered between 2002-2008 from 65 centers. Various demographic data & survival endpoints were recorded & analyzed. Diseases were grouped according to the International Classification of Childhood Cancer. Results: In all 11898 cases, median age was 6 years (M/F⫽ 6786/5112⫽1.32). Distribution in age groups were: 0-4 years, 42.5%; 5-9 years, 27.2%; 10-14 years, 23.4%; 15-19 years, 6.8%; ⬎19 years, 0.1%. Only 3.8% of cases were diagnosed with clinical⫹radiological, the rest with histopathological data Distribution of cases in disease groups were [median age in yrs, M/F]: Leukemias (n⫽3777) 31.7% [5.5, 2137/1640⫽.31]; Lymphomas (n⫽2040) 17.1% [8.3, 1405/635⫽2.21]; CNS tumors (n⫽1588) 13.3% [6.9, 913/ 675⫽1.3 ]; Sympathetic tumors (n⫽889) 7.5% [2.1, 453/436⫽1.03]; Retinoblastoma (n⫽371) 3.1% [2, 181/190⫽0.95]; Renal tumors (n⫽655) 5.5% [3, 333/322⫽1.03]; Hepatic (n⫽166) 1.4% [1.8, 101/65⫽1.5]; Bone tumors (n⫽717) 6% [12.2, 407/310⫽1.3]; Soft tissue tumors (n⫽773) 6.5% [6.5, 442/331⫽1.3]; Germ cell tumors (n⫽531) 4.5% [5, 210/321⫽0.6 ]; Carcinomas and other malignant epithelial tumors (n⫽323) 2.7% [12, 164/159⫽1.03]; Others/unspecified malignant tumors (n⫽68) 0.6% [4.5, 40/28⫽1.4]. Five-year overall survival in all cases was 65%. Conclusions: This registry provides a critical information about the distribution of childhood cancer since this is the only nationwide pediatric cancer registry in Turkey. With the recent trends in non-communicable diseases at global level, registry data will be very helpful for national cancer control plans, which will also be used to compare at national and international level. This will also be a good example for many other countries with similar resources to do such projects.


630s 10068

Pediatric Oncology General Poster Session (Board #41C), Sat, 1:15 PM-5:00 PM

Risk factors for underlying vitamin D deficiency in children with cancer at their diagnosis for cancer. Presenting Author: Nurdan Tacyildiz, Department of Pediatric Oncology, Ankara University Medical School, Ankara, Turkey Background: There is increasing interest in the possible association between cancer incidence and vitamin D. Our recent study showed a prominent Vit D deficiency in our pediatric cancer patients during their admition. Methods: Seventy newly diagnosed Pediatric cancer patients that have been defined as Vit D deficiency at our clinic, enrolled the study between 2010-2013. A questionare with 32 questiones has been performed to each patient’s family. Questiones are designed to determine risk factors for Vit D deficiency like; daily sun light exposure, consumption of food that known as source of the Vit D, suplementation during pregnancy, lactation and during infancy,etc.SPSS 11.5 program used for istatistical analyses Results: This study has been designed as a questionare based research to find out possible risk factors for Vit D deficiency in our patients. Seventy patients with leukemias , lymphomas and solid tumors were included in the study. Fourtysix boys (66%) and 24 girls ( 34%) were between 2 months to 18 years old (median: 9 years). Almost 60 % of the patients have been borned during autumn or winter. Education level : 8 % of the fathers and 19 % of the mothers were not received any education at school. During pregnancy 64% and during lactation 83% of the mothers have not been supplemented with Vit D. Seventy four percent of the mothers did not have any knowledge about importance of the Vit D. Supplementation of the Vit D during infancy was not avaliable for 58% of the patients. Daily exposure to the sun light was between 0 to 6 hours (median:2.2 hours/day). Monthly consumption of fish and egg was between 0 to 5 times (median: 1.3 time/month) for fish and between 0 to 45 eggs (median 13.9 eggs/ month ) respectively. Daily consumption of the milk was between 0 to 2 glases (median: 1 glass/day) . Conclusions: Famillies are not aware of the importance of Vit D. Consumption of Vit D containing foods are much lover than recomended nutrition facts.A special attention has to be given for education of parents for vit D supplementation during pregnancy, lactation and infancy. Besides, it should be started to educate peopele beginning from their childhood to have enough daily sun light exposure and Vit D containing foods as a part of their healthy life style.

10070


10069


Surveillance and follow up of pediatric cancer from a developing country. Presenting Author: Argha Nandy, Netaji Subhas Chandra Bose Cancer Research Institute, Kolkata, India Background: Childhood cancers, a leading cause of childhood deaths, affect more than 200,000 children worldwide, of which ⬎80% are from developing nations. This demands for proper measurement of the incidence of various childhood cancers which led to a novel study in assessing the burden of childhood cancers in eastern India through analysis of hospitalbased cancer registry data from our institute in between January 2001December 2011. Methods: 3,200pediatriccancer patients between 0-15 yearsdiagnosed by means of histological and cytological examinations were included in this study. Based on histopathological classification, cancer cases were distributed into 3 different age groups. Their respective family functioning, mental health, self-esteem and social competence were examined. Details of disease, tobacco usage along with socio demographic data were collected through standard questionnaires. Comparative measures of disease incidence were also calculated. For measuring the tolerance, different drugs were administered to patients. Results: The incidence of different malignancies was recorded which were Leukemia (34.9%), Lymphoma (24.1%), Hodgkin’s disease (18.1%), NHL (6.0%), Ewing’s sarcoma (4.9%), Rhabdomyosarcoma (3.6%), Neuroblastoma (2.0%), Brain tumour (9.9%), Wilm’s tumour (6.0%), Lymphoid Leukemia (26.9%), Myeloid Leukemia (7.9%), Germ cell tumour (4.2%), Osteosarcoma (4.0%), Retinoblastoma (2.0%) and Soft tissue sarcoma (2.3%). The disease free survival (DFS) for ALL was 76%, NHL (84%), Soft tissue sarcoma (78%), CML (98%), AML (48%) and germ cell tumour (95%). Finally, 53.33% patients were subjected to post-therapy assessment, of which 98% showed no after effect of therapy on growth chart, heart and endocrine function. The toxicity of grade III and IV chemotherapy ranges from 10-20%. Conclusions: Based on our study, the most happening cancer was Leukemia (34.9%) followed by Lymphoma (24.1%) and soft tissue sarcoma (18%). The overall disease free survival for pediatric patients was 72% with acceptable toxicity. Our results are comparable with the studies of other developed countries.

10071


Access to cancer chemotherapy and predictors of early mortality for childhood cancers in Uganda. Presenting Author: Innocent Mutyaba, Uganda Cancer Institute, Kampala, Uganda

Screening with whole-body MRI (WB-MRI) in pediatric patients with Li Fraumeni syndrome (LFS). Presenting Author: Allison Frances O’Neill, Dana-Farber Cancer Institute, Boston, MA

Background: Although many childhood cancers respond well to chemotherapy, survival among children with cancer in sub-Saharan Africa is poor. Little is known about children’s access to specialized cancer care in SSA or factors contributing to poor early outcomes. We aimed: 1) To estimate the proportion of childhood cancer patients without access to chemotherapy in Uganda; 2) To describe 30-day survival rates and predictors of mortality post diagnosis among children with lymphoma or Kaposi sarcoma (KS), the two most common pediatric cancers in Uganda. Methods: A retrospective study of incident childhood (age⬍ 20 years) cancers diagnosed in Kyandondo County, Uganda from 2006-2009. We compared records of the population-based Kampala Cancer Registry (KCR) and patient records at the Uganda Cancer Institute (UCI), Uganda’s sole dedicated cancer treatment center. Patient characteristics were compared using MannWhitney and Pearson’s chi-square tests. Kaplan-Meier method and Cox regression models were used to describe mortality. Results: Of the 658 pediatric cases recorded in the KCR, only 238 (36%) presented to UCI. Patients identified in the KCR who did not present for care were more likely to be female, diagnosed in earlier years of the study, and to have a cancer other than KS or lymphoma. Of the 177 lymphoma and KS cases at UCI, 43.7% were Burkitt lymphoma (BL), 32.5% KS, and 23.8% other lymphomas. The post diagnosis 30-day overall survival rate was 77%. In multivariate analysis, age, gender, HIV status, platelets, and stage of cancer did not impact mortality. An increased risk of death at 30 days was predicted by presence of B-symptoms (HR⫽10.3, p⫽0.05), a diagnosis of BL compared to other lymphomas (HR⫽14.8, p⫽0.007), poor performance status (Karnofsky score ⬍70, HR⫽14.7, p⬍0.001), and anemia (HR 1.5-fold per 1g/dL decrease in hemoglobin, p⫽0.002). Conclusions: Childhood cancer patients in Uganda have limited access to comprehensive care. Among those presenting to the UCI, a significant proportion die before they can benefit from chemotherapy. BL diagnosis, B-symptoms, performance status and hemoglobin level may be important predictors of early mortality among childhood cancer patients in sub-Saharan Africa.

Background: LFS is a rare hereditary cancer syndrome characterized by a high risk of developing a wide range of malignancies. Germline mutations in the tp53 gene confer approximately a 12-fold risk of developing cancer by age 20. Given the potential for diverse malignancies, cancer surveillance in LFS patients is challenging. We piloted the use of WB-MRI for pediatric LFS patients as a cancer screening tool. Methods: Eligibility included: documented tp53 mutation, or obligate carrier status based upon family history/genetic testing, and no recent cancer diagnosis. WB-MRI was performed as a research test, in conjunction with recommended clinical screening based upon family history and clinician recommendation. Our primary aim was to determine the feasibility (defined as 87% completion rate) of obtaining two planned annual MRI scans in 15 pediatric LFS patients. Our secondary aim was to calculate the incidence and describe the characteristics of primary cancers detected. Results: Nine pediatric patients from 5 families have been enrolled and all have successfully completed one WB-MRI. Seven patients were known carriers, and 2 underwent genetic testing in order to enroll in the study. Median age was 12 years, range 6 to 15. Scan time was 60-90 minutes and 2 patients required anesthesia with propofol. There were no acute scan complications. Six of the 9 (67%) scans demonstrated incidental findings (T2 cerebral cortex abnormality, L5-S1 synovial cyst, thoracic syrinx, T12 hemangioma, 2 ovarian cysts, and degenerative disc disease). Only one patient underwent a dedicated follow-up imaging study for an abnormality on WB-MRI. None of the patients required biopsy. All patients had normal screening laboratory work. These results are being presented early to foster collaboration. Conclusions: All patients enrolled on our study tolerated WB-MRI; none were diagnosed with a new malignancy. Although preliminary, our results to date are in contrast to previous reports documenting a high incidence of cancers detected during screening of LFS patients. WB-MRI may be a promising approach to screening; a large multi-center trial will be needed to determine its efficacy in detecting incident cancers and true test characteristics.


Pediatric Oncology TPS10072


Pilot study of redirected autologous T cells engineered to contain antiCD19 attached to TCR␨ and 4-1BB signaling domains in patients with chemotherapy-resistant or -refractory CD19ⴙ leukemia and lymphoma. Presenting Author: Stephan A. Grupp, Children’s Hospital of Philadelphia and Perelman School of Medicine, Philadelphia, PA Background: Outcomes remain poor for patients (pts) with relapsed or refractory (r/r) B-cell malignancies such as acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). CD19 is an attractive therapeutic target because it is widely expressed on normal and malignant B cells throughout B-cell maturation but not on pluripotent stem cells or non–B-cell tissues. We have developed chimeric antigen receptor T cells to target CD19⫹ cells (CART-19 or CTL019). This approach involves patientderived T cells that are genetically modified via lentiviral transduction to express a CD19 antigen recognition domain attached to intracellular signaling domains (TCR␨ and 4-1BB) that mediate T-cell activation. A recent study in CLL showed that CART-19 therapy had potent activity with responses in 5/8 evaluable pts (3 CR, 2 PR). Pts achieving CR (two ⬎ 24 months and one ⬎ 5 months) remain in CR with detectable CART-19 cells (Porter et al. ASH 2012). Here we describe a study of CART-19 therapy in pediatric pts with r/r leukemia and lymphoma (NCT01626495). Methods: Pts eligible for this single-arm, open-label study are aged 1 to 24 years with r/r CD19⫹ B-cell malignancies, without a transplant option or having relapsed after allogeneic stem cell transplantation (ASCT). Pts will undergo leukapheresis to obtain T cells, which will be stimulated, expanded, and transduced ex vivo to express the chimeric antigen receptor. Pts may receive lymphodepleting chemotherapy prior to CART-19 infusion. Study objectives: determine the safety and feasibility of administering CART-19 therapy to pediatric pts, assess duration of in vivo survival of CART-19 cells, and measure antitumor response. There are 2 cohorts in the study: Cohort 1 includes pts who have not undergone ASCT and are not currently eligible for a transplant, and cohort 2 includes pts who relapsed after ASCT. Cells are collected from the recipient, not the donor, which allows for this approach to be used in pts s/p cord blood transplant, and which we hypothesize will reduce the risk of GVHD as a result of toleration of the T cells in the recipient. To date, 7 pts have been enrolled. Clinical trial information: NCT01626495.

TPS10073

631s General Poster Session (Board #41H), Sat, 1:15 PM-5:00 PM

Trial of zoledronic acid and interleukin-2 to expand tumoricidal ␥␦ T cells in vivo in patients with refractory neuroblastoma. Presenting Author: Joseph Gerald Pressey, University of Alabama at Birmingham, Birmingham, AL Background: CD3⫹ ␥␦⫹ T cells comprise 2 to 5% of the circulating T cells. V␥9V␦2⫹ cells are the dominant circulating ␥␦ T cell and recognize non-peptide phosphoantigens and stress-associated NKG2D ligands expressed on malignant cells. Strategies that incorporate the tumoricidal properties of ␥␦ T cells represent a promising means of harnessing the innate immune system to treat malignancies including neuroblastoma (NB). Indeed, ␥␦ T cells from both healthy volunteers and NB patients exert a potent cytotoxic effect on NB cell lines and autologous NB in vitro following expansion and activation in culture. V␥9V␦2⫹ cells can also be induced to proliferate in vivo. By blocking farnesyl pyrophosphate synthase in the mevalonate pathway of isoprenoid synthesis in monocytes, the aminobisphosphonate zoledronic acid (ZOL) promotes the accumulation of isopentenyl pyrophosphate which is sensed by ␥␦ T cells. IL-2 is also required for robust expansion ␥␦ T cells. Methods: The trial is a prospective, non-randomized trial that assesses two dose levels of recombinant IL-2 (aldesleukin) in combination with ZOL. To be eligible for the study patients must be 2 to 21 years of age with refractory neuroblastoma with no known curative therapeutic options. Patients must also have adequate organ function and performance status. ZOL is given intravenously on day 1, and aldesleukin is given subcutaneously on days 1 to 5 and 15 to 19 of every 28 day cycle. The single-institution study is being conducted at the University of Alabama at Birmingham. Correlative studies include evaluating the absolute count, phenotype, activation, and effector/memory progression of ␥␦ T cells by flow cytometry and the biological function of autologous expanded/activated ␥␦ T cells by in vitro cytotoxicity assays employing established human NB cell lines. In order to determine the ability of in vivo expanded/activated ␥␦ T cells to infiltrate NB tissue, bone marrow core biopsies obtained before and after the first course of therapy from patients with bone marrow metastasis are assayed for T cell infiltration by immunohistochemistry. The study has currently enrolled 1 of the planned 6 patients. Clinical trial information: NCT01404702.


632s 10500

Sarcoma Oral Abstract Session, Mon, 3:00 PM-6:00 PM

Imatinib failure-free survival (IFS) in patients with localized gastrointestinal stromal tumors (GIST) treated with adjuvant imatinib (IM): The EORTC/AGITG/FSG/GEIS/ISG randomized controlled phase III trial. Presenting Author: Paolo Giovanni Casali, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Background: In 2004 we launched an open-label randomized trial with adjuvant IM for 2 yrs in localized, surgically resected, high/intermediaterisk GIST. Methods: Pts were randomized between 2 yrs of IM, 400 mg daily, and no further therapy after surgery. The primary end-point was OS, while RFS, RFI and toxicity were secondary end-points. Main eligibility criteria were: age ⬎18 yrs, PS 0-2, localized CD117-positive GIST, intermediate or high risk according to the 2002 Consensus classification, R0 or R1 surgical margins, no previous medical therapy. Pts were stratified by risk, tumor site and margins. An accrual of 400 pts was planned, then escalated to 900. Given the prognostic improvement of advanced GIST pts, in 2009 the study IDMC authorized to change the primary end-point into IFS, whose failure was defined as the time when a different tyrosine kinase inhibitor (TKI) is started. We report on a planned interim analysis carried out after 115 events according to the new primary end-point, with a significance level of 1.5%. Hazard ratios (HR) and p-values were adjusted for stratification factors. Results: 908 pts were randomized between 2005 and 2008, 454 to IM and 454 to observation arm; 835 pts were eligible. 17% of pts treated with IM stopped early due to toxicity or refusal. With a median follow-up of 4.7 yrs, 5-yr IFS was 87% in the IM-arm vs 84% in the control arm (HR⫽0.80, 98.5% CI [0.51; 1.26], p⫽0.23); RFS was 84% vs 66% at 3 yrs, and 69% vs 63% at 5 yrs (p⬍0.001); 5-yr OS was 100% vs 99%. Among 528 pts with high-risk GIST by local pathology, 5-yr IFS was 79% vs 73% (p⫽0.11), and 77% vs 73% (p⫽0.44) amongst 336 high-risk GIST pts by centrally reviewed pathology. Conclusions: This study confirms that adjuvant IM has an overt impact on short-term freedom from relapse. In the high-risk subgroup, a non-statistically significant trend in favor of the adjuvant arm was observed in terms of IFS. This new end-point for the adjuvant setting, i.e. survival free from any failure of the first employed TKI, was designed to incorporate secondary resistance, i.e. the currently main factor adversely affecting prognosis of advanced GIST pts. Clinical trial information: NCT00103168.

10501^


Phase III trial of nilotinib versus imatinib as first-line targeted therapy of advanced gastrointestinal stromal tumors (GIST). Presenting Author: JeanYves Blay, University Claude Bernard Lyon I, Centre Léon Bérard, Lyon, France Background: Nilotinib (N) is a Bcr-Abl, KIT, and PDGFR tyrosine kinase inhibitor. This Phase III trial compared N and imatinib (I) as first-line therapy of advanced GIST. Accrual was stopped when a futility boundary was crossed at interim analysis (IA). This final analysis of the core study examined the effect of mutation on outcomes. Methods: Patients (pts) with unresectable and/or metastatic GIST who had no prior antineoplastic therapy or had recurrence ⱖ6 months (mos) after adjuvant I were randomized 1:1 to open-label N 400 mg bid or I 400 mg qd (400 mg bid for KIT exon 9 mutants). The primary endpoint was progression-free survival (PFS) per adjudicated central review. Enrollment targeted 736 pts to observe 375 events, yielding 90% power to detect a hazard ratio (HR) of 0.71 (median, 28 [N] and 20 [I] mos) with two-sided 5% type I error. Prior to IA, crossover was allowed only for pts with progressive disease (PD); after IA, pts on N with or without PD were offered I. Results: At IA, the PFS HR for N vs I of ⬎1.111 suggested a low probability of N superiority to I. Final analysis was performed in 644 pts; both PFS and OS favored I. In subgroup analysis of 401 pts who had mutational data, there was a large PFS difference favoring I in KIT exon 9 mutants, but similar PFS in KIT exon 11 mutants (Table). Based on immature data, OS favored I in all mutants. Conclusions: The IA showed N could not be superior to I for PFS in the overall population as first-line targeted therapy for pts with advanced GIST. PFS of N and I differed according to molecular subtypes, with PFSfavoring Iin KIT exon 9 mutants but roughly similar in exon 11 mutants. Clinical trial information: NCT00785785.

Median PFS, mos (95% CI) (overall) KIT mutant Exon 11 Exon 9 24 mos PFS, % (95% CI) (overall) KIT mutant Exon 11 Exon 9 24 mos OS, % (95% CI) (overall)

HR (95% confidence interval [CI]) (HR >1 favors I)

Nilotinib (nⴝ324)

Imatinib (nⴝ320)

25.9 (19.1–NE)

29.7 (26.6–NE)

NE n⫽125 3.0 (2.8–3.2) n⫽24 51.6 (43.0–59.5)

32.3 (29.7–NE) n⫽141 NE n⫽26 59.2 (50.9–66.5)

1.466 (1.104–1.945)

69.6 (57.6–78.8) NEa 81.8 (76.6–86.0)

67.5 (55.9–76.7) 67.1 (39.9–84.1) 90.0 (85.9–93.0)

1.120 (0.683–1.836) 32.456 (7.113–148.088) 1.850 (1.198–2.857)

NE, nonestimable. aAll exon 9 mutants on N had a PFS event or censoring within 6 mos.

LBA10502


Randomized phase III trial of imatinib (IM) rechallenge versus placebo in patients (pts) with metastatic and/or unresectable gastrointestinal stromal tumor (GIST) after failure of at least both IM and sunitinib (SU): Right study. Presenting Author: Yoon-Koo Kang, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea


10503


Mutational analysis of plasma DNA from patients (pts) in the phase III GRID study of regorafenib (REG) versus placebo (PL) in tyrosine kinase inhibitor (TKI)-refractory GIST: Correlating genotype with clinical outcomes. Presenting Author: George D. Demetri, Dana-Farber Cancer Institute/ Harvard Medical School, Boston, MA Background: The phase III GRID study showed that REG provides a significant improvement in progression-free survival (PFS) compared with PL in pts with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib (IM) and sunitinib (SU; HR 0.27, p⬍0.0001). Determining GIST genotype in TKI-refractory disease has proven challenging due to inter-tumoral heterogeneity and pt preference to avoid serial biopsies. To overcome this, we analysed circulating DNA in plasma as a source of tumor DNA and studied the correlation between mutational status and clinical outcome. Methods: DNA was isolated from both archival tumor tissue (n⫽102) and plasma at baseline (n⫽163) and analyzed for mutations via Sanger sequencing (tissue) or BEAMing (plasma). Results: Mutational frequencies for tumor tissue samples were: KIT, 66%; PDGFRA, 3%; KRAS, 1%; BRAF, 0%. For plasma, frequencies were: KIT, 58%; PDGFRA, 1%; KRAS, 1 out of 2 samples, BRAF, 0%. Detection of primary KIT mutations showed 84% concordance between tissue and plasma. Secondary KIT mutations were more commonly detected in plasma (47%) than in tissue (12%). Subgroup analysis based on mutational status showed an improved PFS in REG-treated pts vs PL in all subgroups by both central and local review of imaging studies. The presence of a secondary KIT mutation in plasma was associated with shorter PFS in pts receiving PL (HR 1.82, p⫽0.05). Pts with a KIT-exon 9 mutation received IM for a shorter period of time, and SU for a longer period of time, relative to other GIST genotypes. Pts with a PDGFRA mutation showed variable clinical responses, while 1/1 KRAS-mutant GIST did not respond well to IM, SU, or REG. Conclusions: KIT mutational status correlated to IM and SU treatment duration. While consistent with prior reports using tissue sampling, this validates the utility of plasma-based circulating DNA analysis of target oncogenes. Secondary KIT mutations appear to have a negative prognostic impact in GIST, while the clinical benefit of REG vs PL was not influenced by KIT mutational status. Clinical trial information: NCT01271712.


Sarcoma LBA10504


MAP plus maintenance pegylated interferon ␣-2b (MAP-IFN) versus MAP alone in patients (pts) with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: First results of the EURAMOS-1 good response randomization. Presenting Author: Stefan S. Bielack, Klinikum Stuttgart, Olgahospital, Cooperative Osteosarcoma Study Group (COSS), Stuttgart, Germany


10506


A randomized, double-blind, placebo (Pbo)-controlled phase III study of ombrabulin plus cisplatin in patients (pts) with advanced-stage soft-tissue sarcoma after failure of anthracycline and ifosfamide chemotherapies. Presenting Author: Zsuzsanna Papai, Állami Egészségügyi Központ, Budapest, Hungary Background: Ombrabulin (AVE8062) is a vascular disrupting agent that damages established tumor vasculature and has demonstrated synergistic antitumor activity with cisplatin in vivo. In a phase I study, ombrabulin 25 mg/m² plus cisplatin 75 mg/m² was identified as the recommended dose in pts with solid tumors (AACR 2008; Abs 08-AB-4925). This phase III study evaluated the efficacy and safety of ombrabulin plus cisplatin in pts with advanced soft-tissue sarcoma (NCT00699517). Methods: Pts (aged ⱖ18 yrs, ECOG PS ⱕ2) with metastatic soft-tissue sarcoma who had received prior anthracycline and ifosfamide, with ⱕ2 prior chemotherapies for advanced disease, were randomized (1:1) to receive either ombrabulin 25 mg/m² or Pbo plus cisplatin 75 mg/m² every 3 weeks. The primary objective was to compare progression-free survival (PFS) between arms; secondary objectives included overall survival (OS) and safety. Results: Overall, 355 pts (median age 52 yrs; 51.5% male) were randomized (176 ombrabulin, 179 Pbo) in 44 centers worldwide. Median duration of follow-up was 27.9 and 30.5 months in Pbo and ombrabulin arms, respectively. PFS analysis showed a statistically significant improvement with ombrabulin (median 1.54 vs 1.41 months Pbo; HR⫽0.76, 95% CI 0.59 – 0.98; p⫽0.0302), with 3- and 6-month rates in favor of ombrabulin vs Pbo: 35.4% vs 24.9% and 19.3% vs 10.6%, respectively. A trend for an improvement with ombrabulin was observed in 3 of the 4 prespecified histology strata: liposarcoma, leiomyosarcoma, and “other”, but not for pleomorphic. Analysis of OS did not show statistically significant improvement with ombrabulin (median 11.43 vs 9.33 months Pbo, HR⫽0.85, 95% CI 0.67–1.09). OS rates at 1 year were in favor of ombrabulin (48.6% vs 42.4% Pbo). Grade 3/4 TEAEs more frequently seen with ombrabulin included neutropenia (19.2% vs 7.9% Pbo) and thrombocytopenia (8.5% vs 3.4% Pbo). Conclusions: Although this trial met its primary efficacy endpoint, the combination of ombrabulin and cisplatin did not demonstrate sufficient clinical benefit in pts with advanced soft-tissue sarcoma to warrant further study. Clinical trial information: NCT00699517.

10505


LMS-02: A phase II single-arm multicenter study of doxorubicin in combination with trabectedin as a first-line treatment of advanced uterine leiomyosarcoma (u-LMS) and soft tissue LMS (ST-LMS): First results in patients with u-LMS. Presenting Author: Patricia Pautier, Institut Gustave Roussy, Villejuif, France Background: U-LMS and ST-LMS are rare tumours with poor prognosis when metastatic or locally advanced, presenting moderate chemosensitivity mainly to doxorubicine (doxo), ifosfamide (ifo), cisplatin, gemcitabine (gem) and trabectidine (trab). Response rates (RR) in combination therapies (1stline) does not exceed 50% for U-LMS and 35% for ST-LMS. The most active ones are doxo combinations (most of the time with ifo or dacarbazine) and gem ⫹ docetaxel (in particular in U-LMS) with a mean response durations of 3 to 6 months. Trab was demonstrated a definite activity on pre-treated LMS (RR of approximately 20% in LMS overall [U-LMS in particular]). In view of these encouraging results on LMS, a study combining trab with doxo as first line therapy for LMS is of interest. Methods: Patients (pts) received every 3 weeks, 6 cycles of doxo 60 mg/m2 followed by trab 1.1 mg/m23-h at day 1, and pegfilgrastim 6 mg on Day 2. Study primary objective: to determine the disease control rate (DCR) (ORR⫹SD). Secondary objectives: PFS 12 wks, RR by RECIST and duration, OS and toxicities. Patients were stratified into U-LMS (n⫽45) and ST-LMS (n⫽62) group. Herein, we report the first results in pts with U-LMS; mature data will be shown in ASCO Meeting. Results: 45 pts with U-LMS have been enrolled until November 2012. Median age is 58 years, 38 where of with data collected for at least 1 cycle, 85% had metastatic disease (mostly lung 30/33, liver and bone), and 26 pts have received 6 cycles. For 33 pts with at least 1 disease assessment (every 2 cycles), the ORR was 55% (18 PR) and 13 SD (39%) had SD disease for a DCR of 94% at that time. Presently, the median PFS at 12 weeks is 94,3% [95%IC:86100]. Main grade 3-4 toxicities in 187 cycles were neutropenia (51%), febrile neutropenia (7%), thrombopenia (14%), anemia (7%), fatigue (5%), vomiting (6%) and transiet transaminase increase (22%). Conclusions: The combination of trab plus doxo seems to be an effective first-line treatment for pts with U-LMS, with meaningful clinical benefits and an acceptable and manageable safety profile. Clinical trial information: 2009-012430-70.

10508


Detection of mutant-free circulating tumor DNA in the plasma of patients with gastrointestinal stromal tumor (GIST) harboring activating mutations of C-Kit or PDGFRA. Presenting Author: Nikolas von Bubnoff, Universitaetsklinikum Freiburg, Freiburg, Germany Background: In gastrointestinal stromal tumor (GIST), there is no biomarker available that indicates success or failure of therapy. We hypothesized that tumor specific CKIT or PDGFRA mutant DNA fragments can be detected and quantified in plasma samples of GIST patients. Methods: We prospectively collected 291 plasma samples from 38 subjects with GIST harbouring activating mutations of CKIT or PDGFRA detected in tumor tissue, irrespective of current disease status or treatment. We used allele-specific Ligation PCR to detect mutant free circulating (fc)DNA. Results: We were able to detect fcDNA harbouring the tumor mutation in 15 out of 38 patients. Patients with active disease displayed significantly higher amounts of mutant fcDNA compared to patients in CR. The amount of mutant fcDNA correlated with disease course. We observed repeated positive test results or an increase of mutant fcDNA in five patients with progressive disease or relapse. A decline of tumor fcDNA or conversion from positive to negative was seen in five patients responding to treatment. A negative to positive conversion was seen in two patients with relapse and one patient with progression. In two cases, we aimed to identify additional mutations, and found four additional exchanges, including mutations not known from sequentially performed tumor biopsies. Conclusions: Our results indicate that free circulating DNA harbouring tumor specific mutations in the plasma of patients with GIST can be used as tumor-specific biomarker. The detection of resistance mutations in plasma samples might allow earlier treatment changes and obviates the need for repeated tumor biopsies. Clinical trial information: NCT01462994.


634s 10509

Sarcoma Poster Discussion Session (Board #2), Sat, 8:00 AM-12:00 PM and 12:00 PM-1:00 PM

10510


Use of ponatinib to inhibit kinase mutations associated with drug-resistant gastrointestinal stromal tumors (GIST). Presenting Author: Michael C. Heinrich, Portland VA Medical Center and Oregon Health and Science University Knight Cancer Institute, Portland, OR

In vitro and in vivo activity of regorafenib (REGO) in drug-resistant gastrointestinal stromal tumors (GIST). Presenting Author: Cesar SerranoGarcia, Brigham and Women’s Hospital/Harvard Medical School, Boston, MA

Background: Ponatinib (PO) is a multi-targeted tyrosine kinase inhibitor with potent pan-BCR-ABL activity that has recently been approved for treatment of CML and Ph⫹ ALL. PO also inhibits the kinase activity of KIT. Approximately 80% of gastrointestinal stromal tumors (GIST) contain primary activating KIT mutations, the majority of which cluster in exon 11. Imatinib (IM) is approved for the 1st line treatment of GIST; however, patients frequently relapse due to the acquisition of secondary resistance mutations located in either the KIT ATP-binding pocket or the activation (A) loop. Sunitinib (SU) is approved for 2nd line treatment of GIST but does not effectively inhibit A-loop mutants. Here we explored the activity of PO against major primary and secondary KIT mutants found in GIST. Methods: The drug sensitivity of KIT mutants was determined using engineered Ba/F3 cells harboring mutant forms of KIT exon 11 with or without ATP binding pocket or A-loop mutations. The abilities of PO, IM, SU, and regorafenib (RE) to inhibit viability and/or KIT kinase activity were compared using this system as well as an isogenic CHO cell system. We also profiled these same drugs using a panel of GIST cell lines, including cell lines with IM-resistant secondary KIT mutations. Results: In all in vitro systems, PO potently inhibited KIT exon 11 mutant kinases, with an IC50 of ⬍ 30 nM. PO also potently inhibited a range of secondary KIT mutants, including multiple A-loop mutant kinases. PO induced substantial tumor regression in Ba/F3 tumor models expressing a KIT exon 11 mutant with or without an A-loop mutation (D816H). Using GIST cell lines, PO inhibited the viability of those harboring primary KIT exon 11 and secondary resistance mutations more effectively than IM, SU, and RE. Importantly, in patients dosed once daily with 45 mg ponatinib, plasma concentrations achieved are predicted to lead to inhibition of all KIT mutants tested with the possible exception of V654A. Conclusions: PO potently inhibits the majority of clinically relevant KIT mutant kinases and has a broader spectrum of activity compared to IM, SU, or RE. Based on these data, a phase 2 study of PO in drug-resistant GIST is being initiated.

Background: KIT and PDGFRA mutations (mut) are the crucial transforming events in most GISTs, and tyrosine kinase inhibitors (TKIs) with activity against KIT and PDGFRA, such as imatinib (IM) (front-line therapy) and sunitinib (SU) (second-line therapy), are effective treatments in GIST patients (pts). Resistance to IM and SU is commonly associated with evolution of secondary kinase mut. REGO is a multi-targeted TKI that inhibits KIT, PDGFR, and other oncologic targets and has recently shown benefit in pts with metastatic GIST after progression on standard treatments. We evaluated the in vitro and in vivo activity of REGO compared with IM, SU, and sorafenib (SOR) (a multi-TKI structurally related to REGO). Methods: REGO, IM, SU, and SOR inhibition of viability and KIT phosphorylation was assessed in human GIST cell lines and in Ba/F3 cells transformed by KIT oncoproteins with IM-resistant ATP binding pocket or activation-loop mut. KIT/PDGFRA genotyping was performed in GISTs responding or progressing on REGO in the academic phase II clinical trial. Results: In GISTs with KIT exon 11 mutant oncoproteins, REGO potently inhibited viability, KIT phosphorylation, and downstream effector phosphorylation (AKT, MAPK, S6). IM-resistant activation loop mut were more potently inhibited by REGO than SU, whereas the gatekeeper IM-resistant mut T670I was inhibited by both REGO and SU, and the common ATP-binding pocket mutant V654A was more potently inhibited by SU than REGO. Two GIST metastases progressing in one pt after initial response to REGO contained KIT V654A mut. SOR and REGO demonstrated comparable in vitro overall activity. Representative GIST cell line viability IC50s are shown in the Table (values in bold indicate expected clinical relevance). Conclusions: In vitro studies confirm REGO is a potent inhibitor of KIT exon 11 mut in GIST and appears to have stronger activity than SU against the most common KIT activation-loop mut observed in GIST. Ongoing clinical correlative analyses from REGO-treated study patients will be presented.

10511

10512


IC50 (nM) Cell line GIST-T1 GIST-T1/816 GIST430 GIST430/654

KIT mutation KIT ex 11 KIT ex 11 ⫹ D816E KIT ex 11 KIT ex 11 ⫹V654A

REGO 110 395 191 3,341

SU 15 3,111 68 194

IM 30 604 61 3,128


Prolonged survival and disease control in the academic phase II trial of regorafenib in GIST: Response based on genotype. Presenting Author: Suzanne George, Dana-Farber Cancer Institute, Boston, MA

Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified liposarcoma. Presenting Author: Mark Andrew Dickson, Memorial Sloan-Kettering Cancer Center, New York, NY

Background: Regorafenib (REGO) is a broad spectrum tyrosine kinase inhibitor with activity against KIT, PDGFR, VEGFR, and FGFR. Phase II and III trials demonstrated significant activity in patients (pts) with advanced GIST following failure of at least imatinib and sunitinib. Pts have continued on the Phase II trial, and we now report longer-term follow-up as related to primary and secondary tumor genotype (KIT, PDGFRA) and SDH expression. Methods: This multicenter Phase II study of RE in GIST enrolled 33 pts with metastatic GIST. REGO was started at a dose of 160mg per day, d1-21 of each 28d cycle. Anatomic restaging was performed every 2 cycles. Clinical benefit rate (CBR) was defined as CR, PR or prolonged SD (⬎16 wks) per RECIST 1.1. KIT genotype was determined for tumors with adequate tissue available. SDHB staining was performed on a subset of patients whose tumors lacked activating mutations in KIT or PDGFRA. Response, progression free survival (PFS), and overall survival (OS) were determined for the entire cohort and for subsets based on KIT genotype and SDHB immunohistochemical status. Results: Median followup as of 20Jan2013 was 20 mos. Four pts remain on REGO without progression. CBR for the entire cohort was 81%, with 9% PR (n⫽3). Median PFS for the entire cohort was 13 mos (95%CI 9-18). Median OS was 27 mos (95%CI 16-NR). Tumor primary KIT mutations and associated median PFS are as follows: exon 11(n⫽19), 13 mos (95%CI 10-21); exon 9(n⫽3), 6 mos (95%CI 2-NR) (log-rank p-value⫽0.93). 6 pts had SDH-deficient GIST, 2 of whom experienced PR. Median PFS of pts with SDH-deficient GIST was 12 mos (95%CI 7-NR). Secondary KITmutations in a GIST lesion were identified prior to enrollment in 9 pts : exon 17 (n⫽7); one each in exon 13 and exon 18. Median PFS for pts with a documented exon 17 mutation was 18 mos (95%CI 6-NR). Conclusions: REGO is an active agent in advanced GIST. Prolonged disease control and OS is demonstrated in heavily pre-treated pts with KIT exon 11-mutant GIST; although with small sample size, there is no statistical significance in outcomes between genotypes. Objective responses were seen in 2 of 6 of pts with SDHB-deficient GIST. Other biomarkers of response and benefit are under active investigation. Clinical trial information: NCT01068769.

Background: Approximately 90% of well-differentiated / de-differentiated liposarcomas (WD/DDLS) have CDK4 amplification. The selective CDK4/ CDK6 inhibitor PD0332991 inhibits growth and induces senescence in liposarcoma cell lines and xenografts. Our prior phase II study demonstrated that treatment with PD0332991 (200mg daily x 14d every 21d) results in clinical benefit in WD/DDLS but moderate hematologic toxicity (48% Grade 3/4 neutropenia; dose reduction in 24%). Aiming to reduce toxicity, we conducted a phase II study to assess progression-free survival (PFS) and toxicity with PD0332991 at a new dose and schedule, 125mg daily x 21d every 28d. Methods: Participants were patients with advanced WD/DDLS. Eligibility criteria were age ⱖ 18 years, measurable WD/DDLS (RECIST 1.1), documented progression on at least one systemic therapy directly before enrollment, CDK4 amplification by fluorescence in situ hybridization and retinoblastoma protein expression by immunohistochemistry (ⱖ1⫹). Pts received oral PD0332991 at 125mg daily for 21 days in 28-day cycles. The primary endpoint was PFS at 12 weeks. Based on historical data, a promising result was defined as a 12-week PFS of ⱖ40% and not promising as ⱕ20%. The sample size was up to 28 evaluable patients. If 9 patients were progression free at 12 weeks, then PD0332991 would be considered to have activity in WD/DDLS. Results: 29 pts were enrolled and 25 were evaluable for the primary endpoint. Median age was 62 (range 42-85); 55% were male; median ECOG score was 0 (range 0-1). PFS at 12 weeks was 56% (14/25 patients; 90% CI 41-100%), and thus the study significantly exceeded its primary endpoint. Median PFS was 23.6 weeks (95% CI: 11.6 to Not Reached). There was 1 confirmed partial response lasting ⬎ 1 year. Grade 3 and 4 adverse events included anemia (grade 3, 21%), thrombocytopenia (grade 3, 7%; grade 4, 3%), and neutropenia (grade 3, 34%). Dose reduction was required in only 1 patient. Conclusions: In patients with WD/DDLS with CDK4 amplification, PD0332991 treatment was associated with a favorable PFS and objective tumor response. This dose and schedule appears active and may have less toxicity than 200mg x 14d. The 125mg x 21d schedule warrants evaluation in a phase 3 study. Clinical trial information: NCT01209598.


Sarcoma 10513


635s

10514


Potentially actionable kinase fusions in inflammatory myofibroblastic tumors. Presenting Author: Christine Marie Lovly, Vanderbilt-Ingram Cancer Center, Nashville, TN

Phase Ib study of RG7112 with doxorubicin (D) in advanced soft tissue sarcoma (ASTS). Presenting Author: Sant P. Chawla, Sarcoma Oncology Center, Santa Monica, CA

Background: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm that harbors anaplastic lymphoma kinase (ALK) gene rearrangements in approximately 50% of cases. ALK inhibitors have been validated as an effective therapeutic approach in this subset of IMTs. The goal of this study was to characterize a series of IMTs using both immunohistochemistry (IHC) and next generation sequencing (NGS). Methods: 30 formalin-fixed, paraffin-embedded IMT specimens from 28 patients were evaluated by IHC for ALK expression using standard techniques. DNA was extracted and sequenced using a targeted capture-based NGS assay for 3769 exons of 236 cancer-related genes and 47 introns of 19 commonly rearranged genes, including 8 tyrosine kinases in a CLIA laboratory (Foundation Medicine). Selected specimens were also evaluated for ALK fusions by fluorescence in-situ hybridization (FISH). Results: 20 samples were ALK positive and 10 samples were ALK negative by IHC. Targeted NGS was successfully performed in 16/20 ALK positive and 10/10 ALK negative cases. Among the 16 ALK positive cases analyzed by NGS, 12 harbored ALK fusions with various 5’ gene fusion partners, including LMNA, TPM3, TPM4, SEC31A, TFG, RANBP2, and CLTC. The remaining 4 were also negative by FISH suggesting a different mechanism of ALK overexpression. Among the 10 ALK negative cases, 2 harbored ALK fusions (EML4-ALK, TPM3-ALK). In the other 8 ALK negative samples, 2 contained distinct ROS1 fusions (YWHAE-ROS1, TFG-ROS1) and 1 contained a PDGFR␤ fusion (NAB2-PDGFR␤), none of which have been described in IMT samples to date. Overall, kinase gene fusions were identified in 18/26 (69%) evaluable samples. Conclusions: This study represents the most comprehensive NGS analysis of IMTs. 12/12(100%) ALK IHC and FISH positive cases contained ALK fusions, while 5/8 (63%) of distinct ALK IHC negative cases harbored kinase fusions, involving ALK, ROS1, or PDGFR␤. Since these fusions are all targetable with existing kinase inhibitors (i.e. crizotinib, dasatinib), this study suggests that IMTs should be routinely profiled for kinase fusions and not just by ALK IHC. Efforts are ongoing to identify “driver mutations” in the fusion-negative specimens.

Background: Preclinical data demonstrate p53-dependent MIC-1 activation by both D and the MDM2 inhibitor RG7112. This study evaluated the tolerability of combining D with RG7112 in ASTS patients (pts) and pharmacokinetic (PK) and pharmacodynamic (PD) parameters of the combination. Methods: A phase 1b 3⫹3 dose escalation study was designed. Pts with ASTS in whom D was considered appropriate were eligible. D was administered IV at either 50 mg/m2 or 60 mg/m2on day 1 with RG7112 administered orally 500 or 1000 mg QD for 3 or 5 days (d1-3 or d1-5) in 28-d treatment cycles. Safety, PK and PD, including serum MIC-1 (an indicator of p53 activation), were assessed. Results: As of January 15, 2013, enrollment was complete with 23 pts with ASTS accrued; safety data for cycle 1 was available for preliminary review in 20 pts. Growth factor support was mandated following the first dosing group (D 60 mg/m2and RG7112 500 mg x 5d) due to febrile neutropenia or grade 4 neutropenia. Of the 20 pts for which cycle 1 safety data is available, 13 pts reported neutropenia (12 grade 3/4); 5 reported grade 3/4 febrile neutropenia (3 following mandatory GCSF prophylaxis); 12 pts developed thrombocytopenia (9 grade 3/4). PK parameters of the combination therapy are similar to single agent values and did not demonstrate evidence of drug-drug interactions. Serum MIC-1 rapidly increased to levels greater than for either agent alone. Best response to date is stable disease in 8/16 pts who have had interim evaluations. Conclusions: Combination therapy with D and RG7112 resulted in a high rate of grade 3/4 neutropenia (60%) or thrombocytopenia (45%). PK analysis does not suggest this is due to changes in the metabolism of either drug. This combination demonstrates apparent potentiation of p53 activation demonstrated by increased MIC-1 levels greater than additive effects of the single agents. Biomarker analyses, safety, PK, and MIC-1 data will be presented. Clinical trial information: NCT01605526.

10515

10516


Reversing the oncogenic roles of misdirected chromatin remodeling: Mechanistic insights into the SS18-SSX fusion protein in synovial sarcoma. Presenting Author: Cigall Kadoch, Stanford University, School of Medicine, Stanford, CA Background: Synovial sarcoma (SS) accounts for ~10% of soft-tissue malignancies and is generally resistant to chemotherapy-based approaches, underscoring the need for a mechanistic understanding of its pathogenesis and the development of disease-specific biologic agents. The hallmark molecular feature is a precise and uniform translocation, t(X;18), which results in the fusion of exactly 78 amino acids of SSX to the SS18 C-terminus. Because the SS18-SSX genetic lesion is observed in 100% of cases, it is likely the driving oncogenic event in these tumors; however, the molecular basis for its role in oncogenesis is undefined. Methods: We performed an affinity purification-/mass spectrometry-based analysis of endogenous mSWI/SNF (BAF) chromatin remodeling complexes in several primary cell types. Using these data in combination with protein biochemical methods, we discovered that SS18 is a dedicated, non-exchangeable subunit of these complexes with a binding affinity comparable to that of ribosomal subunits. Subsequent biochemical and functional investigations were performed to assess the oncogenic consequences of addition of 78aa of SSX to the SS18 subunit in SS. Results: We demonstrate that the SS18-SSX fusion incorporates into BAF complexes, evicting both wild-type (WT) SS18 and the tumor suppressor subunit, hSNF5 (BAF47), known to be biallelically inactivated in pediatric malignant rhabdoid tumors (MRTs). The altered complex binds the Sox2 locus, reversing polycomb-mediated repression and activating Sox2. Sox2, a pro-pluripotency transcription factor, is uniformly expressed in SS tumors and is essential for proliferation. Remarkably, increasing the concentration of WT SS18 leads to reassembly of WT complexes, retargeting of BAF complexes, returned polycomb-mediated repression at the Sox2 locus and cessation of SS cell proliferation. This mechanism of transformation depends on a region of only two amino acids of SSX, and hence provides a strong foundation for therapeutic intervention. Conclusions: These studies provide a novel oncogenic mechanism for SS tumors and inform strategies for therapeutic development in this intractable cancer.

Cohort 1A 2A 2C 3C 4C

# patients

D dose (mg/m2)

RG7112 dose (mg x #days)

RG7112 AUC last day) (␮g*h/mL)

D AUC last day (␮g*h/mL)

MIC-1 (fold change from baseline on last day of treatment)

3 5 3 7 5

60 60 50 50 50

500 x 5 d 500 x 3 d 500 x 5 d 1000 x 5 d 1000 x 3 d

69 46 60 96 NA

1.9 1.9 2.2 1.8 NA

15.4 14.9 13.2 22.8 NA

NA: data not yet available.


An open-label international multicentric phase II study of nilotinib in progressive pigmented villo-nodular synovitis (PVNS) not amenable to a conservative surgical treatment. Presenting Author: Hans Gelderblom, Department of Clinical Oncology, Leiden University Medical Center, Leiden, Netherlands Background: PVNS, also known as tenosynovial giant cell tumor (TGCT), is a rare pathological entity affecting the synovium in young adults. This neoplastic disease is driven by a t(1;2) translocation resulting in the fusion of COL6A3 and M-CSF genes. Nilotinib has inhibitory properties on M-CSF receptor pathway which could be of therapeutic interest in patient (pts) with non resectable PVNS. Methods: In this open-label international, multicentric, non-randomized, phase II study the primary objective is to evaluate the efficacy of nilotinib treatment (800 mg/day) in pts with progressive or relapsing PVNS not amenable to surgery or in whom surgery would be mutilating, as measured by the 12-week progression-free rate (12-w PFR) validated by an independent committee. Using a Bayesian design with a futility stopping rule and a maximum sample size set to 50 evaluable pts, interim analyses (IA) were planned after the inclusion of 10 and then every 5 pts. Results: From December 2010 to September 2012, 56 pts with progressive disease were enrolled by 17 institutions from Europe and Australia. Successive previous IA led to positive results in favour of the study continuation. 47 pts (median age 37 y (range: 18-74), 51% of males) were evaluable at the time of the last IA, with a median follow-up of 11.2 months (range: 0.6-12.7). Median time since diagnosis was 2.5 years (range: 0.02-26). Primary tumour was mainly located on knee (25 pts, 53%), hip (6 pts, 13%), ankle (6 pts, 13%). 4 pts had already received imatinib, 76% of pts had undergone a previous surgery. The 12-w PFR was 93.6% (95%CI, 82.5%-98.7%), without any OR. PR were observed later (2 at w-24 and 1 at w-48). Nilotinib was well tolerated, with only 4 pts experiencing grade 3 adverse events (anorexia: 1 pt; prurit: 1 pt; diarrhea: 1 pt; hepatic failure: 1 pt). 8 pts (17%) had a dose reduction and/or temporary discontinuation of nilotinib due to toxicity. Final results will be further presented. Conclusions: Nilotinib treatment induces disease stabilisation in a large proportion of PVNS patients with non resectable disease or in whom resection would be mutilating. Clinical trial information: NCT01261429.


636s 10517

Sarcoma Poster Discussion Session (Board #10), Sat, 8:00 AM-12:00 PM and 12:00 PM-1:00 PM

Results of the randomized phase III trial of trabectedin (T) versus doxorubicin-based chemotherapy (DXCT) as first-line therapy in patients (pts) with translocation-related sarcoma (TRS). Presenting Author: Andrew Eugene Hendifar, Sarcoma Oncology Center, Santa Monica, CA Background: T is the first of a new class of anticancer agents with a transcription-targeted mechanism of action. In vitro,T interferes with the aberrant transcription factors binding to DNA promoters in TRS. Methods: Pts with advanced TRS of the subtypes: myxoid liposarcoma (ML), alveolar soft part sarcoma, angiomatoid fibrous histiocytoma, clear cell sarcoma, desmoplastic small round cell tumor, low grade endometrial stromal sarcoma, low grade fibromyxoid sarcoma, myxoid chondrosarcoma and synovial sarcoma, stratified by performance status (0 vs 1-2) and subtype (ML vs other TRS) were randomized (1:1 ratio) to T (1.5 mg/m2 in 24h iv infusion q3wk) or doxorubicin, either single agent 75 mg/m2 q3wk, or 60 mg/m2 combined with ifosfamide (6-9 g/m2 q3wk) as 1st line treatment. Primary endpoint: efficacy of T vs DXCT by comparing progression-free survival (PFS). Secondary: PFS at 6 months (PFS6), response rate (RR), PFS/RR by subtype (ML vs other TRS); overall survival (OS), safety. Results: 121 pts enrolled from 22 centers, 88 were confirmed by central pathology review and evaluable for the primary efficacy endpoint by independent review assessment (IR), and all 121 pts randomized were evaluable by investigators’ assessment (IA). The main limitation of the study analyses in both arms was high censoring rate (70% IR; 61% IA) mostly due to surgery (~30%) or chemotherapy/ radiotherapy (~30%). PFS results are shown in the Table. PFS6 was not different between arms (IR: 66.4% vs 80.8% p⫽0.18/IA: 60.7% vs 62.4% p⫽0.88). Current median OS:not reached (NR) for T (24.1-NR) and 21.7 mo. for DXCT (21.2-NR).Safety: Most frequent AEs in both arms were nausea (70% vs 65%), vomiting (44% vs 26%) and fatigue (64% vs 63%). ALT increase G4 occurred in 10% pts treated with T and neutropenia G4 in 25% of pts in the T arm vs 52% in the DXCT arm. Conclusions: Although with a high censoring rate, this prospective study suggests thatPFS/OS with trabectedin are not significantly different from DXCT in first-line treatment. Clinical trial information: NCT00796120. Median PFS (mo.) 95% CI Efficacy population IR nⴝ88 T DXCT P value

18.8 NR

All randomized pts IA nⴝ121 8.6-NR 7.1-NR

0.79

17.2 8.8

5.9-NR 5.7-12.7

10518


Can postoperative radiotherapy be omitted in localized standard-risk Ewing sarcoma? An observational study of the Euro-EWING Group. Presenting Author: Nathalie Gaspar, Institute Gustave Roussy, Villejuif, France Background: Uncertainty exists on the most appropriate use of surgery, radiotherapy (RT) or both for treatment of primary Ewing sarcoma (ES). The objective of this study was to assess the impact of postoperative RT on local control in pts with localized ES and good (⬍10% residual cells) histologic response to chemotherapy (CT). Methods: We analyzed data of all pts included in the EE99-R1 trial (comparing 2 consolidation CT regimens) undergoing surgery after induction CT. Local recurrence (LR) cumulative incidence (CI) was estimated using a competing risk approach. As local therapy was not randomized but tailored to the individual patient and tumor characteristics, impact of RT was assessed in multivariable models, adjusted for possible confounders: country, age, tumor type, site and volume, quality of resection and histologic response. We also evaluated the heterogeneity of RT effect by patient and tumor characteristics (interaction). Results: Among the 599 pts included from 1999 to 2009, 142 (24%) had received postoperative RT. With median follow-up of 6.2 yrs, disease failure was reported in 156 pts, including a LR in 67 (with concomitant metastases in 28), leading to an 8-yr LR-CI ⫽ 12% (se 1.4%). Overall survival ⫽ 21% (se 5%) 3 yrs after LR (31% in isolated LR). Controlling for possible confounders, the risk of LR was halved in pts treated by surgery ⫹ RT (HR⫽0.43, 95%CI, 0.21-0.88, p⫽0.02) compared to surgery alone. Postoperative RT had a rather homogeneous positive effect in all studied subgroups. The benefit of RT was very significant in pts with a tumor volume of ⬎200mL at diagnosis and 100% necrosis. Although not significant, we observed a trend for benefit associated with RT in terms of disease-free, event-free and overall survival. Conclusions: LR contributes significantly to disease failures in this standard risk group who experience few systemic failures. Outcome after LR is very poor. Postoperative RT appears to improve local control for all pts. Good histologic response and complete resection of residual mass may not be sufficient criteria to omit RT. Further study of RT in ES is required to assess the balance between benefit and risk (secondary malignancies, functional sequelae). Clinical trial information: NCT00020566.

0.47

NR: not reached.

10519


10520


Preoperative chemoradiation therapy for localized retroperitoneal sarcoma (RPS): Final results of a phase II study from the Italian Sarcoma Group. Presenting Author: Alessandro Gronchi, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Association of perioperative radiation therapy with outcome in 204 patients with primary retroperitoneal sarcoma: A two-institution study. Presenting Author: Kaitlyn Jane Kelly, Department of Surgery, Memorial SloanKettering Cancer Center, New York, NY

Background: To study the feasibility, safety and activity of the combination of high dose long-infusion Ifosfamide (HLI) and radiation therapy (RT) as preoperative treatment for resectable localized RPS. Methods: Patients received 3 cycles of HLI (14 g/m2). RT was started in combination with the onset of the 2nd cycle and administered up to a total dose of 50.4 Gy. Surgery was scheduled 4-6 weeks after the end of RT. Primary end-point was 3-yr relapse free survival (RFS). The expected 3-yr RFS in the study population treated with surgery alone was 40%. The experimental treatment was aimed at achieving a relative reduction in relapses of at least 1/3, corresponding to a 3-yrs RFS of 55%. With 60 enrolled patients, the study would have had a 90% power to discriminate between the hypotheses of 3-yrs RFS of 40% (H0) and 55% (H1), using a 1-sided 10% level of significance. Results: Between December 2003 and 2010, 86 patients were recruited. 3 patients were ineligible after central pathological review. 63 were affected by primary tumor and 20 by local recurrence. The 3 main histological subtypes were well differentiated liposarcoma (19/83, 23%), dedifferentiated liposarcoma (26/83, 31%) and leiomyosarcoma (14/83, 17%). Median tumor size was 120 mm (IQ range⫽ 82-160). The overall preoperative treatment was completed in 60 patients. CT was completed in 65 patients, while RT in 73. Five patients had progression before surgery (3 distant and 2 local) and were not operated. 78 patients underwent surgery. At a median follow-up of 4.8 years (IQ range⫽3-6.1), 23 and 15 patients developed local recurrence (LR) and distant metastases (DM) respectively; 30 patients died of disease. 3-yr and 5-yr RFS and overall survival were 56% and 44%, and 74% and 59%, respectively. Crude cumulative incidence of LR and DM at 5 yrs were 37% and 26%, respectively. Conclusions: The combination of preoperative HLI and RT was feasible in two thirds of patients, while pre-operative RT could be completed in most (73/83). The primary endpoint of the study was met. Although a systemic coverage can be added to RT when this is felt to be appropriate, the ongoing international Phase III trial is exploring the role of RT alone. Clinical trial information: ITASARC_*II_2004_003.

Background: Radiation therapy (RT) for retroperitoneal and pelvic sarcomas (RPS) is controversial. We examined the association of perioperative, advanced modality RT on outcomes in primary RPS. Methods: Prospectively maintained databases were reviewed to compare primary RPS patients (pts) treated at two institutions between 2003 and 2011. Clinicopathologic variables were analyzed with endpoints of local recurrence-free survival (LRFS) and disease-specific survival (DSS). Results: At one institution 172 pts were treated with surgery alone while at the other 32 pts were treated with surgery and perioperative proton beam or intensity-modulated RT ⫾ intraoperative RT. The groups were similar in age, gender, tumor grade, tumor size, and margin status (p ⫽ NS). The RT group had a lower percentage of retroperitoneal versus pelvic tumors and leiomyo/liposarcoma versus other histologies (p ⬍ 0.05). Median follow-up was 38.7 months (36.9 for RT group, 38.8 for surgery alone). Five-year predicted LRFS was 91% (95% CI, 79-100%) in the RT group and 65% (57-74%) in the surgery only group (p ⫽ 0.06). RT was marginally significant in univariate analysis of LRFS. Upon adjusting for univariate predictors, RT was significantly associated with better LRFS (p ⫽ 0.046; Table). Five-year predicted DSS was 93% (95% CI, 82-100%) in the RT group and 84% (78-91%) in the surgery-only group (p ⫽ 0.25). The only independent predictor of DSS was age. Morbidity was higher in the RT group (41% vs 17%; p⫽ 0.004). Conclusions: In this retrospective study, the addition of advanced modality RT to surgery for primary RPS was associated with a reduced risk of local recurrence, although this did not translate into a statistically significant improvement in DSS. This treatment strategy warrants further investigation in a randomized trial. Multivariate analysis. LRFS Variable Perioperative RT (Y vs N) Grade (high vs low) Histology (leiomyo vs others) Margin (pos vs neg) Size (>18 cm vs 13 years

P

57% (34%, 75%), n⫽27 37% (14%, 59%), n⫽22 51% (35%, 65%), n⫽49

64% (34%, 83%), n⫽22 13% (5%, 26%), n⫽42 28% (17%, 40%), n⫽60

0.64 0.024 0.0073


Clinicopathologic predictors (CP) of survival in patients with endometrial stromal sarcomas (ESS) treated with multi-modality therapy. Presenting Author: Samir Dalia, Sarcoma Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL Background: ESS is a rare uterine neoplasm in which there is minimal data about CP prognostic markers. Our study aims to determine the association of CP variables on overall survival (OS). Methods: Patients at Moffitt Cancer Center between January 1, 1990 and April 30, 2012 with the diagnosis of ESS were identified using our institutional database. Vital status, demographics, and therapeutic information were recorded. Survival time was estimated using the Kaplan-Meier method, and Cox proportional hazard model was used to identify potential risk factors for the time to event data. A p value ⬍ 0.05 was significant. Results: 64 patients were identified. 11 were excluded for incomplete records or inaccurate pathology, and 53 patients were analyzed. Median OS was 214 months (95% Confidence Interval (CI) 60-338). Median follow up was 133 months (95% CI 84-182). Mean age was 53⫾14 years, 45 (85%) underwent oophorectomy at or prior to diagnosis, 12 (23%) were diagnosed with metastatic disease, 37 (70%) were low grade, 19 (36%) were FIGO stage III-IV. Mean BMI was 29⫾8 kg/m2, 23 (43%) received adjuvant therapy (adjT) of any type (hormonal, chemotherapy, or radiation) and 16 (30%) received hormonal therapy at any time (HRT). 27 (51%) patients had ER or PR testing and 19 (70%) were ER(⫹), 20 (74%) were PR (⫹). The sample size was too small for multi-variable analysis. The Table shows the results of select univariable analysis and OS. Conclusions: Age, initial tumor size, ER and PR status had the greatest impact on survival while BMI, FIGO stage, AdjT or HRT did not. The association between survival and ER or PR status was seen independent of if a patient received HRT. Multicenter collaborative efforts are needed in order to further study the effects of ER and PR status on survival in ESS.

10557


Recombinant adenoviral human p53 gene combined with radiotherapy in treatment-advanced sarcoma. Presenting Author: Jianhao Geng, Peking University Cancer Hospital, Beijing, China Background: Advanced soft tissue sarcoma generally are resistant both chemo- and radiotherapy. P53 gene has multiple anti-tumor functions including sensitizing tumor cells to chemo- or radiotherapy. Methods: Thirty-six patients with advanced, unresectable soft tissue sarcoma, with an age of 48.3⫾19.1 years old, 19 males and 17 females, were treated with combination of p53 gene and radiotherapy. Recombinant adenoviral human p53 gene (rAd-p53) was given through intratumoral injection at a dose of 2 x 1012 rAd-p53 viral particles (VP) once per week for 4-9 times. If tumors spread to the peritoneal cavity with or without malignant peritoneal effusions, 2 x 1012 VP diluted into 500 ml of physiological saline was infused into abdominal cavity, once a week for 4 times. Intensity modulated radiation therapy were given at a total dose of 20 – 70 Gy in 2-7 weeks. Results: The overall response rate at 3 months after treatment was 44.4% (16/36, 2/36 in CR and 14/36 in PR). Twenty patients (55.5%) were stable. The tumor in two patients was successfully resected after the combined therapy. Medium overall survival and progress free survival time were 17.8 and 13.5 months, respectively. The survival rates of one year, two years three years, and 5 years were 58.3%, 25.0%, 13.9%, and 8.3%, respectively. Mild or medium fever was observed in all patients after application of rAd-p53. No serious adverse events or complications observed. Conclusions: Combination of local p53 gene and radio-therapy is effective and safe treatment regimen for advanced soft tissue sarcoma.

CP variables and overall survival in ESS. Variable HRT AdjT ER (ⴙ)* PR (ⴙ)* BMI (1kg/m2 increase) Age (1 year increase) Oopherectomy Initial tumor size (1cm increase) FIGO stage (1 stage increase)

Hazard ratio

95% CI

P value

0.76 0.78 0.20 0.25 1.04 1.05 2.23 1.15 1.25

0.31-1.90 0.34-1.80 0.06-0.68 0.08-0.75 0.99-1.09 1.01-1.08 0.29-17.1 1.04-1.28 0.90-1.74

0.56 0.56 0.01 0.01 0.09 ⬍0.01 0.43 ⬍0.01 0.18

*Independent of HRT.


646s 10558

Sarcoma General Poster Session (Board #45H), Sat, 1:15 PM-5:00 PM

A phase Ib/II study of imatinab and everolimus in patients with PDGFRAⴙ synovial sarcoma. Presenting Author: Mary Louise Keohan, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Our group previously reported that PDGFRA is the most highly overexpressed kinase gene in synovial sarcoma. Our preclinical studies also demonstrated synergistic anti-tumor activity by inhibiting both PDGFRA and mTOR signaling with imatinib and rapamycin respectively in PDGFRA ⫹ synovial sarcoma cell lines. Based on these data, a phase Ib/II study to evaluate the toxicity and efficacy of imatinib and everolimus was undertaken. Methods: The primary endpoint of the phase 1b portion of the study was to determine the maximum tolerated dose (MTD) of everolimus administered with imatinib. Starting dose of everolimus and imatinib was 5 mg/day and 400 mg/day respectively. Response rate (RR) by RECIST was the primary end-point of the Phase II study. The phase II study used a Simon two stage design. 9 patients (pts) were to be accrued initially. If there were no responses, further accrual would be stopped and treatment declared ineffective. If there was at least 1 response, an additional 15 pts would be accrued for a total of 24. Key eligibility: metastatic disease, any number of priors. Pre and post treatment tumor biopsies were mandated. Results: 12 pts were treated.5 M and 7 F, median age 44 (range: 22-71), median priors 4 (range: 0 - 6). Two DLTs were observed at dose level 2 (10 mg everolimus /400 mg imatinib) with grade 3 transaminases and hypophosphatemia. Everolimus 5 mg/ imatinib 400 mg was the MTD in the phase II study. 10 pts evaluable for response, included 4 pts treated at the MTD in the Phase 1b study. There were no RECIST responses. Stable disease was observed in 3 pts (7, 7, 19 mos.). Western blot and IHC analysis of matched pair tumor biopsies indicate inhibition of p-AKT, p-S6 and decreases in Ki 67. Conclusions: Imatinib and everolimus failed to achieve its primary response endpoint. However, prolonged stable disease in 3 pts in association with inhibition of PDGFRA and mTOR suggest clinical benefit and biological effect for this drug combination. Clinical trial information: CTEP 8603.

10559

Background: National guidelines for extremity sarcoma recommend multidisciplinary consultation, but treatment approaches are not standardized. Our objectives were to (1) examine trends in the multimodality treatment of extremity sarcoma in the US, (2) examine adjuvant therapy practice patterns, and (3) identify factors associated with the use and sequencing of adjuvant treatment. Methods: Using the National Cancer Data Base (2000-2009), use of multimodality treatment for non-metastatic extremity sarcoma was examined. Regression models were developed to identify factors associated with adjuvant therapy receipt and treatment sequence. Results: A total of 22,051 patients underwent resection (Stage I: 45%, stage II: 28%, Stage III: 27%). Trend analysis demonstrated relatively constant rates of radiation therapy (RT) (58% to 65%), chemotherapy (21% to 23%), and any adjuvant therapy (65% to 72%), however the proportion receiving neoadjuvant therapy increased (RT: 14% to 28%; chemotherapy: 9% to 13%; any: 18% to 27%; all p ⬍0.001). Stagespecific treatment use is shown in the table below. Though RT rates were similar for all histologies, chemotherapy rates for synovial sarcoma were higher for all stages (I: 24.3%; II: 24.9%; III: 53.2%, p ⬍ 0.001). After adjusting for differences in tumor factors, patients were more likely to receive neoadjuvant therapy (chemotherapy and/or RT) if treated at high-volume academic center (p⬍0.001). After adjusting for histology, patients were more likely to receive adjuvant radiation therapy if younger, healthier, privately insured, or tumor size ⬎5cm. Patients were more likely to receive adjuvant chemotherapy if were younger, healthier (fewer comorbidities), underinsured, treated at a high-volume academic center, or tumor size ⬎5cm. Conclusions: Use of a multimodality approach for extremity sarcoma management has increased over time, particularly for neoadjuvant therapy. However, practice patterns are related to hospital type and socioeconomic factors. There may remain opportunities to increase multidisciplinary care and multimodality treatment for extremity sarcoma in the United States. Stage I II III

10560


Relationship of FAP-alpha, ADAM12, WISP1, and SOX11 expression to tumor activity in aggressive fibromatosis: Demonstration of heterogeneity within and between cases. Presenting Author: Benjamin Misemer, University of Minnesota, Minneapolis, MN Background: Aggressive fibromatosis (AF) represents a group of tumors with an unpredictable clinical course and is characterized by a monoclonal proliferation of myofibroblasts. The optimal treatment for AF is unclear. In earlier gene expression studies we identified four genes, ADAM12, WISP1, SOX11, and FAP-alpha, that were uniquely overexpressed in AF compared with 16 different normal tissues. This study was designed to examine the expression of these four proteins in AF. Methods: Immunohistochemistry (IHC) was performed in 29 cases of AF, and analyzed by a pathologist with expertise in the field. Automated imaging analysis was performed to independently quantify IHC staining, nuclear size, and nuclear chromatin density. Nuclear size was determined on control slides. Slides were scanned using ScanScope XT (Aperio) and images were divided into tiled regions of interest (ROIs) for measurements. A nuclear chromatin density ratio (CDR), defined as the measure of nuclear area with light staining divided by nuclear area with dark staining, was quantified as a surrogate for nuclear activity. To compare the image analysis with pathologic examination, an operational definition of “morphologic tumor activity” (MTA) was determined by a pathologist using a scale of 1 (inactive), 2 (probably inactive), 3 (probably active), and 4 (active) on a random set of 322 ROIs. The MTA score was then correlated with the CDR. We also assessed the relationship of CDR to IHC staining intensity for each of the four proteins in ~26,000 ROIs derived from all 29 AF samples. Results: Different areas of AF cases had different degrees of MTA. The expression of the four proteins generally correlated with the areas of tumor that were pathologically more “active.” Staining was more intense in areas with larger more open nuclei suggesting “more active” regions. There was a significant correlation between MTA and log [CDR] (0.46, p⬍0.001). Conclusions: The results confirm, on the protein expression level, our earlier gene expression results, and demonstrate the regional variation of tumor activity within and among AF cases.


Assessment of multimodality therapy use for extremity sarcoma in the United States. Presenting Author: Karen L. Sherman, Department of Surgery and Surgical Outcomes and Quality Improvement Center, Northwestern University Feinberg School of Medicine, Chicago, IL

10561

Surgery alone

Adjuvant RT

Adjuvant chemotherapy

61% 37% 25%

37% 58% 66%

5% 14% 31%


Prediction of metastatic behavior in high-grade pleomorphic soft tissue sarcomas by gene expression. Presenting Author: Keith M. Skubitz, University of Minnesota, Minneapolis, MN Background: The biologic heterogeneity of soft tissue sarcomas (STS) complicates treatment. Metastatic propensity may be determined by gene expression patterns that do not correlate well with morphology. In earlier studies, gene expression patterns were identified that distinguish 2 subsets of clear cell renal carcinoma (RCC), serous ovarian carcinoma (OVCA), and aggressive fibromatosis (AF). We reported the use of a gene set derived from these three studies to separate 73 high grade STS into groups with different probabilities of developing metastatic disease (PrMet). We wished to confirm our findings using an independent data set. Methods: We utilized these gene sets, hierarchical clustering (HC), Kaplan-Meier, and log-rank analyses to examine the Affymetrix HU_133 expression profiles of 309 STS. Results: HC using a pooled gene set derived from the AF-, RCC-, and OVCA-gene sets identified subsets of the STS samples. Kaplan-Meier analysis revealed differences in PrMet between the clusters defined by the first branch point of the clustering dendrogram (p⫽0.048), and also among the 4 different clusters defined by the second branch points (p⬍0.0001). Analysis also revealed differences in PrMet between the leiomyosarcomas (LMS), dedifferentiated liposarcomas (LipoD), and undifferentiated pleomorphic sarcomas (UDS) (p⫽0.0004). HC of the LipoD and UDS samples with the pooled probe set divided the samples into 2 groups with different PrMet (p⫽0.013, and 0.0002, respectively). HC of the UDS samples also showed 4 groups with different PrMet (p⫽0.0007). In contrast, HC found no subgroups of the LMS samples. Each individual gene set (AF-, RCC-, and OVCA-) separated the UDS samples into subsets of different metastatic outcome, but only the AF- gene set separated the LipoD samples, and no gene set identified LMS subsets. Conclusions: These data confirm our earlier studies and suggest that this approach may allow the identification of more than 2 subsets of high grade STS, each with distinct clinical behavior, and may be useful to stratify STS in clinical trials and in patient management.


Sarcoma 10562


10563


Expression of neurotrophins and their receptors in adult sarcomas. Presenting Author: Elke Malenke, Department of Hematology, Oncology and Immunology, University of Tuebingen, Tuebingen, Germany

A large retrospective analysis of trabectedin in 885 patients with advanced soft tissue sarcoma. Presenting Author: Axel Le Cesne, Institut Gustave Roussy, Villejuif, France

Background: Neurotrophins (NT) influence proliferation, survival, death, and differentiation by binding Tropomyosin-related kinase (Trk) receptors and p75NTR(CD271). While the three Trk-receptors TrkA, TrkB, and TrkC display specific binding to their ligands, i.e. TrkA to NGF (nerve growth factor), TrkB to BDNF (brain-derived neurotrophic factor), NT4/5 (neurotrophin 4/5) and TrkC to NT3 (neurotrophin 3), CD271 shows low affinity to all neurotrophins. Notably, CD271 has been suggested as marker for the prospective isolation of bone marrow mesenchymal stromal cells (MSC), and rhabdomyosarcomas have previously been found to express neurotrophins and NT receptors. Methods: RNA was isolated from sarcoma cell lines and freshly obtained sarcoma (src) cells from patients after surgical resection. RNA was reverse transcribed and cDNA products underwent PCR analysis with specific primers. Furthermore, cell lines from the same primary tissues were established and treated with doxorubicin. Effects of K252a (Trk receptor inhibitor), Pep5 (CD271-Inhibitor), and neurotrophins on sarcoma cell proliferation and survival were analyzed. Results: An array of freshly obtained clinical src samples (n⫽10 each subtype) was screened for expression of NT3, NT4/5, BDNF, NGF as well as TrkA, TrkB, TrkC, and CD271. Interestingly, src subtype-specific expression patterns were observed. In the established cell lines, K252a increased doxorubicininduced tumor cell death, while CD271-Inhibitor Pep5 enhanced proliferation in doxorubicin treated cells, especially under serum free conditions and when combined with BDNF and NGF. Conclusions: NT and NT receptors are expressed on all adult src samples screened in this study. Chemotherapy resistant liposrc as well as myxofibrosrc samples displayed the strongest expression of NT3 as well as TrkB, TrkC, and CD271. The concomitant expression of NT and their receptors suggests autocrine self-stimulation, which may propagate survival, proliferation, and treatment resistance. NT receptor tyrosine kinases may represent an interesting therapeutic target in adult src.

Background: Trabectedin (Yondelis) is the first marine-derived antineoplastic drug approved in Europe for the treatment of patients with recurrent ASTS or for patients unsuited to receive anthracyclines and ifosfamide. We retrospectively analyzed the RetrospectYon database with patients’ data treated with trabectedin between Jan 2008 - Dec 2011. Methods: Trabectedin was given at the approved dose of 1.5 mg/m2 as a 24-h infusion every 3 weeks. Patients who achieved partial response (PR) or stable disease (SD) after 6 cycles could receive maintaining trabectedin treatment. Uni- and multivariate analyses of prognostic factors were performed. Results: 885 patients (486 women) from 26 centers in France with ASTS with a median age of 54 years (range 12-84) were included. Most had leiomyosarcoma (36%), liposarcoma (18%) or synovial STS (11%). At baseline, performance status (PS) was 0 in 26%, 1 in 47% and ⬎1 in 27% of patients. A median of 4 trabectedin cycles (range 1-28) was given as a 2nd (41%), 3rd (39%) or ⱖ4th (20% of patients) treatment line. Toxic death and unscheduled re-hospitalization occurred in 0.5% and 8% of patients, respectively.The objective response rate was 15% (6 complete and 127 PR), and SD rate was 45.5% (n⫽403). After a median follow-up of 22.6 months (range 0.03-51.2), the patients who received trabectedin as 2nd, 3rd or ⱖ4th line had the median PFS of 4.3, 4.2 and 3.4 months, respectively, and the median OS of 12.9, 12.3 and 9.5 months. Multivariate analysis identified liposarcoma, leiomyosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma (UPS) and trabectedin line as independent prognostic factors for PFS, and UPS, angiosarcoma, rhabdomyosarcoma, gender, PS and trabectedin line for OS. After 6 cycles, 205 of the 273 patients with non-progressive disease received trabectedin as maintenance treatment and obtained a superior PFS (median 11 vs. 7.2 months, p⫽0.0001) and OS (median 25.1 vs. 16.9 months, p⬍0.0001) that those who stopped trabectedin after 6 cycles. Conclusions: Patients with ASTS treated with trabectedin had PFS and OS comparable or better to those observed in phase II/III trials. Trabectedin maintenance beyond 6 cycles is associated with improved OS and warrants further exploration.

10564

10565


Efficacy and safety of hypofractionated preoperative radiotherapy in treatment of localized extremity/trunk wall soft tissue sarcoma (STS): Final results of the study. Presenting Author: Piotr Rutkowski, Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland Background: The primary treatment of STS is surgical resection combined with pre- or postoperative radiotherapy. Conventional fractionation in neoadjuvant radiotherapy is 50Gy (fractions: 2Gy/day). Radiobiological studies shown that alpha/beta ratios of some sarcoma cells are below 10Gy, what is rationale for hypofractionation. Aim of the study was to assess the efficacy and safety of hypofractionated radiotherapy in preoperative setting in patients with STS treated in one institution. Methods: 220 patients (median age 54years) participated in this prospective study (2006-2010). Median follow up is 34 months. 140 patients (64%) had high grade (G3) tumors, median size -9cm (45% ⱖ10cm), 68% on lower limb. 137 patients (62.2%) had primary tumors. Preoperative radiotherapy 5x5 Gy per 5 consecutive days was applied, with immediate tumor resection. Results: R0 resection was possible in 79%. 61 patients died (3-year overall survival OS 72%), 91 (41%) had disease relapse. Local recurrence (LR) was found in 20% of the patients (3-year LR-free survival 80%). Negative prognostic factors for LR were: tumor size ⱖ10cm (p⫽0.037), grade 3 (p⫽0.0041) and primary vs. recurrent tumor with borderline significance. LRs had significant impact on OS (p⫽0.0001). 101 patients (46%) had any kind of complications, majority on lower limb (early: 17.2% prolonged healing of the wound ⬎1month, 12.7% -wound dehiscence, 4% -prolonged punctures of lymph fluid, 2.7% -acute skin toxicity; late: 0.9% -severe fibrosis with contracture, 11% -prolonged edema. 2.7% -bone fracture), but only 6.3% required additional surgery. Conclusions: In this non-selected group of advanced STS use of hypofractionated preoperative radiotherapy was associated with similar local control (80%) when compared to previously published studies. The early toxicity is tolerable, with small rate of late complications. Presented results warrants evaluation in randomized trial.


Sirolimus in advanced hemangioendothelioma. Presenting Author: Silvia Stacchiotti, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Background: Haemangioendothelioma (HE) is a very rare vascular tumor. The epithelioid variant is characterized by a specific t(1;3)(p36.3;q25) translocation, resulting in the WWTR1-CAMTA1 fusion product. We retrospectively reviewed patients with HE treated with sirolimus, an mTOR inhibitor, at our institution. Methods: We identified 12 patients (M/F: 4/8 – mean age: 46 years – epithelioid HE/ retiform HE: 10/2 – locally advanced/multifocal: 1/11 – pretreated: 6) with advanced HE who were treated with sirolimus, as a single agent, 5 mg/day, from 2005 on. They had evidence of progression in the 3 months before starting treatment. The daily dose of sirolimus was adjusted according to drug blood levels (range 10-20 ng/dl). Response was evaluated with CT/MRI/PET scans after 4-6 weeks of treatment, then every 3 months, by RECIST and Choi criteria. WWTR1 gene rearrangement was evaluated by FISH, and the histochemical expression of mTOR effectors, S6 and 4BP1, is ongoing. Results: 10 patients are evaluable for response (2 pts are too early). Sirolimus daily dose ranged from 3 to 6 mg/day. Best response by RECIST was PR ⫽ 1, SD ⫽ 6 (all ⬎6 months, range 6-48⫹), PD ⫽ 3 cases. In 3 cases, a Choi response could be detected. PET response was observed in 6/6 evaluated case. Median PFS (range) was 24 (3-48) months. Two patients with evidence of tumor stabilization while under sirolimus stopped their treatment after 12 and 24 months of therapy, respectively, with evidence of interval progression in both. A new disease stabilization was obtained after restoring sirolimus. Conclusions: HE is known for its potentially long-lasting course, even in typical cases with multicentric/multifocal disease. Progressive HE may require a medical therapy, but is insensitive to cytotoxic chemotherapy, while mainly andecdotal responses were reported to interferon, bevacizumab and thalidomide. In this retrospective series, sirolimus resulted in a high proportion of mainly non-dimensional, possibly longlasting, tumor responses.


648s 10566


Desmoid tumor (DT): Clinical and treatment characteristics and quality of life (QoL) in a large cohort from a referral center. Presenting Author: Ulrich Ronellenfitsch, University Medical Center Mannheim, Department of Surgery, Mannheim, Germany Background: Due to its low incidence, evidence regarding DT is scarce, and consensus on recommended treatment is difficult to achieve. This study systematically assesses clinical presentation, treatment characteristics and QoL in a large cohort of DT patients (pts). Methods: Demographic and clinical variables were retrieved from a database of 224 pts with histologically confirmed DT presenting to our referral center from 10/04-7/12. For a subset of 46 pts, QoL was assessed with the SF-12 questionnaire. The distribution of variables in the entire pt population and clinically relevant subgroups was calculated and compared with appropriate statistics (t-test, nonparametric tests). Denominators varied due to non-availability of variables for some pts. Results: 153 (68.3%) pts were female. Mean age at first diagnosis was 36.9 (3-73) yrs. Primary tumor site was limb/ intraabdominal/rectus abdominis/trunk in 40/43/43/66 (21/22/22/35%) of 192 pts. 65/108 (60%) pts recalled a trauma or medical intervention at the DT site. 38/43 (88%) pts with rectus abdominis DT were female, and 31/38 (82%) had previous pregnancies, median time to DT diagnosis after end of pregnancy was 17 months. Primary therapy was resection/imatinib/ tamoxifen/watchful waiting in 136/9/8/7 (83/6/5/4%) pts. Resection was R0/R1/R2 in 47/66/22 (35/49/16%) pts. After R0/R1 resection, DT recurred in 46% and 62% resp. after a median of 356/334 days. Physical/mental SF-12 summary scores were 39.2/40.8, 41.5/45.4, and 48.0/44.5 in pts with limb, intraabdominal, and trunk DT and 38.6/42.6 and 43.3/42.5 in pts with and without recurrence (reference population score 50; all p⬎0.05 for subgroup comparisons). Five women delivered a healthy child in parallel to clinically existent DT. 56% of our patients are alive with disease, whereas 44% have no evidence of disease. Conclusions: In 83% of DT pts, resection is the first treatment step and is R0 only in one third. 60% of the pts recall trauma/medical intervention at the DT site. Rectus abdominis DT occur after a median of 1.5 yrs after pregnancy. Despite the fact that 56% of our pts live with disease, their QoL is only slightly decreased, with lowest values for physical QoL in pts with recurrence.

10568


Two doses of NGR-hTNF (N) given alone or in combination with doxorubicin (D) in soft tissue sarcomas (STS). Presenting Author: Stefano Ferrari, Istituto Ortopedico Rizzoli, Bologna, Italy Background: N, a tumor-targeted antivascular agent, displays a biphasic dose response curve with activity shown at low dose (LD) or high dose (HD). Vascular effects involve at LD an early vessel stabilization that enhances intratumor D uptake followed by late vessel damage and at HD a rapid vessel disruption. Methods: STS patients (pts), stratified by prior D dose (⬎ vs ⱕ 300 mg/m2), were randomized to N alone given at LD (0.8 ␮g/m2) in arm A and at HD (45 ␮g/m2/d1/q1w) in B, or combined with D (60 mg/m2/d1/q3w/6 cycles) at LD in arm C and at HD in D. Primary aim of this 4-arm phase II trial was progression free survival (PFS) with CT scans performed q6w until progressive disease (PD). Using 2-stage design, each regimen was rejected if ⱕ 2/14 and ⱕ 7/24 pts were PD free at 3 months after 1st and 2nd stage, respectively (␤⫽20%, ␣⫽10%, n⫽96). Secondary aims: adverse events (AEs), response rate by RECIST criteria and early metabolic response (MR), as quantified by fractional change in SUV using FDG-PET according to EORTC criteria Results: 66 pts have been enrolled and 55 were included in 1st study stage analysis: median age: 57 yrs; male: 30; PS ⱖ 1: 26; leiomyosarcomas: 12; median prior lines: 3 (range, 0-7). In all, 488 weekly cycles were given (mean, 9; range, 1-45). Main grade 3/4 AEs were: neutropenia 18%, chills 7%. After first study stage, primary endpoint was met only in arm C (LD N ⫹ D), with 7/14 pts PD free at 3 months. Median PFS was 1.3 months (95% CI, 1.1-1.5) for arm A, 1.5 (1.1-1.8) for B, 4.5 (3.6-5.4) for C and 1.3 (1.1-1.5) for D (p⫽.01 for trend). By RECIST, there were no objective responses and 20/48 (42%) evaluable pts had stable disease (SD), including 1/12 in arm A, 6/12 in B, 9/12 in C and 4/12 in D. Median SD duration in arm C was 5.5 months (95% CI, 3.7-7.3). By FDG-PET imaging done after 3 weeks, 7/30 (23%) assessable pts had partial MR (4 SD/3 PD per RECIST), with mean change in SUV of -34% (SD, ⫾ 12), while 18 pts (60%) had stable MR (7 SD/11 PD per RECIST), with mean change in SUV of 2% (⫾ 11). Median PFS was 4.2 months in pts who achieved partial MR and 1.5 months in pts who did not (HR⫽0.67). Complete follow-up for arm C and central histology/ radiology review are under way. Conclusions: LD NGR-hTNF plus D is safe, with promising activity as measured by FDG-PET. Clinical trial information: NCT00484341.

10567


Hypoxia, angiogenic markers, and response to neoadjuvant radiotherapy in soft-tissue sarcomas. Presenting Author: Jeremy Lewin, Peter MacCallum Cancer Center, Melbourne, Australia Background: Hypoxia is common in soft-tissue sarcomas (STS) and may correlate with radiotherapy (RT) resistance and worse outcomes. We aimed to quantify intratumoral hypoxia with 18-fluoroazamycin arabinoside (FAZA)PET in resectable STS and correlate this to 18-fluorodeoxyglucose (FDG)PET, tumour response, angiogenesis biomarkers and patient (pt) outcomes. Methods: This phase II prospective study enrolled pts with resectable STS prior to neoadjuvant RT. Pts underwent FDG-PET and FAZA-PET prior to RT. Circulating and immunohistochemical (IHC) markers of hypoxia and vessel architecture were measured weekly. Response to RT was measured by surgically resected pathologic necrosis (PN), radiological response and relapse-free survival. Results: 23 pts were recruited. 47% (8/17) demonstrated hypoxia on FAZA-PET with a possible association between hypoxia and enhanced metabolic activity on FDG-PET (FDG SUVmax⫽15.33 with hypoxia; SUVmax⫽5.86 without hypoxia p⫽.08). FDG-PET response to RT correlated with PN (good/equivocal FDG-PET response: 59% PN; poor FDG-PET response: 19%PN p⫽.008). All relapses were distant (n⫽10) at average follow up of 5 years. Relapse was associated with higher FAZA-PET SUV (1.94 vs 1.28 p⫽0.02), FDG-PET SUVmax (14.4 vs 6.2 p⫽0.05), and poorer response to RT (PN 36% vs 66%, p⫽0.04). Baseline VEGF-C (531⫾82pg/ml, mean⫾SEM) were higher than VEGF-A (35⫾8pg/ml) and VEGF-D (131⫾17pg/ml), and correlated with protein expression on IHC staining. Hypoxia on FAZA-PET correlated with lower baseline VEGF-A/C (VEGF-C: (292pg/ml vs 688pg/ml p⫽0.16) and VEGF–A (14pg/ml vs 46pg/ml p⫽0.13). Low VEGF-C correlated with resistance to RT assessed by FDG-PET. In hypoxic tumors after 1 week of RT, VEGF-A and C levels were significantly increased (VEGF-A 80pg/ml vs 14pg/ml; VEGF-C 541ng/ml vs 292ng/ml). Response to RT correlated with less induction of VEGF-A/C. Relapse was associated with lower baseline VEGF and higher IHC levels of other hypoxic markers (GLUT-1, CA 9). Conclusions: In STS, hypoxia is common, measurable, predicts poorer response to RT and is associated with adverse outcomes. Circulating levels of VEGF-C, the dominant isoform, inversely correlated with hypoxia and is induced by RT.

10569


Epithelioid haemangioendothelioma. Presenting Author: Nadia Yousaf, The Royal Marsden NHS Foundation Trust, London, United Kingdom Background: Epithelioid haemangioendothelioma (EHE) is a rare vascular tumour which can arise in any site. There is little published data about the clinical behaviour and management of these tumours. Methods: A retrospective review of the management of patients with histologically proven EHE presenting to the Royal Marsden Hospital from January 1999 to January 2012. Demographics, site, treatment and survival outcomes were collected. Results: 28 patients (21 females) were identified with a mean (SD) age of 44 (17). 20 patients presented with diffuse disease involving one or more organs at presentation. The predominant site of disease was identified as liver n⫽8, mediastinum n⫽6, lung n⫽ 2, limb n⫽1, pancreas n⫽1, spleen n⫽1, back n⫽1, abdominal wall n⫽1, oesophagus n⫽1, neck n⫽1, pelvis n⫽1, not known n⫽2. Median overall survival (Interquartile range) [OS (IQR)] in months was the longest in 10 patients who had localised operable disease at presentation, 116 (71). Amongst those with inoperable disease (n⫽16), patients with liver disease had the longest OS (IQR), 18 (43) months and those with lung and mediastinal disease had the shortest OS (IQR), 10 (2.5) and 11 (17) months respectively. A variety of treatment modalities were used for patients with inoperable disease and these are summarised in the Table. Conclusions: The clinical behaviour of EHE can vary depending on the site of disease. Surgery, if feasible, has the best outcome. In those with inoperable disease a period of observation to assess the clinical behaviour of the tumour is recommended. Non-steroidal anti-inflammatory drugs are a reasonable, relatively non-toxic first line treatment option. The use of anti-angiogenic drugs merits further exploration. Management of patients with inoperable epithelioid haemangioendothelioma. Treatment modality Observation Cytotoxic chemotherapy Immunomodulatory drugs Immunomodulatory drugs and cytotoxic chemotherapy NSAID NSAID plus other Tyrosine kinase inhibitor Cytotoxic chemotherapy and antiangiogenic Antiangiogenic

Number

Median PFS (IQR) in days

3 (on going) 13 5 3

2,635 (1601) 119 (92) 128 (54) 193 (155)

4 (on going in 3 patients) 1 1 1

110 (136) 38 1095 147

5

137 (225)

PFS, progression-free survival; IQR, interquartile range; NSAID, nonsteroidal anti-inflammatory.


Sarcoma 10570


Guidelines for the definitions of time-to-event endpoints in randomized clinical trials: Results of the DATECAN Project for Sarcomas and GISTs. Presenting Author: Carine A. Bellera, Institut Bergonié, Regional Comprehensive Cancer Center, Bordeaux, France

649s

10571


Synovial sarcoma: Is chemotaxis important to tumor progression? Presenting Author: Emanuela Palmerini, Istituto Ortopedico Rizzoli, Bologna, Italy

Background: With the necessity of reducing randomized clinical trial (RCT) duration, cost and number of patients, surrogate endpoints of overall survival (OS) are increasingly being used as replacement for OS in cancer RCTs. However, most of these endpoints currently lack of standardized definition enabling a comparison of RCT results. Some recommendations have been proposed for specific cancer sites but they do not rely on a formal consensus methodology. The objective of the Definition for the Assessment of Time-to-event Endpoints in Cancer trials (DATECAN) project is to provide guidelines to standardize definitions of time-to-event endpoints in RCTs for different cancer sites. We present results for sarcomas and GISTs. Methods: We relied on the modified Delphi consensus method, a validated formalized consensus process for the development of practice guidelines. International experts with various backgrounds and expertise were involved. First, the coordinating committee, a group of statisticians and epidemiologists involved in the design and conduct of RCTs, led a comprehensive literature review to identify time-to-event endpoints and events of interest. The steering committee, which included additional medical experts, validated the list and prepared the questionnaire sent for rating to an independent expert committee. Results: The consensus process is finalized. It involved 2 rounds of scoring (28 experts) and 1 in-person meeting (in parallel to ASCO’12). Each expert had to rate on a 1-9 scale if s/he agreed or not for including events (e.g. death related to primitive cancer) in the definition of time-to-event endpoints (e.g. progression-free survival). 16 events were rated for inclusion or not in the definitions of 14 time-to-event endpoints. Consensus was reached for 73% of the events after the 2 rounds of scoring. Consensus was finalized at the in-person meeting for the remaining events. Conclusions: The DATECAN guidelines should help standardizing definitions of commonly used endpoints. This process should (i) facilitate the comparison of RCTs and (ii) improve the quality of future RCTs by providing better estimation of sample size and treatment effect.

Background: Synovial sarcoma (SS) is a rare and aggressive soft tissue tumor. In a first study (Palmerini E, Cancer 2009) we analyzed clinical prognostic factors in a retrospective series of 250 patients (pts) who were treated at Rizzoli Institute between 1976 and 2006. Stage, age, size, histology and use of radiotherapy influenced survival, whereas the role of chemotherapy was unproven. In the present study on the same patient population, in order to identify new prognostic factors and potential therapeutic targets, a panel of markers involved in chemotaxis and tumor growth were assessed. Methods: The expression of the chemokine receptor CXCR4 (a marker for chemotaxis which plays a critical roles in cancer progression) and the insulin-like growth factor receptor-1 (IGFR1) (a marker of growth activation ) were evaluated by IHC staining. Results: Tissue samples were available for the analysis in 88 patients (45 female and 43 male); median age was 37 years (range 11-63); size of the lesion was ⬎ 5 cm in 60 patients (71%); histology was biphasic in 30 (34%) of patients. All pts underwent surgery, 56% of pts underwent adjuvant radiotherapy (RT) and 68% adjuvant chemotherapy. With a median follow-up of 6 years (1-30 years), the 5-year overall survival (OS) was 70% (60-81). A positive stain for IGFR1 was detected in 55 pts (62.5%), with expression in the nucleus in 21 pts. CXCR4 was expressed in 74 pts (84%), nuclear pattern in 31 pts. No relation between IGFR1 and CXCR4 expression and clinical variables was found. The 5-year OS was 63% (95%CI 41-85%) for pts with positive IGFR1/nuclear expression and 73% (95%CI 61-85%) p ⫽ 0.05, in pts with negative IGFR1/nuclear staining. Similarly, the 5-year OS was 47% (95%CI 27-66%) in patients with positive CXCR4/nuclear expression and 86% (95%CI 76-96%), p ⫽ 0.003, in negative cases. In a multivariate analysis including age, histology, size and use of RT, nuclear expression of IGFR1 and CXCR4 were confirmed statistically significant independent factor for OS. Conclusions: The nuclear expression of CXCR4 or IGFR1 negatively influences the survival in patients with SS. Further studies addressing the role of CXCR4 as a potential target in this high risk subgroup of SS patients are needed.

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Metronomic continuous oral cyclophosphamide as second and further line in soft-tissue sarcomas (STS) of the adult. Presenting Author: Alessandro Comandone, Piedmontese Group for Sarcomas/Italian Sarcoma Group, Torino, Italy Background: In STS third line treatment is poorly defined. However many patients (pts), after aggressive therapy as first and second line progress in their disease ask to be treated. Oral cyclophosphamide (CPM) was already used in breast cancer, prostate cancer and in elderly pts with STS with favourable results. Aim of our study was to define the feasibility, tolerability and activity of oral CPM as third line and further line chemotherapy Methods: 45 pts (19 M; 26 F) with advanced or metastatic STS heavily pretreated were included. Oral CPM was given daily at total dose of 50 mg/day without interruption excepted for toxicity or progressive disease Results: Median age was 60 (32-81), histological subtypes were: leiomyosarcoma 12, liposarcoma 10, condrosarcoma 5, sinovialsarcoma 4, sarcoma NOS 4, other 10. Primary sites were: extremities 21, retroperitoneum 19, trunk 5. 41 pts were metastatic, 4 locally advanced. 41 pts were pretreated with chemotheraphy (15 were in II line, 17 in III line, 7 in IV line, 2 in V line). Median PS (ECOG) was 2 . Median duration of theraphy was 4 months (1-38). Progression free survival (PFS) ranged from 0 to 42⫹ months (median 4 months). Treatment was well tolerated, we registred only one episode of leucopenia G2 and one of asthenia G2. No complete responses were seen. Only 3 minimal responses and 18 stable disease were seen. Conclusions: Oral CPM showed a mild activity and good tolerability in advanced soft tissue and metastatic STS. It could be an appropriate solution as second line and further therapy and in unfit or elderly pts.


Identification of potential molecular biomarkers for response of soft tissue sarcoma to eribulin: Translational results of EORTC trial 62052. Presenting Author: Agnieszka Wozniak, Laboratory of Experimental Oncology and Department of General Medical Oncology, KU Leuven and University Hospitals, Leuven, Belgium Background: The phase II study EORTC 62052 demonstrated potential antitumor activity of eribulin, a tubulin-interacting cytotoxic agent, which is a synthetic analogue of the natural compound halichondrin B, in patients with various subtypes of metastatic soft tissue sarcoma (STS) including leiomyo- (LMS) and adipocytic (ADI) sarcomas, but not synovial sarcomas (SYN) and other sarcoma histotypes (OTH) (Schöffski P et al. Lancet Oncol. 2011;12:1045). In addition to histotypes, we aimed to identify potential biomarkers responsible for eribulin sensitivity or resistance to eribulin using gene expression and miRNA profiling. Methods: From 68 consenting patients archived tumor tissue was collected, including 22 LMS, 15 ADI, 10 SYN and 21 OTH sarcoma histotypes. Total RNA was isolated from 65 samples and analyzed using GeneChip Human Exon ST Array (for mRNA expression) and Taqman Low Density Array (for miRNA). Progression free survival (PFS) at week 12 (RECIST 1.0) was the primary endpoint of the clinical trial and used for correlative studies. Eighteen out of 56 (32.1%) evaluable patients in this analyzed subset had non progressive disease at week 12 (“responders”). Results: Overall expression of 62 transcripts including ALS2CR11 (uncorrected p⬍0.001) and 26 miRNAs (p⬍0.05) differed significantly between non-responders and responders. Additional transcripts and miRNAs were identified when considering the different histological groups (Table). Conclusions: The level of (mi)RNA expression in soft tissue sarcoma samples may predict response of soft tissue sarcoma to eribulin. Further validation studies are required. Number of differentially expressed transcripts

All STS Subtypes** ADI LMS OTH

Number of differentially expressed miRNAs

Upregulated*

Potential biomarker

Downregulated*

U-regulated*

20

42

ALS2CR11

18

8

miR-17-92 cluster

58 11 66

500 19 93

MYLK3 SLC8A1 IGF2, COL1A2

8 6 1

0 2 0

miR-106b miR-146a; 1271; 590-3p; 29b-2# miR-186

Downregulated*

Potential biomarker

*In responders. ** SYN subgroup not taken into account as only one patient reached PFS at 12 weeks.


650s 10574


10575


Incidence and predictive factors of late relapse in patients with soft tissue sarcomas: Implications for prolonged follow-up. Presenting Author: Maud Toulmonde, Institut Bergonié, Bordeaux, France

Impact of adjuvant treatments on local and metastatic relapse of soft-tissue sarcoma patients in the setting of competing risks. Presenting Author: Antoine Italiano, Institut Bergonié, Bordeaux, France

Background: There is no consensus on how to follow soft-tissue sarcoma (STS) patients after their initial management. In particular, the incidence of late relapse which would justify prolonged surveillance is unknown. Methods: Follow-up data were reviewed from 719 patients with localized STS, included in the French Sarcoma Group database from January 1990 to June 2005, and who achieved complete remission maintained for at least five years after their initial management. The outcomes of interest were the cumulative probabilities of late (⬎ 5 years) local and metastatic relapse with death as a competing event. Estimations and 95% confidence intervals (CIs) were computed with the cumulative incidence function. Patients who did not experience the event of interest or death over the course of the study were censored at their last follow-up. Results: 67 (9.3%) and 42 (5.8%) patients had late local and metastatic relapse respectively. On univariate analysis, internal trunk location, liposarcoma histological subtype, tumor size ⬎ 10 cm, R1 margins, no adjuvant radiotherapy were significantly associated with increased risk of late local relapse. On multivariate analysis, internal trunk location (HR⫽ 3.9, 95% CI 2.2-6.7, p⬍0.001) and tumor size ⬎ 10 cm (HR⫽ 2.1, 95% CI 1.1-4, p⫽0.03) were the two factors independently associated with local relapse. On univariate analysis, leiomyosarcoma histological subtype, and grade ⬎ 1 were significantly associated with increased risk of late metastatic relapse. On multivariate analysis, grade ⬎ 1 (HR⫽ 4.7, 95% CI 1.1-21, p⫽0.04) was the sole factor independently associated with the risk of late metastatic relapse. Conclusions: Late relapse of STS (⬎ 5 years after initial management) is relatively uncommon. However, its existence and our results emphasize the critical role of long-term follow-up to detect late local recurrence in patients with retroperitoneal or very large STS and late metastatic recurrence in patients with high grade disease.

Background: Competing risk is the risk of an event that interferes with the probability of experiencing the disease-specific outcome of interest. Indeed, the occurrence of a competing risk (for instance death by local relapse or another cause) may preclude the onset of the event of interest (for instance metastatic relapse) or at least modify its probability. Competing risk is ignored by Kaplan Meier method and standard Cox survival model. Methods: 3369 adult patients with localized STS were included prospectively in the French Sarcoma Group (GSF) database from January 1990 to December 2009. The outcomes of interest were the cumulative probabilities of local (LR) and of metastatic (MR) relapse with death as a competing event. Estimations and 95% confidence intervals (CIs) were computed with the cumulative incidence function. Results: Median follow-up was 4.5 years. 1-year and 5-year cumulative incidence of LR were 6.4% (95% CI 5.6-7.3) and 25.9% (95% CI 24.2-27.6), respectively. Age, histological subtype, anatomic site and grade were independently associated with the cumulative probability of LR. After adjustment to these prognostic factors, adjuvant radiotherapy was associated with a significant impact on LR (HR⫽0.5 95% CI 0.4; 0.6, p ⬍0.001). The magnitude of this effect was similar whatever the grade or the anatomic site. Because of the competing effect of death, adjuvant chemotherapy had no significant impact on the cumulative probability of LR. 1-year and 5-year cumulative incidence of MR were 7.4% (95% CI 6.5-8.3) and 26.9% (95% CI 25.2-28.7), respectively. Tumor depth, histological subtype, tumor size and grade were independently associated with the cumulative incidence of MR. After adjustment to these prognostic factors, adjuvant chemotherapy was associated with a significant impact on MR (HR⫽0.5 95% CI 0.4-0.7, p ⬍ 0.001) in grade 3 but not in grade 2 patients (HR⫽1.3 95% CI 0.9-1.9, p⫽ 0.1). Conclusions: Adjuvant radiotherapy was associated with improved LR outcome even in patients with high risk of competing death from metastatic disease or other causes. Adjuvant chemotherapy was associated with improved MR outcome in patients with grade 3 but not grade 2 disease.

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Safety of trabectedin (T) in elderly patients (pts) with advanced soft tissue sarcoma (STS). Presenting Author: Roberta Sanfilippo, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Targeted next generation sequencing of sarcomas for identification of therapeutic targets. Presenting Author: Vinod Ravi, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: T is a marine-derived cytoxic alkaloid approved in the European Union for further-line chemotherapy of advanced STS. Most common side effects are fatigue, neutropenia and transient transaminitis. Overall the drug is well tolerated with no cumulative toxicity. Studies in elderly pts are lacking. Methods: We retrospectively reviewed all pts ⱖ65 year-old, with pre-treated advanced STS, who received T at our Institution from January 2002 to January 2013, focusing on tolerability. All patients received premedication with dexamethasone 4 mg p.o. bid 24 hours prior to T administration. Treatment toxicity was graded according to CTCAE (v 4.0). Results: Fourty-two pts were identified (males ⫽ 22, females ⫽ 20; median age ⫽ 69 years, range 65-82; ECOG PS 0 ⫽ 1 pt, 1⫽ 38 pts and 2-3⫽ 3 pts; main histotypes ⫽ 22 liposarcoma: 12 myxoid-round cell liposarcoma, 10 well/dedifferentiated liposarcoma, 17 leiomyosarcoma, 2 synovial sarcoma, 4 others; disease extent ⫽ 34 metastatic and 8 locally advanced; median line of administration of T⫽ 3rd, range 1st-5th; median T dose ⫽ 2.2 mg, range ⫽ 2.7-1.7 mg). A total of 319 cycles were administered (median 6, range ⫽ 1-23). Starting dose was 1.3 mg/mq in 37 pts and 1.1 mg in 5 pts. The most common side effects were: fatigue (all grades: 19% of cycles), reversible myelosuppression, mainly neutropenia (grade 3-4: 50%), transient transaminitis (grade 3-4: 21%). Eighteen pts needed a dose reduction: inter-cycle transient transaminitis (3 pts), neutropenia ( 13 pts), asthenia (2 pts). In 7 patients, cycles needed to be delayed as well. Three pts interrupted T due to toxicity: grade 3 thrombocytopenia in 1 pt and grade 4 neutropenia in 2 pts. Conclusions: This retrospective analysis confirms that T is well tolerated in elderly pts. No major differences were found in the safety profile compared to historical controls, except a higher incidence of myelosuppression, which however was not influential on subsequent T administration.

Background: Sarcomas are a diverse group of mesenchymal tumors with significant heterogeneity. Evolving personalized cancer care strategies require identification of recurrent genomic alterations that can be targeted therapeutically. Due to the rarity of these tumors and lack of fresh or frozen tissue in routine clinical practice, DNA sequencing has been a challenge. Objective: To demonstrate the feasibility of a next-generation sequencing (NGS) platform that utilizes archival formalin-fixed paraffin-embedded (FFPE) tissue to evaluate the spectrum of DNA alterations seen in sarcomas. Methods: Study population included 35 consecutive patients with advanced sarcoma presenting to the sarcoma center at MD Anderson Cancer Center beginning August 2012 with archival FFPE tissue available for NGS. DNA was extracted from FFPE samples and used for hybridization capture and NGS on the Illumina HiSeq 2000 platform. A total of 182 cancer-associated genes and 37 introns of 14 commonly rearranged genes were evaluated for genomic alterations. In the absence of an individual– matched normal control, germline variations were removed using dbSNP and the remaining variants were classified on the basis of current knowledge of specific variants from cancer databases such as COSMIC. Results: 35 patients (10 Angiosarcomas, 9 Leiomyosarcomas, 3 synovial sarcomas, 13 other subtypes) underwent DNA extraction with a median yield of 3376 ng tumor DNA. The average sequencing depth was ⬎900X. 43% of patients had point mutations/indels previously described in COSMIC and/or in known mutation hotspots. 54% of patients showed structural variants such as amplifications, deletions or rearrangements. 68% of genomic alterations are in genes that are actionable. We identified an apparently novel variant in KDR T771R in 2/10 patients with angiosarcoma. KDR amplifications were identified in 20% of patients with angiosarcoma. Outcomes of matched targeted therapy of patients with actionable targets will be presented with more mature follow-up. Conclusions: Targeted NGS of DNA from archival FFPE tissue is feasible with the potential for identifying actionable targets and discovery of novel mutations.


Sarcoma 10578


Prognostic significance of radiologic and histologic response to neoadjuvant chemotherapy in localized synovial sarcoma. Presenting Author: Camille Chakiba, Institut Bergonié, Bordeaux, France

10579


Isolated limb perfusion for soft-tissue sarcoma and regional melanoma. Presenting Author: Olfa Derbel, Centre Léon Bérard, Lyon, France

Background: The role of neoadjuvant and adjuvant chemotherapy in localized synovial sarcoma (SS) is still controversial. Histologic response to neoadjuvant chemotherapy is an independent prognostic variable in bone sarcomas. Data regarding the prognostic value of response to noeadjuvant chemotherapy in STS are limited. Methods: 68 patients with localized STS, treated with neoadjuvant anthracycline/ifosfamide-based chemotherapy and assessable for response to chemotherapy were included prospectively in the French Sarcoma Group (GSF) database from 1985 to 2011. All the cases were reviewed by the pathology subcommittee of the GSF. Radiological response to chemotherapy was assessed according to RECIST criteria. Good response was defined as partial response or stable disease according to RECIST and ⱕ10% recognizable tumor cells in the surgical specimen. Poor response was defined as stable or progressive disease according to RECIST and ⱖ 50% recognizable tumors cells in the surgical specimen. All the other cases were defined as intermediate response. Results: Median age was 38 years. Median tumor size was 8 cm (range 2-20). 56% of tumors were located in the limbs and 52% were grade 3. Response to chemotherapy was considered as good in 9 cases (13%), intermediate in 20 cases (29.5%) and poor in 39 cases (57.5%). Median metastasis-free (MFS) and overall (OS) survivals were 45 (95% CI 11-79) and 84 months (95%CI 88-120), respectively. On univariate analysis, grade, tumor size and response to chemotherapy were significantly associated with metastasisfree survival (MFS). Radiological response according to RECIST has no prognostic value. On multivariate analysis, grade was the sole variable independently associated with MFS (HR⫽3.4, 95% CI 1.5-7.5, p⫽0.003). On univariate analysis, grade, and response to chemotherapy were significantly associated with overall survival (OS). On multivariate analysis, grade was the sole factor independently associated with OS (HR⫽2.5, 95% CI 1.2-5.7, p⫽0.03). Conclusions: Response to neoadjuvant chemotherapy may not have prognostic value in patients with SS. Grade represents the most significant predictive factor of outcome in this setting.

Background: Isolated limb perfusion (ILP) represents a treatment option for locally advanced melanoma and sarcoma confined to a limb. The advantage of this approach is to deliver high-dose regional chemotherapy without serious systemic effects. However, the ILP technique involves a complex and invasive operative procedure, requiring accurate monitoring to avoid major local toxicity. Methods: From November 2004 to December 2011, 58 patients underwent IPL for unresectable soft tissu sarcoma (STS⫽ 34) and advanced in-transit melanoma (n⫽24). IPLs were performed at mild hyperthermic conditions with 1-2 mg of TNF and 40-80 mg of melphalan (M) for arm and leg perfusions, respectively. The response rate, disease free intervals, overall survival, toxicity and limb salvage rate were evaluated. Results: Median age was 68 years (range: 29-91 years), with 58% of women. For sarcoma patients, median tumor size was 60 mm, 16 patients (47%) had a high grade STS. Twenty-one patients (61%) received IPL before definitive surgery. Eight patients finally underwent amputation, giving a long-term limb salvage of 77%. The overall response rate was 73.5% (Complete response rate 14.7%, partial response rate 58.8 %). For melanoma patients, 9 (38%) had an AJCC stage III disease, the median thickness of the primary tumor was 3.5 mm. A complete response was obtained in 21% of patients while 54% exhibited a partial response. The local and metastatic recurrence rates were similar between sarcoma and melanoma patients (41% and 33% respectively). All but one of the patients with non-operated sarcoma presented a local or metastatic relapse.There was no mortality and no systemic toxicity. Regional toxicity (Wieberdink scale) was: grade I (no reaction) 53 %, II (erythema, oedema) 34%, III (blistering) 8% and IV 3%. The median local relapse-free survival was 40 months in sarcoma group (26.6 months for non operated patients) and 10 months in melanoma one. The overall 3-years survival rate was 44% for sarcoma and 25% for melanoma patients. Conclusions: ILP induces a high tumour response rate, leads to a high limb salvage rate but is associated with an important recurrence rate. It provides a limb salvage alternative to amputation when local control is necessary.

10580

10581



Poor prognostic features in angiosarcoma: A single institution retrospective study of 324 patients. Presenting Author: Sandra P. D’Angelo, Memorial Sloan-Kettering Cancer Center, New York, NY

Serum protein acidic and rich in cysteine (SPARC) as a prognostic marker in soft tissue sarcoma. Presenting Author: Sherif S. Morgan, University of Arizona Cancer Center, Tucson, AZ

Background: Angiosarcoma (AS) is a rare, malignant endothelial cell tumor of vascular origin with a five year overall survival (OS) of approximately 35%. It is a heterogenous disease whose natural history is poorly defined. We sought to identify clinical and treatment outcomes to better define this disease. Methods: In a retrospective study using an institutional sarcoma database, we identified all patients(pts) with AS treated at Memorial Sloan-Kettering Cancer Center between 1992-2011 and collected their correlative clinical information.Kaplan-Meier method and Cox’s proportionalhazard models were used to determine OS and prognostic factors. Hazard ratios (HR) are listed with their 95%confidence intervals (CI). Results: We identified 324 pts, median age was 63 (range 15-94), 127(39%) were men. At presentation, 188 (58%), 19 (6%) and 117(36%) had localized disease (L), local recurrences (LR) or distant metastases (M), respectively. L sites included: RT breast 43 (23%,) head&neck 33 (18%,) scalp 30 (16%,) breast 26 (14%,) extremity 23 (12%,) abdomen/pelvis 14 (7%,) thorax 10 (5%) and trunk 9 (5%). The median OS is 3.3 years (2.44-4.33) for pts w L disease and 0.89 years (0.74-1.11) for pts with M disease. Among pts that presented with L disease, 29% had a LR and the median local relapse free survival (RFS) time was not reached (8.71-NA); 31% had distant recurrences with a median distant RFS of 12.8 yrs (4.13-NA.) Among L disease patients, older age (HR 1.04, 1.03-1.06, p ⬍0.0001) and site were independent predictors of decreased OS. Visceral tumors arising in the abdominal/pelvis (AP) (HR 2.89, 1.27-6.61, p ⫽ 0.012) had worse OS compared to those arising the breast. Conclusions: AS remains an aggressive, heterogenous malignancy with poor OS and high rates of local and distant recurrences. Patients with M disease do poorly. Adverse prognostic factors include AP visceral tumors and older age. These factors could be helpful for stratification in future clinical trials. The identification of genomic differences is necessary to define therapeutic targets in AS.

Background: SPARC is a matricellular secreted glycoprotein that performs several functions, including modulating cellular adhesion and proliferation. It has been implicated in tumorigenesis and identified as an adverse prognostic factor in a number of cancers. The specific mechanisms involved have yet to be identified. Agents targeting SPARC-expressing tumors, such as nanoparticle albumin-bound-paclitaxel (NAB-P), have been developed. Soft tissue sarcomas (STS) represent a heterogeneous group of tumors with inadequate systemic therapies. Our objective was to explore the pattern of SPARC expression and its prognostic significance in STS. Methods: Formalin-fixed paraffin-embedded tissue sections were stained by immunohistochemistry using a mouse monoclonal antibody for SPARC (Abnova). Staining intensity was scored blindly. Patient survival was determined from patients’ medical records. Kaplan-Meier and log-rank analyses were used to compare survival by SPARC expression level. Results: 27 tissue specimens of various STS subtypes were investigated (Table). Elevated SPARC expression was observed in 56% of specimens, but did not correlate with underlying histology. Overall survival segregated into 2 groups based on SPARC levels. Patients who expressed low-to-moderate levels of SPARC exhibited median survival of 22.1 months, while the median survival of patients with moderate-to-high expression levels was 4.4 months (log rank; p⫽0.0016). Conclusions: A significant proportion of STS specimens exhibit elevated SPARC expression. Elevated SPARC does not correlate with underlying histology, although analysis of a greater number of specimens might reveal subtypes with more frequently elevated expression. Overall survival segregates strongly by degree of SPARC expression, with elevated expression being adverse. Our results suggest that analysis in STS of agents targeting SPARC, such as NAB-P, should be stratified by extent of SPARC expression. Low SPARC High SPARC

Liposarcoma or leiomyosarcoma

Other STS subtypes

Median survival (months)

Survival range (months)

8/16 8/16

4/11 7/11

22.1 4.4

4 – 32 1.4 – 11.1


652s 10582


10583


Adjuvant radiotherapy (adj RT) for extremity and trunk wall atypical lipomatous tumor/well-differentiated LPS (ALT/WD-LPS): A French Sarcoma Group (GSF-GETO) study. Presenting Author: Philippe A Cassier, Centre Léon Bérard, Lyon, France

Preoperative Tru-Cut biopsy (POB) for the diagnosis of retroperitoneal soft tissue sarcomas (RPS) and risk of local recurrence (LR) compared to primary surgery of the tumor. Presenting Author: Paola Boccone, Medical Oncology, Institute for Cancer Research and Treatment, Candiolo, Italy

Background: The role of adj RT in the management of ALT/WD-LPS remains controversial. Methods: 284 patients (pts) with operable ALT/WD-LPS, no history of previous cancer, CT or RT, treated between 1984 and 2011 and registered in the Conticabase database were included and described. Overall (OS) and local relapse free (LRF) survival were evaluated from the time of first treatment (trt). Their distributions were estimated by KaplanMeier method and compared between RT groups using Log-Rank test. Independent prognostic factors and adj RT, were explored with Cox model. Results: Among the 20 centers, 3 enrolled 58% of the pts. Median age at diagnosis was 61 (range 25-94), 146 pts (51%) were males, 223 (79%) pts had distal tumors while 35 (12%) and 26 (9%) had tumors involving the girdle and the trunk wall. The median size of primary tumors was 17 cm (range 2-48), 272 (96%) lesions were deep seated, 24 (9%) were multifocal within the same anatomical area. Surgery quality was unknown for 42 pts. Among the remaining pts, 102 (43%) were R0, 130 (54%) R1 and 8 (3%) R2. Adj RT was given to 129 pts (45%). Pts who received adj RT had larger tumors (p⫽0.034), involving more often the distal limbs (p⬍0.001) and were more often multifocal in the same anatomical area (p⫽0.009). The use of adj RT varied across centers and along the study period. Other characteristics, including margin resection, were balanced between RT groups. Median follow-up for the whole population was 38.6 months (mo) (CI 95% [34.0-47.6]): 51.9 mo [43.0-62.3] for the RT group and 30.7 mo [23.3-37.8] for the surveillance group (Surv). None of the pts developed metastasis during follow-up. With 23 LR, 4 in the RT group and 19 in the Surv group, 3-years LRF rates were 98.8% [91.8-99.8] vs 90.4% [82.3-95.0] with and without adj RT (p⬍0.001). Once stratified on time period (before/after 2003), adj RT, age and margin resection (R0 vsother) were independently associated with LRFS. No OS difference was observed (p⫽0.151). Conclusions: In this study, adj RT following resection of ALT/WD-LPS was associated with a reduction of local recurrence risk. More prolonged and homogeneous follow-up is required to confirm these results.

Background: Regardless optimal surgery LR is still a major challenge in RPS affecting 60% of the patients (pts). To improve these results pre-operative radiotherapy ⫹/- chemotherapy are under investigation. This strategy requires to perform a POB. The surgical removal of the whole needle track is mandatory for limb sarcomas, but it can hardly ever be achieved in RPS. We explored whether POB did increase the risk of LR in terms of tumor cell seeding (along the needle track) or in the tumor mass area. Methods: We scanned our prospectively (01/2000 to 12/2010) collected RPS database including 176 pts. Complete information (records, CT scans, biopsy-track, follow up data) were available and retrospectively examined in 100 pts. Pts were divided into: group A (POB), group B (direct surgery). The 7 year probability of disease free survival (DFS) was estimated for each pt (ASCO 2012 abs 10000). T student test and Fisher’s exact test were used to compare the estimated DFS and the incidence of LR in the 2 groups, respectively. Kaplan-Meier method was used to estimate DFS and overall survival (OS). Results: In 51 male, 49 female, median age 58 years (22-81) RPS histotype distribution was: lipo 43, leio 28, pleomorphic 9 and other 20. RPS grades were: G1 29%, G2 32%, G3 39%. POB was performed in 25 pts (25%) without major complications. The baseline probability of 7 year DFS was 0.43 and 0.51 (p⫽ .24) for group A and B, respectively. After a median follow up of 71 mos, LR was 8% and 23% (p⬎ .05) for group A and B, respectively. No relapse along the needle track was detected. As expected, liposarcoma was associated with a higher rate of LR (Odds Ratio 5.6 CI 95% 2-13). Median DFS, local DFS and OS were 24, 88 and 71 months, respectively. Conclusions: With the limit of the retrospective nature of our data, we didn’t find any increased risk of LR for POB in RPS. Although surgery is still the standard therapy in RPS, knowledge of histotype and differential diagnosis might encourage to consider inclusion of pts into pre-operative clinical trials and to avoid surgery for other retroperitoneal tumors (e.g. lymphomas, germinal cell tumors, IgG4-related sclerosing disease).

10584

10585



Incidence of brain metastases and overall survival in patients with primary cardiac sarcoma: A retrospective case series. Presenting Author: Maryann Shango, University of Michigan, Ann Arbor, MI

Targeted radiofrequency ablation of metastatic posterior vertebral body lesions in patients with soft tissue sarcomas. Presenting Author: Jessica C. Ley, Washington University School of Medicine in St. Louis, St. Louis, MO

Background: Primary cardiac sarcoma (PCS) is the most common primary cardiac malignancy, but is a rare primary site of sarcoma. We present 21 cases from a tertiary care center to better understand this uncommon malignancy. Methods: A cancer center-based registry and pathology database were searched to identify pts diagnosed with PCS from 1992-2013 at University of Michigan. Kaplan-meier method was used to estimate survival. Cox proportional hazard model was used to associate variables to occurrence of metastases (mets) or death. Results: Atotal of 21 pts (F12, 9M) with PCS were identified, median age 36 (range 11-74). The most common presenting symptoms included dyspnea (16) and chest pain (6; 5 with associated pericardial effusion). Histologies included: angiosarcoma (9), leiomyosarcoma (4), undifferentiated pleomorphic (3), spindle cell (2), fibrosarcoma (1), rhabdomyosarcoma (1) and synovial (1). Sites of origin were R atrium (7), R ventricle (2), L atrium (10) and pericardium (2). Ten pts presented with mets; most common sites were lung (8), liver (2), brain (2), pancreas (2) and bone (2). Surgery was attempted in 12 pts, achieving 1 R0 resection. Pts received a median of 1 (0-7) systemic therapies. Median overall (OS) was 12.6 mos (range 3-79) from diagnosis. Pts without prior surgery were more likely to have mets or death (p⫽0.038). Brain mets were common, occurring in 7 of 21 pts after a median of 7 mos (range 1-75) from diagnosis. Median OS after diagnosis of brain mets was 8 mos. Of the 7 pts who developed brain metastasis, 5 had PCS originating in the left heart. Of the 2 pts with PCS in the right heart, one was evaluated for and had a right to left shunt. The likelihood of developing brain mets did not correlate with age, chemotherapy, or surgery. Conclusions: PCS portends an extremely poor prognosis, marked by inability to achieve complete resection and a high incidence of disseminated disease at diagnosis. Metastatic disease to the brain was much more common in PCS (33%) as compared to STS of any origin (approximately 1-8%), particularly in pts with PCS originating in the left heart. Clinicians should have a low threshold for brain imaging evaluation of PCS pts.

Background: Metastatic spinal lesions can be debilitating with significant impact on patients quality of life. Concern for damage to adjacent neural elements during treatment exist due to high radiation doses required to treat certain radioresistant spinal lesions such as soft tissue sarcoma. Radiofrequency ablation (RFA) of metastatic lesions has been shown to be effective in bone. Spine anatomy presents challenges for minimally invasive (MI) treatment of posterior vertebral body lesions. Targeted RFA (t-RFA) using a novel tumor ablation system, designed for spinal anatomy is evaluated in patients with symptomatic posterior vertebral wall spinal lesions. Methods: Five patients with metastatic leiomyosarcoma or liposarcoma and posterior vertebral body spine lesions, treated by prior radiation with continued progression of lesion size and pain received t-RFA, using a novel spinal tumor ablation system (STAR, DFINE), which contains an articulating bipolar, extensible electrode for navigation. Device thermocouples (TC) permit real time monitoring of the ablation zones to determine size. Sequential post-procedural pain scores, PET and contrast enhanced magnetic resonance imaging, and histopathology of treated area was performed. Results: No complications or thermal injury occurred. Intraprocedural imaging demonstrated the articulated, bipolar instrument was able to navigate to posterior lesions. Post-ablation MRI demonstrated lesion necrosis within a discrete ablation zone. No evidence of malignancy by PET or histopathology was noted through 10 months. All patients reported post procedural pain relief. Systemic therapy was not interrupted. Conclusions: Navigational t-RFA proved a safe and effective, non-ionizing palliative therapy alternative for radio-resistant lesions . Post-ablation imaging and histology confirmed metastatic lesions were necrotic and included in ablation zone with tumor control 10 mos post treatment. Ablation zone was very consistent with real time temperature readings. t-RFA permitted MI targeted treatment of lesions within close proximity of spinal cord, not controlled by systemic therapy. Prospective clinical trial is under preparation.


Sarcoma 10586


Nuclear SMAD4 as a predictor of survival in patientes with extremity soft tissue sarcomas submitted to neoadjuvant chemotherapy. Presenting Author: Isabela Werneck Cunha, Pathology Department, Hospital A. C. Camargo, Sao Paulo, Brazil Background: Neoadjuvant chemotherapy for locally advanced soft tissue sarcomas, although not standard, represents a promising option for resectable tumours. The discovery of biological predictors of chemotherapy response highlights the possibility to develop individualised therapeutic approaches in selected group of patients or predict survival also. The SMAD4 protein, a member of TGF␤ superfamily has a role in progression and tumor metastasis and may be involved sarcomas recurrence. Methods: 30 patients with soft tissue sarcomas (STS) of high-grade located in extremities treated with neoadjuvant doxorubicin and ifosfamide chemotherapy were observed prospectively since January 2005 to June 2011. All patients were submitted to radiation therapy adjuvant. Surgical specimens after neoadjuvant treatment were evaluated of SMAD4 nuclear expression by immuno-histochemistry and percentage of viable cells Results: The median follow-up time was 42 months. The overall survival (OS) was 91.7% in patients with low expression SMAD4 nuclear protein associated with ⱕ10% of viable cells (n⫽12) in the surgical specimen and 68.9% in the remaining patients. Likewise, the disease free survival (DSF) was 91.7% versus 38.6% (p 0.01) respectively. Conclusions: The combination of nuclear SMAD4 low expression and 10% or less of viable cells in the surgical specimen was statistically significant in better DFS in patients with locally advanced extremity STS treated with neoajuvant chemotherapy with benefit in OS.

10588


Phase I and pharmacokinetic study of sorafenib in Kaposi sarcoma. Presenting Author: Thomas S. Uldrick, HIV/AIDS Malignancy Branch, CCR, National Cancer Institute, Bethesda, MD Background: Kaposi sarcoma (KS) is a multifocal angioproliferative disorder. VEGFR2-3, PDGFR and c-kit are implicated in KS pathogenesis and inhibited by sorafenib (So). KS is commonly HIV-associated. The antiretroviral drug ritonavir (R) inhibits CYP3A4, and may affect So metabolism and tolerability. Methods: We performed a phase I study of So in KS. HIV⫹ patients (pts) were eligible if on combination antiretroviral therapy (cART) for ⬎3 months with progressive KS or ⬎4 months with no KS regression. Dose level 1 for pts on R-containing cART (R1) was So 200 mg daily, for pts not receiving R (NR1) So 200 mg every 12 hours. Treatment cycles were 21 days. So pharmacokinetic assessment performed cycle 1 day 8. Adverse event (AE) grade (Gr) by CTCAE v3.0 (2006-10) and v4.0 (2011-12). KS response graded by modified ACTG criteria. Results: 10 pts, R1 (8), NR1 (2). Baseline characteristics: median (med) (range) age 49 (35-72), CD4 in HIV⫹ 500 cells/uL (35, 747), time on cART 9 months (3.5, 27), previous KS therapies 2 (0-5). 9 HIV-infected, 8/9 HIV viral load ⬍50 copies/mL. 6 had KS-associated edema. Med number cycles 4 (1, 13). Common AE at least possibly attributable to So: anemia, AST/ALT elevation, lipase elevation, hypertension, proteinuria, fatigue, infection, voice alteration. Dose-limiting toxicities (DLT): R1- Gr3 asymptomatic elevated lipase (1), Gr4 thrombocytopenia (1, likely due to multicentric Castleman disease); NR1- Gr3 hand-foot syndrome not resolved by week 6 (1). Other Gr 3-4 AE: R1- hand-foot syndrome (1), Gr3 thrombocytopenia (1), Gr3 transient cerebral ischemia (1), Gr3 hypertension (1); NR1- Gr3 hypertension (2). Best response: partial response (PR) (2), stable disease (SD)(5), progressive disease (1), not evaluable (2). Med duration SD 12 weeks (5, 33). 5/6 with KS-associated edema had objective decrease in edema. R was not associated with clear difference in So CMax or AUC at steady state. Conclusions: Preliminary estimate of PR or better is 20%. Even in some cases where KS did not respond, KS-associated edema improved. However, So was relatively poorly tolerated, with DLT observed at R1 and NR1, and these doses did not yield better responses than established therapies. Additional studies evaluating R’s effect on So metabolites are warranted. Clinical trial information: NCT00287495.

10587

653s General Poster Session (Board #50A), Sat, 1:15 PM-5:00 PM

A phase II trial of novel anthracycline amrubicin in advanced soft tissue sarcoma. Presenting Author: Launce Gouw, Huntsman Cancer Institute, Salt Lake City, UT Background: Amrubicin is a 9-aminoanthracycline with significantly less cardiotoxicity than doxorubicin, a current standard against soft tissue sarcoma, and may represent an appealing alternative first line therapy. We report findings in a phase II study investigating tolerability and efficacy of amrubicin in patients with advanced STS. Methods: We enrolled adult patients in a single-arm open label study with locally advanced or metastatic soft tissue sarcoma, no prior systemic treatment, measurable disease, an ECOG PS ⬍2, and adequate organ function. We administered amrubicin (40 mg/m2 IV over 10’) on D#1-3 of a 21D cycle with GCSF support. Six cycles were planned with continuation at clinician discretion. We used RECIST 1.1 to radiologically assess response to therapy. Toxicities were assessed using CTCAE 4.0. The primary objective was overall response rate (CR⫹PR), and clinical benefit (CR⫹PR⫹SD). We employed a 2- stage design, with 15 patients treated in the first stage. Error rates were ␣⫽5% for accepting a poor regimen and ␤⫽10% for rejecting a promising regimen, with planned enrollment of 30 patients through the second stage if activity was observed. Results: 15 of 15 planned patients enrolled in the first stage of this phase II clinical trial; 10 males and 5 females, with median age 59 (range 30-73). Of the 13 evaluable patients, at 6 cycles 3 patients achieved a PR, with best response of 78% reduction of target lesions; 4 patients demonstrated minor response/stable disease (SD), ranging from 11-28% reduction of target lesions, and 4 patients had minor progression/SD (less than 20% progression). Two patients progressed ⬎20%. Clinical benefit is currently 85.7% (12/14). Amrubicin has been well tolerated, with primarily grade I and II AEs. A single dose adjustment has occurred but no treatment delays. No cardiac complications, ECG or significant echocardiogram changes have been noted. Conclusions: Amrubicin is a novel anthracycline with encouraging activity against STS and an extremely well tolerated side effect profile. Further study of amrubicin in STS is warranted. With minor treatment-related morbidity, amrubicin would also be a good candidate for combination therapy with other standard or experimental therapeutics. Clinical trial information: NCT01259375.

10589


A prospective multicenter phase II study of sunitinib in patients with advanced aggressive fibromatosis. Presenting Author: Jae-Cheol Jo, Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea Background: There have been reports on responses and prolonged disease stabilizations with imatinib which may be associated with PDGFR-␤ pathway and KIT mutation in the treatment of aggressive fibromatosis (AF). Sunitinib has not only PDGFRs, KIT, and FLT3 inhibiting activity, but also VEGFRs blockade as antiangiogenesis. The aim of this study is to evaluate the efficacy and safety of sunitinib for patients with advanced AF. Methods: Nineteen patients with pathologically proven AF were accrued between Jun 2008 and Mar 2012. Sunitinib was administered with 37.5 mg/day for 4 weeks without break, comprising one cycle. Primary endpoint was response rate. Results: Ten (53%) patients were female and the median age was 30 years (range, 22-67). Most of the primary sites were intra-abdominal (12, 63.2%), and AF associated with familial adenomatous polyposis was observed in 10 (52.6%). With a median 6 cycles per patients (range, 1-47 cycles), 5 (26.3%) achieved a partial response and 8 (42.1%) had stable disease; the overall response rate was 26.3% (95% CI, 6.3-45.7) in intention-to-treat analysis. With median follow-up time of 20.3 months (range, 1.8-50.7), the 2-year progression-free survival and overall survival were 74.7% and 94.4%, respectively. Grade 3 or 4 adverse events of sunitinib with frequency ⬎ 5% of patients included neutropenia (33.3%), diarrhea (5.3%), and hand-foot syndrome (5.3%). In 3 patients out of 12 patients with mesenteric AF, mesenteric mass bleeding (n⫽1), bowel perforation (n⫽1), and bowel fistula (n⫽1) with tumor mass necrosis, were observed during an early period of sunitinib. Conclusions: Sunitinib showed potential antitumor activity and was relatively tolerated in patients with AF, especially non-mesenteric AF. Further investigation of sunitinib treatment is necessary in patients with AF.


654s

Sarcoma

10590


Evaluating surgery and first-line imatinib (ima) treatment patterns for patients with gastrointestinal stromal tumors (GIST). Presenting Author: Michael Eaddy, Xcenda, Palm Harbor, FL Background: In 2002, ima was FDA approved for advanced metastatic GIST, followed in 2008 with an indication for adjuvant therapy. Real-world data on changing patterns of ima therapy, including adjuvant management, is sparse. This study evaluated changes in treatment patterns, resection rates, and corresponding costs of care among patients receiving first-line (1LT) ima for GIST over an 8-yr period, with a breakpoint around time of initial reporting of phase III adjuvant therapy data showing survival benefit. Methods: The study was conducted Jan 1, 2003–Dec 31, 2010 utilizing pharmacy/medical claims data from a large health plan. Patients with a GIST-related ICD9 code who also received ima were eligible, and excluded if they received any chemotherapy prior to date of first diagnosis or ima. All were designated into 1 of 3 cohorts: metastatic disease at first recognition (MP), non-metastatic non-surgical (NS) patients, and non-metastatic patients undergoing a GIST-related surgical procedure before ima (SP). Patients were followed from diagnosis to end of study period or loss of continuous eligibility. Results: Patient assignment across the disease extent and surgery/no surgery cohorts by the phase III reporting event is shown in the Table. A change in distribution of primary disease presentation and/or management across two time intervals is suggested by marked decrease in percentage of MP (54.9%¡36.1%) and greater than doubling of SP patients presumably receiving adjuvant therapy following initial resection attempt. In the study population, 18.8% of patients who initiated 1LT with ima went on to 2LT (73.7% sunitinib); 5.9% receive 3LT (44.4% nilotinib and 38.9% sorafenib); ⬍1% receive 4LT (66.7% sorafenib). In general, 1LT was more costly than subsequent therapies. Across all lines of care, oral TKI drug acquisition cost was the dominant determinant of total cost of care. Conclusions: A change in distribution of primary disease presentation and/or management across the two time intervals is suggested. In each cohort, overall cost of care was largely a function of TKI acquisition cost. 2003–2006 (nⴝ173)

2007–2009 (nⴝ130)

Total (nⴝ303)

MP NS SP

54.9% 34.7% 10.4%

36.1% 39.2% 24.6%

46.9% 36.6% 16.5%

TPS10592


TPS10591


A randomized, double-blinded, placebo-controlled, multi-institutional, cross-over, phase II.5 study of saracatinib (AZD0530), a selective Src kinase inhibitor, in patients with recurrent osteosarcoma localized to the lung. Presenting Author: Kristin Baird, National Cancer Institute, Bethesda, MD Background: Osteosarcoma is a rare cancer and 33% of patients who have completed primary treatment will recur. The Src pathway has been implicated in the metastatic behavior of several tumors including osteosarcoma where 95% of samples express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor. The recommended phase II dose in adults was found to be 175mg daily. The primary goal of this study is to determine if treatment with Saracatinib can increase progression free survival (PFS) for patients who have undergone complete resection of metastatic osteosarcoma nodules in the lung. Secondary goals are evaluation of overall survival, time to treatment failure, and evaluation of several biological correlatives. Methods: This is a multi-institutional, phase II.5, placebocontrolled study with an accrual goals of 88 randomized patients. Patients between 15 and 75 years, with histological confirmation of recurrent osteosarcoma, localized to the lung, who have potential for complete surgical resection, are eligible for enrollment. After complete resection, patients are randomized to treatment with saracatinib or placebo, of a daily oral dose of 175 mg, continuously for up to 1 year or until progression. Patients who recur in the lung while on-study and who are amenable to complete surgical resection will be un-blinded. Those patients who received placebo may have the option to undergo surgical resection. If fully resected, they will be offered therapy with saracatinib under the same treatment guidelines as above. As of January 2013, 38 patients have enrolled and 32 patients met the criteria to be randomized and began oral therapy with either saracatinib or placebo. An interim analysis is planned after 40 patients have been randomized. Clinical trial information: NCT00752206.

TPS10593


Alliance A091103: Multicenter phase II study of the angiopoietin-1 and -2 peptibody trebananib for the treatment of angiosarcoma. Presenting Author: Sandra P. D’Angelo, Memorial Sloan-Kettering Cancer Center, New York, NY

A phase II study of oral ENMD-2076 administered to patients (pts) with advanced soft tissue sarcoma (STS). Presenting Author: Herbert H. F. Loong, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada

Background: Angiosarcomas (ASs) are rare, aggressive, malignant endothelial cell tumors that constitute 1% to 2% of all soft tissue sarcomas with 5-year survival of 35%. Cytotoxic agents have demonstrated response rates of about 15%. Gene-array data from MSKCC has revealed up-regulation of endothelial associated genes, including active members of the angiopoietin system e.g., Tie2 and Angiopoietin 2 (Ang2). Trebananib (AMG386) is a novel agent that targets Ang1 and Ang2. We hypothesize that inhibition of angiopoietin 2 with trebananib will be an effective therapy in patients (pts) with AS. Methods: This CTEP sponsored, investigator initiated, multi-center phase II study uses trebananib, in pts with AS having metastatic/ unresectable AS and conducted through the Alliance for Clinical Trials in Oncology (Alliance A091103). Pts must have adequate performance status, organ function, and measurable disease (RECIST v1.1). Patients are treated with trebananib 30mg/kg d1, 8, 15, and 22 every 28 days until either progressive disease or unacceptable toxicity. The primary endpoint is objective overall response rate (ORR) via RECIST v1.1. Secondary endpoints include the evaluation of progression-free survival (PFS) and overall survival (OS). Translational objectives include correlation of ORR, PFS and OS with i. baseline and post-treatment expression of Ang2 and Tie2 by immunohistochemistry (IHC), ii. serum levels of Ang1 and Ang2, iii. baseline and post-treatment phospho-receptor tyrosine kinase (p-RTK) status of Tie2, VEGFR-2, PI3K, MEK and MAPK, and iv. mutational status of VEGFR-2 and amplification of MYC/FLT4. A Simon Optimal two-stage phase II study design is used and one confirmed response in the first 12 pts expands enrollment to 25. Pre- and post-treatment biopsies will be performed in up to 10 pts treated at MSKCC. Enrollment began in July 2012. As of January 2013, 7 pts have been recruited. Clinicaltrials.gov#: NCT01623869. Funded by the Alliance Clinical Trials in Oncology. NIH Grant CA-25224. Clinical trial information: NCT01623869.

Background: The use of angiogenic and Aurora kinase inhibitors has been shown to abrogate tumour growth in STS. ENMD-2076 is an oral Aurora A and angiogenic kinase inhibitor that has demonstrated single-agent activity in sarcoma cell lines. Prior phase I dose escalation study has determined the maximum tolerated dose of ENMD-2076 to be 160mg/m2, with a recommended starting dose of 275mg/day. In that study, one patient with STS experienced durable stable disease (21 months). Primary Objective: To determine the activity of ENMD-2076 in advanced STS (with ⱕ1 prior line of therapy) as defined by 6-month progression-free survival rate (PFSR). Secondary Objectives: (i) To determine the safety and tolerability of ENMD-2076, (ii) To determine the objective response rate (ORR) as per RECIST criteria and duration of response, (iii) To perform exploratory analysis of factors associated with survival. Study Design and Methodology: This is a single-center, open-labeled phase II study of ENMD-2076 in advanced STS. Pts are commenced on 275 mg daily dose on a 28 day cycle. Treatment-emergent adverse events will be assessed by the NCICTCAE (4.0). Radiographic or clinical tumour measurements will occur every 2 cycles. Sample Size Justification: It is assumed that ENMD-2076 shall be deemed non-efficacious in this population if the true 6- month PFSR probability is ⬍15% (p0), whilst a 6-month PFSR probability ⬎40% will be considered positive for activity. This translates to a minimum of 21 evaluable subjects required in the study, within which ⱖ6 patients need to have shown lack of progression at 6 months in order for this study to be considered positive. This design has a significance level of 10% and power of 90%. Methods: PFSR at 6-months will be estimated using the KaplanMeier method. ORR will be estimated and 2-sided 95% exact binomial confidence interval will be provided. Study Progress: At deadline for abstract submission, 3 patients have been enrolled onto this study. Clinical trial information: NCT01719744.


Sarcoma TPS10594


Alliance A091102: Phase II study of MLN8237 (alisertib) in advanced/ metastatic sarcoma. Presenting Author: Mark Andrew Dickson, Memorial Sloan-Kettering Cancer Center, New York, NY Background: Approximately 13,000 cases of soft tissue and bone are diagnosed annually in the US. Despite primary surgery many patients develop recurrent disease. Response rates to chemotherapy are low and new agents are needed. Gene array studies have shown Aurora Kinase A (AURKA) commonly overexpressed. Inhibition of AURKA by shRNA or by a specific AURKA inhibitor blocks in vitro proliferation of multiple sarcoma subtypes. MLN8237 (alisertib) is a novel and oral, ATP-competitive, selective small-molecule inhibitor of AURKA. We hypothesize that alisertib will be an effective treatment for advanced/metastatic sarcoma. Methods: This CTEP-sponsored, investigator-initiated, multi-center phase II study uses alisertib in patients with advanced/metastatic sarcoma and is conducted through the Alliance for Clinical Trials in Oncology (Alliance A091102). Patients must have adequate performance status, organ function, and measurable disease (RECIST v1.1). Patients are enrolled in one of five cohorts, depending on histology: 1) liposarcoma, 2) leiomyosarcoma, 3) undifferentiated sarcoma, 4) malignant peripheral nerve sheath tumor, or 5) other. Patients are treated with alisertib 50mg PO BID d1-d7 every 21 days until either progressive disease or unacceptable toxicity. The primary endpoint is objective overall response rate (ORR). Secondary endpoints include progression-free survival (PFS) and overall survival (OS). Translational objectives include correlation of ORR, PFS and OS with baseline and post-treatment markers of AURKA inhibition in tumor biopsies and baseline and post-treatment [F-18] FLT-PET scans. A Simon two-stage design is used for each of the 5 cohorts and one confirmed response in the first 9 patients expands enrollment in that cohort to 24. Enrollment began in December 2012. As of January 2013, 14 pts have been enrolled. Funded by the Alliance for Clinical Trials in Oncology. Clinical trial information: NCT01653028.

TPS10595


Phase I/II study of the safety, pharmacokinetics, and efficacy of pomalidomide in the treatment of Kaposi sarcoma in individuals with or without HIV. Presenting Author: Mark Niccolo Polizzotto, HIV/AIDS Malignancy Branch, CCR, National Cancer Institute, Bethesda, MD Background: Kaposi sarcoma (KS) is a multicentric angioproliferative tumor seen most frequently in people with HIV. It is caused by the gammaherpesvirus Kaposi-sarcoma associated herpesvirus (KSHV, or human herpesvirus 8) and is remarkable for its tendency to progress or regress based on host immune factors. Pomalidomide is an orally available third generation thalidomide derivative with immunomodulatory and antiangiogenic properties that may address unmet clinical needs in KS. Methods: The primary objective is to assess the safety, tolerability and pharmacokinetics of pomalidomide in subjects with KS, whether HIV associated or not, and to explore its antitumor effect at the tolerable dose once determined. This is the first assessment of this agent in patients with HIV and/or KS. Subjects with confirmed KS and no symptomatic pulmonary or visceral KS are eligible. Those with HIV must be compliant with HAART; have achieved an HIV viral load ⬍10,000 copies/mL; and in the phase II portion have KS increasing despite HAART and HIV suppression for ⱖ2months, or stable despite HAART for ⱖ3months. In the phase I portion, up to 6 subjects will be treated with pomalidomide 5mg orally daily for 21 days of a 28 day cycle. Subject to evaluation of adverse events and tolerability, this may be deescalated to 3mg orally daily 21 of 28 days in a second cohort of up to 6 subjects. If either dose proves tolerable, the study will proceed to the phase II portion, and enroll up to 15 HIV positive and 10 HIV negative subjects. Antitumor activity will be assessed using modified ACTG KS response criteria in parallel with quality of life assessment. Key correlative studies include evaluation of immune responses including T cell numbers and activation in peripheral blood and tumor tissue and KSHV specific T-cell responses; HIV and KSHV activity and associated cytokines; and the first exploration of effects of pomalidomide pharmacokinetics when administered with common antiretroviral agents. Progress: The study opened to accrual in January 2012. The phase I portion is complete with no DLTs at the dose of 5mg 21 of 28 days. Phase II has accrued 11 subjects (4 HIV negative, 7 HIV positive) at this dose. Clinical trial information: NCT01495598.


656s 11000

Tumor Biology Oral Abstract Session, Sun, 8:00 AM-11:00 AM

An analysis of ERBB2 alterations (amplifications and mutations) found by next-generation sequencing (NGS) in 2000ⴙ consecutive solid tumor (ST) patients. Presenting Author: Gary A. Palmer, Foundation Medicine, Inc., Cambridge, MA

11001


Integrating molecular profiling into cancer treatment decision making: Experience with over 35,000 cases. Presenting Author: Zoran Gatalica, Caris Life Sciences, Phoenix, AZ

Background: Testing for ERBB2 amplification by FISH and IHC is routine in breast and gastro-esophageal cancer. There are 3 approved and multiple targeted therapies in clinical trials that rely on the results of these tests. ERBB2 amplification and activation by mutation/fusion has also been described in a wide variety of other ST. As these alterations are not routinely tested for but may predict response to anti-ERBB2 agents we sought to determine their frequency in an unselected cohort of specimens from advanced ST patients. Methods: We reviewed genomic profiles from the first 2,223 formalin-fixed, paraffin-embedded specimens received and analyzed by our CLIA-certified lab (Foundation Medicine) with our NGS platform. 3,230 exons in 182 cancer-related genes and 14 genes frequently rearranged were assayed for base pair substitutions, small insertions/ deletions (indels), amplifications, and rearrangements. Results: 110/2,223 (4.9%) specimens had 116 ERBB2 alterations: 67 (58%) amplifications, 29 (25%) substitutions, 16 (14%) indels, 2 (2%) splice site variants and 2 (2%) translocations, including a potential fusion. Six samples (5%) had multiple alterations, and two had both ERBB2 substitution and amplification. 14 ST types had evidence of ERBB2 alterations including 29% of esophageal, 20% of uterine, 14% of breast, and 12% of stomach carcinomas. 6% of all lung cancer samples had ERBB2 alterations. Amplifications predominated, but lung specimens had predominantly indels. Durable responses exist to anti-ERBB2 agents in STs with activating ERBB2 mutations. Conclusions: Use of a broad NGS panel identifies an unprecedented number of actionable genomic changes including a significant rate of ERBB2 alterations across 14 different solid tumor types. The discovery of unanticipated ERBB2 amplifications and activating mutations in a wide variety of ST highlights the need to study a broad range of genes at a high level of sensitivity and specificity when searching for novel targets of therapy. Widespread use of this approach could provide more treatment options and enable more rapid accrual to ongoing and planned trials of agents targeting pathways under study.

Background: Molecular profiling of both common and rare cancer types provides for the identification of actionable targets for chemotherapy with many unexpected associations. Methods: Caris Life Sciences database of ⬎35,000 profiled cancers was reviewed for well-established driver gene mutations and copy number alterations, and protein expression patterns that are relevant for selection of targeted therapy. Based on the published literature, these tumor characteristics were then associated with potential benefit or no benefit to the specific therapeutic agents. All relevant published studies were evaluated using the USPSTF grading scheme for study design and validity. Assay methodologies included sequencing (Sanger, pyrosequencing), PCR, FISH, CISH, and immunohistochemistry. Results: All common malignancies (10 most common cancer types in men and women) and 10 rare cancer types were well represented (minimum of 100 cases in each individual cancer type). Well established driver mutations and protein expression in common cancers were all identified with expected frequencies (e.g. HER2 amplification in breast, PIK3CA mutations in ER⫹ breast cancer, EGFR mutations in NSCLC, etc.). Importantly, unexpected new and potentially actionable targets were identified in common (e.g., 6.7% HER2 amplification in NSCLC, 1.6% KRAS mutation in prostatic adenocarcinoma) and rare cancers (e.g., 8.3% ALK alteration in soft tissue sarcomas, 10.5% c-MET and 26.4% EGFR gene amplification in melanomas, 16.3% KRAS mutation in cholangiocarcinomas, 10% AR expression in STS), as well in cancers of unknown primary site (approximately 4% of all tested cases). Conclusions: This review of the large referral cancer profiling database provided an unparalleled insight in the distribution of common and rare genetic and protein alterations with direct and potential treatment implications. Numerous targets were discovered that had a potential to be treated by the conventional chemotherapy as well as targeted therapy not usually considered for the cancer type. Comparison between an individual patient tumor profile and database for the matched cancer type provides additional level of support for targeted treatment choices.

11002

11003


Princess Margaret Cancer Centre (PMCC) Integrated Molecular Profiling in Advanced Cancers Trial (IMPACT) using genotyping and targeted nextgeneration sequencing (NGS). Presenting Author: Philippe L. Bedard, Princess Margaret Cancer Center, University Health Network, Division of Medical Oncology & Hematology, Department of Medicine, University of Toronto, Toronto, ON, Canada Background: IMPACT is an institution-wide screening program to identify patients (pts) treated at PMCC with somatic alterations that can be matched to targeted therapies. Methods: Pts with advanced breast, colorectal (CRC), non-small cell lung (NSCLC), ovarian cancers and selected other solid tumors treated at PMCC were eligible. Tumor DNA was isolated from a FFPE archived sample and genotyped using a customized Sequenom panel (23 genes, 280 mutations) in a CLIA-certified laboratory. Verified mutations were reported in pts electronic health records. Selected FFPE samples were further characterized by NGS with the Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons, ⱖ500x coverage) for platform validation. Results: From Mar 1/12-Jan 10/13, 485 pts were enrolled with median 1 prior treatment for advanced disease (range 0-6). Of 33 (7%) screen failures, 5% were for insufficient tissue and 2% for clinical deterioration. Median DNA quantity from FFPE ⫽ 4250ng (range 15-32550ng). The median time from tissue receipt to reporting was 5 weeks (range 1-23). Mutations were identified by Sequenom in 137/349 (39%) pts, including 24/79 (30%) breast, 40/80 (50%) CRC, 54/88 (61%) NSCLC, 17/78 (22%) ovarian, and 2/24 (8%) other cancers. Mutations detected were: 76 KRAS, 35 PIK3CA, 22 EGFR, 5 NRAS, 5 ERBB2, 5 CTNNB1, 4 BRAF, and 1 AKT1. MiSeq was concordant with Sequenom in 112/113 (99%) pts, with mutations identified in 94/114 (82%). The average number of mutations detected by MiSeq was 1.72/pt (range 0-7) compared with 0.49/pt by Sequenom (range 0-2). After a median follow up of 5.0 months, 31/137 (23%) pts with mutations have been matched to targeted therapies, including 14 pts enrolled in clinical trials (15 trials) matched to their genotype. Of the 10 trial pts with at least one response assessment, 3 PR (1 confirmed) and 2 SD ⱖ 24 weeks have been observed. Conclusions: Molecular profiling can be integrated into the routine care of advanced cancer pts. Genotyping and targeted NGS are feasible in a clinical laboratory using stored archival FFPE tumor samples. NGS identifies additional actionable mutations to inform clinical-decision making. Clinical trial information: NCT01505400.


Use of mutational profiling of metastatic ERⴙ/HER2- breast cancers and the coexistence of KRAS, MET, BRAF, and FGFR3 with PIK3CA mutations. Presenting Author: Debora Fumagalli, Jules Bordet Institute, Breast Cancer Translational Research Laboratory, Brussels, Belgium Background: ER⫹/HER2- breast cancers (BCs) constitute the most frequent BC subtype. Their response to endocrine therapy and degree of estrogen dependence are heterogeneous. There is little data available about the genetic changes associated with disease progression in this subtype. This information could facilitate drug development. Methods: A series of 132 ER⫹/HER2- BC patients diagnosed between 1982 and 2008, with known local-regional (n⫽10) or distant (n⫽98) relapse or both (n⫽24), and available FFPE blocks from their primary (P; n⫽132) and paired relapse (R; n⫽49) were identified at a single institution. ER and HER2 status were centrally confirmed. 120 mutations from 11 actionable genes and PTEN protein expression were determined using Fluidigm-based real-time PCR and IHC, respectively. Results: At primary diagnosis, median age was 57 years (27-90); median tumor size 2.5 cm (0.5-11); 75% had positive nodes, 26.5% were pre-menopausal; 80% received adjuvant hormonal treatment. Mutation frequency in P and R samples is presented in the Table. PIK3CA mutations were identified in 44% (58/132) P samples. HRAS, AKT1 and PIK3CA mutations were mutually exclusive. 62.5% (5/8) of KRAS-mutated, 75% (6/8) of MET-mutated, 100% (2/2) of BRAFmutated and 33.3% (1/3) of FGFR3-mutated P had coexistent PIK3CA mutations. For the 49 evaluated pairs, high concordance for the mutations status was found between P and R. Conclusions: KRAS, BRAF, MET and FGFR3 mutations, found at relatively high frequency in this population of relapsed ER⫹/HER2- BCs, could represent clinically relevant targets and contribute to mechanisms of recurrence, particularly in PIK3CA-mutated BCs. Mutation profiling of additional paired samples is ongoing and clinical outcome data will be presented. % AKT1 % BRAF % PIK3CA % NRAS % KRAS % EGFR % FGFR3 % FLT3 % HRAS % KIT % MET %PTEN loss All P (132) Matched P (49) R (49)

6.1 6.1 6.1

1.5 0 0

44 34.7 36.7

0 0 0

6.2 8.5 6.1

0 0 0

2.4 0 0

0 0 0

1.5 2 2.2

0 0 0

6.1 6.1 6.1

4.6 8.1 2.1


Tumor Biology 11004


11005


Concurrent driver mutations in non-small cell lung cancer (NSCLC) patients (p) on targeted therapy uncovered by comprehensive molecular profiling. Presenting Author: Collin M. Blakely, University of California, San Francisco, San Francisco, CA

Amplification of the MET receptor to drive resistance to anti-EGFR therapies in colorectal cancer. Presenting Author: Alberto Bardelli, Laboratory of Molecular Genetics - IRCC Institute for Cancer Research and Treatment at Candiolo, Candiolo, Italy

Background: NSCLC p with EGFR mutations respond initially to EGFR tyrosine kinase inhibitors (TKIs) but invariably develop acquired EGFR TKI resistance. Prior studies identified the EGFR T790M mutation and activation of MET, PI3K, AXL, HER2 and the MAPK pathway as drivers of acquired EGFR TKI resistance. To date, comprehensive molecular profiling to identify actionable modifiers of EGFR TKI response has not been conducted in NSCLC p on therapy. Methods: We performed next generation sequencing (NGS) using a 263-gene Nimblegen custom cancer panel on DNA isolated from primary patient lung adenocarcinoma FFPE specimens prior to initiating standard erlotinib treatment and upon the development of acquired erlotinib resistance after only 3 months of therapy. Results: In the pretreatment sample, we confirmed the presence of the EGFRL858R mutation in 95% of the sequencing reads and discovered a concurrent BRAF V600E mutation with a frequency of ~ 6%. NGS performed on the acquired erlotinib resistance sample revealed acquisition of the EGFR T790M mutation with a frequency of ~ 14%. Notably, the frequency of the BRAF V600E mutation increased 10-fold upon acquired erlotinib resistance from ~ 6% in the pretreatment tumor to ~ 60% in the recurrent tumor. We found that overexpression of BRAF V600E in H3255 human NSCLC, which harbor EGFR L858R (but not BRAF V600E) and are erlotinib sensitive, caused resistance to erlotinib treatment (10-fold increase in erlotinib IC50). BRAF V600E-mediated erlotinib resistance was reversed by treatment with the BRAF inhibitor vemurafenib. Additional functional studies are ongoing and the complete dataset will be presented. Conclusions: These results indicate that EGFR-mutant NSCLC can harbor additional oncogenic driver mutations in BRAF at low frequencies prior to therapy. EGFR TKI treatment can lead to expansion of BRAF V600E expressing tumor cells, resulting in acquired EGFR TKI resistance that can be reversed by BRAF inhibitor treatment. The data demonstrate the utility of routine molecular profiling of NSCLC p on targeted therapy and offer unprecedented insight into the genetic basis of therapeutic resistance.

Background: The anti EGFR monoclonal antibodies cetuximab and panitumumab are used to treat metastatic colorectal cancer patients but their clinical efficacy is limited by the development of acquired resistance. We recently reported that secondary KRAS mutations are responsible for acquired resistance in approximately 50% of the patients who initially respond to cetuximab or panitumumab (Misale et al., Nature 2012; Diaz et al., Nature 2012). Here we studied the molecular bases of relapse in CRC patients who do not develop KRAS mutations during the course of anti-EGFR therapy. Methods: Next generation sequencing was applied to tumor biopsies to identify genetic alterations associated with relapse to cetuximab and panitumumab in mCRC patients. Detection and quantitation of genetic alterations in circulating tumor DNA was used to monitor the occurrence of KRAS mutations and MET amplification in blood samples. Results: Molecular analyses of tumor biopsies from patients who did not develop KRAS mutations during anti-EGFR therapy revealed high level of amplification of the MET proto-oncogene in 3/5 cases. Quantitative PCR, FISH and IHC analysis confirmed high level of MET amplification in the post-therapy samples but not in the matched pre-treatment tissues. We developed a PCR based assay to detect the presence of the MET amplicon in circulating, cell-free, DNA. We found that MET amplification could be detected in the blood as early as 3 months after initiation of anti EGFR therapy. To functionally evaluate the role of MET amplification on resistance to anti EGFR antibody therapies we exploited patient-derived CRC xenografts (‘xenopatients). We found that (2/2) xenopatients established from MET amplified tumors were completely refractory to cetuximab but showed sensitivity to the Met inhibitor crizotinib. Conclusions: Amplification of the MET proto-oncogene is responsible for acquired acquired resistance to anti-EGFR antibody therapy in a subset of CRCs. The emergence of MET amplification in circulating, cell-free, DNA may be used to select patients most likely to benefit from anti MET therapies.

11006

11007


Development and validation of an immuno-PET tracer for patient stratification and therapy monitoring of antibody-drug conjugate therapy. Presenting Author: Ohad Ilovich, Stanford University, Palo Alto, CA Background: SAR566658 is an antibody-drug immunoconjugate consisting of a humanized monoclonal antibody (huDS6) against the tumorassociated MUC1-sialoglycotope, CA6, conjugated to a cytotoxic maytansinoid (DM4). SAR566658 is currently undergoing phase I clinical trials in patients with CA6-positive solid tumors. A companion diagnostic based on huDS6 may facilitate patient stratification and early evaluation of therapeutic efficacy. The present study describes the development and preclinical evaluation of three novel Copper-64 (t½⫽ 12.7h) labeled antibody fragments (two Fabs and a diabody) derived from the huDS6 antibody. One fragment was chosen based on imaging figures of merit for further specificity evaluations. Methods: The affinity of all fragments and their DOTA conjugates to CA6 was validated using flow cytometry. The DOTA conjugates were labeled with Copper-64 and evaluated in human serum stability studies, in vivo small animal PET imaging and 24-hour biodistribution studies in nude mice bearing either CA6 positive (WISH) or CA6 negative (A2780) subcutaneous tumors. The specificity of the lead tracer was evaluated in vivo via blocking studies and isotype controls. Results: All fragments and their DOTA conjugates had high affinity (Kd ⫽ 4-20 nM) for WISH cells. 64Cu-DOTA-B-Fab gave superior results in radio-synthesis (RCY - 60%, SA - 55 GBq/␮mole, ⬎99% purity), serum stability (94⫾5%, n⫽3) and biodistribution profile. Its two isotype controls gave statistically significant (P⬍0.05) uptake values in WISH but not A2780 tumors (see table). Blocking with B-Fab or huDS6 prior to tracer administration afforded a 23% (p⬍0.05, n⫽8) and 26% (p⬍0.05, n⫽7) decrease in WISH tumor uptake, respectively. Conclusions: These preclinical studies suggest that 64Cu-DOTA-B-Fab may be a suitable companion diagnostic for SAR566658 in cancer patients and requires further investigation.

64

Cu-DOTA-B-Fab Cu-DOTA-anti lyzosyme-B-Fab 64 Cu-DOTA-antiDM4-B-Fab 64

WISH tumor (%ID/g)

A2780 tumor (%ID/g)

WISH/ A2780 ratio

Liver (%ID/g)

Kidneys (%ID/g)

7.6⫾0.87 4.84⫾1.02

5.1⫾0.92 3.84⫾0.49

1.5 1.26

10⫾0.75 15.2⫾1.3

62⫾4 70⫾9.6

4.04⫾0.43

3.03⫾0.24

1.33

10.4⫾1.6

52⫾8.3


Prognostic relevance at 5 years of the early monitoring of neoadjuvant chemotherapy using FDG PET in luminal HER2-negative breast cancer. Presenting Author: Olivier Humbert, Centre Georges François Leclerc, Dijon, France Background: To evaluate, in the luminal breast cancer subtype, the prognostic value of tumor glucose metabolism at baseline and of its changes after one cycle of neoadjuvant chemotherapy (NAC). Methods: This prospective study included 61 women with immunophenotypically defined luminal HER2-negative breast cancer treated with NAC. 18F-FDG PET was performed at baseline. Hepatic activity was used as a reference to distinguish between low-metabolic and hypermetabolic tumors. In hypermetabolic tumors, a PET exam was repeated after the first course of NAC. The relative change in the maximal Standardized Uptake Value of the tumor (⌬SUV), corresponding to the metabolic response, was calculated. Results: Forty-two women had hypermetabolic tumors at baseline, corresponding to more proliferative breast cancers with higher Ki-67 expression (p⫽0.017) and higher grade (p⫽0.04). Nineteen women had low-metabolic tumors with lower proliferation indexes. Worse overall survival was associated with larger tumor size (⬎5cm, HR⫽6.52, P⫽0.009) and with hypermetabolic tumors achieving a low metabolic response after one cycle of NAC (⌬SUV⬍16%, HR⫽10.63, P⫽0.004). Five-year overall survival in these poor-response patients was 49.22% (95% CI⫽[14.76%-76.90%]). In contrast, overall survival in women with low-metabolic tumors or hypermetabolic/good-response tumors (⌬SUVⱖ16%) was good, 100% and 96.15%, respectively (95% CI⫽[75.69%-99.45%]). Conclusions: In luminal HER2negative breast tumors, tumor metabolism at baseline and changes after the first course of NAC are surrogate markers of patients’ survival. A subgroup of women with hypermetabolic/bad-responding tumors correlated with poor prognosis can be identified. These results may create the ability to tailor the NAC regimen to the metabolic response at an early stage.


658s 11008

Tumor Biology Oral Abstract Session, Sun, 8:00 AM-11:00 AM

Early PET/CT scan compared with RECIST to predict long-term outcome of patients with liver metastases from colorectal cancer treated with preoperative chemotherapy plus bevacizumab. Presenting Author: Maria Carmela Piccirillo, Clinical Trials Unit, National Cancer Institute, Napoli, Italy

11009


The genetic landscape of clinical resistance to RAF inhibition in melanoma. Presenting Author: Eliezer Mendel Van Allen, Dana-Farber Cancer Institute, Boston, MA

Background: Early changes in tumor metabolism measured with positronemission-tomography/computerized tomography (PET/CT) could predict the long-term efficacy of treatment better than dimensional RECIST response. Methods: We performed PET/CT before and after 1 cycle of treatment in patients with resectable liver metastases from colorectal cancer, within a phase II trial of preoperative FOLFIRI plus bevacizumab. For each lesion, the maximum SUV (SUVmax) and the total lesion glycolisis (TLG) were determined. For both, based on previous studies, a ⱕ-50% change from baseline was used as threshold for significant response. Metabolic response was categorized no/yes by using three different methods that enter into the calculation (i) the largest observed value (highest SUVmax/TLG), or (ii) the sum of all the observed values (Total SUVmax/ TLG), or (iii) each observed values (SUVmax/TLG-by-lesion). Standard RECIST response was assessed after 3 months of treatment. The association between metabolic and RECIST response was tested with the Mc Nemar’s test and their agreement was expressed as Kappa statistics; the ability to predict progression-free (PFS) and overall (OS) survival was tested with Log-rank test and a multivariable Cox model. Results: 33 patients were analyzed. After treatment, there was a notable decrease of all PET/CT parameters, with a median change of -33.9% for the highest SUVmax, -61.5% for the highest TLG, -34.9% for the total SUVmax, and -65.5% for the total TLG. The association of SUV-based metabolic response (but not the TLG-based) with RECIST was statistically significant. However, the agreement between RECIST and PET/CT responses was consistently small. PFS and OS were significantly longer among PET/CT responding patients, whichever the measure used. On the contrary, no significant outcome difference was evident according to RECIST response. Conclusions: Early PET/CT response was significantly predictive of long-term outcomes during preoperative treatment of patients with liver metastases from colorectal cancer and its predictive ability was higher than that of RECIST response. Clinical trial information: 2006-006572-38.

Background: Although single-agent RAF inhibition has proved effective in metastatic BRAFV600-mutant melanoma, most patients relapse and some are intrinsically resistant. While several genetic resistance effectors have been identified, a comprehensive assessment of the genetic resistance spectrum in a large patient cohort may further inform resistance patterns and treatment strategies. Methods: Pre-treatment and post-relapse biopsies were obtained from BRAFV600melanoma patients treated with vemurafenib or dabrafenib. Whole exome sequencing of tumor and normal samples was performed to identify exome-wide mutations, insertion/deletions, and chromosomal copy number alterations. Since somatic allelic fraction comparisons across treatment time points must account for variable stromal admixture between biopsies, novel algorithms were applied to impute purity and tumor cell ploidy, thus determining the “cancer cell fraction” (CCF) of each alteration. Those with enriched CCF in post-relapse samples were nominated as potential resistance effectors. Results: 30 patients (towards a goal of 77) were sequenced to a mean depth of 145-fold coverage. In acquired resistance patients (on drug ⱖ 12 weeks, n⫽18), NRAS Q61R (28%) and BRAF amplifications (6%) were observed. The remaining patients had multiple clonally enriched alterations in the post-relapse tumors that may drive resistance, including MEK1 mutations at residues previously noted in an in vitro mutagenesis screen for vemurafenib resistance. In the intrinsic resistance cohort (on drug ⬍ 12 weeks, n⫽12), multiple putative resistance mutations not previously observed in the setting of acquired resistance were identified. Conclusions: In addition to reported genetic resistance mechanisms, we identified new MEK1 mutations in resistant samples. For the majority of patients (67%) without events in these genes, computational algorithms identified new candidate drivers of RAF inhibitor resistance. Alterations that predict intrinsic or acquired resistance may also inform new approaches to melanoma therapy. Future studies incorporating longitudinal biopsies and genetic profiling will underpin a robust assessment of clinical resistance in melanoma and other cancers.

11010

11011


Integrated genomic analysis by whole exome and transcriptome sequencing of tumor samples from EGFR-mutant non-small-cell lung cancer (NSCLC) patients (p) with acquired resistance to erlotinib. Presenting Author: Jonathan S. Weissman, University of California, San Francisco, Howard Hughes Medical Institute, Cancer Therapeutics Innovation Group, San Francisco, CA Background: NSCLC p with EGFR mutations initially respond to EGFR tyrosine kinase inhibitors (TKIs) but ultimately relapse. Sub-genomic molecular studies indicate that the EGFR T790M mutation and the activation of MET, PI3K, AXL, HER2 and MAPK can lead to acquired resistance to EGFR TKIs. To date, no integrated comprehensive genomic investigation of EGFR TKI resistance has been performed. Methods: FFPE biopsies of erlotinib-sensitive and erlotinib-resistant tumors were obtained from 11 EGFR mutant NSCLC p. DNA was extracted from all tumor and corresponding normal tissue samples and underwent whole exome sequencing using the Illumina HiSeq2500. RNA was extracted from all tumor samples and analyzed by whole transcriptome sequencing, also using the Illumina HiSeq2500. Results: Erlotinib resistant NSCLC specimens harbored upregulation of known resistance drivers including MET and AXL and novel alterations including upregulation of genes that are: 1) recurrently mutated in NSCLC, including ALK, STK11; 2) components of established embryonic stem cell signatures, including targets of Nanog, Oct4, Sox2, c-Myc, 3) neuronal lineage specific regulators, including NTRK3, NRCAM, ALK, LRP4. The analysis also revealed downregulation of several genes that are: 1) components of innate and acquired immunity, including HLA-A, -B, DQ, CD40; 2) phosphatases regulating survival signaling pathways, including PTEN, PTPRD, 3) proapoptotic components, including BNIP3L, IKIP. Conclusions: This study demonstrated the feasibility and utility of comprehensive genomic analysis in the clinical management of NSCLC p receiving targeted therapy. We identified known and novel molecular biomarkers of erlotinib acquired resistance in NSCLC p, and uncovered a previously unappreciated role for genetic events governing stem cell and neuronal phenotypes as well as immune evasion in erlotinib acquired resistance in NSCLC p. Together, our data provide unprecedented insight into the molecular pathogenesis of escape from EGFR oncogene inhibition in NSCLC. We are now conducting a prospective observational study in additional NSCLC p.


Tumor markers of efficacy and resistance to cetuximab (C) treatment in metastatic colorectal cancer (mCRC): Results from CALGB 80203 (Alliance). Presenting Author: Herbert Hurwitz, Duke University Medical Center, Durham, NC Background: Beyond KRAS status, there are no validated markers for anti-EGFR therapy in mCRC. While expression of genes within the EGF signaling axis has been reported to correlate with benefit, most reports used data from non-randomized trials which cannot distinguish between general prognostic markers and markers that predict for benefit from C. CALGB 80203 was a 238-patient (pt), 4-arm, randomized phase II study of FOLFOX or FOLFIRI ⫹/- C in mCRC pts. Formalin-fixed, paraffin-embedded (FFPE) tumor samples from CALGB 80203 were analyzed for gene expression of HER family ligands, receptors and regulators. Methods: FFPE tumor samples from consenting pts were analyzed for AREG, BTC, CD73, DUSP4, EGF, EGFR, EPGN, EREG, HB-EGF, HER2, HER3, HER4, PHLDA1 and TGFa by RT-qPCR. Interaction between baseline gene expression levels and treatment (C) with respect to progression-free survival (PFS) and overall survival (OS) was modeled using a multiplicative Cox proportional hazards model. Results: Baseline tumor tissue was available from 103 pts; 55% of tumors were KRAS wild type (WT). Two prognostic markers were identified; higher tumor mRNA levels of HER2 (HR⫽0.64, p⫽0.002) and EREG (HR⫽0.89, p⫽0.016) were associated with longer PFS across all pts. Potential predictive markers of benefit for C were identified. In KRAS WT tumors, lower HER3 expression was associated with longer OS from C treatment while higher HER3 expression was associated with shorter OS from C treatment (chemo ⫹ C: HR⫽1.15; chemo only: HR⫽0.48, interaction p⫽0.029). No association was observed for HER3 and outcome in KRAS mutant (MT) tumors. Interestingly, higher CD73 expression was associated with longer PFS in C-treated pts in both KRASWT (chemo ⫹ C: HR⫽0.91; chemo only: HR⫽1.57, interaction p⫽0.026) and MT tumors (chemo ⫹ C: HR⫽0.80; chemo only: HR⫽1.29, p⫽0.025). Conclusions: In one of the first reports using data from a randomized study, gene expression of HER3 and CD73 were identified as potential predictive markers for C. These data implicate not only HER axis signaling but also immune modulation as potential mechanisms of C action and sensitivity, and warrant confirmation in other large randomized trials.


Tumor Biology 11012


Prognostic impact of changes in circulating tumor cells (CTC) in metastatic breast cancer (MBC). Presenting Author: Markus Wallwiener, Department of Obstetrics and Gynaecology, University of Heidelberg, Heidelberg, Germany

11013

659s Poster Discussion Session (Board #2), Mon, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

Cell-free DNA copy number variations as a marker for breast cancer in a large study cohort. Presenting Author: Julia Beck, Chronix Biomedical, Göttingen, Germany

Background: To prospectively assess the prognostic value of CTC counts at baseline and after one cycle of therapy and their kinetics for response, progression-free (PFS), and overall survival (OS) in MBC. Methods: MBC patients underwent CTC enumeration (CellSearch, Veridex) at baseline (CTCBL), after one cycle of a new line of therapy (CTC1C), and at progression (CTCPD). CTC status was classified as negative (neg (⫺)) or positive (pos (⫹)) for ⬍5 and ⱖ5 CTC/7.5 ml peripheral blood, respectively. CTC kinetics (CTCKIN) from CTCBL to CTC1C were classified as favorable if CTCs remained neg (neg⬎neg) or became neg (pos⬎neg), or as unfavorable (neg⬎pos or pos⬎pos). Tumor response was assessed every 2–3 months using RECIST criteria. CTC status and kinetics were associated with outcome using log-rank and Fisher’s exact tests. Results: Of 326 patients enrolled (median age (range) at first diagnosis: 50 (23– 81) years), 115/326 (35%) were CTCBL⫹, 51/162 (31%) were CTC1C⫹, and 39/108 (36%) were CTCPD⫹. Median follow-up was 15.9 months (mos). Median PFS and OS were significantly reduced in CTCBL⫹ compared to CTCBL⫺ patients (PFS, 4.3 vs. 7.1 mos, p ⫽ .019; OS, 15.0 mos vs. not reached (nr), p ⬍.001) and for CTC1C⫹ compared to CTC1C⫺ patients (p ⬍.001 for PFS and OS). CTCKIN were predictive of progressive disease as best response (neg⬎neg, 33%; pos⬎neg, 38%; pos⬎pos, 60%; neg⬎pos, 75%; p ⫽ .040). PFS and OS for patients with unfavorable CTCKIN were significantly shorter than for favorable CTCKIN (PFS, 3.7 vs. 6.8 mos, p ⬍.001; OS, 7.8 mos vs. nr, p ⬍.001). Conclusions: CTC at baseline, CTC after one cycle and CTC kinetics are highly predictive of outcome in MBC. Serial CTC enumeration could serve as a useful adjunct to standard diagnostic tests in tailoring therapy. Further details of CTCPD will be presented at the meeting. Clinical trial information: S-295/2009.

Background: Massive parallel sequencing provides high numbers of cellfree nucleic acid serum DNA sequences (cfDNA) that can detect trace amounts of tumor derived chromosomal imbalances and copy number variations (CNVs) in patients with cancer. The aim of this study was to determine if there is a difference between the cfDNA CNVs from patients with breast cancer (BrCa) compared to healthy controls. Methods: DNA extracted from serum samples of 225 BrCa (Stage 1 to 4) and 205 gender and age-matched healthy controls (HC) was amplified using random primers, tagged with a unique molecular identifier per sample, sequenced on an Illumina HiSeq system and aligned to the human genome (Build 37). Hits were counted in sliding 1Mbp interval regions and normalized. Using a Random-Resampling procedure, a model was established to distinguish BrCa from HC using the copy number variations (CNV) and cross validated. Results: From 1,100 rounds of random resampling (50/50), a set of 31 regions was selected, based on the frequency of occurrence in the models. Using 20 random sets of a 10-fold cross validation, the selected regions were found to be highly significant discriminators between BrCa and HC (p⬍10-5). When using a final linear model with 16 regions the AUC of a diagnostic ROC curve was found to be 0.895 for all samples, for Stage I and II the AUC was 0.86 compared to 0.93 for the higher stages. The final model included three regions from chromosome 8 and 1 and two regions from chromosome 15, the remaining regions were found as one per chromosome. Conclusions: Using comparative massive parallel sequencing of cfDNA from cancer patients vs. controls, we were able to show that a 16-region model based on CNV, is useful to distinguish patients with breast cancer from matched controls. Genomic instabilities that are shed into the circulation from breast cancer may play a role in screening, monitoring or as companion diagnostic tests in breast cancer.

11015

11016


Massively parallel sequencing (MPS) of circulating DNA in patients with metastatic colorectal cancer (mCRC): Prognostic significance and early changes during chemotherapy (CT). Presenting Author: Jeanne Tie, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia Background: Prognostic and predictive biomarkers in mCRC are urgently needed. Circulating tumor cells are a promising blood biomarker, but are detectable in only a minority of pts. Recently, analysis of circulating tumor DNA (ctDNA) has shown promise as a liquid biopsy, reflecting the evolving mutational status of the tumor. Here we explored baseline ctDNA as a prognostic marker, and early changes in ctDNA as a marker of CT response. Methods: Serial plasma samples and CEA were collected at baseline (D1), day 3 (D3) and cycle 2 day 1 (C2D1) from 40 mCRC pts receiving standard combination CT. Restaging scans performed at 8 weeks were centrally assessed using RECIST criteria. Samples were analyzed at Johns Hopkins Kimmel Cancer Center. Initially tumor tissue was analyzed for hotspot mutations in TP53, APC, KRAS, BRAF, PIK3CA and FBXW7. The same mutation was queried and quantified in plasma using a MPS platform (Safe-SeqS). Log-rank test was used to compare survival curves and Wilcoxon matched pairs test was used to compare paired plasma samples. Results: Preliminary data is available on 19 pts in this ongoing study. Using our initial panel at least 1 mutation was found in 16 of 19 (84.2%) tumors (7 KRAS, 3 TP53, 3 BRAF, 2 APC and 1 PIK3CA), with matching ctDNA found for each pt. For the remaining 3 cases a further panel of mutations is being analyzed. Median D1 cell free DNA (cfDNA) and ctDNA levels were 1.98 ng/ul (0.15 – 57.18) and 523 mutant fragments (frag)/ml (0.4 – 109,876), respectively. Pts with D1 cfDNA of ⱖ 2.5 compared with ⬍ 2.5 had shorter median overall survival (OS; 6.9 v 12.2 months, p ⫽ 0.0086), with a trend for shorter progression-free survival (PFS; 3.6 v 8.2 months, p ⫽ 0.3477). A surge of ctDNA level from D1 to D3 was typically observed (median increase: 91.2 frag/ml, p ⫽ 0.0313), followed by a drop (median decrease from D1 to C2D1: 208.8 frag/ml, p ⫽ 0.0098). All pts with a decrease in ctDNA at C2D1 had a reduction in tumor size at 8 weeks. Conclusions: In all cases of mCRC where tumor mutation was identified, matching ctDNA was detected in plasma. Circulating DNA is a promising marker of prognosis. Early changes in DNA levels may be a useful marker of tumor response.


Real-time clinical application of next-generation sequencing (NGS): Results from a multicenter program. Presenting Author: Aaron Richard Hansen, Princess Margaret Cancer Center, University Health Network, Division of Medical Oncology & Hematology, Department of Medicine, University of Toronto, Toronto, ON, Canada Background: NGS techniques enable the identification of actionable mutations in clinical tumor samples. The objective of this study is to assess feasibility and explore the impact of real-time targeted NGS on therapeutic decision-making. Methods: Patients (pts) with advanced solid tumors underwent a biopsy of a metastatic lesion. The first phase was performed with Sequenom MassARRAY somatic genotyping and Pacific Biosciences RS-targeted NGS. The second phase broadened genomic coverage in both Sequenom and Illumina MiSeq. All pts had a molecular profiling (mp) report issued after identified actionable mutations were verified by Sanger sequencing in a CLIA-lab and reviewed by an expert panel. “Actionability” was defined as having prognostic, predictive or diagnostic implications on patient management. Details of clinical outcomes and subsequent matched therapy, if applicable, were captured. Referring physicians were surveyed on the impact of mutation results on their treatment recommendations. Results: These are summarized in the Table. Conclusions: Broader mp platforms resulted in more identified actionable mutations which required a longer time for verification prior to reporting, but may yield a greater impact on clinical decision-making. However, the matching of pts to drugs based on their molecular profiles depends highly on drug access. For mp to be clinically relevant, it must be coupled with access to approved drugs or to investigational agents on clinical trials. Clinical trial information: NCT01345513. Elements

Phase I

Phase II

Platforms

Sequenom 19 genes, 238 mutations PacBio 19 genes, 63 amplicons 89 enrolled, all profiled

Sequenom 23 genes, 280 mutations MiSeq 54 genes, 660 amplicons 56 enrolled, 49 profiled

25 to 80 yrs (54yrs) 37% 20 days

28 to 85 yrs (58 yrs) 55% 29 days

41 in 33 patients: 1 AKT, 1 BRAF, 1 CDK4, 5 EGFR, 3 KIT, 16 KRAS, 11 PIK3CA, 1 NRAS, 1 HRAS, 1 PDGFR 46/51 pairs (90%)

35 in 27 patients: 1 APC, 2 BRAF, 1 CDH1, 2 EGFR, 1 ERBB2, 13 KRAS, 2 PIK3CA, 1 PTEN, 12 TP53

10/33 (30%) 3 PRs, 2 SD 19/89 pts (21%)

3/27 (11%) 1 SD 12/49 pts (24%)

No. of pts Age range (median) % with actionable mutations Time from consent to report (median) Verified mutations

Fresh and archival mutation concordance Matched treatment Treatment impacted

11/17 pairs (65%)


660s 11017

Tumor Biology Poster Discussion Session (Board #6), Mon, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

11018


A survey of thousands of tumor exomes and transcriptomes to expand clinical opportunities for crizotinib. Presenting Author: Emma Bowden, Compendia Bioscience, Ann Arbor, MI

Fusion transcript discovery in formalin-fixed paraffin-embedded human breast cancer tissues and its relation to tumor progression. Presenting Author: Yan Ma, Genomic Health, Inc., Redwood City, CA

Background: Cancer driver events occur as a result of chromosomal rearrangements. There are several examples where targeted inhibition of the resulting fusion produces dramatic clinical response. For example, the EML4-ALK fusion in non-small cell lung cancer (NSCLC). Other ALK fusions have been described in NSCLC and other diseases including the NPM-ALK fusion in anaplastic large cell lymphoma (ALCL). The efficacy of crizotinib and other ALK inhibitors are being investigated in these diseases. ALK is also subject to activation via mutation and sensitivity to crizotinib is reported in ALK mutation positive neuroblastoma. Finally, crizotinib has activity not only against ALK, but also against ROS1, MST1R and MET. ROS1 fusions have been found in NSCLC and glioblastoma, and MET amplification events in gastric adenocarcinoma identify additional settings that may benefit from crizotinib treatment. Methods: To further understand the full therapeutic potential of Crizotinib, we undertook a genomic survey of ALK, ROS1, MET and MST1R across 1,000’s of patients from the The Cancer Genome Atlas (TCGA) and Oncomine. Results: We confirmed the presence of EML4-ALK fusions in both lung and colorectal cancer (CRC), and also identified a novel ALK fusion in CRC. ALK hotspot mutations and focal amplifications were confined to neuroblastoma, as previously described. Our survey of ROS1 identified rare novel fusions in NSCLC and glioblastoma, and high-level amplifications in liposarcoma (2%) and rarely in breast cancer (0.2%). No fusions were identified for MET, however high-level amplifications were observed in 1-5% of papillary renal cell carcinoma, the intestinal subtype of gastric adenocarcinoma, oliogodendroglioma, glioblastoma and lung adenocarcinoma. Hotspot mutations were frequently observed in squamous head and neck (11%), and more rarely in hepatocellular carcinoma, small cell lung and ovarian cancers. Conclusions: These results leverage all available genomic profiling data to provide a broadened scope of therapeutic opportunity for inhibitors like crizotinib. With the growing availability of next-generation sequencing, such surveys can support hypothesis-driven development of targeted therapies.

Background: While several recently discovered gene fusions already play an important role in personalized cancer treatment, many cancer gene fusions remain to be discovered. Next generation sequencing has enabled identification of many rare gene fusion events in fresh or frozen solid tumors. There is a need to detect gene fusions in transcriptomes of formalin-fixed paraffin-embedded (FFPE) tumor tissue, for which there is long-term clinical outcome data. We therefore sought to develop bioinformatics methods to detect fusion transcripts in FFPE tissue and to characterize their association with clinical outcomes. Methods: RNA sequencing libraries were created and sequenced from tumor biopsy tissues (Plos One 2012 7(7): e40092) of two ER⫹ breast cancer cohorts consisting of 136 and 77 patients, for which clinical outcomes were available. The fusion junctions were nominated by the RNA-seq aligner GSNAP and further filtered to consider discontinuous expression patterns at exon/intron levels. Results: A total of 108 candidate fusion transcripts were detected and RT-PCR assays confirmed 89% of the top ranking fusion transcript candidates. The majority (82%) of identified fusion gene partners are listed in the COSMIC database of known cancer sequence variations. Of note, several patients expressed multiple fusion transcripts that are significantly associated with tumor progression (P⬍0.001), including genes associated with cell proliferation and cellular metabolism. Furthermore, these patients also harbored inter-chromosomal gene fusions. It is noteworthy that several gene fusions were present in multiple patients. In one of these recurrent fusions the estrogen receptor gene acts as the fusion pair donor. Conclusions: Novel bioinformatics approaches developed here demonstrate the ability to detect fusion transcripts as biomarkers from archival FFPE tissues that associate with breast cancer progression. Some gene fusions were common in multiple patients and deserved further study.

11019

11020



Sensitivity for detecting PIK3CA mutations in early-stage breast cancer with droplet digital PCR. Presenting Author: Julia A. Beaver, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD

Use of next-generation sequencing (NGS) to identify actionable genomic alterations (GA) in diverse solid tumor types: The Foundation Medicine (FMI) experience with 2,200ⴙ clinical samples. Presenting Author: Vincent A. Miller, Foundation Medicine, Inc., Cambridge, MA

Background: PIK3CA is mutated in up to 30% of breast cancers. Classically somatic mutations are identified by Sanger sequencing of the primary tumor specimen. However third generation droplet digital PCR technologies offer a novel platform for quantitative mutation detection with improved sensitivity. Methods: Thirty stage I-III breast cancer patients were consented on an IRB-approved prospective repository study at Johns Hopkins for collection of their primary breast tumor specimen. Formalinfixed paraffin embedded (FFPE) samples were analyzed by standard sequencing for three PIK3CA hotspot mutations. The DNA from these samples was then analyzed using the RainDrop digital PCR platform with TaqMan probes in a triplex format to simultaneously detect and quantitate hotspot mutations and genome equivalents. Results are expressed as a percentage of mutant to wild-type PIK3CA molecules for each sample. Results: Standard sequencing of all tumors (n⫽30) identified seven PIK3CA Exon 20 mutations (H1047R) and three Exon 9 mutations (E545K). Samples were scored as PIK3CA mutation positive by digital PCR if the tumor DNA contained at least 5% mutant molecules. All ten mutations identified by sequencing were verified by digital PCR with quantities of mutant molecules ranging from 20.3-55.6% in a given sample. Digital PCR identified additional PIK3CA mutations that were wild type by standard sequencing including three mutant Exon 20 samples, two mutant Exon 9 samples and one sample with an Exon 20 and Exon 9 mutation. Quantities of mutant molecules in these additional samples ranged from 5-28.9%. Conclusions: RainDrop digital PCR offers improved sensitivity and quantification for detecting PIK3CA mutations in FFPE samples using nanograms of DNA. Additional mutations identified by digital PCR may reflect genetic heterogeneity or possibly tissue contamination. The clinical utility of identifying a small proportion of mutations is unknown but may impact eligibility for targeted therapies and clinical trials. Ongoing studies will also address whether the identification of solid tumor mutations in circulating cell-free plasma DNA by digital PCR can improve diagnostics and aid in therapeutic decisions.

Background: ST oncology has been transformed by the linkage of GA with targeted therapeutics. Unfortunately, most STs still have no target detected by clinically available assays. More comprehensive testing platforms are needed to determine GA in ST and thus broaden treatment options. We developed a ST NGS diagnostic assay, optimized for routine clinical FFPE specimens including core and fine needle biopsies and malignant effusions, and analyzed ⬎ 2,200 patients’ tumors in a CLIA-certified lab (Foundation Medicine). Methods: Hybridization capture of 3,320 exons from 182 cancer-related genes and 37 introns of 14 genes commonly rearranged in cancer was applied to ⱖ 50ng of DNA extracted from 2,200⫹ consecutive FFPE tumor specimens and sequenced to high unique coverage. GA (base substitutions, small indels, rearrangements, copy number alterations) were categorized as “actionable” if directly linked to a clinically available targeted treatment option or a mechanism-driven clinical trial. Results: 2,112/2,221 (95%) of specimens (most common 1° sites: lung 18%, breast 14%, colon 7%, other 34%) were successfully profiled (mean coverage 1134X). Alterations were reported in 155/182 (85%) of genes. Seventy-six percent of cases harbored ⱖ1 actionable GA, mean 1.6 (range 0-16); sixty-two percent harbored at least one actionable GA not assayed by available tumor-type specific tests or hotspot panels. This approach has led to novel insights into advanced cancer including: 13 novel, potentially druggable kinase gene fusions; alterations in known drug targets (e.g. ALK, EGFR, ERRB2, KIT, MET, PDGFR ␣ and ␤, RAF1 and RET) in novel tumor types and new mechanisms of resistance to approved targeted therapies. Several patients demonstrated dramatic responses to treatment with targeted therapies directed against these alterations. Conclusions: Comprehensive NGS genomic profiling was successful in profiling ⬎2,200 unselected clinical cases, identified actionable alterations in 76% of cases and provided additional treatment options for 62% of patients targeting alterations in genes not assayed by available hotspot panels.


Tumor Biology 11021


Protein tyrosine kinase 6 (PTK6, BRK) amplification in HER2ⴙ breast cancer as a mechanism of HER2 resistance. Presenting Author: Tatyana A. Grushko, The University of Chicago Medical Center, Chicago, IL Background: PTK6 gene on chromosome 20q13 encodes the intracellular non-receptor tyrosine kinase. Studies in vivo and in vitro revealed a role for PTK6 in cell proliferation and survival, particularly in HER2⫹ breast cancer cells suggesting that PTK6 may associate with the HER2 pathway and confer resistance to HER2-targeted therapy. PTK6 protein is frequently overexpressed in breast cancer, however, the mechanism(s) underlying PTK6 overexpression and its role in cancer remains unclear. To address this problem, we analyzed the frequency of PTK6 gene copy number variation (CNV) and expression in association with breast cancer subtypes. Methods: Retrospectiveparaffinsamples of invasive tumor and normal epithelium, and matching DCIS and metastases were mounted on TMA. PTK6 CNV was determined using PTK6:CEP20 FISH assay. Tumor subtypes were defined using the five-marker IHC classifier. The correlation between PTK6 CNV and mRNA expression and association of both with the intrinsic PAM50 tumor subtype were studied using TCGA database (547 cases) and publicly available seven breast cancer data sets (1005 cases). Data were normalized, gene median centered and standardized for the purpose of the study. Results: By FISH, 20% of 41 invasive tumors carried PTK6 CNV: amplification (10%) and gene polysomy (10%). The proportion of PTK6 amplified cases differed by subtype, with the largest proportion in HER2-enriched (17%) and LumB (14%). Strikingly, amplified invasive cases also showed amplification in matching DCIS and metastases. Analysis of the public datasets confirmed the frequent PTK6 amplification in breast cancer. Both low and high levels of amplification were detected with the largest proportion in HER2⫹ tumors (HER2-enriched and LumB; p⫽2.05e-26). None of the basal-like tumors showed high levels of PTK6 amplification. A high correlation between PTK6 gene copies and mRNA expression was observed (p⫽1.13e-08). Conclusions: PTK6 gene is amplified early in breast cancer progression, particularly in HER2⫹ tumors. Further studies on PTK6 biology may help clinicians to understand its potential role in HER2 resistance. Supported by BREAST CANCER SPORE, NCI K12CA139160 and CTSA-ITM CS UL1 RR024999.

11023


BRCA1 like copy number profiles to predict benefit of intensified alkylating chemotherapy in breast cancer. Presenting Author: Philip C. Schouten, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands Background: DNA copy number profiles can identify patients with a defect in BRCA1. We previously showed that patients with a BRCA1-like profile benefit from intensified alkylating chemotherapy (IA, 4 cycles 5-fluorouracyl, epirubicin, cyclophosphamide ⫹ 1 cycle carboplatin, thiotepa and cyclophosphamide with autologous stem cell transplantation (ASCT)). Presumably, this is because of the defect in error free homologous recombination DNA repair. Here we present an independent study of BRCA1-like profiles to predict benefit of IA chemotherapy (2 cycles induction chemotherapy consisting of 2500 mg/m2 ifosfamide and 40 mg/m2 epirubicin, followed by 12 g/m2 ifosfamide, 900 mg/m2 carboplatin, 180 mg/m2 epirubicin with ASCT) versus adriamycin-cyclophosphamide or cyclophosphamide-methotrexate-5-fluorouracyl regimens in high risk breast cancer. Methods: We isolated tumor DNA from 117 patients of a case-control study of high risk breast cancer patients to apply a marker by treatment interaction study design to assess overall survival. We generated copy number profiles and classified them to be BRCA1-like or non-BRCA1 like. We used Fisher Exact tests to calculate correlations and performed Kaplan-Meier and Cox regression analyses to investigate whether patients with a BRCA1-like tumor benefit from IA chemotherapy compared to an AC/CMF regimen. Results: 16 of 117 (14%) patients had a BRCA1-like profile. BRCA1-like status was associated with high tumor grade (p⫽0.03), triple negative status (p⫽0.0005) and high N stage (p⫽0.03). When corrected for hormone receptor and HER2 status, size, positive lymph nodes, and grade we found that BRCA1 like patients had a 6-fold decreased chance of death (HR: 0.15, 95% confidence interval: 0.03-0.80, p: 0.03) compared to non-BRCA1 like patients (HR: 0.94, 95% confidence interval: 0.53-1.67, p: 0.84). The interaction test between IA chemotherapy and marker status was significant (p: 0.04). Conclusions: We provide independent validation of the previous finding that breast cancer patients with a BRCA1 like copy number profile benefit highly from intensified alkylating chemotherapy.

11022

661s Poster Discussion Session (Board #11), Mon, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

Trefoil factor 1 as a predictive factor of bone metastases in breast cancer. Presenting Author: Laura Mercatali, Osteoncology and Rare Tumors Center, IRCCS Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy Background: Patients with breast cancer frequently develop bone metastases, which are responsible for high morbidity and reduced quality of life. The early identification of patients with a high probability of relapsing in this site could be used to select candidates for tailored therapy with bone-specific drugs such as bisphosphonates or RANK-L inhibitors. We aimed to identify a pattern of tissue markers in primary breast cancer that could predict bone metastatization. Methods: Expression of different markers was retrospectively analyzed in frozen breast cancer tissue samples from 90 patients comprising 30 cases with no evidence of disease (NEDP), 30 with bone metastases (BMP) and 30 with visceral metastases (VMP). Eight transcripts were analyzed by Quantitative Real time PCR: trefoil factor 1(TFF1), bone sialoprotein (IBSP), heparanase (HPSE), secreted protein acidic and rich in cysteine (SPARC), connective tissue growth factoe (CTGF), B2 microglobulin (B2M) and receptor activator of Nf-kB (RANK). Immunohistochemistry of TFF1 was performed on a part of the case series. Results: Marker expression analysis in the 3 different subgroups showed at least twofold higher median values of all markers in NEDP and VMP subgroups than in BMP. In particular, TFF1, B2M and CXCR4 levels showed statistically significant values. Median TFF1 value in BMP patients was 430.64 compared to 115.83 and 32.79 in VMP and NEDP, respectively (p⫽0.0043). Considering markers as dichotomous variables, TFF1 expression in BMP reached 59% compared to 21% and 23 % in NEDP and VMP, respectively (p⫽0.0022). Univariate analysis confirmed that TFF1 predicted the relapse and also the site of relapse. Immunohistochemistry data on TFF1 revealed that this protein was expressed only by cancer cells. Furthermore, the accuracy of the marker did not change at RNA or protein level, thus excluding a post transcriptional control of the RNA. Conclusions: In this preliminary study we identified a gene expression pattern in primary breast cancer that can identify patients destined to relapse to the bone. In particular, TFF1 would seem to be a suitable marker for bone metastatization and a possible target for the development of new drugs.

11024


Olaparib monotherapy in patients with advanced cancer and a germ-line BRCA1/2 mutation: An open-label phase II study. Presenting Author: Bella Kaufman, Chaim Sheba Medical Center, Tel Hashomer, Israel Background: The oral PARP inhibitor olaparib has shown antitumor activity as monotherapy in patients (pts) with breast and ovarian cancer with gBRCA1/2 mutations. This multicenter non-comparative study evaluated whether tumors in gBRCA1/2 mutation carriers are responsive to olaparib regardless of tumor type (NCT01078662). Methods: Heavily pretreated pts with advanced cancer refractory to standard therapy (98% of breast cancer pts had ⱖ3 lines of prior chemotherapy for metastatic disease) and with a gBRCA1/2 mutation, received olaparib 400 mg bid (capsule) until disease progression. Primary objective: tumor response by RECIST 1.1. Secondary objectives: PFS, OS and safety. Results: 298 pts received treatment and were evaluable. Enrollment is complete, 33 pts remain on study. Median duration of treatment in this heavily pretreated population was 5.5 months (range ⬍1–28.5 months). Most common AEs (generally grade 1/2) were fatigue (59%), nausea (59%) and vomiting (37%). Grade ⱖ3 AEs were reported for 162 pts (54%); most common was anemia (17%). 11 pts (4%) had AEs that led to treatment discontinuation. Conclusions: The observedtumor response rates indicate antitumor activity of olaparib monotherapy in gBRCA mutated pts with advanced cancer refractory to standard therapy. A clinical benefit was seen in prostate and pancreatic cancer and activity in ovarian and breast cancer was confirmed. Prolonged responses to olaparib across all tumor types support the hypothesis that therapy directed against a genetically-defined target has activity regardless of anatomic organ of origin. Olaparib was generally well tolerated with toxicities consistent with prior studies. Clinical trial information: NCT01078662.

Ovarian (nⴝ193) Response rate [RR; CR ⴙ PR], n (%) pts Complete response (CR), n (%) pts Partial response (PR), n (%) pts Stable disease (SD) >8 weeks, n (%) pts % progression free at 6 months % alive at 12 months

Full analysis set Breast Pancreas (nⴝ62) (nⴝ23)*

Prostate (nⴝ8)

Other (nⴝ12) 1 (8.3)

60 (31.1)

8 (12.9)

5 (21.7)

4 (50)

6 (3.1)

0

1 (4.3)

0

0

54 (28)

8 (12.9)

4 (17.4)

4 (50)

1 (8.3)

78 (40.4)

29 (46.8)

8 (34.8)

2 (25)

7 (58.3)

54.6

29

36.4

62.5

NC

64.4

44.7

40.9

50

NC

NC, not calculable; *all with progression following gemcitabine.


662s 11025

Tumor Biology Poster Discussion Session (Board #14), Mon, 8:00 AM-12:00 PM and 11:30 AM-12:30 PM

Fibroblast growth factor receptor 1 (FGFR1) and SRY-related HMG-box (SOX2) amplification in squamous cell carcinoma (SCC) of the lung. Presenting Author: Amaya Gasco, Pangaea Biotech, Clinical Unit, Barcelona, Spain Background: SOX2 is a key transcription factor that is amplified in lung SCC. FGFR1 is a receptor tyrosine kinase that promotes cell proliferation, survival and apoptotic resistance through the PLC␥/PKC, RAS/MAPK and PI3K-AKT pathways, respectively. FGFR1 is amplified in 15-25% of lung SCC. Pre-clinical studies of targeted inhibitors showed a growth dependency on FGFR1 amplification both in vitro and in vivo. A European, multicenter clinical trial of second-line treatment with BIBF1120, an FGFR1 inhibitor, will be performed in p with lung SCC with FGFR1 amplification. Methods: We have examined FGFR1 and SOX2 gene copy number (GCN) in 76 lung SCC p by multiplex ligation-dependent probe amplification (MLPA). Genomic DNA (gDNA) was isolated from enriched tumor cells by laser capture microdissection from formalin-fixed paraffin embedded (FFPE) tumor tissue. 50-100 ng of gDNA was analyzed in each of three independent replicates per tumor sample. Two independent probe sets were used for each gene analyzed. For inter-patient GCN comparisons, the results from each patient were normalized against the GCN values derived from FFPE peripheral blood leukocytes. In order to study intratumor heterogeneity (TH), we examined FGFR1 and SOX2 GCN in different areas of 4 tumors. In 2 p, TH was examined in serial tumor biopsies and/or resections obtained at different points of disease progression. Results: High FGFR1 amplification was detected in 13/76 (17.10%) and low amplification in 7/76 (9.21%) p. High SOX2 amplification was observed in 38/63 (60.32%) and low amplification in 9/63 (14.28%) p. 46.15% of the FGFR1-amplified tumors were also co-amplified for SOX2. Intra-TH was observed in 2/4 tumors. Survival according to FGFR1 and SOX2 GCN will be presented. In addition, GCN changes in FGFR1, SOX2, PIK3CA, PDGFRA, KDR, EGFR and MET over 10 years of follow-up will be presented for one surgically resected SCC lung p. Conclusions: FGFR1 and SOX2 co-amplification could represent a novel therapeutic target and warrants further research.

11027


11026


Genetic and molecular biomarker characterization of KRAS mutant nonsmall cell lung carcinoma (NSCLC) tumors. Presenting Author: Li Liu, GlaxoSmithKline, Oncology, Collegeville, PA Background: Preclinical studies demonstrated Brahma related gene 1 (BRG1) mutations or loss of expression, and mutations of LKB1 may be associated with lack of sensitivity for MEK inhibitor trametinib in a subset of KRAS mutant NSCLC lines. This study aimed to evaluate the frequency of KRAS, LKB1 and BRG1 mutations in NSCLC tumors; and determine whether KRAS mutations in corresponding plasma samples could be detected by evaluating circulating cell-free DNA (cfDNA). Methods: Human NSCLC FFPE tumor tissue and matched plasma samples were procured from Indivumed GmbH. KRAS mutation status of 101 NSCLC tumors and matched plasma were determined by direct sequencing of genomic DNA (gDNA) from tissue and/or BEAMing on tissue gDNA or plasma cfDNA. Genetic mutations of LKB1 and BRG1 were determined by direct sequencing. Additional mutations were determined using the Ion Torrent AmpliSeq Cancer Panel. BRG1 protein expression was evaluated by IHC. Results: By direct sequencing and BEAMing we found 27/101 (28.4%) NSCLC tissue and/or plasma samples harbored KRAS mutations: G12V (37.0%), G12C (29.6%), G12D (18.5%), G12S, G13C, G13D and Q61H (3.7% each). The KRAS mutation status concordance (mutant or wild-type) between tumor gDNA and plasma cfDNA was 79-81%. Among the KRAS mutant tumors, LKB1 and BRG1 mutations were detected in 10/26 (38%) and 1/26 (3.8%) tumors respectively by direct sequencing. By IHC, loss of BRG1 expression was detected in 1/21 KRAS mutant tumors. The mutation frequency and variants for KRAS and LKB1 in patient samples were comparable with KRAS mutant NSCLC cell lines and COSMIC database. However the frequency of BRG1 mutation and protein loss were much lower in patient tumors. In a subset of 15 KRAS mutant tumors, Ion Torrent confirmed KRAS and LKB1 mutations and provided additional mutations found in TP53, FGFR2, FGFR3, GNAS, KDR, KIT and MET. Conclusions: This study demonstrates that KRAS mutant NSCLC tissues have high frequency of LKB1 mutations along with other mutations. It also supports the feasibility of detection of KRAS mutations in cfDNA from blood of NSCLC patients using BEAMing technology, providing an alternative to invasive biopsy.

11028


ROR1 mRNA expression in EGFR-mutant non-small-cell lung cancer (NSCLC) patients (p) with the T790M mutation: A potential therapeutic target. Presenting Author: Niki Karachaliou, Pangaea Biotech, Laboratory of Translational Oncology, Barcelona, Spain

Components of homologous recombination and translesion synthesis (TLS) in pemetrexed/cisplatin-treated non-small-cell lung cancer (NSCLC) patients (p). Presenting Author: Guillermo Lopez-Vivanco, Department of Medical Oncology, Hospital de Cruces, Barakaldo, Spain

Background: Progression-free survival (PFS) is short in NSCLC driven by EGFR mutations treated with erlotinib alone, due to crosstalk with other signaling pathways that can cause secondary dependency. ROR1 knockdown inhibited the growth of NCI-H1975 cells (with EGFR L858R and T790M mutations). A pro-survival function for ROR1/MEK/ERK signaling has been demonstrated, with cooperation with AKT. In a subset of 95 p in the EURTAC trial (clinicaltrials.gov NCT00446225), 65% had pretreatment T790M mutations. We have assessed ROR1 expression in 45 of these 95 p. Methods: The T790M mutation was determined by Taqman with a PNA to inhibit amplification of the wild-type (wt) allele. Tumor samples were run in octuplicates; this method can detect 1 mutated allele among 10,000 wt alleles. ROR1 mRNA expression was examined by quantitative RT-PCR and categorized by terciles. p were classified as having low/ intermediate or high ROR1 expression. The impact of ROR1 expression on outcome was examined in all 45 p and in a subset of 15 p with concomitant T790M mutations. Results: Median age 65; 68.9% female; 57.8% never-smokers; 95.6% ECOG PS ⬍2; 91.1% adenocarcinoma; 68.9% exon 19 deletion. No differences in baseline characteristics were observed according to ROR1 expression levels. 24 p (53.3%) were treated with erlotinib and 21 p (46.7%) with chemotherapy. 10 (41.7%) erlotinibtreated p and 6 (28.6%) chemotherapy-treated p had ROR1 mRNA levels in the top tercile. Among erlotinib-treated p, response rate was 40% for p with high ROR1 levels vs 71.4% for p with low/intermediate levels (P⫽0.0918). Among chemotherapy-treated p, only p with low ROR1 levels responded (6.7%). PFS was 11.8 months (m) for erlotinib-treated p with low/intermediate ROR1 levels vs 5.8 m for p with high levels. PFS for chemotherapy-treated p was 5.6 and 9 m, respectively (P⫽0.033). Among 15 erlotinib-treated p with concomitant T790M mutations, PFS was10.8 m for p with low/intermediate ROR1 levels vs 2.7 for p with high levels (P⫽0.0174). Conclusions: HighROR1 expression significantly limits PFS in p with T790M mutations. ROR1-directed therapies can enhance the efficacy of erlotinib in EGFR-mutant NSCLC p overexpressing ROR1. Clinical trial information: NCT00446225.

Background: REV3, the catalytic subunit of the TLS polymerase ␰, can continue replication past DNA adducts. Depletion of REV3 sensitizes A549 lung cancer cells to cisplatin. REV3 expression is part of a gene signature that predicted pemetrexed sensitivity in 17 NSCLC cell lines. Homologous recombination and TLS pathways have non-redundant functions in response to cisplatin. We hypothesized that low REV3 mRNA expression – alone or in combination with low expression levels of genes involved in homologous recombination – could correlate with better outcome to cisplatin/pemetrexed in NSCLC. Methods: REV3, BRCA1, RAP80, TS and AEG1 mRNA was examined by quantitative RT-PCR and categorized by terciles. Expression of each gene was correlated with outcome in 47 cisplatin/pemetrexed-treated NSCLC p. Results: 63.8% male; 47% smokers; 80.9% ECOG PS 1; 80.8% adenocarcinoma. Overall response rate was 51%, with no differences according to expression levels of any of the genes. Progression-free survival (PFS) for p with low, intermediate and high BRCA1 levels was 13.4, 5.5 and 3.9 months (m), respectively (P⫽0.005). Similar differences in PFS were observed according to TS (P⫽0.003) and AEG1 (P⬍0.001) expression. Hazard ratio (HR) for PFS for p with high BRCA1 levels was 4 (P⫽0.002). Overall survival (OS) for p with low, intermediate and high BRCA1 levels was 29.7, 7.4 and 6.3 m, respectively (P⫽0.05). Similar differences in OS were observed according to TS (P⫽0.005) and AEG1 (P⫽0.001) expression.HR for OS for p with high BRCA1 levels was 3.6 (P⫽0.004). There were no differences in PFS or OS according to REV3 or RAP80 levels. However, the joint effect of BRCA1 and REV3 was significant for predictive modeling. PFS for p with low, intermediate and high levels of both genes was 14.9, 7.2 and 2.8 m, respectively (P⫽0.001). OS for p with low, intermediate and high levels of both genes was 29.7, 7.8 and 6.3 m, respectively (P⫽0.04). Conclusions: Low BRCA1 expression predicts longer PFS and OS in pemetrexed/cisplatintreated NSCLC p. Low TS and AEG1 levels have similar predictive value. Analysis of these genes could be useful for customizing pemetrexed/ platinum chemotherapy.


Tumor Biology 11029


Nondisruptive mutations of TP53 and overall survival (OS) in advanced non-small-cell lung cancer (NSCLC) patients (p). Presenting Author: Enric Carcereny Costa, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain Background: The tumor suppressor TP53 is the most commonly mutated gene in lung cancer. Early-stage NSCLC p with TP53 mutations may have worse prognosis and be more radio/chemoresistant. However, few studies have addressed the issue of TP53 mutations in advanced NSCLC. We have retrospectively examined the influence of TP53 mutations on OS in 241 advanced NSCLC p. Methods: 99 EGFR-wild-type (wt), chemotherapytreated p from 5 European hospitals and 142 EGFR-mutated (mut), erlotinib-treated p from two clinical studies were included. Exons 5, 6, 7 and 8 of TP53were analyzed by high resolution melting (HRM). All mutated samples were reconfirmed by sequencing. Mutations were classified as disruptive or non-disruptive based on their predicted effects on the function of the p53 protein. Results: TP53 mutations were detected in 31% of EGFR-wt and 24% of EGFR-mut p. OS results are available for 57 EGFR-wt p and 90 EGFR-mut p. Among EGFR-wt p, OS was 22 months (m) for p without TP53 mutations, 20m for p with disruptive TP53 mutations, and 9 m for p with non-disruptive TP53 mutations (P⫽0.09). Among EGFR-mut p, OS was 31 m for p without TP53 mutations, not reached for p with disruptive TP53 mutations, and 15 m for p with non-disruptive TP53 mutations (P⫽0.05). Complete OS results for all 241 p will be presented. Conclusions: Non-disruptive mutations in the TP53 gene are associated with shorter OS in advanced NSCLC p, both in EGFR-wt p treated with chemotherapy and in EGFR-mut p treated with erlotinib.These p could benefit from treatment to reactivate mutant p53.

11031


Phase I study (A8471004) in Asian patients of PF-03446962, a fully human mab against ALK-1 receptor involved in tumor angiogenesis: Safety, pharmacokinetics (PK), and pharmacodynamics (PD). Presenting Author: Kyung-Hun Lee, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea Background: Activin receptor like kinase 1 (ALK-1) is a member of the TGF-␤RI family selectively expressed in proliferating endothelial cells, and plays an important role in regulating tumor initiation and metastasis. PF-03446962 is a fully human IgG2 mAb anti ALK-1 evaluated within two phase 1 studies in Western and Asian pts. Herein we report the preliminary safety, PK and PD data of the Phase I study. Methods: Primary objective is to identify the maximum tolerated dose (MTD) in Asian cancer pts; secondary objectives include the safety profile, PK, antitumor activity, and potential PD markers in blood and tumor samples. PF-03446962 is administered IV on Day 1, 29 and then q 2 weeks. Results: Study A8471004 consists of two parts: a 3⫹3 dose escalation (Part 1) and a dose expansion (Part 2) at 2 dose levels. In Part 1, 16 pts have been enrolled at 3 dose levels (4 pts at 4.5 mg/kg, 3 pts at 7.0 mg/kg, and 9 pts at 10 mg/kg). No DLTs occurred in Part 1 and 10 mg/kg was confirmed as MTD in the Asian population. The observed AUC0-28day for the 4.5, 7 and 10 mg/kg doses, were 12960, 22190 and 28030 ␮g·h/mL and Cmax were 97.1, 131.5 and 179.8 ␮g/mL, respectively. Drug exposure (mean Cmax and AUC) increased in a nearly dose proportional manner in Asians. In Part 2, expansion cohorts at doses of 7.0 mg/kg (10pts) and 10.0 mg/kg (8pts) of pts previously treated with VEGF inhibitors (VEGFi) have been enrolled, and the most common drug related adverse events observed (⬎10%) being thrombocytopenia, pyrexia, epistaxis, and telangiectasia (an anti-ALK-1 mediated toxicity) similarly in the 2 dose levels. Telangiectasia was observed in 1 CRC and 3 HCC patients. 4 patients who progressed after VEGFi treatment (RCC, sarcoma, 2 HCC patients) presented a SD lasting for 290, 248, 247 and 208 days, respectively, suggesting the ALK-1 could serve as mechanism of escape for VEGF. Conclusions: PF-03446962 is a first in class mAb targeting ALK-1. Treatment with PF-03446962 is well tolerated in the Asian pts and preliminary observation of clinical activity supports ALK-1 as a viable target. Update of study results and potential PD effects obtained on blood and tumor samples will be presented. Clinical trial information: NCT01337050.

11030


Angiogenic marker associated with resistance to neoadjuvant chemoradiotherapy in rectal cancer. Presenting Author: Hanjo Kim, Soonchunhyang University Hospital Cheonan, Cheonan, South Korea Background: The ability to achieve pathologic down staging after neoadjuvant chemoradiotherapy (CRT) is correlated with improved survival. However, there is no effective method of predicting which patients will response to neoadjuvant CRT. Neoadjuvant CRT can change the expression of angiogenic factors. However, little is known about its possible changes in response to preoperative CRT. We examined the expression of angiogenic factors in rectal cancer tissues before preoperative CRT and after surgery. Methods: Fifty five patients with locally advanced rectal cancer were studied. All patients were given preoperative CRT of 5040 cGy for 5-6 weeks with concurrent administration of 5-fluorouracil and leucovorin. Surgical resection was performed 6 – 8 weeks later in all patients. Immunohistochemical staining for angiogenenic markers (vascular endothelial growth factor [VEGF], placenta growth factor [PLGF], hypoxia inducible factor 1␣ [HIF 1␣], stromal cell derived factor [SDF 1␣]) were performed on specimens obtained before preoperative CRT and after surgery. A semiquantitative-immunohistochemical score established from the extension and intensity of the angiogenic factors was used for analysis. Results: The positive expression rate of VEGF, PLGF, SDF 1␣, and HIF 1␣ was 56.4% (31/55), 65.5% (36/55), 70.9% (39/55), and 47.3% (26/55), respectively. The expression rate of VEGF, PLGF, SDF 1␣, and HIF 1␣ was increased by 3.6% (2/55), 7.3% (4/55), 30.9% (17/55), and 1.8% (1/55) after neoadjuvant CRT, respectively. Expression of VEGF, PLGF, and HIF 1␣ protein was downregulated after neoadjuvant CRT in the rectal cancer tissues (P ⬍ 0.001, P ⫽ 0.001, P ⫽ 0.044, respectively). However, SDF 1␣ was upregulated after neoadjuvant CRT (P ⬍ 0.001). And also, upregulated expression of SDF 1␣ after neoadjuvant CRT was significantly associated with resistance to CRT (P ⫽ 0.035). However, SDF 1␣ showed no correlation with other clinical factors (age, sex, clinical stage). Conclusions: Expression of SDF-1␣ was increased in the rectal cancer tissue after neoadjuvant CRT, as well as has been associated with CRT resistance. Our data suggests that SDF 1␣ should be evaluated as new target for antiangiogenic therapy.

11032


Elevated CSF-1 serum concentrations to predict lymph node metastasis and overall survival in women with early breast cancer. Presenting Author: Christian F. Singer, Medical University of Vienna, General Hospital, Vienna, Austria Background: Colony-stimulating factor-1 (CSF1) is a key modulator of tissue macrophages and contributes to the physiological function of the mammary gland. It has, however, also been associated with breast cancer since expression of its receptor CSF-1R is a strong predictor of poor outcome in early breast cancer and results in tumor cell invasiveness and pro-metastatic behavior in vitro. Methods: We have prospectively measured circulating CSF-1 with ELISA in 572 women with early breast cancer and in 688 women with benign breast lesions; and correlated these values with overall survival, nodal status and other clinical and histological parameters. Results: Serum CSF-1 concentrations were significantly elevated in patients with early breast cancer when compared to those with benign tumors (p⬍0.0001). Within breast cancer patients, CSF-1 was higher in women with involved axillary lymph nodes (p⫽0.04). CSF-1 concentrations were correlated with tumor size (p⫽0.002), age (p⬍0.001), and Ki67 expression (p⫽0.006). Log CSF-1 serum concentrations were predictive of poor survival in both univariate (HR: 3.77, CI: 1.65-8.65, p⫽0.002) and multivariate analyses (HR: 3.1, CI: 1.03-9.33, p⫽0.04). Post- but not premenopausal women with CSF-1 serum concentrations ⬎873 pg/ml experienced a significantly poorer outcome (p⫽0.004 log rank test). Conclusions: CSF1 serum concentrations are elevated in women with malignant breast tumors. In early breast cancer, elevated serum CSF-1 is associated with nodal involvement, and in postmenopausal women also with poor overall survival.


664s 11033

Tumor Biology General Poster Session (Board #42D), Mon, 1:15 PM-5:00 PM

11034


Differential luminal breast cancer (LBC) reprogramming in response to BIBF1120 (BIBF) or bevacizumab (B). Presenting Author: Miguel QuintelaFandino, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain

LAMC2 as a prognostic marker that promotes metastasis of lung adenocarcinoma through epithelial-mensenchymal transition (EMT). Presenting Author: Yongwha Moon, National Cancer Institute, Bethesda, MD

Background: FVB MMTV PyMT is a great mouse model for studying LBC due to its stochastic nature, immune system preservation, natural growth kinetics and ER/HER2 status. We approached the transcriptomic (T), proteomic (P), phospho-proteomic (P-P) and metabonomic (M) layers of regulation of the tumor phenotype attempting to unravel mechanisms of resistance to antiangiogenic drugs (ADs) and find new targets. Methods: Treatments started when tumors measured 0,1cm3; with the VEGFR/ PDGFR inhibitor BIBF 85mg/kg/day; a murine analog of B 10mg/kg/ biweekly; or vehicle (V). Tumors were harvested at time 0, week 1 (T1), or at sacrifice (Tend, 1cm3). Cd31 and pimomidazole measured vascularization and O2. T; P/P-P; and M layers were interrogated with sure print 3G arrays; titanium separation - HPLC fractionation - orbitrap spectrometer run; and GC/MS and LC/MS. Gene ontology pathways were discovered with GSEAS; kinase networks by consensus domain analysis; metabolic pathways rearrangement with in-house built bioinformatic tools. Pairwise comparisons included ⬎15 mice/condition. All results: p or false-discovery ratio⬍0,05. Results: Total mice in study:2,327. BIBF-treated showed: early (T1 vs. 0) 2glycolysis (55%) and 1pyruvate diversion to Krebs mediated by 2800% phosphorylation of PDH, 1 ketones uptake and degradation (220%), mediated by 2700% 1AMPK activity; late (Tend) 900% 1 lipid uptake and aerobic degradation mediated by ⬎800% 1 ERK/B-adrenergic/ PKA and PPARg (1600%) signaling. All changes supported by GSEAS. Adding blockade of AMPK, ERK, B-adrenergic or PPARg (ShRNAs or compounds) to BIBF yielded at least 50% growth delay (Anova). Tend B-treated tumors showed 210% 1degradation of tryptophan to immunosuppressive (IS) kynurenine, and ⬎200% 1 levels of IS/vasodilator prostaglandins. Celecoxib added to B delayed growth 90%. B and V induced similar 1of hypoxic/necrotic areas (T0-1-end: 5%-15%-52%, Poisson), no change in CD31. BIBF avoided necrosis/hypoxia despite ⬎30% 2 in CD31. Conclusions: Our strategy identified differential mechanisms of action of ADs in LBC. BIBF induces a switch from Warburg to aerobic metabolism; B reprograms the immune response. Regulators of these processes constitute targets.

Background: Metastasis is the main cause of death in non-small cell lung cancer (NSCLC) patients. Genes responsible for NSCLC metastasis are unknown. LAMC2 is one of the 3 chains (␣3, ␤3, ␥2) of laminin 332, an important component of basement membranes, and LAMC2 involvement in metastasis is unclear. Methods: We have established a metastasis model in nude mice by repeated intracardiac injection of A549 lung adenocarcinoma cells. After 3-4 rounds of intracardiac injections, 100% metastasis penetrance was obtained. Microarray analysis was performed to identify genes differentially expressed between parental (A549P) and round-3 (A549R3) cells. In vitro migration/invasion and in vivo metastasis assays were performed in LAMC2-overexpressed A549P, LAMC2-knockdown A549R4, PC9, H358, and H322 cells. Public RNA microarray data of human NSCLC (GSE8894, GSE3141; n⫽249) and LAMC2 immunohistochemistry (IHC) of stage I NSCLC TMA samples (n⫽250) were analyzed to correlate LAMC2 and prognosis. Results: We identified LAMC2 as a putative metastasis marker of NSCLC through gene expression profiling of A549 cells enriched for metastasis in mice. Ectopic LAMC2 expression increased migration/invasion, whereas LAMC2 knockdown decreased migration/ invasion in vitro. Conditioned media containing secreted LAMC2 promoted cell migration/invasion, which were blocked by LAMC2 knockdown or LAMC2 neutralizing antibody. Ectopic LAMC2 expression induced mesenchymal but decreased epithelial markers, indicating EMT, whereas LAMC2 knockdown elicited the opposite. A549R4 LAMC2 knockdown cells showed less metastatic activity than A549R4shRNA control cells in mice. In public microarray data high LAMC2 mRNA predicted high risk of recurrence (GSE8894, P⫽0.022; GSE3141, P⫽0.029) in adenocarcinoma (AC) but not squamous carcinoma (SC). Our IHC study showed that high LAMC2 predicted high risk of recurrence (hazard ratio ⫽1.8; P⫽0.040) and death (hazard ratio⫽1.9; P⫽0.028) in AC but not SC by multivariate analysis. Conclusions: LAMC2 promotes metastasis through activation of EMT pathways, and is a potential prognostic marker and therapeutic target of metastasis in lung adenocarcinoma.

11035

11036



Association of downregulation of toll-like receptor 3 (TLR3) expression with aggressive breast cancer (BC). Presenting Author: Elias Obeid, The University of Chicago Medical Center, Chicago, IL

Correlation of Src activation with response to dasatinib, capecitabine, oxaliplatin, and bevacizumab in advanced solid tumors. Presenting Author: John H. Strickler, Duke University Medical Center, Durham, NC

Background: Inflammation in the tumor microenvironment plays a key role in human breast cancer. We previously showed that a high proportion of alternatively-activated, tumor-associated macrophages (M2) are associated with increased microvessel density (MVD) and worse outcomes in BC. The anti-tumor effect of TLR3 is well recognized. To our knowledge, there are no studies evaluating TLR3 expression and characteristics of inflammation in primary breast tumors. Methods: 48 breast tumors were obtained from the University of Chicago Breast Cancer SPORE tissue bank under IRB approved protocols. Tissue microarrays were constructed and molecular subtypes assigned based on immunohistochemical (IHC) staining into: luminal A, luminal B, HER2-like, and basal-like. Macrophage density was determined using double staining with CD68/CD163. MVD was measured by IHC using anti-CD34. Staining quantification was done by a pathologist. To evaluate the association between M2 macrophages, TLR3 and MVD, Spearman’s rho correlation coefficients were calculated. Survival comparison analysis was done using Wilcoxon statistic. Results: Of the tumors studied, 46% were LumA, 38% basal-like, 4% HER2-like, 2% LumB. We found a significant association between high MVD and high M2 content in tumors (p⬍0.000). Tumors with high MVD exhibited shorter survival (Wilcoxon statistic 4.845, p⫽0.028). Spearman’s rho nonparametric correlations showed low TLR3 expression correlated with higher MVD (p⫽0.014), advanced pathologic tumor stage (p⫽0.046) and a trend for nodal disease (p⫽0.069). There was no statistically significant association between TLR3 expression and number of M2 macrophages (p⫽0.21). Conclusions: Neovascularization is promoted by tumor-associated macrophages and in turn poorer prognosis in BC. Our results suggest that reduced TLR3 expression is associated with more aggressive breast cancer. Future studies are needed to elucidate a mechanism by which TLR3 is downregulated in highly angiogenic BC. Thus, activation of TLR3 with TLR3-ligands such as poly (A:U) can potentially be coupled with anti-angiogenic therapies in patients with BC exhibiting low TLR3 expression and high MVD to improve treatment outcomes.

Background: Src inhibition may augment sensitivity to chemotherapy, but in unselected patients (pts) with advanced solid tumors, src inhibitors have shown limited clinical activity. Biomarkers to predict benefit from src inhibitors in advanced solid tumors are not yet known. Methods: 22 pts (dose escalation cohort⫽ 12 pts; colorectal cancer [CRC] expansion cohort⫽ 10 pts) were enrolled in a phase I study to determine the safety and tolerability of the src inhibitor dasatinib with capecitabine, oxaliplatin, and bevacizumab (J Clin Oncol 29: 2011 [suppl; abstr 3586]). Src activation (src-a) was assessed in tumors from 16 evaluable pts. Src-a was measured by immunohistochemistry (IHC) in formalin-fixed, paraffinembedded tumor samples using an antibody that selectively recognizes the active conformation of src (clone 28). A GI pathologist who was blinded to pt outcomes graded membranous src-a using a standard semi-quantitative method. The endpoint of this exploratory analysis was objective response rate ([ORR]⫽ PR⫹CR). 2-sided Fisher’s Exact test was used to evaluate the association between ORR and src-a. Results: Across all tumor types, 8 tumors had no/faint src-a (IHC⫽0/1); 8 tumors had moderate/strong src-a (IHCⱖ2). Benign colonic epithelium had no src-a (IHC⫽0). The ORR was 75% (6/8) for pts with moderate/strong src-a versus (vs) 0% (0/8) for pts with no/faint src-a (p ⫽0.007). In the CRC expansion cohort, the ORR was 83% (5/6) for patients with moderate/strong src-a vs 0% (0/2) for pts with no/faint src-a (p⫽0.107); progression free survival range was 7.9-24.4 months for pts with moderate/strong src-a. Conclusions: In this small phase I study, src-a is associated with benefit from the combination of dasatinib and oxaliplatin-based chemotherapy. Further evaluation of dasatinib in patients whose tumors demonstrate high levels of src-a may be warranted. Clinical trial information: NCT00920868.


Tumor Biology 11037


A loss of microRNA expression as a characterization of synchronous peritoneal secondary localizations of epithelial ovarian cancer as compared to primary tumors. Presenting Author: Delia Mezzanzanica, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Background: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy and one of the most challenging areas of cancer research being a highly heterogeneous disease difficult to diagnose and treat. EOC has a peculiar dissemination process due to the sloughing-off of cells from primary tumors and their spread throughout the peritoneal cavity. A better characterization of the mechanism involved in tumor spreading might help in design new therapeutic intervention. Methods: Forty-four couples of chemo naïf primary tumors and synchronous secondary peritoneal localizations, obtained at primary surgery from MITO2 clinical trial, have been profiled for microRNA (miRNA) expression on an Agilent Platform. Total RNA was extracted from formalin-fixed paraffin embedded tissues. An independent validation set of samples with similar characteristics, has been collected at INT Milan. Results: By class comparison analysis, imposing a false discovery rate ⬍10%,45 miRNAs were identified as differentially expressed: 32 down-modulated and 13 up-modulated in secondary localizations compared to primary tumors. Among the miRNAs down-modulated in the secondary localizations we detected most of the miRNA belonging to the Xq27.3 cluster, whose low expression we previously described to be associated with EOC early relapse, and a number of miRNAs related to epithelial/mesenchimal transition (EMT) whose modulation could be related to dissemination of the disease and response to drug treatment. In particularly loss of has-miR-506 resulted associated to platinum resistance since its ectopic expression in EOC cell lines increased their sensitivity to the drug. Furthermore preliminary data indicated that has-miR-506 regulated N-cadherin linking its modulation to EMT. Conclusions: To our knowledge, the present study is the first attempt to characterize a miRNA signature differentially expressed between EOC primary tumors and synchronous secondary peritoneal localizations. The validation of the miRNA profile as well as of target genes might help in elucidating EOC dissemination mechanisms and in defining possible new therapeutic targets.

11039


Effect of nonmalignant accessory cells from the metastatic microenvironment on breast cancer cell resistance to antiestrogens. Presenting Author: Eugen Dhimolea, Harvard Medical School, Boston, MA Background: To address the role of the local metastatic microenvironment in the antiestrogen (AE) resistance exhibited by disseminated breast cancer (BrCa), we assembled heterotypic in vitro three-dimensional (3D) tissue cultures comprised of estrogen receptor-positive (ER⫹) BrCa cells and non-malignant accessory cells from organs frequently targeted by metastatic disease, to model the composition and architecture of metastatic lesions. Methods: MCF7 cells expressing luciferase, cultured alone or with accessory cells, were exposed to dose-ranges of hydroxytamoxifen (4-OHT), fulvestrant or raloxifene. MCF7 cells were also injected s.c. in nude mice either alone or with HS-5 bone marrow stromal cells (BMSCs). Tumor spheroid viability or xenograft growth were measured by bioluminescence. Results: MCF7 response to AEs in 3D conditions (collagen type I and/or Matrigel) was marked by acinar differentiation of tumor spheroids that resembles normal breast epithelium. Co-culture of MCF7 and immortalized accessory cells from the bone (BMSCs; HOBIT and hFOB osteoblasts), brain (SVGp12 astrocytes), liver (THLE3 hepatocytes), and lung (MRC9 fibroblasts) in 3D (but not 2D) conditions, conferred resistance to 4-OHT, raloxifene, and fulvestrant at clinically relevant doses. Heterotypic xenografts (MCF7 ⫹ BMSCs) had reduced response to tamoxifen compared with monotypic xenografts (MCF7 alone). BMSCs induced in MCF7 cells downregulation of TGF␤2; upregulation of a transcriptional signature enriched for genes associated with high-grade tumors, including genes involved in interferon response, signaling through EGFR superfamily members, NFkB and other antiapoptotic pathways; and elevated c-Myc protein levels. Exogenous TGF␤2 or neutralizing antibodies against INF␥ partially re-sensitized MCF7 cells to 4-OHT in co-cultures. Conclusions: Our results indicate that accessory cells representing the microenvironment of metastatic sites confer AE resistance to BrCa cells in 3D tissue cultures and xenograft models. The mechanisms of stroma-induced AE resistance may reveal new therapeutic targets for refractory BrCa patients with metastatic disease.

11038


NOTCH1 as a potential prognostic biomarker for anti-VEGF therapy in patients with metastatic colorectal cancer. Presenting Author: Tadeu Ferreira Paiva, Hospital A.C. Camargo, São Paulo, Brazil Background: There are no validated biomarkers for clinical response or survival benefit in patients treated with bevacizumab (Bv) in advanced metastatic colorectal cancer (mCRC). The aim of this study was to evaluate the predictive value of putative biomarkers in mCRC. Methods: One hundred and five mCRC patients who received Bv combined with FOLFOX or FOLFIRI were retrospectively evaluated for clinical and pathological characteristics. VEGFR1, VEGFR2, VEGFR3, PlGF, DLL4 and NOTCH1 expression were assessed by immunohistochemistry on formalin-fixed, paraffin-embedded neoplastic tissue of either primary or metastatic tissue in a tissue microarray. High levels of expression were defined as less than or equal to or more than the median. Survival curves were calculated by the Kaplan-Meier method and compared by the log-rank test. For multivariate analysis the Cox proportional hazards model was used. Results: Grade 1 or 2 (p⫽0.01), non-mucin-producing histology (p⫽0.04) and presence of liver metastasis (p⫽0.001) were associated with a higher response rate. There was no difference between the expression of markers and the response rate. ECOG 0 or 1 (p⫽0.002), grade 1 or 2 (p⫽0.02), liver metastasis (p⫽0.003), no lymph node metastasis (p⫽0.01) no peritoneal metastasis (p⫽0.02) and resection of metastasis (p⬍0.001) were correlated with higher progression-free survival (PFS). There was also a strong correlation between ECOG 0 or 1 (p⫽0.001), grade 1 or 2 (p⫽0.006), no lymph node metastasis (p⫽0.004), liver metastasis (p⬍0.001) and resection of metastasis (p⬍0.0001) with better overall survival. There was a trend between high expression of NOTCH1 (p⫽0.06) and worst PFS.High expression of VEGFR2 (p⫽0.07) was slightly associated with a better overall survival, while high expression of NOTCH1 was associated with a worse overall survival (p⫽0.01). Using multivariate analysis, NOTCH1 proved to be an independent variable for adverse overall survival (HR 2.01, IC 1.07 – 3.77, p⫽0.02). Conclusions: High NOTCH1 expression assessed by immunohistochemistry is capable of predicting poor survival in advanced colorectal cancer patients treated with bevacizumab.

11040


Targeted next-generation sequencing (NGS) of circulating tumor cells (CTCs) in hormone-sensitive prostate cancer (HSPC). Presenting Author: Stephen V. Liu, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA Background: Recently a succession of new hormonal therapies has emerged, highlighting the need for biomarkers to guide the management of HSPC. Biomarker development in HSPC has been hampered by the absence of primary tumor tissue in men who undergo radiation or present with metastatic disease. CTCs can address this challenge by providing real-time cancer tissue for biomarker analysis in HSPC. To test this approach we conducted a pilot of CTC capture and targeted NGS in HSPC. Methods: Under IRB approval, blood samples from patients with HSPC were labeled with EpCAM ferrofluid and placed into the LiquidBiopsy platform (Cynvenio Biosystems, Inc.), an immunoaffinity-based microfluidic device tailored to query genomic events. CTCs were identified by CK, CD45 and DAPI expression. A matched WBC pellet served as a control representing germline sequence. Amplicon libraries were generated using Life Technologies AmpliSeq 2.0 and sequenced on an Ion Torrent platform. Somatic single nucleotide variants (SNV) present in CTCs but not in WBC were identified. Results: CTCs were detected in all 8 patients with HSPC (CTC median 64.5, range 17-217). Germline variants were consistently detected in matched CTC and WBC samples. Significant SNVs (occurring in ⬎ 1% of DNA in a sample) were found in 4 of 8 CTC samples (range 1-5 SNVs/sample, frequency 1.2%-11.9% with 620X-14,422X coverage). Notably, 3 patients had biochemical recurrence only (no clinical metastases) yet still yielded CTCs associated with SNVs in KIT, APC, RET, SMAD4 and PTEN. One patient who had untreated metastatic disease had the highest number of CTCs which harbored 4 SNVs. Conclusions: This pilot demonstrates the feasibility of using CTCs as real-time disease relevant substrate for NGS to identify personalized genomic targets in HSPC. A high number of CTCs were detectable in all patients and CTC germline variants correlated with matched WBC controls. Encouragingly, even with a relatively narrow, primary tumor-derived AmpliSeq platform, cancer relevant SNVs were detected in half of the patients including those with only biochemical recurrence, making targeted NGS of CTCs a promising approach for biomarker discovery and validation in HSPC.


666s 11041


Circulating tumor cells as a prognostic marker in metastatic non-small-cell lung cancer patients receiving chemotherapy. Presenting Author: Yuichi Sakamori, Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan Background: Radiographic response remains the gold standard for assessment of the chemotherapy effect and has been used as a surrogate endpoint in clinical trials. Recently, circulating tumor cells (CTC) have emerged as a novel prognostic marker in many types of cancer; however, their significance has not been fully examined in patients with non-smallcell lung cancer (NSCLC). Methods: We conducted a prospective study to evaluate the clinical significance of CTC in metastatic NSCLC patients treated with chemotherapy. Peripheral blood samples were collected for CTC analysis before chemotherapy, after 1 cycle of chemotherapy, and after 2 cycles of chemotherapy. CTC analysis was performed using CellSearch (Veridex). Results: One hundred and forty-eight patients wereenrolledbetween August 2009 and January 2012, and 121 patients were eligible for the analysis. CTC was positive (CTC ⱖ1) in 30.6% (37/121) before chemotherapy, in 21.0% (26/118) after 1 cycle of chemotherapy, and in 21.6% (24/111) after 2 cycles of chemotherapy, respectively. CTC counts were higher in patients with N3 lymph node metastases (vs. N0-2, p ⫽ 0.0001), M1b status (vs. M1a, p ⫽ 0.0081) or ⱖ2 metastasis sites (vs. 1 metastasis site, p ⫽ 0.0342). Although not statistically significant, a positive trend was observed between the radiographic response and the dynamic change of CTC counts (p ⫽ 0.0734). In multivariate analysis, including the radiographic response (responder vs. non-responder), baseline CTC was a significant negative predictive factor for PFS (HR ⫽ 1.867; p ⫽ 0.0080) and OS (HR ⫽ 2.753; p ⫽ 0.0006). Considering pre- and post-treatment time points (before and after 2 cycles of chemotherapy) together, CTC-positive patients at either time point experienced significantly worse PFS (HR ⫽ 1.747; p ⫽ 0.0143) and OS (HR ⫽ 2.031; p ⫽ 0.0123) than those who were CTC negative at both time points. Conclusions: CTC was an independent prognostic factor in patients with metastatic NSCLC who was treated with chemotherapy.

11043


11042


Evaluation of prevalence, number, and temporal changes of circulating tumor cells as assessed after 2 and 5 years of follow-up in patients with early breast cancer in the SUCCESS A study. Presenting Author: Emanuel C. A. Bauer, Department of Gynecology and Obstetrics, University Ulm, Ulm, Germany Background: Recent studies revealed that temporal changes in circulating tumor cells (CTC) prevalence assessed before and immediately after adjuvant chemotherapy (CT) might indicate treatment response in early breast cancer (EBC). However, there is limited knowledge on CTC status one or more years after chemotherapy treatment. Here we present descriptive data on CTC status prospectively evaluated 2 and 5 years after primary diagnosis in the German SUCCESS A study. Methods: The SUCCESS A trial is a large, randomized, open-label, 2x2 factorial design Phase III study comparing disease free survival (DFS) in patients with EBC treated with 3 cycles of Epirubicin-Fluorouracil-Cyclophosphamide (FEC) followed by either 3 cycles of Docetaxel (D) or 3 cycles of Gemcitabine-Docetaxel (DG), and comparing DFS in patients treated with 2 years or 5 years of Zoledronate. CTC status at various time points was assessed using the FDA-approved CellSearch System (Veridex, USA). Results: Data on CTC status both at 2 years and at 5 years after primary diagnosis were available for 983 (26.2%) out of 3754 randomized patients. After 2 and 5 years, CTCs were found in 132 (13.4%; median 1; range 1 – 99) and 88 (9.0%; median 1; range 1 – 60) patients, respectively. The majority of patients (n ⫽ 779; 79.2%) had no CTCs at any of the two time points. CTCs were found at 2 years but not at 5 years after primary diagnosis in 116 (11.8%) patients, at 5 years but not at 2 years of follow-up in 72 (7.3%) patients, and both at 2 and at 5 years of follow-up in 16 (1.6%) patients. Conclusions: CTCs in peripheral blood were detected in a subset of early breast cancer patients without relapse up to five years after primary diagnosis. These CTCs may indicate the presence of occult “dormant” micrometastases.

11044


Persistence of HER2 overexpression on circulating tumor cells in patients after systemic treatment for HER2-positive breast cancer: Follow-up results of the German Success B trial. Presenting Author: Julia Katharina Neugebauer, Department of Gynecology and Obstetrics, Klinikum der Ludwig-Maximilians-Universitaet, Munich, Germany

Characterization and identification of specific EGFR mutations in circulating tumor cells (CTCs) isolated from non-small cell lung cancer patients using antibody independent method, ApoStream. Presenting Author: Hai T. Tran, Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX

Background: The discordance between HER2-expression on circulating tumor cells (CTC) in peripheral blood and the primary tumor has already been shown by our study group for early breast cancer patients with HER2-positive tumors. Here, we compare the results to CTC prevalence and HER2-status of CTC after adjuvant chemotherapy. Methods: The SUCCESS B trial compares FEC-Docetaxel vs. FEC-Docetaxel-Gemcitabine and HER2targeted therapy as adjuvant treatment for patients with early, HER2positive, node positive or high risk node negative primary breast cancer. We prospectively analyzed 23ml peripheral blood before and after chemotherapy. CTC and HER2-status were assessed with the CellSearchSystem (Veridex, USA). After immunomagnetic enrichment with an anti-Epcamantibody, cells were labeled with anti-CK 8/18/19, anti-CD45 antibodies as well as a fluorescein conjugate antibody for HER2-phenotyping. Cutoff for CTC positivity was ⱖ 1 CTC. HER-positivity of CTC was assigned if at least one CTC showed strong HER2 staining (3⫹). Results: CTCs and their HER2-status both before and after chemotherapy were available for 392 patients. In 179 (45.7%) patients no CTC were detected before and after chemotherapy. CTC status changed from positive before to negative after chemotherapy in 104 (26.5%) patients and from negative before to positive after chemotherapy in 69 (17.6%) patients, while 40 (10.2%) patients had a consistently positive CTC status. Patients were significantly more likely to change their CTC status from positive to negative than from negative to positive (p ⫽ 0.01). Of the 40 patients with CTC both before and after chemotherapy, 14 (35%) patients had HER2-positive CTC before and after therapy, and 9 (22%) patients had HER2-negative CTC at both time points. 7 (18%) patients had HER2-positive CTC before but not after chemotherapy, while 10 (25%) patients showed the reverse pattern (p ⫽ 0.63). Conclusions: Cytotoxic treatment does not seem to influence the HER2-status on CTC. Follow-up data within the Success B trial will analyze the relevance of the HER2-expression of CTC to predict the efficacy of targeted treatment.

Background: A variety of methods for isolation of CTCs of epithelial origin are available; most employ antibodies to epithelial cell adhesion molecule (EpCAM). Using classic phenotypic definition, a CTC is nucleated, cytokeratin CK(⫹), CD45(-) cell. However, some CTCs may elude capture as they originate from primary tumor cells which have undergone epithelialmesenchymal transition (EMT). We report here the use of ApoStream, a novel dielectrophoresis field-flow-assisted, antibody-free method to isolate CTCs from blood. Methods: Blood was collected from consented NSCLC patients and processed using ApoStrea. For CTC enumeration comparison, CellSearch FDA-approved kit was used. Isolated cells were evaluated with multiplexed immunofluorescent assay and laser scanning cytometry analysis were applied to identify multiple combinations of positive and/or negative staining for CK/CD45/DAPI and EpCam. To determine specific EGFR mutations from captured CTCs, samples were analyzed using Improved and Complete Enrichment with CO-amplification at Lower Denaturation temperature (ICE COLD-PCR). Results: Blood samples from 32 NSCLC patients and 3 healthy volunteers were processed. ApoStream isolated 0 to 65 CK(⫹)/CD45(-) CTCs(n⫽32) and CellSearch isolated 0 to 13 EpCAM(⫹)/CK(⫹)/CD45(-) CTCs(n⫽7). Additionally, ApoStream™ recovered 37-3536 CK(-)/CD45(-) and 4-10702 CK(⫹)/CD45(⫹) cells. EpCAM expression was detected in 7-100% of CK(⫹)/CD45(-) and 0-5% of CK(-)/CD45(-) cells, and 18-100% of CK(⫹)/CD45(⫹) cells. EGFR mutations [exon 19 deletion and exon 21 L858R] were determined and found to be concordant when compared to tumor tissue analysis by Sanger sequencing. Conclusions: The ApoStream platform enriched EpCAM(⫹) and EpCAM(-) CTCs from the blood of NSCLC patients demonstrating utility in recovering cancer cells with multiple phenotypes. From recovered CTCs, detection of EGFR mutations was possible indicating the clinical relevance and potential utility of CTCs as an alternative to tissue biopsy. Complete mutation analysis will be presented.


Tumor Biology 11045


mRNA expression profiles in circulating tumor cells (CTCs) of patients with metastatic breast cancer (MBC) treated with aromatase inhibitors (AI). Presenting Author: Esther Anneke Reijm, Erasmus MC, Department of Medical Oncology and Cancer Genomics Netherlands, Rotterdam, Netherlands Background: Enumeration of CTCs can be used to assess prognosis in MBC and to evaluate treatment response. Besides enumeration, molecular CTC characterization is a promising tool to develop a more personalized treatment approach. Here, we evaluated the association between mRNA expression of currently known CTC-specific genes and response to first-line AI in MBC patients with estrogen receptor (ER)⫹ primary tumors. Methods: CTCs were isolated and enumerated from blood of 25 MBC patients before first-line therapy with an AI. Fourteen patients received a non-steroidal AI (8 letrozole, 6 anastrozole) and 11 patients were treated with exemestane. mRNA expression levels of 96 genes were measured by quantitative RT-PCR as previously described (Sieuwerts et al. Clin Cancer Res. 17:3600-3618, 2011). Expression levels of these genes were studied for their association with time to progression (TTP) after start first-line AI. Results: Median TTP was 338 (range 14 –1,239) days. Median baseline CTC count for the 25 patients was 14 (range 0 –753). In this relatively small cohort, the clinically relevant cut-off level of ⱖ5 CTCs in association with TTP did not reach statistical significance (Hazard Ratio [HR] 4.76, 95% Confidence Interval [CI]: 0.59 –38.22, P⫽0.14). For type of AI, when comparing steroidal with non-steroidal AI, the measures in Cox univariate regression analysis were HR 2.54 (95% CI: 0.67–9.64), P⫽0.17. A 10-gene CTC profile was constructed based on the Wald statistics of the contribution of the individual genes in univariate Cox regression analysis of TTP. To identify patients with good and poor outcome, the Wald corrected sum of the 10 genes was used to dichotomize the continuous 10-gene predictor (HR 12.87 [95% CI: 1.60 –103.56], P⫽0.016). In multivariate analysis, corrected for the clinically relevant variables type of AI and CTC count, only the 10-gene CTC profile was an independent factor associated with TTP (HR 12.46 [95% CI: 1.29-120.08], P⫽0.029). Conclusions: A 10-gene CTC predictor was constructed which distinguishes good and poor outcome to first-line AI in MBC patients. This profile is currently being validated in an independent group of patients.

11047


Sequential monitoring of androgen receptor expression and copy number variation in castration-resistant prostate cancer (CRPC). Presenting Author: Mitchell E. Gross, University of Southern California, Los Angeles, CA Background: The high-definition circulating tumor cell (HD-CTC) assay provides for an enrichment-free approach to identify and characterize CTCs. Here, we utilized the HD-CTC assay to study androgen receptor (AR) expression combined with single-nucleus sequencing for genome-wide analysis of copy number variation (CNV) in sequential samples obtained from patients with CRPC treated with abiraterone acetate (AA). Methods: Patients were approached for participation in a study to provide peripheral blood at baseline, at 2-5 weeks, and at 9-12 weeks (or at progression). In each sample, 106cells (defined with a DAPI-intact nucleus) were quantitatively examined for the presence of cytokeratin and AR (CTCs) and CD45 (leukocytes). Initial results are available from 9 subjects treated with AA as standard of care. Results: At baseline, the median (range) CTC was 7.8 (1.1-57.2) cells/ml. Using a definition of AR positive (AR⫹) as ⬎6 standard deviations over mean signal observed in leukocytes, the median (range) of AR⫹ and total CTCs observed at baseline were 3.1(0-33.8) and 7.8 (1.1-57.2) cells/ml, respectively. Detailed single-nucleus CNV analysis was performed in sequential samples in a single subject (Table). Complex genomic rearrangements were observed including AR amplification and 8p deletion in both AR⫹ and AR- negative (AR-) cells at baseline. During AA treatment, the frequency of AR⫹ CTCs decreased along with changes in the CNV pattern including loss of AR amplification. At 10 weeks, disease progression occurred coincident with re-emergence of an AR⫹ CTC population exhibiting AR amplification and a novel CNV pattern only distantly related to that of the baseline CTCs. While multiple complex abnormalities were noted, MYC amplification was observed at higher frequency in cells present at progression. Conclusions: Overall, our results demonstrate the feasibility of monitoring of CTCs for treatment emergent changes in protein which may be used to better monitoring and predict therapeutic responses in patients with metastatic cancer. Baseline 4 wks AA 10 wks AA

PSA (ng/ml)

CTC/ml

%ARⴙ CTC

51.8 15.5 28.8

57.2 58.8 27.3

59 3 97

11046


Low cytokeratin- and low EpCAM-expressing circulating tumor cells in pancreatic cancer. Presenting Author: Daniel Adams, Creatv MicroTech, Inc., Rockville, MD Background: To date, detecting circulating tumor cells (CTCs) in the peripheral blood of pancreatic patients using standard immuno-capture techniques has met with limited success. As pancreatic cancer is prone to metastasize at distant sites, and therefore should have high numbers of CTCs, it is possible that immuno-capture methods are not suitable for this disease. Using a microfiltration approach, we show that CTCs are present in the peripheral blood in over 75% of pancreatic cancer patients, and that two distinct subtypes can be identified. Methods: Pancreatic patient samples were provided by Medical College of Wisconsin, Milwaukee, WI. CellSieve microfilters, with precision 7 micron diameter pores distributed in uniform arrays were employed. 7.5 mL of whole blood was diluted in pre-fixation solution and filtered through CellSieve microfilters. CTCs collected by this size exclusion technique were fixed, permeabilized, and stained with DAPI, an antibody cocktail against cytokeratin 8, 18 and 19 (FITC), EpCAM (PE), and CD45 (Cy5). CTCs, defined as cytokeratin positive and CD45 negative, were found in two distinct subtypes. One subtype had the “classic” characteristics of a CTC, with high EpCAM and cytokeratin expression, identifiable cytokeratin filamentation, and a cancer-like nuclear structure. The second subtype is indicative of a CTC undergoing epithelialmesenchymal transition (EMT), with low or no EpCAM, weak cytokeratin expression, and a smooth oval nuclear structure. Results: The “classic” CTCs were found in ~20% (n⫽40) of patient samples. The EMT-like CTCs were found in ~75% of the same patient cohort. Neither cell was present in any healthy subjects (n⫽30). EMT-like CTCs consistently lacked EpCAM expression and commonly presented as multi-cell clusters, or microemboli, in ~40% of the cases. Conclusions: We show that two distinct CTC subtypes circulate in the blood of most pancreatic patients. The low expression of cytokeratin and EpCAM of the EMT-like subtype implies that immunocapture based CTC isolation methods have limited utility for pancreatic cancer. Further, this subtype provides a useful strategy for tracking pancreatic CTCs over the course of treatment.

11048


Detection and genomic interrogation of invasive circulating tumor cells (iCTCs) derived from men with metastatic castration resistant prostate cancer (mCRPC). Presenting Author: Terence W. Friedlander, University of California, San Francisco, San Francisco, CA Background: Isolation, enumeration, and genomic profiling of CRPC CTCs offers the potential to discover genetic changes that occur in advanced disease. The Vitatex VitaCap platform captures CTCs based on their ability to invade a collagenous matrix (CAM), allows for capture of invasive CTCs (iCTCs) independent of EpCAM status, and yields viable cells suitable for comprehensive genomic study. Here we sought to compare CTC yields between the CAM and CellSearch platforms, to determine the utility of prostate-specific membrane antigen (PSMA) as an iCTC biomarker, to identify iCTC clusters and iCTCs expressing stem-like markers, and to explore the feasibility of iCTC epigenomic analysis. Methods: CTCs were isolated and enumerated simultaneously using the CellSearch and CAM platforms in 23 men with mCRPC. CAM-isolated iCTCs were defined as EpCAM⫹PSMA⫹ and were enumerated immunocytochemically (ICC) and by flow cytometry. iCTC clusters were enumerated by ICC. The Illumina Infinium HumanMethylation27 BeadChip was used to determine whole genome methylation status for CAM isolated cells. Results: 35 samples were collected for CAM analysis. A median of 27 (range 0-800) and 23 (range 2-390) iCTCs/ml were detected by ICC and flow respectively. In a subset of 20 samples, a median of 7 CTCs/ml (range 0-85) were detected by the CellSearch platform. CTCs were detectable by either CAM or CellSearch in ⬎95% of samples. iCTC clusters were observed in 23% of samples with a median 7 clusters/ml (range 1-200). iCTCs expressing stem-like markers CD44 and Seprase were detected in 70% and 97% of samples by ICC and flow respectively, with a median of 9/ml (range 1-264) by flow. The iCTC methylation profile highly resembled mCRPC. Conclusions: The CAM and CellSearch platforms yield comparable CTC counts. iCTC clusters and iCTCs expressing stem-like markers are detectable using the CAM platform, and the iCTC methylome closely resembles that of mCRPC. Correlation with clinical data may yield further insight into the functional significance of these findings.


668s 11049


Evaluation of UGT1A1 genotyping for predicting individual toxicity of irinotecan plus platinum analog regimens: Interim safety analysis of a prospective observational study. Presenting Author: Masashi Takano, Department of Obstetrics and Gynecology, National Defense Medical College, Tokorozawa, Japan Background: Irinotecan (IRI)⫹platinum (Pt) therapy works synergistically and is widely used for solid carcinomas. Although UGT1A1 genotyping has been implemented in daily practice since long, recommended doses of IRI⫹Pt therapy according to UGT1A1 genotyping remain undetermined. Risk factors for severe toxicities of IRI⫹Pt regimens remain uncertain. We conducted a prospective observational study to examine the correlation between UGT1A1 genotyping and toxicity/efficacy in IRI⫹Pt regimens (NCT 01040312). Methods: During October 2009 and March 2012, 321 patients were enrolled. Eligible patients had histologically confirmed SCLC, non-SCLC, cervical, ovarian, or gastric cancer; had PS 0-2; and were receiving IRI⫹Pt (cisplatin, carboplatin, and nedaplatin) regimen, following UGT1A1 genotyping: hetero (*1/*6, *1/*28) and homo (*6/*6, *6/*28, *28/*28). Primary endpoint was to evaluate overall toxicity profile during first 3 cycles of treatment. In this interim analysis, incidences of grade 3/4 toxicities were compared among UGT1A1 phenotypes, and logistic regression models were used to identify independent risk factors for these toxicities. Results: At the time of abstract writing, toxicity data from 137 patients were available. There were 110 (80%) hetero and 27 (20%) homo genotypes. Combination therapy of IRI (57.2 ⫾ 12.2 mg/m2 for average initial dose) and Pt analogs (cisplatin, 63%; carboplatin, 20%; nedaplatin, 17%) was administered. Incidences of grade 3/4 toxicities during first 3 cycles of treatment in hetero and homo were as follows: leukocytopenia, 38% and 59%; neutropenia, 55% and 67%; thrombocytopenia, 7% and 22%; and diarrhea, 9% and 7%. Overall grade 3/4 hematological toxicity was 50% (55/110) in hetero and 78% (21/27) in homo; the adjusted odds ratio was 3.379 (p ⫽ 0.0185) in homo compared with hetero. Conclusions: A higher rate of grade 3/4 hematological toxicity in homo than in hetero was confirmed with IRI⫹Pt therapy. Thus, UGT1A1 genotyping could be a potential biomarker of toxicity with individualized chemotherapy using low-dose IRI regimens. At the presentation, analysis of ⬎250 patients’ data will be shown. Clinical trial information: NCT01040312.

11051


Prognostic significance of ATP-binding cassette (ABC) and solute carrier (SLC) transporters in pancreatic ductal adenocarcinoma (PDAC). Presenting Author: Beatrice Mohelnikova-Duchonova, Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Olomouc, Czech Republic Background: Resistance against anticancer drugs significantly limits the clinical use and efficacy. One of the most important mechanisms of the multidrug resistance is low accumulation of the drug in cancer cells caused by an increased efflux (mediated mainly by ABCs) or by a decreased uptake (mediated by some members of SLCs). The aim of the present study was to investigate prognostic importance of 13 anticancer drug-relevant SLCs and all 49 human ABCs in PDAC patients in association with clinical and pathological characteristics and the tumor KRAS mutation status. Methods: Tumors and adjacent non-neoplastic pancreatic tissues were obtained from 50 patients with histologically verified PDAC. The transcript profile of ABCs and SLCs was assessed using quantitative real-time PCR. KRAS mutations in exon 2 were assessed by high-resolution melting analysis and sequencing. Associations of transcript levels with clinical parameters were assessed by non-parametric Mann-Whitney tests. The Kaplan-Meier method with the log-rank test and Cox regression were used for analysis of overall survival (OS). Results: Most transporters investigated were deregulated in PDAC and 14 ABCs or SLCs were associated with clinical characteristics. Upregulation of 7 drug resistance-associated ABC efflux transporters and down-regulation of 5 drug uptake-relevant SLC transporters was observed in tumors vs. non-neoplastic tissues. Moreover, expression levels of SLC28A1 and SLC22A1 were associated with OS of all patients (P⫽0.001). High transcript levels of SLC29A3 and SLC22A3 significantly predicted longer OS in chemotherapy-treated patients (P⫽0.004 and P⫽0.038, respectively). No association of ABC and SLC expression with KRAS mutation status was observed. Conclusions: Up-regulation of numerous drug resistance-associated ABCs and down-regulation of SLCs implicated in drug uptake may explain the generally very poor response of PDAC to cytotoxic agents. This study also identified some ABCs and SLCs as potential prognostic and predictive factors in PDAC. Supported by the Czech Science Foundation grant P301/12/1734 and CZ.1.05/2.1.00/ 03.0076 European Regional Development Fund.

11050


Fecal metabolome and microflora differences between colorectal cancer patients and healthy adults. Presenting Author: Tiffany Weir, Department of Food Science and Human Nutrition, Graduate Program in Cell and Molecular Biology, Fort Collins, CO Background: High throughput genomic technologies such as 454 pyrosequencing and metabolomics platforms are now available to explore the relationships between gastrointestinal microflora, metabolism and colorectal cancer (CRC). Recent efforts to characterize the colorectal cancer microbiome have led to the identification of numerous bacteria whose presence or absence is associated with diseased tissue. Methods: Stool samples were collected from 10 healthy adults and 11 colorectal cancer patients prior to surgery at the University of Colorado Health-Poudre Valley Hospital in Fort Collins, CO. Fecal samples were processed for isolation of microbial DNA and sequenced using the 454 pyrosequencing platform. Metabolites were extracted using acidified water for short chain fatty acids (SCFA) and 3:2:2 isopropanol:acetonitrile:water to obtain global metabolite profiles utilizing Gas Chromatography-Mass Spectrometry (GC-MS). Results: There were no significant differences in the overall microbial community structure associated with disease state, but several bacterial genera, particularly butyrate-producing species, were under-represented in the CRC samples, while a mucin-degrading species, Akkermansia muciniphila, was about 4-fold higher in CRC (p⬍0.01). Consequently, the chemoprotective SCFA, butyrate, was significantly lower in CRC samples than in those from healthy adults (p⬍0.0001) and GC-MS profiling revealed that there were higher levels of amino acids in stool samples from CRC patients and higher poly and monounsaturated fatty acids in stool from healthy adults (p⬍0.01). Conclusions: This systems biology approach may allow us to identify functional groups of gastrointestinal bacteria and their associated metabolites as novel therapeutic and chemopreventive targets. The Colorado Agricultural Experiment Station, Shipley Foundation and the NIH R03CA150070 supported this work.

11052


Clinical significance of BIM deletion polymorphism in non-small cell lung cancer with epidermal growth factor receptor mutation. Presenting Author: Kazutoshi Isobe, Department of Respiratory Medicine, Toho University Omori Medical Center, Tokyo, Japan Background: Germ line alterations in the proapoptotic protein BCL2-like 11 (BIM) can have a crucial role in how a tumor responds to treatment. To clarify the clinical usefulness of detecting BIM deletion polymorphism in non-small cell lung cancer (NSCLC) with positive epidermal growth factor receptor (EGFR) mutation we examined the prognosis in patients with or without the BIM changes. Methods: Seventy NSCLC patients with positive EGFR mutation treated with EGFR-tyrosine kinase inhibitor (EGFR-TKI) between January 2008 and January 2013 were enrolled in this study. BIM deletion polymorphism was analyzed by PCR in 58 peripheral blood samples, 24 formalin-fixed paraffin-embedded (FFPE) slides of surgical specimens (lung tissue in 20, brain tissue in 4), and 12 samples that included both blood and tissue specimens. We performed retrospective analyses on clinical characteristics, response rate and toxicity of EGFRTKI, and estimated the prognosis in patients with or without BIM deletion polymorphism. Results: BIM deletion polymorphism was present in 13 of 70 patients (18.6%) with homozygous deletion in 1 and heterozygous deletion in 12. There was no discordance between the two types of samples among the 12 patients. There were no significant differences between patients with or without BIM deletion polymorphism on clinical characteristics, response rate to EGFR-TKI and incidence of EGFR-TKI toxicity. Patients with BIM deletion polymorphism showed significantly shorter PFS that in patients without BIM deletion polymorphism (median: 216 days vs. 430 days, p ⬍ 0.001). There was no significant difference in OS. In multivariate analyses using the Cox regression model, BIM deletion polymorphism (hazard ratio ⫽ 4.2, p⬍ 0.001, 95% CI ⫽ 2.026-8.777) was identified as an independent factor for shorter PFS. Conclusions: BIM deletion polymorphism could be detected by PCR on peripheral blood samples and FFPE slides of surgical specimens. BIM deletion polymorphism has emerged as an independent prognostic factor for shorter PFS. Therefore, new treatment strategies should be established for patients with BIM deletion polymorphism.


Tumor Biology 11053


A genome-wide association study (GWAS) of docetaxel-induced peripheral neuropathy in CALGB 90401 (Alliance). Presenting Author: Daniel Louis Hertz, University of Michigan, Ann Arbor, MI Background: There are currently no effective methods for predicting, preventing, or treating chemotherapy-induced peripheral neuropathy. We performed a genome-wide association study in a clinical trial of castrationresistant prostate cancer (CRPC) to discover variants that may be useful for identifying patients at high risk of neuropathy during docetaxel treatment. Methods: Treatment and toxicity data were collected prospectively on the Cancer and Leukemia Group B (CALGB) 90401 trial of chemotherapy naïve CRPC patients treated with docetaxel and prednisone ⫾ bevacizumab. Genotyping was performed by the RIKEN Institute using the Illumina HumanHap610-Quad platform. Genetically defined European subjects were included in the discovery analysis of all single nucleotide polymorphisms (SNPs) that passed quality control. The primary endpoint was the cumulative dose level triggering a grade 3⫹ sensory neuropathy. The inference was conducted within the framework of a competing risk model accounting for early treatment termination induced by death or progression, or other toxicities. SNPs that were highly associated with neuropathy were assessed for a broader taxane effect in a cohort of paclitaxel-treated patients from a breast cancer clinical trial, CALGB 40101. Results: 623 Caucasian patients and 498,022 SNPs were included in the discovery analysis. The incidence of grade 3 neuropathy was 8%. One intergenic SNP (rs11017056) was associated with increased risk of neuropathy (HR⫽2.83, p⫽4.7x10-7). This association surpassed the genome-wide significance threshold after covariate adjustment (p⫽7.2x10-8). However, none of the 7 SNPs selected for replication were associated with neuropathy in the paclitaxel-treated breast cancer cohort. Conclusions: Using a prospectively enrolled prostate cancer patient cohort we identified multiple SNPs that may identify risk of docetaxel-induced peripheral neuropathy, but not paclitaxel-induced neuropathy. However, since it is unknown whether the genetic factors that affect taxane neuropathy are drug-specific, further replication studies in docetaxel-treated cohorts are of great interest.

11055


The usefulness of UGT1A1 polymorphism testing before starting irinotecanbased chemotherapy. Presenting Author: Taishi Harada, Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan Background: A few studies have revealed an association between UGT1A1 genotype and irinotecan-induced neutropenia. However, the usefulness of UGT1A1 polymorphism testing before starting irinotecan-based chemotherapy is controversial, even now. We assessed the clinical usefulness of UGT1A1 polymorphism testing before chemotherapy. Methods: 136 lung cancer patients were treated with nedaplatin and irinotecan combination chemotherapy as initial chemotherapy. Except for the patients with low enzyme activity of UGT1A1, 70 patients were treated after UGT1A1 polymorphism testing. (test group) 66 patients were treated without UGT1A1 polymorphism testing. (non-test group) We retrospectively analyzed adverse events and compared the test group with non-test group. Results: We could not confirm any reduction in hematologic or nonhematologic toxicity statistically in the test group. In 9 patients with non-hematologic toxicity of grade 4 and 5, 6 patients had febrile neutropenia (FN). All patients with FN were older than 70 years old. Adverse events in elderly patients were significantly more frequent than in the non-elderly. Conclusions: In patients treated with nedaplatin and irinotecan combination chemotherapy, UGT1A1 polymorphism testing before starting chemotherapy did not reduce adverse events. With UGT1A1 polymorphism testing only, it was difficult to predict the onset of severe adverse events. Therefore, it is more important to manage adverse events carefully, especially in elderly patients.

11054


Genomic profiling of breast cancer in African-American women. Presenting Author: Raquel Nunes, Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC Background: Molecular profiling of breast cancer (BC) identifies intrinsic subtypes with distinct gene expression and clinical characteristics. In the US, BC is less frequent in African-American females (AAF); however mortality is higher, particularly among younger women. Unfavorable subtypes of BC seem to be more frequent in premenopausal AAF. Methods: Tumor gene expression in AAF presenting with early stage or locally advanced BC was performed using the Symphony platform on fresh and paraffin-embedded tissue (Agendia inc), a microarray-based method which classifies tumors according to prognosis (MammaPrint, MP), molecular subtype (BluePrint, BP) and estrogen receptor (ER), progesterone receptor (PR) and Human Epidermal Growth Factor Receptor 2 (HER2) mRNA levels (TargetPrint, TP). Genomic information is correlated with clinical and pathologic characteristics and Oncotype DX recurrence score (RS) when available. We plan to enroll 100 patients. Results: Results available in 46 patients. Median age 62 years (range 24-100), 20 stage I, 15 stage II, 11 stage III disease. There was no significant association between MP risk and stage, but MP risk was significantly associated with grade 3 disease (p⫽.006). 9 cancers were triple negative by IHC; using BP, 8 of these were Basal-type and 1 HER2-type. Basal-type was the most common subtype in patients ⱕ 40 years old (p ⬍ .001). In the 6 cases ER positive by IHC but negative by TP, 3 were Basal-type and 3 were HER2-type.14 patients had Oncotype RS results available: 2 were High Risk by Oncotype and MP; 3 had intermediate RS, 2 of which were High Risk by MP; 9 had a low RS, 4 of which were High Risk by MP. Conclusions: African-American women with stage I to III BC often present with High-Risk disease irrespective of stage. BP classified all young patients (ⱕ40) as Basal-type. Molecular subtyping confirmed the biologic heterogeneity in triple negative and hormone positive tumors. Oncotype RS and MP offered different prognostic information. Follow up will be needed to determine correlation with outcome. Funding: MP, BP and TP test provided by Agendia. Biostatistical support by GHUTTCS-CTSA. ER/PR positive

HER2 positive

Low risk (nⴝ14/30%)

MP High risk (nⴝ32/70%)

IHC

TP

IHC

TP

Luminal Basal HER2

14 0 0

17 11 4

31 3 3

31 0 0

0 0 3

0 0 3

11056


BP

Induction of an aggressive phenotype and poor survival in early-stage lung adenocarcinoma and epigenetic inactivation of microRNA-34b/c. Presenting Author: Ernest Nadal, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI Background: The microRNA-34b/c (miR-34b/c) is a transcriptional target of TP53 that is frequently mutated in primary lung adenocarcinoma (AC). We investigated the clinical implications of miR-34b/c methylation in early stage lung AC patients and the functional role of miR-34b/c re-expression in lung AC cell lines. Methods: DNA methylation of miR-34b/c promoter was assessed by real-time PCR temperature dissociation in 15 lung AC cell lines and 140 early stage lung AC resected at the Bellvitge Hospital (Barcelona) and at the University of Michigan (Ann Arbor). Patient characteristics: 65% males, 88% smokers, 68.5% stage I and 31.5% stage II. Expression of miR-34b/c was determined by TaqMan RT-PCR. Two lung AC cell lines (NCI-H1838 and SK-LU-1) were transfected with an expression vector containing both miRs and the effects upon cell proliferation, migration and invasion were determined. Results: MiR-34b/c was methylated in 40% of cell lines and in 46% of primary tumors with significant association with higher tumor stage (P⫽0.033), recurrence (P⫽0.017) and death (P⫽0.005). In the training set (n⫽58), patients with higher levels of miR-34b/c methylation had significantly shorter median DFS (28.5 months) compared to low to medium levels (not reached, log-rank P⫽0.016). In the test set (n⫽82), higher levels of miR-34b/c methylation were also associated to shorter median DFS (19 months) compared to patients with low to medium levels (not reached, log-rank P⫽0.005). MiR-34b/c methylation remained an independent prognostic marker for DFS after adjusting by age, gender and stage. Tumors harboring TP53 mutations and miR-34b/c methylation expressed significantly lower levels of miR-34b/c (Pⱕ0.001). Stable cells expressing miR-34b/c had lower proliferation rate relative to cells transfected with empty vector (Pⱕ0.001). Expressing miR-34b/c in SK-LU-1 cells reduced migration and invasion ability. Conclusions: Epigenetic inactivation of miR-34b/c by DNA methylation is an independent prognostic marker in early stage lung AC. Ectopic expression of miR-34b/c generated a less aggressive phenotype in lung AC cell lines suggesting a potential for therapeutic targeting.


670s 11057


11058


Effect of BRM promoter variants on survival outcomes of stage III-IV non-small cell lung cancer (NSCLC) patients. Presenting Author: Sinead Cuffe, Department of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada

Impact of IVS14ⴙ1G>A and 2846A>T DPYD polymorphisms on toxicity outcome of patients treated with fluoropyrimidine-containing regimens. Presenting Author: Marzia Del Re, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

Background: BRM, a key catalytic subunit of the SWI/SNF chromatin remodeling complex, is a putative tumor susceptibility gene in NSCLC. Loss of BRM expression occurs in 15% of NSCLC, and has been linked to adverse outcome. Recently, our group has shown that variants of two novel BRM promoter insertion polymorphisms (BRM-741, BRM-1321) lead to loss of BRM expression by recruiting histone deacetylases; individuals carrying homozygous variants for both polymorphisms have doubled NSCLC risk; pharmacological reversal of these epigenetic changes is a potentially viable therapeutic strategy. We thus evaluated the effect of BRM promoter variants on survival outcomes of advanced NSCLC patients, where initial clinical trials are likely to be focused. Methods: 564 stage III-IV NSCLC patients were genotyped for the BRM promoter variants using Taqman. Association of BRM variants and overall (OS) and progression-free survival (PFS) were assessed using Cox proportional hazard models adjusted for prognostic variables. Results: Among our patients, 73% were Caucasian, 52% male, median age 63yrs, 55% stage IV disease, and 67% adenocarcinoma. Median OS was 1.6yrs; median follow up, 3.6yrs. The frequency of homozygosity was BRM-741, 23%; BRM-1321, 21%; both, 12%. Homozygous variants of BRM-741 were strongly associated with worse OS (adjusted HR [aHR] 2.3 [p⫽2x10E-8]) and PFS (aHR 2.0 [p⫽2x10E-7]) compared to the wild types. Similar findings were observed for BRM-1321 homozygous variants (aHR for OS 1.8 [p⫽8x10E-5] and aHR for PFS 1.6 [p⫽2x10E-4]). Carrying homozygous variants of both BRM-741 and BRM-1321 was associated with substantially worse OS (aHR 2.3 [p⫽1x10E5]) and PFS (aHR 2.2 [p⫽3x10E-6]), with similar associations seen among the stage III (aHR for OS 2.3 [p⫽6x10E-6]) and stage IV (aHR for OS 2.5 [p⫽5x10E-6]) patients. Conclusions: The same two homozygous BRM promoter variants that are associated with increased risk of NSCLC are also strongly associated with adverse OS and PFS in this cohort of stage III-IV NSCLC patients. Validation of results in a clinical trial dataset is underway, and will better elucidate the prognostic significance of these BRM promoter variants.

Background: DPD deficiency is an inherited syndrome resulting from loss-of-function mutations within the DPYD gene. The IVS14⫹1G⬎A variant is associated with DPD deficiency as a result of a 165-bp deletion in the DPD mRNA. A rare mutation, 2846A⬎T, is characterized by a change of the acidic aspartic acid to the aliphatic valine with potential impairment of enzyme activity (Amstutz et al., 2011). In this study, we describe the spectrum of toxicities of 5-FU and capecitabine in patients carrying the IVS14⫹1G⬎A and 2846A⬎T variants. Methods: Data were collected from 450 patients with gastrointestinal, breast and pancreas cancers. They were evaluated for DPD genotype upon development of grade ⱖ2 nonhematological and ⱖ3 hematological toxicities (CTCAE v. 4) secondary to standard fluoropyrimidine-containing regimens in combination with other cytotoxic agents and/or EGFR and VEGF antibodies. DNA was extracted from blood and IVS14⫹1G⬎A and 2846T⬎C DPD variants were screened on a Real-Time Life Sciences 7900 HT platform. The study was approved by the local Ethics Committee. Results: A total of 23 IVS14⫹1GA, four 2846AT, one IVS14⫹1AA and one 2846TT subjects were identified. Toxicities in all subjects were G3/4 diarrhea (100%), G3/4 mucositis (48%), febrile neutropenia (45%), G3/4 thrombocytopenia (38%), G3/4 anemia (24%), G2/3 hand-foot syndrome (14%), G3 dermatitis (7%) and G2/4 alopecia (7%). The homozygous IVS14⫹1AA patient survived because she was given a reduced 5-FU 250 mg/sqm test dose without folates, while the 2846TT patient deceased after the first cycle of FOLFOX4 treatment. Conclusions: Patients carrying the deleterious IVS14⫹1G⬎A and 2846T⬎C variant alleles display severe toxicities which is fatal in homozygous variant subjects. This finding suggests the usefulness of pre-treatment screening of DPD in patients candidates to fluoropyrimidine treatment. Acknowledgmnents. This study was supported by the Italian Association for Cancer Research (AIRC, Milano) and the Istituto Toscano Tumori (ITT, Firenze, Italy). Reference. Amstutz U, Froehlich TK, Largiadèr CR. Pharmacogenomics 2011;12:1321-36.

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11060



Patient segmentation assay for MAPK pathway mutations. Presenting Author: Matthew John Marton, Merck & Co, Inc, Rahway, NJ

Modulation of breast cancer cell-free DNA with surgical resection. Presenting Author: Howard B. Urnovitz, Chronix Biomedical, Göttingen, Germany

Background: Mutational status of solid tumors is increasingly important for identifying the best treatment options. Tumors harboring activating mutations in RAS and RAF result in constitutive activation of the RAS/MAPK signal transduction pathway and do not respond well to MAPK pathway inhibitors. Scientific attention is mostly focused on the major mutational hotspots in these genes (e.g., KRAS codons 12, 13 and 61, BRAF codon 600). However, there is increasing evidence that other mutations can be tumorigenic. Thus, there is a need for highly sensitive and specific assays to detect these mutations. To address this need, we developed and analytically validated an assay that detects 33 mutations that activate the MAPK pathway. Methods: We constructed a set of multiplexed single nucleotide primer extension (SNPE) assays that detect 33 activating mutations in KRAS, NRAS, or BRAF. The assays were analytically validated using a set of 60 formalin fixed paraffin embedded (FFPE) tissue samples from various tumor types, cell lines, and oligos with specific mutations. Performance was compared to dideoxy sequencing. Discordant calls were resolved with next generation sequencing (NGS). The limit of detection was determined by serial dilution of mutant DNA into wildtype DNA. Results: The developed multiplexed assay requires only 15 ng genomic DNA, relies on established technology, is cost effective, is amenable to high throughput, and can yield a patient eligibility decision in a CLIA lab in 4 days, making it a practical alternative to a NGS-based assay. Since low allele frequency mutations may be critical to patient survival, we devised a replicate strategy to increase the specificity and sensitivity of the assay. We showed that analysis of technical triplicates relative to no replicates increased the sensitivity from 97 to 100% and the specificity from 91 to 100%. Limit of detection varied from 2 -12%, depending on the mutation. Conclusions: We developed a selective and sensitive SNPE assay capable of detecting 33 hotspots in the MAPK pathway. Our approach reduced false positive and false negative calls of low allele frequency samples. The assay has clinical applicability for the selection of patients for early phase clinical studies.

Background: Recently we demonstrated the ability to detect the presence of invasive breast cancer by next generation sequence (NGS) analysis of cell-free DNA (cfDNA) in serum without prior knowledge of the specific gene perturbations of the neoplasm (J. Clin. Oncology 2010; 28 (15S): 10505). We hypothesized that cfDNA levels would hold promise as a marker to monitor therapeutic efficacy in breast cancer. In this study, we sought to determine whether cfDNA decreases after surgery in patients with operable invasive breast cancer. Methods: Serum was collected before and 1-4 weeks after surgery from 16 breast cancer patients and also from 24 age and gender matched controls. cfDNA was isolated from the serum, amplified by Chronix proprietary method and sequenced on an Illumina HiSeq platform. The breast cancer derived cfDNA sequences from each patient were compartmentalized in 250kbp bins, normalized, and compared to the mean (⫹/- 3SD) of the controls to identify regions of chromosomal number imbalance (CNI). Genomic DNA was isolated from the primary tumor and blood WBC buffy coat, pre-amplified, sequenced and subjected to comparative analysis with cfDNA. Results: Analysis of preand post surgery serum demonstrate that CNIs are present in the presurgery serum cfDNA that correlated with the associated tumor CNI and was not observed in WBC genomic DNA. The number of tumor associated CNI DNA biomarkers ranged from as low as 3 to as high as 865. In 13 of 16 patients (81%) analyzed, the post-surgery cfDNA was free of detectable tumor related-CNI DNA. In the remaining 3 patients, only a partial reduction in tumor specific CNI DNA serum biomarkers was observed, since some markers were still detectable after surgery. Conclusions: cfDNA from primary breast carcinomas accurately reflects tumor CNI. Removal of the primary tumor results in the elimination of tumor cfDNA in the majority of patients. Thus cfDNA may be of clinical value in evaluation of therapeutic efficacy on a real time basis. Further work is needed to determine if residual tumor CNI in cfDNA after surgery is a marker of minimal residual disease which can be pursued as a prognostic marker.


Tumor Biology 11061


PIK3CA mutations in primary HER2-positive and triple negative breast cancer. Presenting Author: Sibylle Loibl, German Breast Group, NeuIsenburg, Germany

11062


Correlation of ERCC1 mRNA expression with KRAS mutation status in colorectal, pancreatic, and lung adenocarcinoma. Presenting Author: Diana L. Hanna, USC Norris Comprehensive Cancer Center, Los Angeles, CA

Background: Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in breast cancer (BC), PIK3CA mutations being the most common. Mutations are frequently found in hot-spots located in the helical and kinase domains (exons 9 and 20). Reported data is discrepant with regard to prognostic or predictive value of PIK3CA mutations especially in HER2⫹ve BC. We therefore investigated the frequency and prognostic associations of PIK3CA mutations in HER2⫹ve and triple negative (TN) primary BC by treated with neoadjuvant therapy. Methods: We prospectively evaluated PIK3CA mutations in the 595 participants of the neoadjuvant Geparsixto study (NCT01426880). The study investigates the effect of adding carboplatin to a liposomal doxorubicin/taxane combination for the treatment of patients with HER2⫹ve and TN primary BC. All HER2⫹ve patients received trastuzumab and lapatinib, the TN patients received bevacizumab. HER2, hormone receptors (HR), and Ki67 were centrally assessed. PIK3CAwas genotyped in tumor material from formalin-fixed, paraffin embedded core biopsies taken before therapy using classical Sanger sequencing of exon 9 and 20. Results: From 09/2011 to 11/2012, 595 patients with HER2⫹ve or TN primary BC have been randomized in the Geparsixto study. Median age was 47 years (range 21-78); most tumors were cT2 (65%); cN0 (57%); ductal invasive (93%), grade 3 (65%); within the HER2⫹ve group 28% were HR positive. So far, PIK3CA genotype was evaluated in 395 randomized patients - 176 with HER2⫹ve and 219 with TN disease. Overall, 11.1% were found to have at least one mutation, in HER2⫹ve: 18.2% and TN BC: 5.5%. An exon 9 mutation was detected in 6.3% of the HER2⫹ve and 2.7% of the TNBC cases and an exon 20 mutation in 11.9% of the HER2⫹ve and 3.6% of the TN cases. A mutation in both exons was detected in 2 TN cases. PIK3CAmutations were more frequent in the HER2⫹ve/HR⫹ve compared to the HER2⫹ve/HR-ve group: 22.8% vs 10.6% respectively (p⫽0.047). Conclusions: PIK3CAmutations are more frequent in HER2⫹ve then in TN BC which is in line with previous reports. Results on all 595 patients and the correlation with response to therapy (pCR) will be presented at the meeting. The project has been funded within the EU-FP7 project RESPONSIFY No 278659. Clinical trial information: NCT01426880.

Background: KRAS is mutated in about 40% of colorectal cancers; it is the only validated predictive marker used in patients with metastatic disease. ERCC1 is a critical enzyme in nucleotide excision repair and is associated with response, progression free and overall survival in patients with NSCLC, colorectal, and gastric cancer treated with platinum based chemotherapy. We tested whether ERCC1 mRNA expression correlates with KRAS and BRAF mutation status in patients with colorectal, pancreatic, and lung cancer. Methods: Formalin fixed paraffin embedded tumor specimens from 1,514 patients (573 colorectal; 91 pancreatic; 850 lung) were microdissected; DNA and RNA were extracted. Specifically designed primers and probes were used to detect 7 different base substitutions in codons 12 and 13 of KRAS and the V600E BRAF mutation. ERCC1 mRNA expression levels were measured by quantitative RT-PCR in a CLIA approved laboratory. Results: Mt KRAS tumors had significantly lower ERCC1 mRNA levels relative to wt KRAS tumors in both colorectal (0.89 vs. 1.06; p⬍0.001) and pancreatic (1.20 vs. 1.80; p⫽0.006) groups. While mt KRAS lung tumors showed decreased ERCC1 expression (1.25 vs. 1.39), the trend did not meet significance (p⫽0.069). Within the colorectal subset, mt BRAF cancers trended towards less ERCC1 expression than tumors harboring both wt KRAS/BRAF genes (0.96 vs. 1.06; p⫽0.25). Conclusions: This is one of the first reports linking KRAS mutation status with ERCC1 gene expression in colon, pancreatic and lung cancer. KRAS mutation status may predict sensitivity to platinum based therapy in colon and pancreatic cancer. Colorectal tumors with either the BRAF or KRAS mutation have decreased ERCC1 expression, relative to those that carry both wildtype genes. This may explain the poor sensitivity to oxaliplatin based regimens in these patients. Furthermore, this suggests that ERCC1 expression may be driven by MAPK activation given the uniform ERCC1 downregulation amongst mt KRAS and mt BRAF cancers. Thus, MEK inhibitors may improve the efficacy of oxaliplatin based chemotherapy. Prospective biomarker driven studies should validate these principles, guide clinical decision making and improve outcomes.

11063

11064


Ribonucleotide reductase subunit-2 (RRM2) and thymidylate synthase (TS) to predict shorter survival in patients (pts) with resected stage I-III non-small cell lung cancer (NSCLC). Presenting Author: Francesco Grossi, Lung Cancer Unit, National Institute for Cancer Research, Genova, Italy Background: Tumor biomarkers can help to identify pts with early-stage NSCLC with high risk of relapse and poor prognosis. The aim of this study was to investigate the prognostic value of 7 biomarkers involved in DNA synthesis and repair. Methods: Tumour tissues from 82 radically resected, stage I-III NSCLC pts were consecutively collected to investigate the following biomarkers: excision repair cross-complementation group 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunit 1 (RRM1), ribonucleotide reductase subunit 2 (RRM2), subunit p53R2, thymidylate synthase (TS) and class III beta-tubulin (TUBB3) using immunohistochemistry (IHC) and quantitative real time-polymerase chain reaction (qRT-PCR). Expression levels of these genes were also investigated in a large publicly available NSCLC microarray dataset (Director Challenge Consortium, DCC). Results: RRM2 expression (p⫽0.031), TS expression (p⫽0.023), and pathologic stage (p⬍0.001) were found as independent prognostic factors for shorter survival. The expression of ERCC1, RRM1, p53R2, TUBB3, BRCA1, as well as other clinical characteristics, failed to show any statistically significant association with the survival. Despite the lack of statistical significance, patients with lower RRM2 expression (i.e., ⱕ 140) survived longer than pts with higher RRM2 levels (p⫽0.069). There was a trend towards longer survival for BRCA1-, ERCC1-, RRM1- and TS-negative pts and for p53R2- and TUBB3-positive pts. For all of the biomarkers except TUBB3, the OS trends relative to the protein expression levels were in agreement with those relative to the respective gene expression levels, although the differences were not statistically significant. In the larger DCC dataset, TS (p⫽0.005), and BRCA1 (p⫽0.021) were identified as prognostic markers for OS, independent of tumour stage. Conclusions: This study has shown that high RRM2 and TS protein levels are negative prognostic factors for resected, stage I-III NSCLC pts. The data obtained by qRT-PCR confirmed these results. Analysis of the DCC microarray dataset detected TS and BRCA1 as independent prognostic markers of OS.


Exploration of a plucked hair gene signature as a potential pharmacodynamic marker for the dual PI3K/mTOR inhibitor VS-5584. Presenting Author: David T. Weaver, Verastem, Inc., Cambridge, MA Background: The PI 3-kinase/mTOR pathway plays a central role in cancer cell proliferation, survival, and cancer stem cell mechanisms. Depending on the mode of pathway activation, different PI3K isoforms and mTOR complexes have been shown to play essential roles in oncogenesis. VS-5584 inhibits PI3K/mTOR signaling with equipotency against all four human Class I PI3K isoforms and the mTOR kinase. VS-5584 has been shown to induce broad and robust antitumor activity with corresponding inhibition of PI3K/mTOR downstream targets in human xenograft models. Considering the inhibitory activity of VS-5584 against multiple targets within the PI3K/mTOR pathway, multiple clinical pharmacodynamic biomarkers need to be assessed. Methods: Due to its vascularization, ease of sampling and epithelial origin, anagen hair represents a practical surrogate tissue for monitoring drug effects in patients. Human anagen hair from volunteer donors were treated ex vivo with VS-5584 and another PI3K/ mTOR dual inhibitor, BEZ235. Following 6, or 24 hour exposure to various drug concentrations, RNA was extracted, amplified and analyzed on Affymetrix PrimeView microarrays. Results: Transcriptomic profiles indicated a robust and dose-dependent response to VS-5584. A VS-5584specific 91 gene signature was identified by 3-way ANOVA, and a Connectivity map evaluation indicated a strong positive correlation with other agents targeting the PI3K/mTOR pathway (wortmannin, LY-294002 and sirolimus). Likewise, VS-5584 exposure ex vivo in human anagen hair follicles resulted in a dose responsive suppression at both 6 and 24 hrs with an alternative PI3K/mTOR dual inhibitor 115 gene signature trained on BEZ235. A seven gene subset was consistently reduced by both VS-5584 and BEZ235 at 6 hrs and 24 hrs. Conclusions: Gene signatures from plucked anagen hair may provide a non-invasive approach to assess pharmacodynamic effects of VS-5584 in cancer patients.


672s 11065


Association of IGF2 DMR0 hypomethylation in esophageal squamous cell carcinoma with poor prognosis. Presenting Author: Yoshifumi Baba, Kumamoto University, Kumamoto, Japan Background: The insulin-like growth factor 2 gene (IGF2) is normally imprinted. Loss of imprinting (LOI) of IGF2 in humans is associated with an increased risk of cancer and is controlled by CpG-rich regions known as differentially methylated regions (DMRs). Specifically, the methylation level at IGF2 DMR0 is correlated with IGF2 LOI and is a suggested surrogate marker for IGF2 LOI. A relationship between IGF2 DMR0 hypomethylation and poor prognosis has been shown in colorectal cancer. However, no study has examined the relationships among the IGF2 DMR0 methylation level, LOI, and clinical outcome in esophageal squamous cell carcinoma (ESCC). Methods: The IGF2 imprinting status was screened using ApaI polymorphism, and IGF2 protein expression was evaluated by immunohistochemistry with 30 ESCC tissue specimens. For survival analysis, IGF2 DMR0 methylation was measured using a bisulfitepyrosequencing assay with 216 ESCC tissue specimens. The Cox proportional hazards model was used to calculate mortality hazard ratios (HR) adjusted for clinical, epidemiologic, and pathological variables.The term “prognostic marker” is used throughout this article according to the REMARK Guidelines. Results: Twelve (40%) of 30 cases were informative (i.e., heterozygous for ApaI), and 5 (42%) of 12 informative cases displayed IGF2 LOI. IGF2 LOI cases exhibited lower DMR0 methylation levels (mean, 23%) than IGF2 non-LOI cases (37%). The IGF2 DMR0 methylation level was significantly associated with IGF2 protein expression. Among 202 patients eligible for survival analysis, IGF2 DMR0 hypomethylation was significantly associated with higher cancer-specific mortality (log-rank P⫽0.013; univariate HR⫽2.03, 95% confidence interval: 1.14 –3.58, P⫽0.017; multivariate HR⫽2.34, 95% CI: 1.29-4.22, P⫽0.0054). Conclusions: The IGF2 DMR0 methylation level in ESCC was associated with IGF2 LOI and IGF2 protein expression. In addition, IGF2 DMR0 hypomethylation was associated with a shorter survival time, suggesting its potential role as a prognostic biomarker.

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11066


Micro-RNA signature differences in lung adenocarcinoma with specific driver alterations. Presenting Author: Lorenza Landi, Istituto Toscano Tumori, Department of Medical Oncology, Civil Hospital of Livorno, Livorno, Italy Background: Oncogenic driving alterations define types of lung adenocarcinoma with different prognosis and sensitivity to targeted agents. MicroRNAs (miRNAs) are a new class of non-coding RNAs involved in gene expression regulation. How miRNAs are dysregulated in lung cancer with ALK translocation, EGFR or KRAS mutation is unknown. In this study we aimed to identify miRNA signatures according to the presence of specific driver and to correlate miRNAs deregulation with patient outcome. Methods: The study was conducted in a cohort of 70 lung cancer patients (pts) including 18 ALK⫹ tumors, 11 ALK-/EGFR mutation⫹, 15 ALK-/KRAS mutation⫹, 26 ALK-/EGFR and KRAS wild-type and defined as triple negative. Matched normal lung tissue from 18 cases representative of the entire cohort were also included onto the analysis. RNA was isolated from formalin-fixed paraffin-embedded tissue (FFPE), using the Recover ALL kit (Ambion). NanoString nCounter system platform was used to generate the miRNA profile. We used Limma to test for differential expression analysis of data. The miR-515 family expression between tissues was validated by RT-qPCRs, analyzed using the parametric t-test (unpaired, 2-tailed for validation). Results: miRNA expression profile clusters distinctly ALK⫹ pts from ALK- and normal lung tissue. Within the ALK- group we found specific miRNAs subsets able to sub-stratify KRAS versus EGFR careers clustering sharply triple negative versus EGFR mutation⫹ and triple negative versus KRAS mutation⫹. miRNAs belonging to the miR-515 family seems to be the most deregulated in the ALK⫹ versus ALK-. Although their expression is stably high in normal tissues and ALK⫹ class, they are highly downregulated in KRAS mutated versus EGFR mutated and versus triple negative (p-value ⬍0.001 for all comparisons). Conclusions: miRNAs profile significantly differs in pts with ALK translocation, EGFR mutations and KRAS mutations. Analysis of miR-515 family members is ongoing in order to correlate their expression levels with pts’ outcome. In vitro modulation of miR-515 family expression levels, together with drugs treatment are ongoing in order to find possible chemo-resistance/chemo-sensitivity miRNA dependent, in ALK⫹ and ALK- model.

11068


Integrated genomic analysis of EGFR-mutant non-small cell lung cancer immediately following erlotinib initiation in patients. Presenting Author: Trever Grant Bivona, University of California, San Francisco, San Francisco, CA

Frequency of MET amplification determined by comprehensive nextgeneration sequencing (NGS) in multiple solid tumors and implications for use of MET inhibitors. Presenting Author: Norma Alonzo Palma, Foundation Medicine, Cambridge, MA

Background: Major obstacles limiting the clinical success of EGFR TKI therapy in non-small cell lung cancer (NSCLC) patients are heterogeneity and variability in the initial anti-tumor response to treatment. The underlying molecular basis for this heterogeneity has not been explored in patients immediately after initiation of therapy. Methods: We conducted CT-guided core needle biopsies immediately prior to erlotinib treatment initiation and at 6 days post erlotinib initiation in a patient with histologically confirmed NSCLC harboring an established activating mutation in EGFR. DNA from the paired frozen biopsies and matched normal tissue was analyzed by whole exome sequencing and RNA from the biopsies was analyzed by whole transcriptome sequencing. High-resolution CT images were obtained at the time of each biopsy to compare the degree of molecular and radiographic response observed. Results: Two established activating somatic mutations were identified in EGFR (p.G719A and p. R776H). Selective depletion of each EGFR mutant allele, but not the EGFR wild type allele, was observed upon erlotinib treatment. Gene expression analysis of the paired transcriptomes revealed that erlotinib treatment resulted in significant upregulation of proapoptotic genes including BAD, BAX, BID, CASP3 and growth inhibitory genes including CDKN1A, GADD45B, GADD45G and downregulation of growth-promoting genes including CCNB1 and CCND3. Several unexpected and novel molecular biomarkers were identified by transcriptome analysis and the complete dataset will be presented. High-resolution CT scans revealed no interval radiographic changes in the target lesion and no clinical complications were encountered. Conclusions: This study is the first reported integrated genomic analysis of EGFR-mutant NSCLC immediately following EGFR TKI initiation. We documented the feasibility, safety and utility of this strategy to establish initial drug efficacy at the molecular level prior to any radiographic evidence of response. Additional, serial integrated genomic analysis is ongoing in the index patient and others on therapy to enhance the management of NSCLC patients on targeted therapy.

Background: MET expression has been shown to be prognostic and possibly predictive in several tumor types and both small molecule inhibitors of MET kinase as well as monoclonal antibodies are under study as therapies for this subset of patients. However, the methods to assess MET overexpression are not well standardized. In the clinic, NGS is an advanced diagnostic method for identifying known and unknown targeted-therapy options. We therefore sought to explore the ability of NGS to detect high level MET amplifications in a general oncology population. Methods: We review here the results from analysis of 2,221 FFPE tissue samples across a range of tumor types by an NGS assay in a CLIA-certified laboratory (Foundation Medicine). We specifically report base pair substitutions, small insertions/ homozygous deletions (indels), high level (⬎ 6 copies/nucleus) amplification (amp) and select rearrangements in 189 genes, including MET. Results: MET was altered in 28/2,223 (1.2%) of patient samples. MET alterations were limited to amplifications (median 15X, range 6X-40X); no base pair substitutions, indels, or rearrangements were found. MET amp was present in 3/48 (6.2%) primary bone sarcomas, 1/20 (5.0%) myogenic sarcomas, 2/58 (3.4%) gastric, 1/38 (2.6%) kidney, 2/78 (2.5%) hepatocellular, 1/41 (2.4%) uterine, 4/188 (2.1%) unknown primary, 2/99 (2.0%) ovarian, 8/386 (2.0%) lung, 3/157 (1.9%) colorectal, and 1/109 (0.9%) pancreatic carcinomas. Conclusions: Use of NGS to characterize MET alterations in a 2,000⫹ patient population provides evidence for the role of NGS in identifying the future use of MET-targeted therapy in a variety of common and uncommon solid tumors. Clinical follow-up of the subset of cases treated with a MET inhibitor is ongoing.


Tumor Biology 11069


Prognostic value of microRNAs (miRs) expression in stage I-IIIA lung adenocarcinoma (AC). Presenting Author: Marcin Tomasz Skrzypski, Medical University of Gdansk, Department of Oncology and Radiotherapy, Gdan´sk, Poland Background: About 50% of NSCLC patients (pts) will develop distant metastases following pulmonary resection. Currently, apart from clinical stage at diagnosis, there are no reliable factors to select high-risk pts for adjuvant chemotherapy. We previously demonstrated prognostic value of 22 miRs in frozen samples of early squamous cell lung carcinoma, and the feasibility of their assessment in formalin fixed paraffin embedded (FFPE) samples (Skrzypski et. al. J Clin Oncol 2010;28;15s). In this study, we investigated the expression of 350 microRNAs in operable AC pts. Methods: FFPE tumor samples were obtained from 80 stage I-IIIA pts who underwent curative pulmonary resection, 48% of whom subsequently developed distant metastases. Median follow-up of pts who were disease recurrencefree was 5.8 years (range, 4.0-9.1 years). RNA was isolated from tumor tissue with RecoverAll kit (Ambion). Expression of 350 miRs was analyzed by qRT-PCR (Appliedbiosystems). Raw data were normalized vs. the geometric mean of U6, RNU48 and RNU44 expression. Relative miRs expression was correlated with distant metastases-free survival (MFS) and the mean expression was compared between the groups with and without relapse. Results: Expression of 41 miRs correlated with MFS in Cox regression analysis and 21 of these showed different level in pts with and without relapse in the t-Student test (both at p⬍0.05 level). The top prognostic miRs included miR-99a* (p⫽0.006), miR-1255B (p⫽0.005), miR-1233 (p⫽0.013) and miR-1303 (p⫽0.03); all previosly shown to be prognostic in AC or NSCLC. We also found 14 new microRNAs (patent pending) potentially prognostic for relapse in AC. Conclusions: Expression of selected miRs may aid in prediction of distant relapse in AC pts undergoing pulmonary resection.

11071


Inflammatory phenotype of classical (CD14ⴙⴙCD16-) monocytes in patients with advanced non-small cell lung cancer. Presenting Author: Fiona Margaret McCarthy, Barts Cancer Institute, Queen Mary, University of London, London, United Kingdom Background: Monocytes are intrinsic members of the innate immune system and play an important role in immunity and inflammation. Human monocytes are subdivided into three populations depending on cell surface CD14 ⫹and CD16 expression: Classical (CD14⫹⫹ CD16-), intermediate (CD14 CD16- ) and non-classical (CD14- CD16⫹⫹). These populations have diverse functions and have been postulated to play both anti and pro-inflammatory roles in a variety of diseases including atherosclerosis, sarcoidosis and other rheumatological conditions. However, the prevalent monocyte populations in cancer have not as yet been identified. We aim to define the prevalent monocyte populations in non-small cell lung cancer as well as further characterising them using flow cytometry and Affymetrix technology. Methods: Blood was obtained from 24 newly diagnosed patients with advanced non-small cell lung cancer and 12 age matched healthy donors. Monocyte subpopulations were sorted using flow cytometry. Gene expression profiling was performed using Affymetrix Human U133 Plus 2.0 array. Results: The classical (CD14⫹⫹CD16-) monocyte population is significantly increased in non-small cell lung cancer patients when compared to healthy donors (p⬍0.01). The intermediate (CD14⫹CD16⫹) and non-classical (CD14- CD16⫹⫹) populations are unchanged. Analysis of the gene expression profile of the classical monocyte subset identified 265 up-regulated and 261 down-regulated genes in cancer patients compared to healthy donors (p⬍0.05, fold change ⬎2). These genes were assigned to biological processes with gene ontology annotation. Functional annotation reveals a strong association of regulated genes with the G.O term “inflammation” (p⫽0.009). Among these inflammatory genes are a cluster of chemokines including CXCL2 and CXCR4. Conclusions: By identifying the prevalent monocyte subsets as well as characterising their function in cancer, there is the potential to target detrimental effects and promote their beneficial functions. As such, monocytes subsets may be used as a possible therapeutic target.

11070


Clinical and analytical performance of non-small cell lung cancer biomarkers. Presenting Author: Steven M. Anderson, Laboratory Corporation of America, Research Triangle Park, NC Background: A variety of biomarkers are currently used to help guide treatment decisions for patients with non-small cell lung cancer (NSCLC). These include mutation analysis for the EGFR and KRAS genes, along with gene rearrangement analysis for the ALK and ROS1 loci. In this study we have evaluated the clinical and analytical performance features of these assays in a series of formalin-fixed paraffin-embedded (FFPE) tissue samples. Methods: FFPE samples submitted for analysis of the EGFR, KRAS, ALK and ROS1 genes were evaluated using molecular and FISH assays. EGFR mutation analysis was performed using Sanger nucleic acid sequencing methods for exons 18-21. KRAS mutations were detected using allele specific PCR or pyrosequencing methods. Rearrangements involving the ALK gene were detected using break-apart FISH probes (Abbott Molecular). Genetic alterations involving the ROS1 gene were determined using FISH probes (Kreatech Diagnostics). Over 6,200 test results for these 4 markers are included in this analysis. Results: Mutations in the EGFR gene were detected in 10.1% of samples evaluated (n⫽3,872). A slightly higher percentage of samples from female patients (13%) had a detectable mutation compared to samples from males (7%) (chi-square p⬍0.0001). Deletions in exon 19 (51%) were the most common alterations detected, followed by point mutations in exon 21 (35%). KRAS mutations were detected in approximately 22% of specimens. ALK gene rearrangements were observed in 3.1% of samples (n⫽1,524). Specimens from individuals ⬍50y of age were more likely to provide a positive result (11%) compared to samples from individuals ⬎50y of age (2.5%) (chi-square p⬍0.0001). Gene amplification for the ALK gene was a common finding in the NSCLC samples evaluated. ROS1 alterations were detected in 2.8% of the specimens. In this cohort, no specimens were positive for both an EGFR mutation and an ALK gene rearrangement. Conclusions: Biomarker testing is well established in clinical practice for NSCLC, with results from the tests used to guide important therapy decisions. Assays for biomarkers such as EGFR, KRAS, ALK and ROS1 are robust, allowing for the analysis of multiple analytes in FFPE samples, even when the amount of tissue may be limiting.

11072


Cancer-testis antigens in triple-negative and locally advanced breast cancer. Presenting Author: Samuel John Harris, Joint Austin-Ludwig Oncology Unit, Austin Health, Melbourne, Australia Background: Cancer-Testis Antigens (CTAs) are immunogenic molecules that have increased expression in triple negative breast cancers (TNBC), a phenotype that whilst associated with poorer survival, is chemosensitive. We investigated expression of the CTAs MAGE-A, MAGE-C1, and NY-ESO-1 in women with Locally Advanced Breast Cancers (LABC) and TNBC to determine the association between CTA expression, survival and response to chemotherapy. Methods: We reviewed patient charts, treated for either TNBC or LABC between 1997 and 2011. Tissue samples were used for immunohistochemical (IHC) staining for MAGE-A, MAGE-C1 and NYESO-1 and compared using Fisher’s exact test. Positive expression was defined as any antigen staining above background.. Clinicopathological features were correlated with IHC results and survival estimated using the Kaplan Meier method. Results: A total of 106 cases were investigated (64 TNBC and 42 LABC). In the TNBC cohort the median age was 58 and TNM stages 1 to 3c. CTA expression occurred in 56, 51 and 43% for MAGE-A, MAGE-C1 and NY-ESO-1 respectively. CTA expression was not associated with overall survival (OS) or time to progression. In the LABC cohort the median age was 54 and consisted of stage IIIb tumors. All breast cancer subtypes were represented. CTA expression occurred in 26, 64 and 21% for MAGE-A, MAGE-C1 and NY-ESO-1 respectively. There was no association between CTA expression and response to chemotherapy. In a univariate analysis MAGE-A expression in the LABC group was associated with poorer OS (median 25 vs 76 months, HR 3.347 95% CI 1.44 to 21.68, p⫽0.015). However, there were more TN patients and Grade 3 tumors in the MAGE-A positive group. Across the two groups, MAGE-A (51 vs 14% p⫽0.002) and NY-ESO-1 (37 vs 2% p⫽0.006) but not MAGE-C1 had significantly higher expression in ER -ve tumors. There was higher expression of MAGE-A (51 vs 25% p⫽0.025) and NY-ESO-1 (43 vs 10% p⫽0.002) in Grade 3 tumors. Conclusions: MAGE-A, MAGE-C1 and NY-ESO-1 are highly expressed in TNBC and high-grade subsets of early breast cancer. CTA expression in TNBC was not predictive of survival nor response to chemotherapy in LABC. However, MAGE-A expression was found to be associated with poorer overall survival in LABC.


674s 11073


Analysis of the prognostic impact of Treg-related genes in tumor and stroma in resectable NSCLC. Presenting Author: Marta Usó, Fundación para la Investigación del Hospital General Universitario de Valencia, Valencia, Spain Background: Immunosuppressive regulatory T lymphocytes (Tregs) have been proved to play a critical role in immune tolerance to tumor. In this study we have analyzed the expression of 11 genes related to Tregs in both tumor and stroma samples of resectable NSCLC patients. Methods: Primary tumor tissues of FFPE samples from 125 early-stage NSCLC patients were used in this retrospective study. The most representative areas of tumor cells and tumor stroma of each sample were carefully micro-dissected. RTqPCR using hydrolysis probes (TaqMan, Applied Biosystems) was performed to assess the expression of Treg markers such as: CD127, CD25, FOXP3, CTLA-4, IL-10, TGFB-1, LAG-3, GITR and TNF-a as well as CD4 and CD8. Relative gene expression was assessed using GAPDH and CDKN1B as endogenous controls and results were normalized against a human cDNA (Clontech) as a reference. All statistical analyses were considered significant at p⬍ 0.05. Results: In both tumor and stroma, we found over-expression of CD25 (5.40X and 7.95X, respectively) and down-expression of CD127 (0.28X and 0.37X, respectively). There was a tendency toward higher expression of FOXP3 (1.67X and 2.01X, respectively) and CTLA-4 (1.92X and 1.76X, respectively) as well. Paired Wilcoxon test showed significant gene expression differences between tumor and stroma in FOXP3 (p⫽0.006), CD25 (p⬍0.0001), CD4 (p⬍0.0001), CD8 (p⫽0.028), IL-10 (p⬍0.0001) and TGFB-1 (p⬍0.0001). Kruskal-Wallis test showed that FOXP3 expression was higher in adenocarcinoma than in SCC samples (2.56X vs 1.79X, p⫽0.002). Survival analyses revealed that patients with a “Treg profile” (1CD25 and 2CD127) had a reduced overall survival (OS) (median 29.90 vs 74.33 months, p⫽0.003). We also found that those patients with higher levels of the ratio FOXP3 stroma/tumor had worse time to progression (TTP) (median 32.50 vs NR, p⫽0.04). Conclusions: Treg markers in the tumor microenvironment seem to play an important prognostic role in early-stage NSCLC patients. Supported by grants PS09-01149 and RD06/0020/1024 from ISCIII.

11075


11074


A mouse model for cancer immunoediting with renal cell carcinoma to explore mechanisms of immune escape. Presenting Author: Elizabeth Bigger, Duke University, Durham, NC Background: Cancer immunosurveillance is the immune system’s ability to recognize and destroy newly arising malignant cells. Recent data suggests that the immune system functions also to apply a selective pressure, leading to growth of less immunogenic tumors, a process termed cancer immunoediting. However, direct experimental evidence to support this hypothesis has been lacking. Methods: We examined the interaction between tumor and tumor-specific CD8 T cells in vivo with a model tumor antigen, influenza hemagglutinin (HA), in a renal cell carcinoma cell line (Renca-HA) and studied the HA-specific CD8 T cell response to Renca-HA in vivo. Naïve HA-specific CD8 T cells (Thy1.1⫹) purified from HA-TCR transgenic mice that recognize a Kd-restricted HA epitope were transferred into congenic Thy1.2⫹recipients inoculated the day prior with Renca-HA or wild type Renca (Renca-WT). At subsequent time points, recipient lymphocytes and pulmonary tumors were harvested and analyzed. Results: Four days after transfer, vigorous proliferation of HA-specific CD8 T cells was detected in Renca-HA inoculated mice, but not Renca-WT inoculated mice, leading to activation and effector differentiation of HA-specific T cells. HA-specific CD8 T cell activation resulted in destruction of Renca-HA in vivo, causing a significant (p ⬍0.001) reduction of tumor burden and prolongation of survival. However, a small fraction of Renca-HA tumor cells survived immune-mediated killing and evaded immune surveillance. Microarray technology identified upregulation of transforming growth factor ␤-3 (TGF-␤3) expression in edited Renca-HA, but not in unedited RencaHA, compared with Renca-WT, confirmed by real-time quantitative PCR. Functional abrogation of TGF-␤3 signaling on tumor-specific CD8 T cells delayed Renca HA tumor growth in vivo. Conclusions: These data provide direct evidence for the cancer immunosurveillance and immunoediting processes, and suggest that tumor induction of TGF␤-3 during the immunoediting process suppresses tumor-specific CD8 T cell function in vivo, allowing tumor immune escape. Our results provide mechanistic insights as well as potential strategies to block cancer immune evasion.

11076


Clinical significance of programmed death ligand-1 expression in nonsmall cell lung cancer (NSCLC). Presenting Author: Vamsidhar Velcheti, Yale University, New Haven, CT

Using 124I-PU-H71 PET imaging to predict intratumoral concentration in patients on a phase I trial of PU-H71. Presenting Author: John F. Gerecitano, Memorial Sloan-Kettering Cancer Center, New York, NY

Background: Programmed cell death ligand-1 (PDL1) is expressed on various human cancers and is a major mechanism for immune evasion. Preliminary evidence suggests that PDL1 expression on cancer cells predicts response to anti-PD-1 therapy. Here we report our findings using automated quantitative immunofluorescence (QIF) to determine the frequency and prognostic value of PDL1 in two independent NSCLC cohorts. Methods: Five antibodies against PDL1 were screened for sensitivity and specificity using PDL1 transfected cells, normal human placenta and tonsil. Only one monoclonal antibody (clone 5H1) met criteria for specificity. This antibody was used to assess two cohorts of NSCLC cases in TMAs. The cohorts represented 204 cases from Yale University and 340 cases from hospitals in Greece. PDL1 protein was measured using QIF analysis using AQUA method. In addition, in-situ PDL1 mRNA levels were measured in the Greek cohort using the RNAscope paired-primer assay with AQUA method. Results: PDL1 protein expression was detected in 25% and 36% of the studied cohorts, respectively. PDL1 positivity was significantly associated with the presence of tumor-infiltrating lymphocytes (TIL) in both series. Patients with PDL1 protein positivity had better outcome in both series (Log Rank: p⫽0.036 for Yale cohort, p⫽0.027 for Greek cohort). Multivariate analysis showed that PDL1 expression was associated with better outcome independent of histology, presence of TILs, and stage in the Greek cohort and marginally significant in the Yale cohort. These findings were further validated by the PDL1 in-situ mRNA measurement in the Greek cohort. PDL1 protein and mRNA levels showed a positive non-linear relationship (R2⫽0.14, P⬍0.001). Positive PDL1 mRNA was found in 53% of patients with NSCLC and was also associated with the presence of TILs and longer overall survival (31 vs. 43 months, p⫽0.017). Conclusions: Tumor PDL1 protein positivity is detected in 25-30% of NSCLCs and associates with increased TILs and better outcome. Elevated PDL1 mRNA occurs in a higher proportion of NSCLC cases and provides comparable prognostic information. Measurement of in situ PDL1 protein and mRNA could be of more clinical value than either method alone.

Background: PU-H71 is a Heat Shock Protein 90 inhibitor that can be labeled with 124I without altering its biochemical properties. Intratumoral drug concentration can be calculated based on 124I-PU-H71 (*PU-H71) region of interest analysis and dilution principle. A microdose pilot study has shown uptake of *PU-H71 in a variety of tumors. *PU-H71 PET is currently being used to estimate intratumoral concentrations in subjects on our phase I study. Methods: Patients with previously treated solid tumors or lymphoma are eligible for this phase 1 trial. PU-H71 is given twice-weekly for 2 weeks each 21 days at escalating dose levels. A mix of *PU-H71 and unlabeled PU-H71 is given during cycle 2 followed by serial PET imaging. Patients on the pilot study are administered a microdose of *PU-H71 alone, followed by serial PET scans. Intratumoral PUH-71 concentration is measured directly in optional pre- and post- treatment core needle tumor biopsies (CNB). Results: To date, 13 patients have received PU-H71 on the phase I trial. Of these, 10 have undergone *PU-H71 PET imaging. 4 imaged patients also volunteered for CNBs, with results reported in the table. Of the 10 patients who underwent *PU-H71 imaging in the phase 1 study, 5 also underwent prior *PU-H71 imaging in the microdose pilot. Intratumoral concentrations as calculated in the pilot and phase I studies were in close concordance. Conclusions: *PU-H71 can be used to visualize PU-H71 uptake in a variety of solid tumors and lymphoma, and *PU-H71 PET scans can be used to estimate intratumoral concentrations of PU-H71. Direct intratumoral measurements of PU-H71 correlate reasonably closely with concentrations calculated from *PU-H71 PET imaging. Further refinement of this imaging tool will allow quantitative assessment of PU-H71 uptake in tumors during the ongoing phase I trial. Clinical trial information: NCT01393509. Patient number (dose on phase I trial) 9 (20 mg/m2) 12 (35 mg/m2) 13 (35 mg/m2) 14 (50 mg/m2)

Tumor type

*PU-H71 PET estimate of intratumoral PU-H71 concentration (␮M)

Direct assessment of intratumoral PU-H71 concentration using CNB (␮M)

HER2-positive breast Mantle cell lymphoma Triple-negative breast Marginal zone lymphoma

0.5788 0.9012 1.5152 0.8059

0.614308 0.345916 0.928249 0.577078


Tumor Biology 11077


Target lesion selection as a source of variability of response classification by RECIST 1.1. Presenting Author: Christiane K. Kuhl, University of Aachen, RWTH, Aachen, Germany Background: Response classification in RECIST is based on manual uni-dimensional quantification of changes of target lesion size. In RECIST 1.1, the maximum number of target lesions was reduced to 5, with a maximum of 2 per organ. We analyzed the importance of different factors (manual vs. automated size measurement, uni- vs. three-dimensional size assessment, and between-reader-variability of target lesion selection) on response categorization. Methods: 41 female patients (58.1⫾13.2 y) with metastatic breast cancer underwent contrast-enhanced thoraco-abdominal CT for initial staging and first follow-up after systemic chemotherapy. Data were independently and prospectively interpreted by three radiologists. In addition, response was evaluated by a CAD system that allowed automated uni- and three-dimensional assessment of target lesions. Results: Response classification differed between readers in 19/41 patients (46%). In 25/41 patients, readers chose the same target lesions. In 6 of these 25 patients (24%), readers disagreed with regards to response classification. In 16/41 patients, readers chose different target lesions. In 13 of these 16 patients, readers disagreed (81%) (p ⬍ 0.001). When dichotomizing response classification according to its therapeutic implication into progressive vs. non-progressive disease, readers disagreed in 11/41 patients (27%). In 9 of these 11 patients, readers had chosen different target lesions. Classification by manual vs. automated uni-dimensional measurement differed in 11/41 of patients (27%). Classification by uni-dimensional vs. volumetric measurements differed in 6/41 of patients (15%). Conclusions: Response classification by RECIST suffers from substantial between-reader variability. Major source of variability is not the manual or uni-dimensional measurement, but the variable choice of target lesions between readers. Same target lesions selected (n ⴝ 25; 100%) n % Agreement (n ⴝ 22) Disagreement (n ⴝ 19) Dichotomized analysis* Agreement (n ⴝ 30) Disagreement (n ⴝ 11)

Different target lesions selected (n ⴝ 16; 100%) n %

19 6

76 % 24 %

3 13

19 % 81 %

23 2

92 % 8%

7 9

44 % 56 %

11078


The predictive role of integrated BRCA1 and HERC2 mRNA expression in advanced non-small cell lung cancer (NSCLC) patients (p) treated with platinum-based first-line chemotherapy. Presenting Author: Laura Bonanno, Istituto Oncologico Veneto, Medical Oncology, Padova, Italy Background: The use of cis- or carboplatin is the backbone of first-line treatment for advanced NSCLC p, and currently no molecular markers of platinum sensitivity are used in routine clinical practice. Preclinical data and retrospective analyses have shown that high BRCA1 expression is associated with resistance to platinum. HERC2 is an E3 ubiquitin ligase promoting DNA repair by interacting with the E3 ubiquitin ligase RNF8 to facilitate the assembly of the RNF8-UBC13 complex, leading to the recruitment of BRCA1 and other DNA repair components responsible for double-strand break repair. Methods: We retrospectively analyzed 71 tumor samples from advanced NSCLC p treated with cis- or carboplatin plus gemcitabine or pemetrexed in the first-line setting. BRCA1 and HERC2 mRNA levels were determined by real-time PCR and categorized using medians as cut-off points. Results: Overall survival (OS) for all 71 p was 10.7 months (m), and progression free survival (PFS) was 7.2 m. Expression of both genes was successfully analyzed in 53 p (74. 6%). Neither gene as a single variable influenced outcome. However, the joint effect of BRCA1 and HERC2 was significant for predictive modeling. Among 30 p with low BRCA1 levels, OS was 15.3 m and PFS was 7.4 m in the 21 p with low HERC2 levels, compared to 7.4 m and 5.9 m, respectively, in the 9 p with high HERC2 levels (OS, P⫽0.008; PFS, P⫽0.01). The multivariate analyses identified the combination of low BRCA1 and low HERC2 expression as predictive of longer OS and PFS. In contrast, high levels of either gene were associated with an increased risk of death (HR⫽3.7, P⫽0.004) and of progression (HR⫽1.4, P⫽0.03). Conclusions: The integrated analysis of multiple DNA repair components can improve available predictive models in NSCLC. BRCA1 and HERC2 low expression levels can predict improved outcome to first-line platinumbased chemotherapy.

*Aggregation of response classes in progressive (PD) versus non-progressive (SD, PR, CR).

11079


The clinical impact and prognostic value of 18F-fluorodeoxyglucose PET/CT in the initial staging non-small cell lung cancer at MD Anderson Cancer Center. Presenting Author: Satoshi Takeuchi, The University of Texas MD Anderson Cancer Center, Houston, TX Background: 18F-fluorodeoxyglucosePositron Emission Tomography/Computed Tomography (FDG-PET/CT) has an important role for Non-Small Cell lung cancer (NSCLC) management, especially in staging. Our objective was to assess stage migration, the clinical impact, and prognostic value of PET/CT in patients with NSCLC at MD Anderson Cancer Center (MDACC). Methods: We retrospectively reviewed the database from MDACC, and identified 729 NSCLC patients referred for staging between 2006 and 2011. Stage was classified using TNM classification. FDG-PET/CT and conventional imaging staging were compared with all-cause mortality and the survival rates of the respective clinical stage. The management impact of FDG-PET/CT was determined based on conventional imaging and PET/CT management plans. A change in stage was confirmed by histopathology and/or further imaging. Results: We identified 598 NSCLC patients with FDG-PET/CT and conventional imaging performed. FDG-PET/CT changed stage in 28.1 % (16.4 % upstaged, 11.7 % downstaged). Based on FDG-PET/CT, treatment plans were modified in 38 % of patients. Median progression free survival (PFS) and overall survival (OS) was significantly worse in patients with management impact of FDG-PET/CT than patients without impact (PFS, 24.9 v 60.6 months, P ⬍ 0.001; OS, 66.7 v 115.9 months, P ⬍ 0.001). Multivariate analysis showed that the impact of FDG-PET/CT impact on management was an independent prognostic factor for DFS (hazard ratio [HR] ⫽ 2.08; 95 % CI, 1.63 to 2.65; P ⬍ 0.001) and OS (HR ⫽ 2.16; 95 % CI, 1.56 to 2.99; P ⬍ 0.001). Stage migration from stage I (40/249 patients) showed worse outcome than those without change (PFS, 21.0 v 60.0 months, P ⬍ 0.001; OS, 64.7 v 115.9 months, P ⫽ 0.003). Conclusions: FDG-PET/CT has major role in NSCLC management. The added staging information provided by FDG-PET/CT as compared to conventional imaging resulted in a change in management in more than one third NSCLC patients. FDG-PET/CT is also a powerful tool for outcome prediction. Even in patients diagnosed as stage I by conventional method, FDG-PET/CT at initial diagnosis may have an impact on survival.

11080


Molecular tumor profiling (MTP) of poorly differentiated neoplasms (PDN) of unknown primary site. Presenting Author: F Anthony Greco, Tennessee Oncology, PLLC/SCRI, Nashville, TN Background: The inability to definitively determine the lineage of neoplasms is less common with modern immunohistochemistry (IHC) and genetic profiling. Nonetheless some PDN defy lineage classification by extensive standard pathologic evaluation. The advent of MTP may provide a new method of improving the diagnosis of these challenging cancers. Methods: A total of 30 of 751 (4%) patients (pts) seen from 2000 – 2012 with cancer of unknown primary (CUP) had PDN without a definitive lineage determined by IHC (median 18 IHC stains, range 9 – 51). From 2008 – 2012 the 30 biopsies had MTP (RT-PCR mRNA CancerTYPE ID, bioTheranostics, Inc.). Additional IHC, genetic sequencing, fluorescent in situ hybridization for specific chromosomal changes and repeat biopsies were performed when feasible to support the MTP diagnosis, and clinical features correlated. Results: MTP lineage diagnoses were made in 25 of 30 (83%), including 10 carcinomas (3 germ cell, 2 neuroendocrine, 5 others), 5 melanomas, 8 sarcomas (3 peritoneal mesothelioma, 1 PNET) and 2 hematopoietic neoplasms (1 lymphoma, 1 chloroma). Additional IHC, genetic testing [BRAF, i(12)p] or repeat biopsies confirmed the MTP diagnoses in 11 of 15 tumors, and the clinical features were consistent with the MTP diagnoses in the majority of patients. Conclusions: This MTP assay can frequently provide a diagnosis for CUP pts and PDN without a definitive lineage defined by extensive IHC. The earlier application of MTP will likely provide an expedited diagnosis, and for some neoplasms is the only test capable of defining lineage and a more specific diagnosis. Appropriate therapy, particularly for pts with germ cell tumors, melanoma, and lymphoma depends on a specific tissue of origin diagnosis.


676s 11081


Noninvasive measurement of prostate-specific membrane antigen (PSMA) expression with radiolabeled J591 imaging: A prognostic tool for metastatic castration-resistant prostate cancer (CRPC). Presenting Author: Scott T. Tagawa, Weill Cornell Medical College, New York, NY Background: PSMA is nearly universally expressed by PC, upregulated with increased grade and castration-resistance. Evidence points towards PSMA expression as a downstream cellular biomarker of androgen receptor (AR) activity and non-invasive measurement of PSMA expression has recently been demonstrated to be a novel biomarker of AR activity. Methods: Planar gamma camera images following radiolabeled J591 (111In-J591 or 177LuJ591) were semi-quantitatively scored using 2 methods by 2 independent radiologists blinded to outcome.A 5-point visual score (VS) of 0 - 4⫹ was assigned. Tissue Targeting Index (TTI), a novel metric designed to semiquantitatively score images was calculated using the ratio of lesion count density (corrected for background) to whole body count density, with maximum (TTImax) and mean (TTIave) scores recorded. Follow up tabulating subsequent therapies and overall survival (OS) was recorded and imaging scores were associated with OS using Cox regression analysis. Results: 130 men with metastatic CRPC underwent radiolabeled J591 imaging. 86.2% had bone metastases, 51.5% lymph node, 16.9% lung, 9.2% liver. 87.7% had accurate targeting of known sites of disease by planar imaging. CALGB (Halabi) nomogram scores were prognostic for the population. As continuous variables, TTImax (p⫽0.013) and TTIave (p⫽0.002) were associated with worse survival. VS demonstrated a trend for worse survival (p⫽0.09). In multivariate analysis, TTI maintained independent prognostic value when controlling for Halabi score: TTImax HR 1.05 [95% CI 1.01, 1.10; p⫽0.02], TTIaveHR 1.09 [1.03, 1.16; p⫽0.004]. Conclusions: Level of PSMA expression measured by planar gamma-camera imaging following radiolabeled J591 is associated with OS in men with metastatic CRPC. High PSMA expression may indicate more aggressive tumor biology with increased AR pathway dysfunction. Improvements in quantitative molecular imaging techniques such as PSMA PET/CT with 89Zr-J591 may prove to be a valuable prognostic and predictive biomarker, particularly in the setting of AR- and PSMA-targeted therapy. Clinical trial information: NCT00195039, NCT00538668.

11083


Developing a molecular imaging agent for Met using onartuzumab (MetMAb). Presenting Author: Cara Elizabeth Wright, Urologic Oncology Branch, National Cancer Institute at the National Institutes of Health, Bethesda, MD Background: Developing an imaging agent to assess Met expression would aid in diagnosis and monitoring tumor response to Met-targeted therapies. Onartuzumab (MetMAb), a Met selective humanized one-armed monoclonal antibody, has been studied in Phase I-II clinical trials in which it was generally well tolerated and has shown the most benefit in patients with MET positive tumors. Methods: Studies to assess Met-binding were executed using the human gastric carcinoma cell line MKN-45 which exhibits a high level of Met expression. Murine PET studies and biodistribution assays were performed using MKN-45 xenografts. Results: Plasma shed Met concentration is directly related to total tumor burden (p ⬍ 0.001). The absence of a positive correlation between shed Met and %ID in blood indicates that binding of tracer to shed Met present in plasma is unlikely. There are positive correlations between tumor mass, Met abundance, and phosphoMet content and uptake of 89Zr-df-onartuzumab in MKN-45 mouse xenografts. Lastly, tumor mass, Met, pMet and 89Zr-df-onartuzumab uptake were all significantly decreased by drug treatment. Conclusions: MKN-45 tumor uptake of 89Zr-df-onartuzumab correlated significantly with tumor mass and Met abundance. Blood tracer uptake did not positively correlate with the presence of plasma shed Met. The amounts of Met, pMet, as well as 89Zr-df-onartuzumab image intensity correlated significantly with tumor size (all Spearman p values ⬍ 0.001).Tumor volumes and Met content were significantly decreased in TKI treated versus control mice, which correlated with imaging results.89Zr-df-onartuzumab has potential utility for imaging Met to identify patients for treatment with Met-targeted therapeutics and to identify the emergence of Met-driven acquired resistance to other molecularly targeted cancer therapies.

11082


Prognostic value of waterfall plots with the addition of nontarget lesion data. Presenting Author: William Leonard Mietlowski, Novartis Oncology, East Hanover, NJ Background: In patients with solid tumors, the use of a waterfall plot displaying the best percentage change in sum of the longest diameters of target lesions per patient is a common way to depict anti-tumor activity for cytostatic agents (Booth 2008, Dhani 2009). This representation assumes that the best percentage change represents the maximum anti-tumor activity for each patient. Information about new lesions and/or changes in non-target lesions is not incorporated in the waterfall plot; yet these additional events were found to be significant prognostic factors for overall survival adjusting for change in the target lesions (Litiere 2012, Suzuki 2012). Methods: We analyzed two phase III lung cancer trials of 1st and 2nd line combination chemotherapy ⫾ ASA404 (ATTRACT-1,n⫽1299, ATTRACT-2, n⫽ 920). For patients whose best response in the target lesions was shrinkage, we calculated how often this best response was synchronously accompanied by non-target disease progression. Results: See Table. Conclusions: There can be substantial tumor shrinkage in target lesions synchronously with progressive disease outside the target lesions. Therefore, graphical displays of anti-tumor activity should consider incorporating new and non-target lesion information, as well as target lesion tumor burden. We propose an extended waterfall plot presenting a more complete assessment of anti-tumor activity by incorporating non-target lesion information. We illustrate its utility in an additional data set, the RECORD-1 phase III renal cell cancer trial. Clinical trial information: NCT00662597. Best shrinkage (%) in target lesion diameters

Fraction (%) of patients with non-target PD at time of best target lesion response. ATTRACT-1 ATTRACT-1 ATTRACT-2 ATTRACT-2 ASA-404 Control ASA-404 Control

>30% 20/231* (9) 26/238 (11) 8/68 (12) 8/65 (12) >0% (some shrinkage) 70/484 (14) 62/460 (13) 35/231 (15) 47/255 (18) * 231 patients achieved at least a 30% shrinkage in the target lesion tumor burden. Of these 231, 20 patients (9%) had synchronous disease progression outside the target lesions.

11084


Recall rate in a semi-annual breast surveillance program for high-risk women. Presenting Author: Hiroyuki Abe, The University of Chicago Medical Center, Chicago, IL Background: High recall rate and unnecessary biopsies are a concern with screening mammogram (MMG) and magnetic resonance imaging (MRI) in young women at high risk for breast cancer. The aim of this study is to investigate the overall recall rate (ORR) and its consequences in a semi-annual MRI surveillance protocol. Methods: A multi-modality surveillance program for women at high-risk for breast cancer was initiated in 2004. Yearly MMG was supplemented with semi-annual MRI. After 5 years of this protocol, an additional 5 years of follow-up with yearly MMG and MRI were offered only to mutation carriers. Defining positive screening as BIRADS 0, 4 and 5, ORR were analyzed and biopsies findings characterized. Fisher’s exact test was performed to evaluate association between the effect of MMG density, menopausal status, mutation status, age (⬍50y or ⬎ 50y), and previous breast cancer with recalls. Results: With a mean follow-up of 3.6 years, 226 patients (pts) underwent 1,467 MRI and 851 MMG. Among 56 abnormal MRI and 18 abnormal MMG, 62 pts (27%) were recalled for further tests (6 recalled at two screening episodes). The MRI and MMG ORR were 3.8% and 2.1%, respectively. Only six cases (8.8%) were abnormal for both tests. Overall, 50 additional breast ultrasound, 10 additional MMG, 8 additional MRI were performed. Of the 40 biopsies in 38 pts (2 pts were biopsied twice), 11 cancers were detected (ductal in situ: 3; invasive: 7 ductal and 1 lobular). Abnormal MRI findings led to 37 biopsies, of which 10 (27%) detected cancers. One high-grade ductal carcinoma in situ was exclusively detected by MMG. The first and second MRI screening rounds together showed 27/56 (66%) abnormal findings which led to 23/40 (58%) of the biopsies, and detected 5/11 (45%) of the tumors. No statistically significant predictors of recall were identified (p ⬍ 0.05). Conclusions: Semi-Annual MRI protocol did not show increased ORR when compared to annual MRI/MMG surveillance. Approximately twothirds of all recalls were in the first two rounds of screening which is consistent with previous results. Ongoing work will evaluate clinical and MRI features associated with recall to improve practice. Clinical trial information: NCT00989638.


Tumor Biology 11085


11086


The CAP-IASLC-AMP molecular testing guideline for the selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors. Presenting Author: Marc Ladanyi, Memorial Sloan-Kettering Cancer Center, New York, NY

BRAF mutation testing with a novel, rapid, fully automated molecular diagnostics prototype platform. Presenting Author: Helen J. Huang, Department of Investigational Cancer Therapeutics (Phase I Program), University of Texas MD Anderson Cancer Center, Houston, TX

Background: The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) jointly initiated an effort to establish evidencebased recommendations for the molecular analysis of lung cancers required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. Methods: Three co-chairs without relevant conflicts of interest were selected, one from each of the sponsoring societies: CAP (P.T.C.), IASLC (M.L.), and AMP (N.I.L.). Writing and advisory panels were formed from additional experts from these societies. Unbiased literature searches were performed to capture articles up to February 2012, yielding 1,533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for relevance. Evidence was formally graded for each of the recommendations first formulated by the co-chairs and panel members at a public meeting. Each guideline section was assigned to at least two panelists. Successive drafts were circulated for comments to the writing panel, the advisory panel, the public (online posting), and the three professional societies. Results: We generated 37 guideline items addressing 14 areas of EGFR and ALK testing. The major, evidence-based recommendations are to test for EGFR mutations and ALK fusions in all patients with advanced stage adenocarcinoma, regardless of sex, race, or smoking history, and to prioritize EGFR and ALK testing over other molecular predictive tests. Recommendations and expert consensus opinions were generated for all other key aspects of EGFR and ALK testing in lung cancer related to oncology and pathology practice and technical issues in molecular testing. Conclusions: As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards and thereby improving patient outcomes.

Background: Mutations in the BRAF gene provide actionable targets for cancer therapy in melanoma and other tumor types. Novel, fast, and accurate diagnostic systems are needed for further implementation of personalized therapy. Methods: The molecular diagnostics (MDx) prototype platform (Biocartis, Mechelen, Belgium) is a fully integrated real-time PCR-based system with high sensitivity (1% mutant in wild-type [wt] background) and fast turnaround time (⬍ 90 minutes), which requires no sample preparation and ⬍2 min hands-on time. Archival formalin-fixed paraffin-embedded tumor samples (1 to 5 shavings of 10 ␮m) from patients (pts) with advanced cancers previously tested for V600 BRAF mutations in a CLIA-certified Molecular Diagnostic Laboratory (PCR-based sequencing or Sequenom MassARRAY) were tested for BRAF V600 mutations using the MDx prototype platform. Concordance between methods and treatment outcomes with BRAF/MEK inhibitors were analyzed. Results: Forty-seven pts (melanoma, n⫽26; colorectal, n⫽8; papillary thyroid, n⫽3; other cancers, n⫽10) with available tissue and CLIA laboratory BRAF results were selected (BRAF V600 mutant, n⫽37; BRAF V600 wt, n⫽10). Of the 40 pts for whom the same tissue block was used for MDx and CLIA, BRAF status was concordant in 38 (95%; kappa 0.87; 95% CI 0.69-1.05) of them. BRAF status by MDx was discordant with CLIA in 3 of 47 cases (mutant by CLIA, but not MDx); one discrepant case contained a different mutation subtype (resp. V600E vs. V600K/R), and in another case different tissue blocks were used for MDx vs. CLIA testing. Of 34 pts with BRAF mutations detected by MDx, 28 were treated on protocols (on the basis of the CLIA results) with BRAF/MEK inhibitors and 8 (29%) had a partial (n⫽7) or complete response (n⫽1). Of interest, 1 pt with prostate cancer (V600E by CLIA, wt by MDx) received a BRAF/MEK inhibitor and did not respond. Detailed patient characteristics, mutation types and discrepancy analysis will be presented. Conclusions: The BRAF V600 mutation MDx prototype assay is a fast (turn-around time about 1.5 hours) and simple (⬍2 minutes hands-on time) test to determine BRAF mutation status with 95% concordance with CLIA laboratory if identical tissue blocks are used.

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Tumor, skin, and plasma concentrations of protein kinase inhibitors (PKIs) in patients with advanced cancer. Presenting Author: Mariette Labots, Department of Medical Oncology, VU University Medical Center, Amsterdam, Netherlands

Objective measurement of breast density, a marker of breast cancer risk, using fully automated radiation- and compression-free MRI. Presenting Author: Georg Wengert, Medical University Vienna, Department of Radiology, Division of Molecular and Gender Imaging, Vienna, Austria

Background: PKIs are selective for target receptors at low concentrations, but they act promiscuously at higher concentrations (PMID 18183025). This lack of selectivity may be relevant for their antitumor activity and for the development of PKI treatment selection tools. To obtain more insight in their clinical mechanism of action, we designed a pilot study to determine PKI tumor, skin and plasma concentrations in patients (pts) after 2 weeks of treatment. Results are related to cell line sensitivity data. Methods: Prior to standard palliative systemic treatment, pts were allocated to standarddose PKI treatment (N⫽5 per PKI) for 10-14 days. Plasma, tumor and skin biopsies were collected within 24 hours of last dose. Sample PKI concentrations were determined by liquid chromatography – tandem mass spectrometry (LC-MS/MS); tissue concentrations in pg/mg were converted to molarity for comparison with preclinical sensitivity data (PMID 21980135). Concentrations of sunitinib (SUN), sorafenib (SOR), erlotinib (ERL), dasatinib (DAS) and everolimus (EVE) that inhibit 50% of cell proliferation (IC50) were determined by MTT assay in 1 RCC (786-O) and 8 CRC cell lines (HCT 116, HT-29, RKO, SW480, SW1398, DLD-1, COLO 205, CaCo-2). Results: Since August 2011 samples were obtained from 27 pts; 5 received SUN, 4 SOR, 4 ERL, 5 DAS and 5 EVE. After 12 ⫾ 1 days of treatment, median tumor concentration (TC) was 9.0 ␮M (2.3-50.0) (range) for SUN, 8.5 ␮M (3.7-22.0) for SOR, 5.3 ␮M (0.9-10.8) for ERL and 2.1 ␮M (0.2-64.0) for DAS. EVE was measurable in 2 of 5 tumors: 3.5 ␮M (3.4-3.6). On average, PKI skin concentrations were 2.4-fold lower than TCs. SOR and ERL plasma concentrations (PCs) were in the range of TCs while SUN and DAS PCs were at least 14-fold lower than in tumors. Mean IC50 of the cell line panel was 1.3 ␮M (0.8-1.4) for SUN, 2.2 ␮M (1.4-3) for SOR, 8.2 ␮M (4-11.5) for ERL, 0.06 ␮M (0.02-1.8) for DAS and 1.2 ␮M (0.05-11) for EVE. Conclusions: PKI tumor concentrations may vary considerably from plasma concentrations, but are in the IC50 range of cancer cells in vitro. These results are indicative for the inhibitory concentrations of PKIs in patient tumors and should be considered for the development of individualized treatment strategies. Clinical trial information: NCT01636908.

Background: Women may have contraindications to mammography (MG) or simply refuse the test due to subjective reservations usually concerning compression and/or radiation. Other than the detection of suspicious findings these women do not have standardized information concerning their breast density (BD), one of the strongest independent predictors of breast cancer (BC) risk. We developed a fully-automated quantitative magnetic resonance imaging (MRI) based BD measurement system, provided correlation to MG BD estimation and compared BD in BC patients and age-matched healthy controls. Methods: In this IRB-approved prospective study 35 healthy women and 19 BC patients age-matched to one of the healthy controls were included. BD for healthy women and BC patients was assessed using a) subjective qualitative radiologist´s review allocating 1 of 4 ACR BIRADS BD categories, b) Cumulus, a MG based semi-automatic method and c) a radiation- and compression-free MRI measurements system, which automatically calculates volume of breast (cm3), % of fatty tissue and % of glandular tissue. Descriptive statistics were used to define the typical range of quantitative MRI BD readings corresponding to the qualitative four ACR BIRADS BD categories. Áppropriate statistical tests were used to compare mean values of method b) and c) and BD readings of cancers and controls. Results: % MRI BD correlated well with % MG BD (r ⫽ 0.83; P ⬍ 0.0001). MRI BD measurements ranged from 1.7% to 61.9% (mean 29.05%). MG BD measurements ranged from 5.42% to 74.33% (mean 40.23%). Equivalent values were found with MRI BD readings of 0-7.2%, 7.3-26%, 26.1-39.6% and ⬎39.7% respectively for each of the four ACR BIRADS BD categories. Mean BD (%) was higher in BC patients than in healthy controls: 24% (SD 16.9%) vs. 18.4% (16.6). Conclusions: MRI BD measurement strongly correlates with MG based BD readings. The data suggest that objective, radiation- and compression-free MRI BD measurement is a convenient alternative to MG for assessment of BD. MRI BD measurement confirms higher breast density in BC patients compared to healthy women. The data is entirely consistent with the fact that BD is a strong independent risk factor for BC.


678s 11089


Thymidylate synthase expression as predictive biomarker of pemetrexed sensitivity in advanced cancer patients. Presenting Author: Federico Rojo, Translational Oncology Division. Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain Background: Although a high level of thymidylate synthase (TS) expression in malignant tumours has been suggested to be related to a reduced sensitivity to the antifolate drug pemetrexed, no direct evidence for such an association has been demonstrated in routine clinical samples from patients treated with this drug. The purpose of this study was to evaluate the impact of quantitative TS expression in tumor cells as predictor of the efficacy in patients with advanced non-small cell lung cancer, small cell lung cancer (SCLC) and mesothelioma treated with pemetrexed in our institution. Methods: 54 patients were included in this study: 40 stage IV NSCLC (26 adenocarcinomas, 11 large cell, and 3 squamous cell carcinoma), 3 SCLC and 11 mesothelioma. 21 patients received platinspemetrexed as first line NSCLC, 20 pemetrexed in monotherapy as second and further lines and 3 carboplatin-pemetrexed fo extensive disease SCLC. Total RNA was isolated by RNeasy FFPE procedure (Qiagen). The expression of TS was analyzed by RT-qPCR using appropriate mRNA specific primers and probes in LightCycler 480II platform at 45 cycles. TS levels was calibrated to expression in normal tissue. Results: From 54 cases, TS expression data were available in 32 cases, detecting overexpression in 23 (71.8%) and low expression in 9 (28.2%) patients. The response rate for patients with low TS expression was 0.63 compared with 0.15 in patients with overexpression (p⫽0.015). A significant benefit in time to progression was observed in patients with low expression (median TTP 12 vs. 2 months respectively, p⫽ 0.002), whereas did not impact on overall survival (median OS 20 vs. 19 months respectively, p⫽ 0.595). Conclusions: TS overexpression in tumor cells correlated with a reduced response to pemetrexed-containing chemotherapy and might be used as a predictive biomarker in advanced lung and mesothelioma cancer patients.

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11090


Molecular subtyping to predict better clinical and pathologic tumor response in operable early-stage breast cancer treated with docetaxelcapecitabine with or without trastuzumab. Presenting Author: Stefan Gluck, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL Background: Classification into molecular subtypes is important for the selection of therapy for patients with early breast cancer. Here we determine rates of pathological complete response (pCR) in early stage breast cancer to neoadjuvant capecitabine plus docetaxel, ⫹/- trastuzumab, and investigate MammaPrint together with the molecular subtyping profile BluePrint as markers of pathological response in comparison to other biomarkers. Methods: This analysis was carried out on data from 122 patients enrolled in a multicenter study (XeNA) of neoadjuvant therapy for four 21-day cycles with capecitabine 825 mg/m2 plus docetaxel 75 mg/m2if HER2-, and a standard trastuzumab dose if HER2⫹ (Glück , BCRT 2011). Clinical and pathological features, TP53 mutation analysis and PAM50 results were collected through GEO at NCBI (GSE22358). MammaPrint and BluePrint outcomes were determined from the available gene expression data and resulted in 4 distinct molecular groups: Luminal A (MammaPrint Low Risk/Luminal-type), Luminal B (MammaPrint High Risk/ Luminal-type), Basal-type and HER2-type. Results: In patients who completed 4 cycles of chemotherapy and surgery the overall pCR rate was 16%. Stratified by BluePrint pCR was observed in 1/15 (7%) of the Luminal A and 2/44 (5%) of Luminal B, in 10/22 (45%) of the HER2-type and in 7/41 (17%) of the Basal-type. The response rate among TP53 mutated patients was 6/61 (26%), which was significantly higher than TP53 wild-type patients (3/54 4%; p⫽0.012). Concordance of BluePrint/MammaPrint with PAM50 molecular subtyping was 61%. Conclusions: Molecular Subtyping with BluePrint and MammaPrint can identify better outcomes of patients in the neo-adjuvant setting. Patients with Luminal A breast cancer have a good baseline prognosis with excellent survival and may not benefit from chemotherapy (Glück, SABCS 2013). MammaPrint and BluePrint provide predictive information for patients treated with treated with docetaxel-capecitabine ⫹/- trastuzumab.

11092


Tumoral MET/HGF expression and MET gene amplification in patients with ALK 2p23 fusion driven lung cancer. Presenting Author: Yan Feng, Cleveland Clinic Taussig Cancer Institue, Cleveland, OH

Application of next-generation sequencing (NGS) for evaluation of advanced epithelial cancers: A single institution experience. Presenting Author: Patrick McKay Boland, Fox Chase Cancer Center, Philadelphia, PA

Background: MET receptor and its ligand HGF are both promising targets in non-small cell lung cancer (NSCLC) therapy. Crizotinib, a recently approved ALK inhibitor for NSCLC harboring oncogenic ALK 2p23 fusion (ALK⫹), was initially developed as a bona fide MET inhibitor. The role of MET/HGF pathway in ALK⫹ NSCLC is still unknown. Methods: The study included 73 NSCLC patients tested for ALK rearrangements at Cleveland Clinic (2000-2012), including 21 ALK⫹ and 52 ALK-. Immunohistochemistry (IHC) on FFPE tumor tissue was performed for c-MET using a monoclonal CONFIRM antibody (SP44, Ventana) with Ventana Benchmark XT automated immunostainer and for HGF using a polyclonal antibody (R&D) following a manual protocol. IHC scoring was interpreted on a 4-tier system (0, 1⫹, 2⫹, 3⫹). MET gene amplification by MET/Chromosome 7 dual probe in-situ hybridiazation (DISH) (Ventana) was also performed. Statistical analysis was performed using Fisher exact test in JMP. Results: Of the tested tumors, 61 were adenocarcinoma (21 ALK⫹ and 40 ALK-), 6 squamous cell, 4 large cell and 2 NSCLC-NOS. None received any MET inhibitor prior to tissue collection. MET expression by IHC score 0-3 was: 35%, 33%, 15% and 17% in ALK-, and 5%, 37%, 42% and 16% in ALK⫹ tumor group, respectively. HGF IHC score 0-3 was 34%, 55%, 11% and 0% in ALK-, and 0%, 63%, 32% and 5% in ALK⫹ tumor group, respectively. The percentages of high MET or HGF expression (2⫹ or 3⫹) were higher in ALK⫹ group compared to ALK- (58% vs 32%, p⫽0.06, and 37% vs 11%, p⫽0.03). The correlation coefficient between MET and HGF expression was 0.48. MET gene amplification by DISH was detected in 15% (7/47) ALK- tumors but 0% (0/15) ALK⫹ tumors (difference not statistically significant, p⫽0.18). The correlation coefficient between MET IHC and MET gene amplification was 0.33. Conclusions: MET and HGF expression is commonly seen in NSCLC, with more frequent high expression levels in ALK⫹ than ALK- tumors. Using a newly developed DISH method, we show that MET gene amplification tend to be less frequent in ALK⫹ tumor. A prospective study with larger sample size is warranted to further define the role of MET/HGF as biomarkers in the biology of NSCLC with ALK rearrangements and their targeted therapy.

Background: The use of molecular targeted therapeutic agents may require the application of sophisticated diagnostic technologies for patients’ selection. Next generation DNA sequencing (NGS) has the ability to identify genetic alterations (GA) including mutations, copy number alterations, insertions/deletions, and rearrangements in tumor specimens. We sought to evaluate patients with advanced and refractory epithelial tumors to detect potentially actionable molecular abnormalities. Therapeutic intervention driven by GA findings was determined solely by the patient’s treating physician. Methods: Tumor samples from 77 patients ⱖ 18 years old with any solid malignancy were sequenced. NGS of 186 genes was performed by FoundationOne through funding from Foundation Medicine using archival or newly acquired tumor tissue. Results: Seventy-four patients had specimens with adequate material for DNA extraction and analysis. Characteristics: 74% female, median age 55 years (19-82). Tumor sites included inflammatory breast (50%), colon (12%), unknown primary (5%) and other (33%). At least one genetic alteration was seen in 71 (96%) patients. The most common GA included mutations in 65 (60%) samples revealing TP53 (32%), KRAS (10%), PIK3CA (8%), and APC (6%) and amplifications in 38 (35%) samples which included MYC (18%), MCL1 (14%), CCND1 (12%), and ERBB2 (7%). Copy number loss (4%), fusion (1%) and deletions (2%) were also discovered. An actionable GA was seen in 46 of 74 patients successfully tested (62%), with 54% of GAs being amplifications and 43% mutations. Patients had a median of 3 GA (range 0-7). One patient with anal cancer had a concomitant PIK3CA mutation and amplification. NGS in association with immunohistochemistry helped identify site of origin for one patient with an occult primary. Conclusions: NGS identified GAs in the majority of patients with advanced epithelial cancers, including actionable abnormalities in a large fraction of this heterogeneous population. NGS shows promise in the diagnostic evaluation of advanced malignancies. Future studies should include the potential prognostic implications of genomic-driven personalized therapy.


Tumor Biology 11093


Diffusion-weighted imaging using ADC mapping as an imaging biomarker for breast cancer invasiveness. Presenting Author: Hubert Bickel, Medical University Vienna, Vienna, Austria Background: Recently, functional imaging techniques such as diffusion weighted imaging (DWI) have been added to routine MR and have shown great potential for improving breast cancer diagnosis. DWI depicts cellular diffusivity on a molecular level and can be quantified using the apparent diffusion coefficient (ADC). In malignant tumors diffusivity is restricted, leading to lower ADC values than benign tumors. The aim of this study was to proof, that DWI can be used to differentiate benign from malignant tumors and to elucidate if ADC can serve as an imaging biomarker for breast cancer invasiveness. Methods: In this IRB-approved study 250 patients with 267 suspicious breast lesions (BI-RADS IV-V) were included. All patients underwent routine MR at 3T. A DWI-sequence was added to a standard imaging protocol, increasing measurement time by 2:30 min. The lesions were identified in routine MR and DWI sequences and ADC values of the lesions were calculated. Histopathology was used as the standard of reference for all lesions. Appropriate statistical tests were used to compare the ADC values of benign and malignant tumors (cut-off value 1.25⫻103mm²/s), of invasive and non-invasive disease and between different invasive tumor subtypes. Results: There were 91 benign (mean ADC 1.58⫻10-3mm²/s) and 176 malignant (.94⫻10-3mm²/s) lesions, sensitivity and specificity were 94.3% (PPV 95.4%, CI 0.91-0.98) and 91.2% (NPV 89.2%, CI 0.81-0.94). 155 lesions were invasive cancers (median ADC .90⫻10-3mm²/s), while 21 were non-invasive ductal carcinoma in situ (1.22⫻10-3mm²/s). The invasive cancers were 130 invasive ductal (median ADC .91⫻10-3mm²/s) and 25 invasive lobular cancers (.83⫻10-3mm²/ s). ADC was significantly different between benign and malignant lesions (p⬍.001) and between invasive and non-invasive cancers (p⬍.001), while no significant difference could be found between the invasive cancer subtypes (p⫽.163). Conclusions: Diffusion-weighted imaging reliably allows differentiation of benign and malignant breast tumors. The data suggest that ADC can be used as a non-invasive imaging biomarker for breast cancer invasiveness and may be of importance to treatment planning and outcome in breast cancer patients.

11095


MRI apparent diffusion coefficient in a murine orthotopic glioblastoma model as a clinically translatable early readout of efficacy for AMG 595, an antibody drug conjugate targeting EGFRvIII. Presenting Author: Brittany Yerby, Amgen, Inc., Thousand Oaks, CA Background: Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively active mutant of EGFR present in thirty to fifty percent of glioblastoma (GBM) patients. AMG 595, currently in Phase I trials, is composed of a fully human anti-EGFRvIII-specific antibody conjugated to the maytansinoid DM1 via a non-cleavable linker. The MRI apparent diffusion coefficient (MRI ADC) has been shown to correlate with tissue cellularity, and changes in MRI ADC can be an early indicator of therapeutic efficacy. The aim of this work is to evaluate MRI ADC as a clinically translatable early readout of tissue changes due to AMG 595 treatment in a murine orthotopic GBM model. Methods: D317 human GBM cells were intracranially injected into in female CB17 SCID mice at Day 0. Mice were randomized at Day 7, using tumor volumes calculated by MRI, and were treated with vehicle, 6.5, 11, or 22 mg/kg AMG 595 i.v. twice per week, or temozolomide 10 mg/kg p.o. daily five days per week (N⫽8/group). MRI was repeated at days 14 and 21. Tumor volumes were manually traced on multi-slice T2-weighted RARE images covering the entire tumor volume. The mean MRI apparent diffusion coefficients for each tumor in the vehicle and 22 mg/kg AMG 595-treated groups were calculated from diffusionweighted spin echo images (b ⫽ 100-1200 s/mm2). Results: A dosedependent effect of AMG 595 on tumor volume was observed at Day 21; growth was inhibited in both the temozolomide and AMG 595-treated groups (22 and 11 mg/kg) relative to vehicle (p⬍0.0001). At Day 14, this significant treatment effect on tumor volume was not yet detectable. However, mean MRI ADC values were already significantly higher in the AMG 595 (22 mg/kg) treated group than in the vehicle group (23% higher at Day 14, p⬍0.01 vs vehicle; 32% higher at Day 21, p⬍0.0001 vs vehicle). The increase in MRI ADC in the AMG 595-treated group preceded observable tumor growth inhibition in the AMG 595-treated animals. Conclusions: Increases in tumor MRI ADC in response to AMG 595 treatment precede measurable inhibition of tumor growth, supporting the use of MRI ADC as a clinically relevant early biomarker for therapeutic efficacy.

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Utilizing a collaborative working model to optimize molecular analysis of solid tumors in the Cancer Research UK’s Stratified Medicine Programme. Presenting Author: Ian Walker, Cancer Research UK Institute for Cancer Studies, London, United Kingdom Background: The Stratified Medicine Programme is demonstrating large scale molecular testing of solid tumours in the UK using a range of technologies. The collaborative model has allowed three laboratories to share and compare data on mutation frequencies including mutation exclusivity, test turnaround times and failure rates, to inform a future routine service for clinical care. Methods: Phase One is a two-year pilot study of molecular analysis of surplus diagnostic FFPE tumour tissue obtained from patients with cancer of the breast, colorectum, lung, ovary, prostate or malignant melanoma. Samples are tested for specified genes of clinical and research interest (for example KRAS, BRAF, NRAS, PIK3CA, TP53, PTEN, TMPRSS2-ERG, EGFR, EML4-ALK and KIT). The labs have developed and validated protocols with comparable sensitivity for the simultaneous molecular analysis of multiple genes. Results: By 31 December 2012, 4,734 sets of molecular results were completed with 60% of tumour-site specific reports issued within the target 15 days (from sample receipt). Failure rates vary with both sample quality and the type of analysis performed. The Table illustrates the link between turnaround times and failure rates, showing that repeat testing for specimens which initially fail may reduce overall failure rates but consequently increase average turnaround times. Conclusions: We will report comparative data across the three testing labs and identify multiple factors that affect mutation detection rates, failure rates, turnaround times and reporting procedures. The Stratified Medicine Programme acknowledges funding from Cancer Research UK, AstraZeneca, and Pfizer. A comparison of turnaround times and whole test failure rates for clinically relevant genes. Molecular analysis Lab 1 Lab 2 Lab 3 BRAF EGFR EML4-ALK KRAS

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Average TAT* Complete fail rate Mutation rate (melanoma) Average TAT* Complete fail rate Mutation rate (lung) Average TAT* Complete fail rate (lung) Mutation rate Average TAT* Complete fail rate Mutation rate (colorectal)

10 1.1% 48% 2 6.0% 5% 6 6.5% 1% 6 0.9% 35%

8.5 1.5% 49% 8 1.1% 5% 7 4.0% 1% 10 1.0% 42%

5 9.1% 41% 4 11.2% 11% 7 5.2% 4% 4 8.5% 38%


Liquid biopsy-based assays to monitor residual disease in cancer. Presenting Author: Gangwu Mei, Guardant Health Inc., Redwood City, CA Background: One of the main challenges in cancer management is monitoring the non-organ-confined disease post metastasis. Recently analysis of circulating tumor nucleic acids has generated a new paradigm for monitoring the progression and molecular pathology of the residual disease through a non-invasive test. Methods: We have developed a new sequencing workflow, which increases the sensitivity and specificity of detecting and quantifying rare tumor-derived nucleic acids among healthy fragments by at least ten-fold. Unlike conventional sequencing library preparation protocols, the majority of extracted circulating DNA fragments are hybridized to sequencing flow cells with minimal modifications. The sequencing data are processed using our proprietary bioinformatics pipelines to search for rare genetic abnormalities within the heterogeneous circulating fragments. Results: To study the performance of our technology, we first evaluated its sensitivity in analytical samples. We spiked varying amounts of LNCaP cancer cell line gDNA into a background of normal gDNA and were able to successfully detect somatic mutations down to 0.1% sensitivity. Subsequently, we investigated the correlation of circulating DNA and tumor gDNA in human xenograft models in mice. In seven different mice models of two different human tumors, we found very strong correlation between somatic mutations detected in all pairs of tumor gDNA and mouse blood cfDNA. After preclinical studies, we initiated a pilot study on human samples across different cancer types. We found more than 90% correlation between tumor mutations in stage IIIb CRC cancer patients and the mutations detected in their circulation (n⫽7). In a pilot study in prostate cancer patients (n⫽3), we detected chromosomal abnormalities in multi locations in circulating DNA genome in both advanced and post-relapse stages of the disease. Conclusions: The present work indicates the potential of using circulating nucleic acids to facilitate the integration of real-time molecular pathology into routine cancer care. Our assay will be used to identify residual disease after neoadjuvant chemotherapy and/or surgery, but may also identify a subset of patients who may benefit from alternative therapies.


680s 11097


11098


Association of tumor perivascular desmin expression with survival in patients with sunitinib-treated renal carcinoma. Presenting Author: Magnus Frodin Bolling, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

Comparison of [99mTc] tilmanocept and [99mTc] sulfur colloid for identification of sentinel lymph nodes in clinically node-negative breast cancer patients. Presenting Author: Jennifer L. Baker, UC San Diego Moores Cancer Center, La Jolla, CA

Background: The introduction of tyrosine kinase inhibitors has markedly improved the outcome for patients with metastatic renal carcinoma (mRCC), but lack of reliable response-predictive markers makes it difficult to individualize treatment. Pericytes surround endothelial cells of capillaries and regulate vessel function. Associations between pericyte marker expression and response to sunitinib have not been well characterized. Methods: A tissue micro array with samples from 67 mRCC patients ( 34 males, 33 females, age 42 – 84) treated at Dept. of Oncology, Karolinska University Hospital where constructed from primary tumors. All patients included had received at least one course with the tyrosine kinase receptor inhibitor sunitinib. Data of treatment, progression free survival and overall survival was collected in a clinical registry. Tissues were double-stained with the endothelial cell marker CD 34 and either of three pericyte markers desmin, PDGF beta receptor and alpha smoth muscle actin (ASMA). By semi-quantitative visual scoring, the perivascular staining of these markers was evaluated and cases dichotomized into negative/low- or positive/highexpressing groups. Results: For patients with desmin positive/high vessels ( n ⫽ 12), median PFS where 5.0 months (2.9 – 7.1, 95% CI) vs 7.0 months for patients with desmin negative/low vessels (n ⫽ 55, 3.8 – 10.2, 95% CI, Mantel Cox log rank test p⬍0.02). The median OS in the desmin-positive/ high group was 24 months ( 7 – 41, 95% CI) vs 46 months in the negative/low group ( 34 – 58, 95 % CI, Mantel Cox log rank test p⬍0.014). No significant associations were seen between PFS or OS and the expression of perivascular PDGF beta receptor or ASMA. Conclusions: Metastatic RCC displays a clinically relevant variation in perivascular desmin expression which is associated with survival in sunitinib-treated patients. Future studies are warranted which further explores the prognostic and/or response-predicative capacity of this novel candidate renal cell cancer biomarker.

Background: Receptor-targeted (CD206) [99mTc] tilmanocept is a radiopharmaceutical specifically engineered for sentinel lymph node (SLN) identification that has recently completed phase III clinical trials. The agent has been compared to vital blue dye in prior studies, but has not yet been compared to radio-labeled sulfur colloid. We compared the performance of [99mTc]tilmanocept vs. filtered [99mTc]sulfur colloid (fTcSC) in two cohorts of clinically node-negative breast cancer patients (BCP) who underwent SLN mapping at a single institution. Outcomes were degree of SLN localization and % positive nodes among those removed. Methods: The [99mTc]tilmanocept cohort was composed of UCSD-specific patients pooled from two phase III clinical trials (Jun 2008-Jun 2009, Jul 2010-Apr 2011); the fTcSC cohort was composed of consecutive BCP undergoing SLN mapping at UCSD (Mar 2011-Feb 2012). Demographic, lymph node-specific, and cancer characteristics were compared between groups. A zero-inflated binomial model compared %-positive nodes among nodes removed. Results: There were 85 vs.120 patients in the [99mTc]tilmanocept and fTcSC cohorts, respectively. The groups did not differ in demographic or clinicopathologic factors predictive of axillary metastatic disease (age, race, cancer stage, histologic subtype and grade, hormone and HER2-Neu status or presence of lymphovascular invasion). The [99mTc]tilmanocept group had significantly fewer SLNs removed (mean 1.9 vs. 3.9, p⬍0.001), achieved higher gamma counts/node (28 vs. 1.6 kcps, p⬍0.001), and detected a significantly higher percent of tumor-positive SLNs (73% vs. 49%, p⫽0.016) while identifying the same rate of node-positive patients (24% vs. 18%, p⫽0.4). Conclusions: [99mTc]Tilmanocept identified the same rate of node positive patients and removed fewer SLNs compared to fTcSC among BCP with similar risk of axillary metastatic disease. These data suggest that [99mTc]tilmanocept more precisely targets true SLNs and may minimize morbidity while maintaining or improving the accuracy of axillary staging in clinically node-negative breast cancer patients.

11099

11100


Performance of next-generation sequencing for detection of clinically actionable genetic variants in cancer. Presenting Author: Mohammed Omar Hussaini, Washington University in St. Louis, St. Louis, MO Background: Next-generation sequencing (NGS) allows for simultaneous detection of numerous actionable somatic variants in cancer. We have implemented a clinical NGS panel to detect genetic alterations in 25 genes with established roles in cancer and report here the frequency of clinically actionable genetic variants in a variety of cancer types. Methods: NGS testing was performed in a CAP-certified, CLIA-licensed environment on DNA extracted from FFPE tissue in 209 cases spanning 41 histologic tumor types. DNA was enriched by hybrid capture and sequenced to ⬎1,000x average coverage on Illumina sequencers with 2x101bp or 2x150bp reads. Variants were called using clinically validated parameters using the Genome Analysis Toolkit, Pindel, and the custom-written Clinical Genomicist Workstation. Results: Non-small cell lung cancer (45%), pancreatic cancer (10%), and colorectal cancer (8%) were the most common tumors sent for NGS analysis. An average of 3 (range 1- 16) non-synonymous, non-SNP sequence variants per case (SNVs and indels) were detected in the 130kb exonic target. Variants were most commonly seen in TP53, KRAS, and EGFR. 27% of cases (56/209) had one or more variants with therapeutic implications for the tumor type tested (e.g., EGFR mutation in NSCLC). 15% of cases (32/209) showed actionable variants not generally associated with the malignancy tested (e.g., detection of an activating KITvariant in thymic carcinoma). 10% of cases (21/209) had variants that were prognostically significant but not directly targetable. Some cases (9%) had variants that were prognostic/diagnostic and targetable. In 117 cases (56% of total), no therapeutically or prognostically significant variants were identified. Overall, in 92 cases (44%), NGS testing yielded information with therapeutic (majority), prognostic, or diagnostic ramifications. Conclusions: We found that 44% of unselected cancer cases have clinically relevant sequence variants in a set of 25 commonly mutated cancer genes. Our data suggest that clinical NGS testing may serve as an integral tool in realizing the potential of precision medicine in oncology.


Clinical next generation sequencing (NGS) of fine needle aspiration (FNA) biopsies in non-small cell lung (NSCLC) and pancreatic cancers. Presenting Author: Matthew J. Hawryluk, Foundation Medicine, Inc., Cambridge, MA Background: FNA is a common diagnostic procedure for the evaluation of pulmonary and pancreatic masses. We sought to determine whether NGS could be performed on these small specimens and to characterize heterogeneity across classes of genomic alterations (GA) in a subset of paired FNA and matched resected primary tumors. Methods: DNA was isolated from formalin fixed paraffin embedded (FFPE) sections of FNA cell blocks using 40␮m total sections for NSCLC and 20␮m total sections for pancreatic cancers in a CLIA-certified lab (Foundation Medicine). DNA sequencing was performed for 3,320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on indexed, adaptor ligated, hybridization-captured libraries to a median depth of 931x for the NSCLC and 416x for the pancreatic FNAs. Results: Genomic profiles were successfully generated from 19/19 of the NSCLC and 22/23 of the pancreatic FNA cases. We found 97 GA in the 19 NSCLC FNAs (range 2-9, average 5.1 GA per patient). 68% of the patients had GA in TP53 and 21% in KRAS. Only 16% (3/19) patients did not exhibit an actionable alteration. We found 99 GA in the 23 pancreatic cancer FNAs (range 0-12, average 4.3 per patient). 74% of the patients had GA in KRAS. There was 94% concordance of GA found in 4 matched FNA and primary tumor pairs for the pancreatic cases. For the single discordance, manual inspection of the reads of the discordant allele indicated evidence of loss of heterozygosity. Conclusions: NGS can be reliably performed on small FNA samples processed into cell blocks, and the GA discovered significantly correlates with the GA found in matched primary tumors. This study demonstrates the feasibility of NGS in analyzing FNA samples and further broadens the spectrum of commonly encountered specimen types to which this approach can be successfully applied.


Tumor Biology 11101


The role of the glucocorticoid receptor (GR) in inhibiting chemotherapyinduced apoptosis in high-grade serous ovarian carcinoma (HGS-OvCa). Presenting Author: Erica Michelle Stringer, University of Chicago Medical Center, Chicago, IL Background: Ovarian cancer is the leading cause of death from gynecologic malignancies. High-grade serous ovarian cancer (HGS-OvCa) is often initially sensitive to platinum-based therapy, but relapse rates remain high. The TCGA recently found that HGS-OvCas have a gene expression and mutational profile similar to that of triple negative breast cancer (TNBC). Previously, our group demonstrated that dexamethasone treatment decreased chemotherapy-induced tumor cell apoptosis in TNBC and HGSOvCa cell lines. We have also shown that glucocorticoid receptor (GR) activation induces expression of anti-apoptotic genes SGK1 and MKP1/ DUSP1 in both HGS-OvCa and TNBC cell lines and in primary human ovarian and TNBC tumors. Methods: We examined glucocorticoid receptor (GR), estrogen receptor (ER), and progesterone receptor (PR) expression in a panel of HGS-OvCa cell lines by Western analysis and qRT-PCR. We also performed apoptosis assays with and without mifepristone, glucocorticoid and/or chemotherapy treatment using IncuCyte live-cell imaging technology in order to measure the effect of GR modulation of chemotherapy sensitivity. Results: HGS-OvCa cell lines (including CAOV3, HeyA8, SKOV3, Monty-1) all had detectable GR expression; HeyA8, SKOV3, and Monty-1 cell lines expressed very low levels of ER-alpha while all other HGS-OvCa cell lines did not express any detectable ER-alpha. Furthermore, none of the HGS-OvCa cell lines tested expressed PR.Apoptosis assays revealed that GR activation significantly inhibited gemcitabine/carboplatin-induced apoptosis in HGS-OvCa cell lines and that mifepristone could reverse this cell survival effect, presumably through GR antagonism. Conclusions: These results suggest that treatment with mifepristone, a GR antagonist, reverses GR-mediated cell survival signaling in HGS-OvCa and increases chemotherapy-induced tumor cell death. To further investigate the role of GR activity in HGS-OvCa, we are currently performing xenograft experiments with chemotherapy ⫹/- mifepristone treatment.

11103


11102

681s General Poster Session (Board #52D), Mon, 1:15 PM-5:00 PM

A community-based program for personalized cancer care using nextgeneration sequencing (NGS). Presenting Author: Shile Liang, Sarah Cannon Research Institute, Nashville, TN Background: Despite growing interest and need, molecular profiling of tumor samples is largely unavailable in community cancer centers, where nearly 80% of cancer patients (pts) are treated. In 10/12, Sarah Cannon Research Institute (SCRI) launched a community-based molecular profiling program to: 1) better understand the molecular constituency of cancer patients, 2) identify appropriate pts for phase I and II clinical trials of targeted agents, and 3) identify pts with molecular abnormalities responsive to FDA-approved agents. Methods: Eligible pts consented to testing of available biospecimens, which were interrogated for alterations in 35 cancer-related genes using NGS (1000X average coverage) in a CLIA/CAP laboratory. Results were reported to the treating physician within 14 days and stored in a database to enable correlation with clinical outcomes. Results: As of 1/13, 209 pts had been enrolled with 84% having sufficient material for assay. At least 1 mutation was detected in 46% of tumors. Results in the 3 most commonly assayed tumor types are summarized (Table). Mutations for which there are FDA-approved targeted agents were found in 14 off-label tumors (EGFR 4, KIT 3, SMO 3, BRAF 2, HER2 2). 40 pts (27%) were subsequently enrolled in clinical trials; in 19 of these, assay results influenced clinical trial selection. Conclusions: This program provides molecular profiling data to community oncologists for clinical decision making. Experience to date indicates this information can be provided in a timely manner for incorporation into clinical practice. Profiling results will enable: 1) selection of pts with appropriate tumor targets for investigational targeted agents, 2) enhanced study enrollment, 3) evaluation of FDA approved targeted agents in off-label tumor types, and 4) correlation of treatment outcomes with patterns of tumor molecular abnormalities. # of patients

Mutation frequency

Lung

32

50%

Colorectal

25

72%

Breast

18

33%

11104


Tumor type

Mutations KRAS(22%), EGFR(19%), STK11(6%), FGFR3(3%), GNA11(3%), KIT(3%), MAP2K1(3%), SMO(3%), WT1(3%) KRAS(56%), PIK3CA(24%), ABL1 (4%), BRAF (4%), ERBB2(4%), GNAS(4%), IDH1(4%), KIT(4%), NRAS(4%), PIK3R1(4%), RUNX1(4%), SMO(4%) PIK3CA(28%), KRAS(6%), NPM1 (6%)

Application of MET pharmacodynamic assays to compare effectiveness of five MET inhibitors to engage target in tumor tissue. Presenting Author: Apurva K. Srivastava, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD

Characterization of a lung cancer growth factor, LASEP1, as a serologic and prognostic biomarker and a therapeutic target. Presenting Author: Atsushi Takano, Department of Medical Oncology, Shiga University of Medical Science, Otsu, Japan

Background: Several MET inhibitors are currently being developed that block aberrant HGF/MET signaling in different cancers. We utilized validated MET pharmacodynamic (PD) assays to compare time course, magnitude, and reversal of MET suppression by 5 MET inhibitors in preclinical models. Methods: Immunoassays (total MET, pY1234/35MET, and pY1356MET) were developed and validated to measure modulation of MET by 5 MET inhibitors (crizotinib, tivantinib, cabozantinib, foretinib, and EMD1214063). The comparison was implemented in 3 sequential stages: 1) establish time course and magnitude of MET inhibition after single drug administration of 4 different doses; 2) determine dose(s) and schedule for sustained MET inhibition and downstream signaling at optimal levels; and 3) compare efficacy of MET inhibitors at MTD and equal MET inhibition. The preclinical models include an autophosphorylation gastric tumor (SNU5) model and a paracrine MET activation model in hHGF knock-in mice. Plasma and tumor exposures were measured using LC-MS/MS to correlate with PD effects. Results: We completed phase one in the SNU5 model and determined inhibition of pY1234/35MET and total MET in tumor tissues after single administration of MET inhibitors. Time course and magnitude of pY1234/35MET inhibition varied considerably among MET inhibitors, with the most rapid (⬎80% suppression in 30 min) and sustained inhibition (up to 48 h) observed with EMD1214063 at a dose of 30 mg/kg. The maximal inhibition of pY1234/35MET and time taken for biomarker recovery were wide-ranging among MET inhibitors. Tumor drug exposures were concomitantly higher than plasma for all drugs and correlated inversely with pY1234/35MET, except for tivantinib which, unlike other drugs, is not ATP competitive inhibitor. Conclusions: We applied validated PD assays to directly compare similarities and differences in extent and duration of MET inhibition by 5 MET inhibitors. Our results provide important foundation for head-to-head comparison of efficacies of MET inhibitors at MTD and equal MET inhibition. Funded by NCI Contract No HHSN261200800001E.

Background: Identification and evaluation of oncoproteins are an effective approaches to develop novel diagnostic/prognostic biomarkers or therapeutic targets. Methods: We established a strategy as follows. i)To identify up-regulated genes in non-small cell lung cancers (NSCLCs) using the cDNA microarray, ii) To verify the candidate genes for their no or low expression in 23 normal tissues by northern-blot, iii)To validate clinicopathological significance of their protein expression by tissue microarray, iv)To verify whether they are essential for the growth of cancer cells by siRNA, and v)To measure their serum protein levels by ELISA. Results: We identified LASEP1 (Lung cancer Associated Serum Protein 1) as a candidate target molecule. Immunohistochemical staining using tumor tissue microarrays consisting of 374 NSCLC confirmed positive staining of LASEP1 was observed in 210 (56.1%) of 374 NSCLC. In addition, a high level of LASEP1 expression was associated with poor prognosis of NSCLC patients. Serum LASEP1 levels were higher in NSCLC than in healthy volunteers. The proportion of serum LASEP1-positive cases was 127 (38.6%) of 329 lung cancers, while 4 (3.9%) of 102 healthy volunteers were falsely diagnosed. Furthermore, treatment of lung cancer cells with siRNAs against LASEP1 suppressed its expression and resulted in growth suppression of the lung cancer cells; on the other hand, induction of exogenous expression of LASEP1 conferred growth-promoting activity in vitro. We found its 50-kDa receptor (LASEPR) which interacts with LASEP1 on lung cancer cell surface. Suppression of LASEPR expression by siRNAs inhibited the growth of cancer cells. The LASEP1-LASEPR interaction promoted the cell growth in an autocrine manner. In addition, the growth activity of the LASEP1-positive cells was neutralized by the addition of originally developed anti-LASEP1 monoclonal antibodies into their culture media. The systemic administration of the anti-LASEP1 antibody to tumor-implanted mice significantly suppressed tumor growth without any adverse events. Conclusions: We have identified LASEP1 as potential targets for development of biomarkers and therapeutic target for lung cancer.


682s 11105

Tumor Biology General Poster Session (Board #53B), Mon, 1:15 PM-5:00 PM

Cross-species synthetic lethal interaction screening as a strategy for the identification of novel therapeutic targets in cancer. Presenting Author: John P. Shen, University of California, San Diego, La Jolla, CA Background: Mutation, deletion, or epigenetic silencing of tumor suppressor genes is a near universal feature of malignant cells. However, therapeutic strategies for restoring the function of mutated or deleted genes have proven difficult. Synthetic lethality, an event in which the simultaneous perturbation of two genes results in cellular death, has been proposed as a method to selectively target cancer cells. Identifying and pharmacologically inhibiting proteins encoded by genes that are synthetic lethal with known tumor suppressor mutations should result in selective toxicity to tumor cells. Methods: To identify candidate target proteins we measured all pair-wise genetic interactions between all known orthologs of human tumor suppressor genes (162 genes) and all orthologs of druggable human proteins (~400 genes) in the model organism S. Cerevisiae. Analysis of the data uncovered 2,087 distinct synthetic lethal interactions between a tumor suppressor and druggable gene. A computational algorithm was then developed to identify those interactions which were likely to be conserved in humans based on conservation of the synthetic lethal relationship in the distant fission yeast S. pombe. Results: Our bioinformatic analysis suggested a high probability of conservation of the synthetic lethal interactions between the yeast RAD51 (ortholog of BRCA1) and RAD57 (ortholog of XRCC3) with HDA1 (a histone deacetylase; HDAC). We confirmed this by treating LN428 cells with stable lentiviral knockdown of BRCA1 or XRCC3 with the HDAC inhibitors vorinostat (SAHA) and entinostat (MS-275). Both the BRCA1 and XRCC3 knockdown cell lines were significantly more sensitive to HDAC inhibition relative to wild-type (non-silencing lentiviral control) cell line (Table). Conclusions: These results demonstrate that high-throughput approaches for screening synthetic lethal interactions in model organisms such as S. cerevisiae and S. pombecan serve as a valuable resource in helping to identify novel therapeutic targets in human cancer. IC50 (uM) , (95% CI) SAHA Wild type BRCA1-kd XRCC3-kd

11107

0.57 0.39 0.34

(.52 - .62) (.35 - .45) (.32 - .37)

MS-275 0.90 0.48 --

(.78 - 1.0) (.41 - .56) --


Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human AML. Presenting Author: Kapil N. Bhalla, University of Kansas Medical Center, Kansas City, KS Background: The bromodomain-containing protein 4 (BRD4) is a member of the BET (bromodomain and extraterminal) protein family, which regulate the assembly of chromatin complexes and transcriptional regulators at the target gene promoters, e.g., of Myc and BCL2. JQ1 competitively binds and inhibits the bromodomains of the BET proteins, including BRD4. Treatment with JQ1 attenuates Myc and BCL2 levels and promotes growth arrest, differentiation and apoptosis of AML cells. Methods: Here, we determined the growth inhibitory, differentiation and apoptotic effects of JQ1 (100 to 500 nM) alone and in combination with low concentrations of the deacetylase inhibitor panobinostat (PS) (5 to 20 nM) (gift from Novartis) in cultured (OCI-AML3, MV4-11 and MOLM13) and primary AML blast progenitor cells. We also determined the in vivo anti-AML activity of JQ1 (50 mg/kg/day IP) and/or PS (5 mg/kg/MWF IP) for 3 weeks against the OCI-AML3 xenograft in the NOD/SCID mice. Results: Treatment with JQ1 decreased the binding of BRD4 at the chromatin associated with Myc and BCL2 promoters (by ChIP-qPCR) and attenuated the mRNA and protein levels of Myc, BCL2 and cyclin D1, while increasing the levels of p21, CEBP␣, BIM and cleaved PARP in the cultured and primary AML blasts. This was associated with an increase in the % of G1 phase cells, attenuation of the colony growth, and induction of apoptosis of the cultured (OCI-AML3 ⬎MV4-11 ⬎MOLM13) and primary AML cells. JQ1 treatment also dose-dependently inhibited the viability of CD34⫹ primary AML progenitor cells (n⫽10). Gene expression microarray analysis revealed a JQ1 treatment-associated signature of the most up- and down-regulated mRNAs that correlated with its anti-AML effects. Co-treatment with JQ1 and PS synergistically induced apoptosis of AML cells (by isobologram analysis; CI ⬍ 1.0). As compared to the mice treated with vehicle alone, or with each agent alone, co-treatment with JQ1 and PS, without inducing toxicity, significantly improved the survival of the OCI-AML3 engrafted NOD/SCID mice (p ⬍ 0.01). Conclusions: These pre-clinical findings warrant further in vivo evaluation of the efficacy of the combination of a BRD4 antagonist and PS, and its predictive biomarkers, against human AML.

11106


Hyperactivated mTOR and JAK2/STAT3 pathways: Crucial molecular drivers and potential therapeutic targets of inflammatory breast cancer (IBC). Presenting Author: Komal L. Jhaveri, New York University School of Medicine, New York, NY Background: IBC is an aggressive form of breast cancer with poor prognosis. Combined multimodality Rx results in 5 year median OS of 30-50%, underscoring the unmet need for novel targeted strategies. Our preclinical research in cell lines and xenografts suggests a role for activated PI3K/AKT/ mTOR pathway in IBC. IBC cells not only express high levels of IL-6 and IL-8 but can recruit tumor activated macrophages (TAMs), which can further induce IL-6, IL-8 and activate JAK2/STAT3 pathway. We therefore investigated independent and combined activity of these pathways. Methods: Archived tissue specimens of 42 IBC pts (1999 - 2009) and 13 controls (normal breast) were analyzed using IHC and scored by 3 independent pathologists. Results were defined as: 0, 1⫹ ⫽ neg; 2⫹ ⫽ pos for activated mTOR (phosphorylatedS6) and 0 ⫽ neg; 1⫹, 2⫹ ⫽ pos for activated nuclear JAK2/STAT3 (pJAK2; pSTAT3), cytokine (IL-6), macrophage infiltration (CD68) and TAMs (CD163). Proportion of IBC cases with pos expression were compared to proportion among controls (Fishers exact test). Clinical and survival data were obtained. Results: Median age at diagnosis - 44.5 yrs (29-64). 22 had HER2 overexpression (8 also ER⫹) and 9 were ER-/HER2-; ER & HER2 unknown for 1 and 2 pts respectively. Majority were Rxed with neoadjuvant anthracycline and/taxane without adjuvant trastuzumab. There were 24 deaths. Median OS: 67 mths (95% CI: lower 41). Proportions of IBC cases with pos expression when compared to controls are listed in the table (Fishers p value: ⬍0.0001). Of the 31 pts with complete biomarker data who were PS6 pos, 97% had activated JAK2 & 58% had activated STAT3 (McNemar’s chi square, p ⬍0.001). 24/31 (80%) showed strong infiltration of macrophages and TAMs. All cases had widespread IL6 staining. Conclusions: This study validates our preclinical findings and shows hyperactivation of mTOR and JAK2 signaling in vast majority of IBC specimens, with close association between mTOR, TAMs, cytokines and JAK2/STAT3 pathways. These findings support a role for dual blockade of mTOR and JAK/STAT pathways in clinical trials. Biomarker N ⴝ 42 PS6 pJAK2 pSTAT3 CD68 CD163

11108

Pos N (%)

Neg N (%)

No tumor

35 (90) 37 (97) 22 (59) 32 (86) 36 (90)

4 (10) 1 (3) 15 (41) 5 (14) 4 (10)

3 4 5 5 2


NGS-based targeted RNA sequencing for expression profiling and relative quantitation of specific gene isoforms and fusions in tumor-specific panels. Presenting Author: Gordon Vansant, Althea Technologies, San Diego, CA Background: Gene expression signatures have become a useful tool for the identification of tumor subtypes and response to specific therapies. Expression of tumor, metastatic and macrophage specific transcripts utilizing alternative promoters and transcriptional start sites can further characterize these tumors . NGS is a powerful tool for gene expression analysis, however larger sample input requirements (⬎100ng) and excessive sequencing depth requirements (30-40M tags/sample) to detect the expression of rare isoforms or fusions in tumor samples are prohibitive for clinical assay development. We describe the development of a targeted RNA sequencing assay for the relative quantitation of specific gene expression signatures, known splice variants and gene fusions from less than 100 ng of starting material in a single tube universal amplification format. Methods: Primers for 52 genes, isoforms and gene fusion products were designed using the universal amplification strategy. 10 ng of RNA from 5 matched tumor/adjacent normal breast cancer tumor pairs were assayed. Libraries were prepared for sequencing by emPCR and sequenced on Ion Torrent PGM. Data were aligned via TMAP. Relative expression was determined vs. housekeeping genes or wild type transcripts. Results: All gene targets were detected at significant levels in at least one tumor sample. Robust expression profiling (5 log dynamic range) was obtained from FFPE macrodissected tumor and normal samples with as little as 200K reads/sample. Immune specific transcripts demonstrated differential expression (CCL3, AIF, FCGR3A and CSF1) across patients and matched pairs as well as an upregulation of CXCL12, indicative of tumor associated macrophages. Conclusions: Targeted RNAseq demonstrates detection and quantitation of relative expression levels of not only tumor subclass specific gene expression signatures, but immune cell specific transcripts from 10ng of FFPE derived total RNA derived from macrodissected tumor samples. The lower input requirements, quicker turnaround time and incredible sensitivity of targeted RNAseq make this assay a useful tool for clinical assay development.


Tumor Biology 11109


11110


Plasma osteopontin and the prognosis of pleural mesothelioma. Presenting Author: Harvey I. Pass, New York University School of Medicine, New York, NY

The role of Pirh2 C-terminal residues and ubiquitin lysine chains in ubiquitination mechanism. Presenting Author: Rami Mahmoud Abou Zeinab, University of Alberta, Edmonton, AB, Canada

Background: Cytoreductive surgery for malignant pleural mesothelioma (MPM) should be reserved for patients with favorable tumor biology. Osteopontin (OPN) and the ratio of absolute neutrophil to absolute lymphocyte counts (NLR) have been reported as possible prognostic biomarkers. These were studied with other clinical/ laboratory variables in a mixed surgical/non-surgical MPM population to define independent predictors of survival (OS) and progression (TTP). Methods: Forty-four MPM patients (12 F, 32M; 26 cytoreduction, 18 no cytoreduction; 31 epithelial, 13 non-epithelial; 15 Stage I/II, 29 Stage III/IV) were examined with regard to pretreatment plasma OPN (ELISA, R&D, Minneapolis, MN), NLR age, gender, therapy, histology, stage, platelet count and WBC count. Cut points for age, OPN, NLR, platelets, and WBC were determined by X-tile Software (Yale, New Haven, CT) and univariate/multivariate Cox analyses performed. Results: Median OS were 11 m, 21m, and 8m for all 44 MPMs, cytoreduced and non-cytoreduced MPMs, respectively. Of platelet count, WBC, NLR, and OPN, only OPN was statistically significant between Stage I/II and Stage III/IV (80.3 ng/ml vs 148 ng/ml, p⬍0.018). The only independent covariate predictive of OS was plasma OPN. For TTP in cytoreduced patients, only age, stage, platelet count, and OPN were significant in univariate analysis, and multivariate modeling retained stage (p⫽0.04, HR⫽2.75, 95% CI⫽1.0517 to 7.1879) and OPN (p⫽0.0008, HR⫽17.471, 95% CI⫽3.3054 to 92.3461). Conclusions: Plasma OPN is promising for the stratification of tumors into good or bad risk categories and to help select potential candidates for cytoreduction and further postoperative therapy.

Background: Pirh2, a p53 inducible gene, is proposed to be a main regulator of p53 family proteins fine tuning the DNA damage response by acting as an E3 ligase. A negative feedback loop between Pirh2 and p53 exists where under unstressed conditions, Pirh2 induces p53 ubiquitination followed by proteosomal degradation. In case of cellular stress when the activity of tumor suppressors is essential, Pirh2 is self-ubiquitinated releasing p53 continuous repression. Interestingly among all E3 ligases, Pirh2 is the only one to be over-expressed in a wide range of human tumors. This over-expression indicates a disruption in the self-ubiquitination mechanism or a defect in the degradation mechanism post ubiquitination. Based on that, we aimed to analyze Pirh2 ubiquitination mechanism through mapping Pirh2 domains to reveal the essential residues for this process and the ubiquitin chains utilized. Methods: Pirh2 constructs deleting major residues in the three domains were designed, and also ubiquitin mutant constructs were designed through single/multiple mutations at specific positions where lysine residues are mutated to arginine. Using these constructs and in comparison to WT proteins, we tested Pirh2 in-vitro self and p53 ubiquitination activity. Results: Regarding Pirh2, we were able to reveal that residues 240-250 of the c-terminal along with the ring domain are essential for self-ubiquitination.K63R and K48R ubiquitin did not affect Pirh2 self-ubiquitination minimizing the impact of ubiquitin mutations on Pirh2 self-ubiquitination. However, KO, which had all lysine residues mutated to arginine, showed total inhibition of Pirh2 selfubiquitination confirming the importance of lysine residues. Interestingly, Pirh2 self-ubiquitination reaction showed no difference in the presence or absence of p53 proteins. Concerning Pirh2-p53 ubiquitination, K48 was found to be critical for E3 ubiquitin ligase activity because K48R and not K36R showed defective ubiquitination. All results were confirmed by quantifying ubiquitin. Conclusions: Our data added knowledge to the Pirh2 self-ubiquitination mechanism that can resolve the constant overexpression of Pirh2 proteins hence maximizing p53 response to DNA damage.

Univariate Variable

P value

HR

Multivariate 95%CI

P value

HR

95%CI

Age > 61 0.0008 2.95 1.5279 to5.7074 NR* Male vs female 0.8141 1.09 0.5318 to 2.2278 Other vs epithelial 0.2129 1.54 0.7036 to 3.3918 Cytoreduced 0.0018 0.3885 NR yes vs no Stage III/IV vs stage I/II 0.007 2.6 1.3531 to 5.0144 NR Platelet count>376 0.0026 2.96 0.9345 to 9.3749 NR WBC>8.0 0.0327 1.93 0.9711 to 3.8540 NR NLR>7.2 0.0009 4.11 0.7407 to 22.8346 NR Plasma OPN>99.8 ⬍ 0.0001 5.56 2.7564 to 11.2000 2.9585 19.2692 5.5652 to 66.7184 *NR: not retained in the final multivariate model.

11111


Prognostic significance of the maximal value of the baseline standardized uptake value on fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography for predicting pathologic malignancy of operable breast cancer. Presenting Author: Takayuki Kadoya, Hiroshima University, Hiroshima, Japan Background: [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) is potentially useful in predicting prognosis of breast cancer patients. Methods: 344 breast cancer patients (mean age: 58.0 ⫾ 12.5) with clinical stage IxIII between January 2006 and December 2011, were prospectively evaluated (median follow-up period: 52.0 months). Patients underwent a whole-body FDG PET/CT before operation. The maximal value of the baseline standardized uptake values (SUVmax) were assessed for predicting disease free survival (DFS). For the evaluation of relationship between SUVmax values and prognostic factors such as hormone receptors, human epidermal growth factor receptor 2 (HER2), nuclear grade, lymph node metastasis and tumor size, statistical analyses were performed using Student t test and log-rank test, and p values of less than 0.05 were considered to indicate statistically significant differences. Results: Clinical stage included were I (n ⫽194), II (n⫽134) and III (n⫽16). Tumors with estrogen receptor (ER) positive were 292 (84.9%) and negative were 52 (15.1%). Patients were divided into two groups according to cut-off SUVmax established on the basis of receiver operating characteristic analysis (ⱕ3.0 vs ⬎3.0, AUC⫽0.713). There was a significant difference in DFS between two groups (p⫽0.001) and, hormone receptor, HER2, nuclear grade, lymph node metastasis were found strong relation to SUVmax values. SUVmax and ER status were predictive factors with multivariable analysis using cox proportional hazard regression model (p⫽0.033 and p⫽0.004, respectively). Conclusions: SUVmax on FDG PET/CT before operation has a predictive value for high-grade malignancy and prognosis in operable breast cancer. Factors Revised maxSUV Age Clinical T stage Clinical N stage Nuclear grade Estrogen receptor status HER2 status

Odds ratio (95% CI)

P value

4.350 (1.127-16.786) 1.338 (0.496-3.607) 1.668 (0.597-4.656) 1.183 (0.418-3.344) 0.955 (0.332-2.745) 4.624 (1.635-13.082) 1.247 (0.407-3.824)

0.033 0.565 0.329 0.751 0.932 0.004 0.699

11112


Hormone receptor-dependent regulation of ABAT and beta-alanine metabolism in breast cancer. Presenting Author: Jan Budczies, CharitéUniversitätsmedizin Berlin, Berlin, Germany Background: Recently, we identified beta-alanine as biomarker for breast cancer using GC-MS based metabolomics. Beta-alanine is increased in breast cancer compared to normal tissues and in the more aggressive ERsubtype compared to ER⫹ breast cancer. Beta-alanine is a substrate of 4-aminobutyrate aminotransferase (ABAT), can be catabolised to malonate semialdehyde and used for reduction of NAD and acetylation of coenzyme A. The aim of the current study is to analyze ABAT protein and RNA expression in a large cohort of breast cancers. Methods: The specificity of a polyclonal antibody against ABAT was validated using siRNA in MFC7 cells. A cohort of 164 paraffin-embedded breast cancer tissues from the METAcancer biobank was investgated by immunohistochemistry. Tumor cells were evaluated separately for staining intensity (low, moderate or high) and percentage of stained cells. A cohort of 156 METAcancer samples was investigated for gene expression using whole genome DASL. Results: ABAT protein intensity correlated strongly with estrogen receptor (ER) status (p ⬍ 0.001), but not with HER2 status. In particular, the ABAT protein was highly expressed in 41% of the ER⫹ tissues, but only in 2% of the ER- tissues. Further, ABAT intensity correlated strongly with tumor grade (p ⬍ 0.001). ABAT intensity did not correlate with tumor stage or nodal status. Explorative evaluation of ABAT protein in normal cells revealed weak expression in some of the ducts and negative expression in adipose cells. ABAT protein and RNA expression strongly correlated in the subcohort investigated by DASL. Analysis of a large external data set (publicly available at www.kmplot.com) showed that low ABAT expression is associated with an unfavorable prognosis of breast cancer. Both, ABAT protein and RNA expression, showed a strong negative correlation with beta-alanine abundance. Conclusions: We reported on changes in betaalanine metabolism that occur between the molecular subtypes of breast cancer and normal breast tissue. High expression of ABAT in ER⫹ breast cancer is compatible with catabolic use of beta-alanine. Differently, beta-alanine might be preferable used anabolic in ER- breast cancer, possibly for the synthesis of carnosine.


684s 11113


Roles of cMET/ErbB3 activation and overexpression in the development of resistance to EGFR inhibitors in NSCLC patients. Presenting Author: Myung-Ju Ahn, Samsung Medical Center, Seoul, South Korea Background: Multifaceted efforts in the molecular and cellular research of lung cancer revealed many critical pathway dysregulations due genetic and epigenetic alterations to alter balances in signal transduction leading to carcinogenesis. Methods: US guided FNAs or pleural fluid were collected from 44 NSCLC patients enrolled in on-going prospective study involving EGFR inhibitors (gefitinib, erlotinib, or afatinib) and evaluated for EGFR as well as other various receptor tyrosine kinases (RTKs, i.e. ErbB2, ErbB3, cMET, IGF1R, ALK, etc) and downstream AKT and MAPK pathway proteins for their level of expression and activation in order to 1) Compare objective response rate according to the expression/activation of RTK and pathway proteins; 2) Evaluate the modulation of the RTK and pathway proteins during the treatment of EGFRi; 3) Correlate between activating EGFR gene mutations and RTK activation in patients treated with EGFRi. Results: Majority of patients over-expressed EGFR. While not overexpressed, varying and significant levels of cMET and ErbB3 were found and quantitated in each patient. A striking difference in PFS was observed with respect to relative levels of cMET to EGFR in pretreatment FNA. Regardless of EGFR mutation status, patients with higher levels of EGFR to cMET (or higher E/M-Index) showed superior PFS. With an increase in cMET involvement (or decrease in E/M-Index; continuous variable), NSCLC patients exhibited worse clinical outcome with reduction in PFS (as shown in the Table). Furthermore, patients with shorter PFS (⬍ 8 months) had significantly higher levels of total and phosphorylated ErbB3 (67% positive) than patients with longer PFS (⬎8 months, 27% positive). Conclusions: This study clearly demonstrates the critical roles of cMET and ErbB3 in resistance to EGFR inhibitors in NSCLC patients. E/M-Index and activation may serve as predictive markers for treatment selection with EGFRi and cMETi, and should be validated in prospective clinical studies. E/M-Index 100 80 60 40 20

11115

11114


Two lipids based on lipidomics as novel biomarkers for early detection of squamous cell lung cancer. Presenting Author: Youping Deng, Rush University Medical Center, Chicago, IL

> E/M-Index (N) < E/M-Index (N)

Median PFS (M)

P value

Background: Lipids play roles in membrane structure, energy storage, and signal transduction as well as lung cancer. Lipidomics, a new technology aims to measure all the lipids in a cell, has not been applied to diagnostic test development for a variety of cancer types. Here, we adopt lipidomics as a means to identify plasma lipid markers for the early detection of lung cancer and complement CT-based methods for lung cancer screening. Methods: Using mass spectrometry, we profiled 390 individual lipids in a training discovery cohort comprised of cohorts that were either at “highrisk” for lung cancer (n⫽22) and squamous cell carcinoma at early stages (n⫽22). Cases had a minimum of two years clinical follow-up and were matched in terms of race, sex, age and smoking status. Gain ratio feature selection and local weighted classification model were employed to find the best training classifier, which was further validated against an additional cohort, including high-risk individuals (n⫽ 20) and squamous cell carcinoma patients (n⫽17). Results: In the training discovery stage, we found 20 distinct lipids that were significantly distributed between high-risk and cases of squamous cell carcinoma. We further defined a two lipid marker panel had a training accuracy at 95.5% sensitivity, 90.9% specificity and 95.2% AUC (Area under ROC curve). The validation accuracy against the additional cohort is 100.0% sensitivity, 90.0% specificity and 99.0% AUC (Table). The power for sample size we used in both discovery training and validation stages were over 90%. Conclusions: Using lipidomics we identified two lipid markers capable of discerning cases of squamous cell carcinoma from individuals at high risk for lung cancer, with a high sensitivity, specificity and accuracy. The markers maybe further developed as a quick, safe blood test for early diagnosis of squamous cell lung cancer and reduce unnecessary follow-up imaging or invasive procedures.

10 19 11 18 14 15 19 10 25 4

12.2 5 12.2 5 11.2 1.1 9.8 1.1 6.1 0.1

0.054

The training and validation results using a two lipid marker panel.

0.026 0.0001 0.001

Stages Training Validation

Sensitivity Specificity 95.45 1

0.909 0.900

PPV

NPV

Odds ratio

AUC

0.913 0.952 ⫹ inf. 0.952 0.895 1.000 ⫹ inf. 0.99

Sample size power 0.99 0.96

0.018


Targeting radiation resistance in p53 mutant tumors with AKT inhibitors. Presenting Author: Aswin George Abraham, Gray Institute for Radiation Oncology and Biology, Department of Oncology, Oxford, United Kingdom Background: Increasing our understanding of how resistance to radiation occurs, helps us develop more efficient and personalised radiotherapy treatments for cancer patients. Through molecular dissection of events that drive tumour initiation and progression, we have uncovered a functional connection between the most frequent oncogenic mutations that are likely to contribute to therapeutic resistance in 30% of all human tumours. Mutations activating the ⬙AKT⬙ signalling pathway and inactivation of the “TP53” tumour suppressor gene are common mechanisms that cancer cells require to proliferate and escape pre-programmed cell death. We find that in combination these events lead to therapeutic resistance that is reversible by the AKT clinical candidate, MK-2206 and the PI3K inhibitor PI-103. Methods: Using a combination of in vivo and in vitro techniques we have tracked the molecular mechanism for AKT mediated resistance to treatment in solid tumours. This has helped us to simultaneously derive potential biomarkers that could highlight where the greatest efficacy may be achieved in clinical practise. Results: Tumours employ many strategies to inactivate p53; however sequence mutations that result in mutant p53 protein (p53mut) are most often observed. p53mut tumours not only fail to respond to DNA damaging therapy, but are also described to promote therapeutic resistance by dominant negative suppression of p53 dependent promoter activity. We demonstrate that AKT inhibitors- and as proof of concept, the clinical candidate AKT inhibitor, MK-2206, and PI3K inhibitor, PI-103, are effective in treatment of mice with therapeutically resistant tumours with elevated AKT and carrying p53mut. AKT inhibition promotes reduced cellular levels of p53mut via a novel mechanism and promoted re-engagement of cell cycle arrest, senescence and increased sensitivity to ionising radiation in both in vivo and in vitro systems. Conclusions: We show that AKT inhibitors sensitise xenografts carrying p53 mutations to DNA damaging therapy. We have also been identifying potential molecular markers to select the cohort of patient most likely to benefit from this treatment.

11116


Comparison of in vivo skin and in vitro blood lymphocyte models for the prediction of late normal tissue responses in breast radiotherapy (RT) patients. Presenting Author: Melvin Chua, University College London Cancer Institute, London, United Kingdom Background: Critical opinions for the lack of success of DNA double-strand break (DSB) repair as a predictive marker of normal tissue radiosensitivity include the argument that in vitro cellular responses correlate poorly with in vivo responses due to the modifying influence of tissue environment. In this study, we test the hypothesis that a DNA damage assay based on in vivo irradiated skin tissues better predicts clinical responses in human skin, as opposed to the same assay performed in ex vivo irradiated lymphocytes. Methods: DSB levels (24 h post-4 Gy) were quantified using ␥H2AX/53BP1 immunostaining in irradiated skin tissues and G0 lymphocytes of 35 breast RT patients. Patients were selected on the basis of late RT effects in their breast and individuals with marked or minimal effects were classified as cases and controls, respectively. Risk factors of late effects established from multivariate analyses of outcomes of two breast RT trials were also considered in patient selection. They were 1) total RT dose, 2) RT dosimetry, 3) tumour bed boost, 4) breast size, 5) surgical cavity, and 6) axillary treatment. Results: Clinical parameters were balanced in both patient groups. Residual foci levels in skin epidermis and dermis were comparable between cases (n ⫽ 20) and controls (n ⫽ 15). Mean foci per cell were 3.29 in cases, 2.80 in controls for dermal fibroblasts (p ⫽ 0.07); 3.28 in cases, 2.60 in controls for endothelial cells (p ⫽ 0.08); 2.87 in cases, 2.41 in controls for superficial keratinocytes (p ⫽ 0.45); 2.32 in cases, 2.35 in controls for basal keratinocytes (p ⫽ 0.27). Residual foci levels in lymphocytes were however significantly higher among cases (foci per cell ⫽ 12.1) compared to controls (foci per cell ⫽ 10.3, p ⫽ 0.01). Of the different cell types, only residual foci levels of dermal fibroblasts and lymphocytes correlated with clinical severity (R ⫽ 0.722, p ⬍ 0.001; 0.593, p ⫽ 0.01, respectively). Interestingly, foci levels were not correlated between skin cells and lymphocytes of the same patients. Conclusions: DSB repair of ex vivo irradiated lymphocytes appears to be a better predictive marker of late effects to breast RT than DSB repair of in vivo irradiated skin.


Tumor Biology 11117


Can BCL2L12 be a promising favorable prognostic biomarker in breast cancer? Presenting Author: Alexandros Tzovaras, First Medical Oncology Department of Â“Saint SavvasÂ” Anticancer Hospital, Athens, Greece Background: Many genes of the BCL2 family were found to be implicated in breast carcinogenesis and to serve as possible prognostic markers. BCL2like 12 (BCL2L12) is a new member of BCL2 gene family which was discovered and cloned by members of our group and found to be expressed in the mammary gland. The aim of the study was the quantification and the evaluation of the prognostic value of BCL2L12 in breast cancer. Methods: BCL2L12 mRNA levels were determined in 140 samples (81 cancerous and 59 adjacent non-cancerous) of breast tissue using a highly sensitive quantitative real-time polymerase chain reaction (qRT-PCR) method. Relative quantification analysis was conducted using the comparative CT (2-ddCT) method, whereas the association between BCL2L12expression and clinopathological data, disease free survival (DFS) and overall survival (OS) were defined by statistical analysis. Results: Significant relationships between BCL2L12 expression and early TNM stages (P⫽0.021), absence of metastasis (P⬍0.001), Estrogen Receptor (ER) positivity (P⫽0.031) and breast tumors of 2-5cm diameter (P⫽0.032) were observed. Moreover univariate analysis indicated that BCL2L12 expression is a significant prognostic factor of disease-free survival (DFS) and overall survival (OS), whereas multivariate analysis revealed strong association between BCL2L12 expression and DFS. Conclusions: With regard to breast cancer, patients bearing BCL2L12-positive tumors have significantly longer DFS and OS. These results denote a promising, independent favorable prognostic marker and a significant association of BCL2L12 expression with good outcome.

11119


A Ki-67 proliferation index cutoff value of 1% to predict 5-year RFS and OS in patients with pulmonary carcinoid tumors. Presenting Author: Thanyanan Reungwetwattana, Mayo Clinic, Rochester, MN Background: Evaluation of prognostic factors in carcinoid tumors of the lung is limited due to the rarity of disease. This study assessed Ki-67 expression and other clinical variables as prognostic factors in 262 patients. Methods: A systematic search of Mayo Clinic lung cancer epidemiology and tumor registry databases from 1997 to 2009 identified 449 consecutive patients, with 262 having available tissue blocks [40 atypical carcinoids (AC) and 222 typical carcinoids (TC)]. Clinical data were collected by chart review. Tissue blocks were reviewed by 1/3 pathologists using WHO criteria. Tumors were tested for the Ki-67 index using digital image analysis (tumor tracing) by two operators. The association and predictive value of the factors with recurrence-free and overall survival (RFS and OS) were explored using univariable Cox proportional Hazards model and concordance (c) index. Results: Age, stage, smoking history, lymph node (LN) involvement and Ki-67 index were significant prognostic factors for RFS and OS. Median follow-up on alive-patients is 5 years (range: 0.006-5). Median percentage of Ki-67 index of AC and TC were 1.61% and 0.56% (P⬍0.0001), respectively. Patients with Ki-67 ⱖ 1% had significantly worse RFS (HR⫽3.69, P⬍0.0001) and OS (HR⫽3.69, P⫽0.0007) compared with Ki-67 ⬍ 1% group. The c-index of Ki-67 (0.65) was comparable to the pathologic distinction between AC and TC (0.62 for original diagnosis and 0.63 for central-reviewed diagnosis). Conclusions: Ki-67 index cutoff value of 1% is a valuable prognostic biomarker for pulmonary carcinoids based on this large cohort. Our data also provide strong evidence for clinical variables such as age, stage, smoking history, and LN involvement as clinical prognostic factors in pulmonary carcinoids. A prognostic calculator incorporating Ki-67 and clinical variables is under development.

Outcomes Ki-67 > 1% vs. < 1% AC vs. TC (original diagnosis) AC vs. TC (central-reviewed diagnosis)

RFS HR; 95% CI (p value) 3.69; 2.08-6.53 (⬍0.0001) 3.85; 2.17-6.84 (⬍0.0001) 4.24; 2.40-7.48 (⬍0.0001)

C-index 0.65 0.62 0.63

OS HR; 95% CI (p value) 3.69; 1.73-7.90 (0.0007) 2.72; 1.23-6.02 (0.0214) 4.02; 1.90-8.50 (0.0007)

C-index 0.66

11118


Analysis of prognostic factors after 16 years of follow-up in a randomized phase II trial of neoadjuvant FAC compared with CMF in stage III breast cancer. Presenting Author: Julieta Leone, Grupo Oncologico Cooperativo del Sur, Neuquen, Argentina Background: Neoadjuvant chemotherapy is a standard treatment in stage III breast cancer. Prognostic factors can help to identify patients (pts) with high risk of recurrence. The aim of this study was to assess several prognostic factors after a long follow-up, in stage III breast cancer pts, treated with neoadjuvant chemotherapy. Methods: We evaluated 126 pts with stage III breast cancer that participated in a phase-II randomized trial of neoadjuvant 5-fluorouracil, doxorubicin and cyclophosphamide (FAC every 21 days) compared with cyclophosphamide, methotrexate and 5-fluorouracil (CMF days 1 and 8 every 28). Chemotherapy was administered for three cycles prior to definitive surgery and radiotherapy, and then for six cycles as adjuvant. Response was assessed by WHO criteria. Results: The median age was 52 years (range 24-75). Median follow-up was 4.5 years (range 0.2-16.4), disease free survival (DFS) 4.8 years and overall survival (OS) 6.4 years. Results of the phase-II study showed no difference in efficacy between groups. Univariate analysis showed that the number of pathologically involved lymph nodes (pLN), pathologic response and estrogen and progesterone receptor status correlated with DFS and OS. Number of pLN was the only prognostic factor with statistical significance in Cox regression test for both, DFS and OS (P⫽0.0004 and P⫽0.0006, respectively). In a subgroup analysis of pts with pLN, we found no difference in survival when we compared FAC with CMF. Conclusions: The prolonged follow-up of this study provides a unique opportunity to evaluate factors that predict long-term outcomes. After 16 years of follow-up, the number of pLN remains the most powerful predictor of survival. The subset of pts with pLN had similar survival regardless of the regimen used. Clinical trial information: NCT00002696.

TPS11120


Identification and validation of an assay predictive of response and prognosis following anthracycline-based chemotherapy for early breast cancer. Presenting Author: Jude M. Mulligan, Almac Diagnostics, Craigavon, United Kingdom Background: Currently there is no biomarker to predict specific benefit from DNA-damaging anthracycline and cyclophosphamide-based chemotherapy in the clinic. Loss of the Fanconi anemia/BRCA (FA/BRCA) DNA-damage response pathway occurs in approximately 25% of breast cancer and results in sensitivity to DNA-damaging agents. We therefore developed an assay to detect loss of the FA/BRCA pathway, for the purpose of predicting benefit from chemotherapy. Methods: 21 FA patient samples were analyzed to identify genetic processes associated with loss of the FA/BRCA pathway. Unsupervised hierarchical clustering was then performed using 60 BRCA1/2 mutant and 47 sporadic tumor samples and a molecular subgroup was identified that was defined by the molecular processes representing loss of the FA/BRCA pathway. A 44-gene DNA Damage response deficient (DDRD) assay was developed that could identify this subgroup from formalin fixed, paraffin embedded (FFPE) samples in the clinic. Results: In a publicly available independent cohort of 204 patients, the assay predicted response to neoadjuvant DNA-damaging chemotherapy (5-fluorouracil, anthracycline and cyclophosphamide) with an odds ratio of 4.01, (95% Cl:1.699.54). We also analysed samples from an independent cohort of 114 node-negative breast cancer patients treated with adjuvant 5-fluorouracil, epirubicin and cyclophosphamide treatment at the Northern Ireland Cancer Centre. The DDRD assay significantly predicted 5-year relapse free survival with a hazard ratio of 0.27 (95% Cl:0.10-0.83). The assay was not predictive of survival in patients who did not receive chemotherapy. Conclusions: An FFPE tissue-based assay that detects loss of the FA/BRCA pathway has been developed and independently validated as a predictor of response and prognosis following DNA damaging anthracycline/cyclophosphamide-based chemotherapy in the neoadjuvant and adjuvant settings.

0.59 0.64


686s TPS11121


Correlation of 64Cu-DOTA-trastuzumab positron emission tomography (PET) imaging with HER2 status by immunohistochemistry (IHC). Presenting Author: Joanne E. Mortimer, City of Hope, Duarte, CA Background: We have developed 64Cu-DOTA-trastuzumab for PET imaging of HER2-positive breast cancer. We have determined that administering trastuzumab (45 mg) prior to 64Cu-DOTA-trastuzumab sharply reduces liver uptake of the radiotracer. We are now testing whether tumor uptake of 64 Cu-DOTA-trastuzumab correlates with variable IHC staining in women with advanced breast cancer. Methods: Eligibility criteria included biopsy confirmation of metastatic disease that was HER2 1⫹, 2⫹, or 3⫹ by IHC, no anti-HER therapy within the prior 4 mo, and at least 1 non-hepatic site of metastasis ⬎ 20 mm outside the biopsy site. Staging workup included 18 F-FDG PET-CT. Patients received 45 mg of cold trastuzumab prior to 64 Cu-DOTA-trastuzumab. PET-CT scans were obtained at 21-25 h (Day 1) and 47-48 h (Day 2) over axial fields of view chosen in reference to 18 F-FDG. Uptake in prominent lesions was measured in terms of maximum single-voxel SUV (SUVmax). Lesions identified on CT and judged to have image intensity ⬎ adjacent tissue by an expert radiologist were considered positive on PET. Results: Fourteen women (median age 56, range 35-75 y) have undergone imaging. HER2 status by IHC was 3⫹ in 9 pts., 2⫹ in 5 and 1⫹ in 1. Two women with IHC 2⫹ disease were FISH⫹. In the patients considered clinically HER2 positive (IHC 3⫹ or 2⫹, FISH⫹), 64Cu-DOTAtrastuzumab sensitivity was 75 and 90%, respectively, on Days 1 and 2, compared with 94% for 18F-FDG. Tumor uptake of 64Cu-DOTA-trastuzumab was also readily visualized in HER2-negative patients (measured detection sensitivity 90%). There were no false positive findings with 64 Cu-DOTA-trastuzumab. Lesion uptake of 64Cu-DOTA-trastuzumab was higher in HER2⫹ than in HER2- patients (SUVmaxmean ⫾ sem: Day 1 8.9⫾0.6 vs 4.3⫾0.2; Day 2 9.9⫾0.8 vs 5.4⫾0.3, p ⬍ 0.001). Conclusions: 64 Cu-DOTA-trastuzumab PET visualizes HER2 1⫹, 2⫹ and 3⫹ metastatic breast cancer with high sensitivity and specificity. Tumor uptake of 64 Cu-DOTA-trastuzumab-PET in IHC 1⫹ and 2⫹ patients implies possible benefit from anti-HER2 therapies for individuals whose cancers are currently considered HER2 negative. Research Support: DOD1024511. Clinical trial information: NCT01093612.

TPS11123


TPS11122


The prospective MammaPrint MINT (Multi-Institutional Neo-adjuvant Therapy) study. Presenting Author: Charles E. Cox, USF Health, Tampa, FL Background: Patients with locally advanced breast cancer (LABC) are often treated with neo-adjuvant chemotherapy to reduce the size of the tumor before definitive surgery. Complete pathologic Response (pCR) predicts better long term outcome. Genomics assays that measure specific gene expression patterns in a patient’s primary tumor have become important prognostic and predictive tools for early breast cancer. This study is designed to test the ability of molecular profiling, as well as traditional pathologic and clinical prognostic factors to predict responsiveness to neo-adjuvant chemotherapy in patients with LABC. Methods: Women ⱖ 18 yrs with histologically-proven invasive breast cancer T2(ⱖ3.5cm)T4,N0M0 or T2-T4N1M0, with measurable disease, adequate bone marrow reserves and normal renal and hepatic function who signed informed consent are enrolled. Axillary lymph nodes will be staged according to protocol. MammaPrint risk profile, BluePrint molecular subtyping profile, TargetPrint ER, PR and HER2 single gene readout, and the 56-gene TheraPrint Research Gene Panel will be analysed using the whole genome expression array. Patients will receive neo-adjuvant chemotherapy treatment according to protocol. Response will be measured by centrally assessed Residual Cancer Burden (RCB). Objectives are: (1) To determine the predictive power of MammaPrint and BluePrint for sensitivity to neo-adjuvant chemotherapy as measured by pCR. (2) To identify and/or validate predictive gene expression profiles of clinical response or resistance to neo-adjuvant chemotherapy. (3) To compare TargetPrint ER, PR and HER2 with local and centralized IHC and/or CISH/FISH assessment. (4) To identify correlations between TheraPrint and response to neoadjuvant chemotherapy. (5) To compare BluePrint molecular subtype with IHC-based subtype classification. To achieve a difference of 20% in chemotherapy sensitivity for patients stratified by MammaPrint, a total of 226 samples is needed (significance level 0.05 and power of 0.90). So far 45 patients have been enrolled from multiple institutions. Clinical trial information: NCT01501487.

TPS11124


A pilot study utilizing molecular profiling to find potential targets and select individualized treatments for patients with metastatic breast cancer. Presenting Author: Gayle S. Jameson, Virginia G. Piper Cancer Center at Scottsdale Healthcare, Scottsdale, AZ

A randomized, phase II trial of AEZS-108 in chemotherapy refractory triple-negative (ER/PR/HER2-negative) LHRH-R positive metastatic breast cancer. Presenting Author: Stefan Buchholz, University Medical Center Regensburg, Regensburg, Germany

Background: The objective of this prospective pilot study was to determine if treatment selected by molecular profiling (MP) of metastatic breast cancer (MBC) tumors at time of disease progression provides greater clinical benefit than empiric treatment selection. Methods: Eligible pts had MBC, ⱖ 3 prior lines of therapy, and ⬎ 6 wks - ⬍ 6 months time to progression on last treatment prior to study entry. Fresh core biopsy samples were taken from the metastatic site for MP. Analysis by IHC, FISH, DNA microarray and reverse phase protein microarray (RPMA) a quantitative protein pathway activation mapping technique using laser capture micro dissected tumor cells was done, with results in ⱕ14 days reviewed by a Treatment Selection Committee. The primary objective was to compare the progressionfree survival (PFS) using a MP selected treatment regimen to the preceding PFS. Clinical benefit for the pt is defined by PFS ratio (PFS on MP selected therapy/PFS on prior therapy) is ⱖ 1.3, (JCO,28:4877-83:2010). N⫽ 25 was determined (exact single-stage design for phase II studies, type I error rate of 5% [one-sided], power of 90%). MP selected therapy would warrant further investigation if ⱖ 35% of the pts demonstrate a PFS ratio of ⱖ 1.3. Results: Three U.S. sites enrolled 25 evaluable pts who were treated based on MP results. Pts were heavily pretreated with 4 -11 prior therapies (median 7.24). Ten pts (40%) met or exceeded the PFS ratio of 1.3. The most common targets used in drug treatment selection were TOPO1, TS, ER/PR, TOP2A, HER2. Sixty percent of pts’ samples had activation of drug targets determined by RPMA in 3 major clusters: pan-HER-AKT; EGFR/SRC/ ERK/mTOR; IGFR/RAF/MEK/PLK1. Days on MP selected treatments range from 9 - 816⫹. 3 pts continue on treatment for 199, 254 and 816 days. Conclusions: This study demonstrates the feasibility of a highly multiplexed genomic and proteomic MP study for treatment selection in a timely fashion. Patient-specific target driven treatment selection based on MP of a metastatic lesion provided clinical benefit for 10 of 25 heavily pretreated MBC pts. Thus, this approach merits further investigation in future studies. Funded by The Side-Out Foundation. Clinical trial information: NCT01074814.

Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is clinically negative for expression of estrogen and progesterone receptors (ER/PR) and human epidermal growth factor receptor-2 (HER2). It is characterized by its unique molecular profile, aggressive behavior, distinct patterns of metastasis, and lack of commercially available targeted therapies. Chemotherapy has been the mainstay of treatment for women with TNBC, but this current standard-of-care is suboptimal. AEZS-108 is an LHRH-cytotoxic hybrid drug whose rational design covalently couples the carrier D-Lys6-LHRH (an LHRH agonist) to the cytotoxic doxorubicin radical. Because LHRH receptors are expressed in a majority of TNBC, AEZS-108 represents a novel way to selectively deliver cytotoxic chemotherapy in patients with TNBC via a new therapeutic target. Methods: In this open label randomized two-arm multicenter phase II study, patients will be randomized in a 1:1 ratio into one of the two treatment arms: AEZS-108 (267 mg/m2 every 21 calendar days) [Arm A] or SSC (standard single agent cytotoxic chemotherapy [Arm B]) at discretion of treating oncologist cycled every 21 calendar days. Stratified randomization will be used with number of prior lines of therapies (1-2 vs. ⬎2), ECOG performance status 0-1 vs. 2, and liver metastases (absent vs. present). Analysis of the main study endpoint, TTP, will follow a group sequential design with two interim analyses, including the final analysis. O’Brien Fleming stopping boundaries will be used. The primary endpoint is to evaluate the median time to progression (TTP) of AEZS-108 in patients with chemotherapy resistant advanced TNBC treated with AEZS-108 in relation to patients receiving standard single agent cytotoxic chemotherapy. Secondary endpoints include: overall response, clinical benefit, duration of response, overall survival, toxicity profile and quality of life (QoL). Clinical trial information: NCT01698281.


Publication-Only Abstracts Publication-only abstracts, which are selected to be published in conjunction with the 2013 Annual Meeting, but not to be presented at the Meeting, can be found online in full-text, fully searchable versions at abstract.asco.org and JCO.org. The publication-only abstracts are not included in the print volume, but are citable to this Journal of Clinical Oncology supplement. Please refer to the following example when citing publication-only abstracts: J Clin Oncol 31, 2013 (suppl; abstr e12000)

Abstract Author Index Numerals refer to abstract number Accepted abstracts not presented at the meeting (designated by e) are available in full-text versions on ASCO.org. A A’Hern, Roger 535 A, Martinez e14559 A, Rodriguez 1125 Aapro, Matti S. LBA9514, e20616 Aarab Terrisse, Safae 10578 Aardalen, Kimberly e13590 Aasebø, Ulf 7504 Abad Esteve, Albert e14609 Abad, Maria Fernandez e11531 Abadeer, Benjamin 570, 3582 Abadie Lacourtoisie, Sophie 510 Abajo Guijarro, Ana Maria 2005^ Abakay, Abdurrahman e18544 Abakay, Ozlem e18544 Abali, Huseyin e15175 Abate, Annalisa e17548 Abbadessa, Giovanni TPS4159 Abbas, Ghulam 7577 Abbas, Mahmoud e22076 Abbas, Tahir e14619 Abbas, Vivienne 9590 Abbe, Adeline e12554 Abbi, Kamal Kant Singh e18012 Abbott, Brian 1544 Abbott, Caroline H. 9522 Abboud, Miguel 10052 Abbruzzese, James L. 4064 Abbruzzi, Alyson 630 Abd-El-Moneim, Salah-Eldin 1075, 3083 Abdallah, Al-Ola A. 8595 Abdel Aziz, Mohamed e12004 Abdel Halim, Inas Ibraheim e12004, e18505 Abdel Karim, Nagla e13518 Abdel Malek, Raafat Ragaie 7013 Abdel-Fatah, Tarek M. A. 1016 Abdel-Hafeez, Zeinab Mohamed e11599 Abdel-Misih, Sherif e14535 Abdel-Wahab, May e15015 Abdel-Wahab, Reham e15505 Abdelaziz, Ahmed 2034 Abdelfatah, Mohamed e18011 Abdelghany, Ehab Mosaad e20613 Abdelrahim, Maen e15618 Abdelshafy, Mohamed e11614 Abderrahim-Ferkoune, Anissa 3596 Abdi, Salahardin e20568 Abdolzade-Bavil, Afsaneh e13548 Abdul Jalil, Khairun Izlinda 3549 Abdullaev, Zied 7513 Abdullah, Kashif e17506 Abdulrahman, Ramzi 8074 Abe, Hajime 613, 4092, e11555, e12014 Abe, Hiroaki 3034 Abe, Hiroyuki 1506, 11084 Abe, Masaichi e13504

Abe, Masakazu e16507 Abe, Masato 7582 Abe, Tetsuya TPS4152 Abe-Sandes, Kiyoko 1539 Abegglen, Lisa 2026 Abel, Gary 6621 Abel, Gregory Alan 6547, 7128 Abela, Elma Maria 8567 Abella, Esteban 3575 Abella, Vanessa e22021 Abenhaim, Lucien 1578 Aberle, Denise R. 7562, 7566 Abern, Michael e15560 Abernethy, Amy Pickar 6506, 6516, 9560, TPS9649, e15508, e15572, e15605, e17521, e17560, e20674 Abi Jaoude, Wassim e17595 Abidoye, Oyewale O. 9619 Abidoye, Sunday David e12553 Abiko, Tomohiko 7536 Abisaid Baker, Rana e20664 Ablah, Elizabeth e13006 Aboagye, Eric 635, e22194 Aboagye, Jonathan K. e17534 Abolfotouh, Mostafa A. e17528 Abonour, Rafat 8586, 8592, 8596, e19517 Aboody, Karen S. 2018 Abou Ali, Bilal 10052 Abou El Azm, Nihad 3083 Abou El-Ezz, Khaled Mohamed e14642 Abou Zeinab, Rami Mahmoud 11110 Abou-Alfa, Ghassan K. 4017 Abou-Jaoude, Dory e13006 Abouelkhair, Khaled Mahmoud 3591 Abouharb, Sausan 601 Aboumohamed, Ahmed A. e15604 Abrahão, Carina Meira e15176 Abraham, Aswin George 11115 Abraham, Gineesha 2587 Abraham, Jean 1015 Abraham, Joseph e20567, e20685 Abraham, Linn A. 559 Abrahamova, Jitka e15581 Abrahamse, Paul 9579 Abrahamsen, Torveig Weum 3547 Abramov, Tigran e14620 Abramova, Natalya A. e14701 Abramowicz, Jacques S. 5579 Abramowitz, Wattanaporn 2557 Abrams, Keith R. 9040, 9044 Abrams, Thomas Adam 4090 Abramsohn, Emily 9528 Abramson, David H. 10019 Abramson, Vandana Gupta 515, 1034, 1052 Abrantes, Fernanda L. 10054 Abrey, Lauren E. 2057 Abrial, Catherine 1057, 1058, e11615, e16021

688s NUMERALS REFER TO ABSTRACT NUMBER

Abruzzese, Elisabetta 7048 Abruzzo, Lynne 7010 Abu Hazeem, Mahmoud 6568 Abu Hejleh, Taher 6542, 6602, e19065 Abu Kar, Sarah M. e12525 Abu Zaid, Mohammad 8562 Abu-Hijlih, Ramiz Ahmad e16500 Abu-Khalaf, Maysa M. 619, 1046, 2587 Abu-Taleb, Fouad 4537 Abudayyeh, Ala e15618 Abulkhair, Omalkhair A. M. e11518 Abuodeh, Yazan Asad e16500 Abuzalouf, Sadeq e12023 Accettura, Caterina e20681 Acevedo, Andres 9541 Acevedo, Jose Antonio e11533 Acevedo-Gadea, Carlos Rodrigo 6076, e19158 Acharya, Sandhya Chapagain e12572 Achatz, Maria Isabel Waddington e22154 Achenbach, Marina 8569 Achermann, Rita e20542 Achim, Mary F. 5069 Achimas, Patrick 5569 Acikalin, Arbil e19512 Ackerl, Michael 2078 Ackler, Joann R. e17578 Acoba, Jared David e17513 Acquaviva, Jaime e19097 Acs, Peter e13045 Acuna, Claudia Lorena e20657 Acunzo, Julie e16067 Adair, Jennifer E. e13041 Adam, Rene 3599, 3606, 3619^, e20519 Adamakis, Ioanis 4558 Adamo, Barbara 1011, 1062 Adamo, Vincenzo 1062, e11526, e14557, e19084, e19086 Adamoli, Laura 1061, e22078 Adams, Ashley e17500 Adams, Bonne J. 3057, 3059 Adams, Daniel 11046 Adams, George 5016 Adams, Hans-Peter 3634, e14513, e14562 Adams, Julia M. TPS10073 Adams, Kathleen 6523 Adams, Nathan Bradley e20509 Adams, Richard A. 3509, 3533, TPS3645 Adams, Shari 2553 Adams, Sylvia 1042, TPS3122 Adane, Eyob e14673 Adaniel, Christina 1500, 9021 Adavikolanu, Kesava Ramgopal e14694, e16545, e17028

Addamo, Gianfranco Addeo, Raffaele Addepalli, Murali Addioui, Anissa Addison, Christina L.

e12021 e19084 3060 10048 8048, e11574, e16074 Adebamowo, Clement Adebayo 1576 Adelaiye, Remi 4582 Adelstein, David J. 4087, 6035, 6061, e15000 Adenis, Antoine 605, 3514, 3636, 3637, 10542, 10546, 10548 Ader, Jeremy 10035 Ades, Felipe e12515 Ades, Steven e15044, e15106 Adesina, Adekunle 2036 Adessi, Celine 2522 Adeyomoye, Adekunle Ayokunle e11612 Adiga, Giridhar U. e22196 Adjei, Alex A. 2504, 2528, 2551, 2557, 2594, 2609, 3621, 7509, 7510, TPS8125 Adjogatse, Delali Akosua e15101 Adkins, Douglas 3539, 6029, TPS10592, e21501 Adlis, Susan e20560 Adra, Nabil 4557 Adriaens, Lieve 2502, 2517, TPS2618 Adsay, Volkan e14612 Adua, Daniela e14717, e15154, e18509 Adusumalli, Jayanth 6568 Advani, Anjali S. 7028 Advani, Ranjana TPS8620 Aebersold, Daniel M. 5012 Aerts, Isabelle 10026, 10027 Aerts, Joachim 8014 Aessopos, Athanassios e18542 Afchain, Pauline 3585 Afenjar, Karen LBA4001 Affronti, Hayley e13549 Afrit, Mehdi e20721 Afrough, Aimaz e12550 Afsharimani, Seyedamirhossein 6567 Aft, Rebecca 633 Aftab, Dana T. 5026, 6000 Aftimos, Philippe 547 Agans, Robert P 6530 Agar, Nathalie Y.R. 1132 Agarwal, Amit Balkrishna 7062 Agarwal, Devika Ravindra 1016 Agarwal, Jaiprakash e18525 Agarwal, Namrata e12039 Agarwal, Neeraj LBA4509, 4524, 4565, 4578, 4586, e15549, e15555 Agarwal, Piyush K. 4543, TPS4589 Agarwal, Priya 5020 Agarwal, Shyam 6084

Agarwal, Vijay e22123 Agarwal, Vikash e21519 Agarwala, Sandeep 10527, e21522 Agarwala, Sanjiv S. 3022, 4576 Agarwala, Sanjiv S. e20033 Agati, Raffaele 2048 Agbor-Tarh, Dominique 525 Agelaki, Sofia 1045, e22101, e22105 Agemi, Yoko 8054 Agerbaek, Mads 4502, 4533 Aggarwal, Anita e12531 Aggarwal, Charu 8106 Aggarwal, Rahul Raj 5077 Aggarwal, Shyam e11546 Aggouraki, Despoina e14639 Agha, Mounzer E. 7059 Aghajanian, Carol 3077, TPS3121, 5524, 5545, 5550, 5595 Aghakhani, Nozar 2068 Aglietta, Massimo TPS3648, 4129, 9035, 9065, 9070, 9548, 10552, 10583, e11581, e14654, e16099 Agloria, Maliha e17585, e20600 Agnes, Geniaux TPS2622 Ago, Boniface Uji e12568 Ago, Tetteh 5048 Agostino, Nicole Marie e20046 Agrawal, Amit e11567 Agresta, Samuel V. 4125 Agudo-Lopez, Alba 9641 Aguiar, Samuel 10586, e14688, e14691, e21507 Aguiar, Suzana Sales de 1587 Aguilar Marin, Ivan Carlos e12566 Aguilar, Alfredo e12566, e12570, e22165 Aguin Losada, Santiago e16095 Aguirre, Mercedes e19027 Aguirre, Roxana e20544 Agullo Ortuno, M. Teresa 9641 Agulnik, Mark LBA10507, 10559 Agunwamba, Blessing 9012^ Agus, David B. LBA4509, 11047 Aharinejad, Seyedhossein 11032 Ahern, Charlotte H 2538 Aherne, Sinead e11536 Ahlers, Christoph Matthias TPS3109, TPS3112, TPS3114, 8030 Ahlers, Silke 1040 Ahles, Tim TPS9647 Ahluwalia, Dharmendra e13527 Ahluwalia, Manmeet Singh 2070, 2096, TPS2104, 9086, e13031, e15537 Ahmad, Ateeq 577 Ahmad, Aziah 6618, 8107, 9509 Ahmad, Delshad 6567 Ahmad, Imran 577, e20613 Ahmad, Nazish e16546 Ahmad, Saif 3018 Ahmadi, Tahamtan TPS8614^ Ahmed, Asra Z. 8543 Ahmed, Gul 3627 Ahmed, Ivy A. 9578 Ahmed, Omar e13532 Ahmed, Rosina e12039

Ahmed, Sairah 7010 Ahmed, Shahid 3580, 7596, e14619 Ahn, Chul 8074 Ahn, Daniel H. 8046 Ahn, Eugene e22062 Ahn, Hanjong e15516, e15519 Ahn, Hee Kyung 3595, e19129 Ahn, Hyo Seop 10051 Ahn, Inhye 3046 Ahn, Jae-Sook e20621 Ahn, Jennifer 4552 Ahn, Ji Yeong e15144 Ahn, Jin Seok 637, 1088, 9633, 11113, e19051, e19128 Ahn, Jin-Hee e15516, e15519 Ahn, Joong Bae 3570 Ahn, Kwang Woo 10006 Ahn, Mi Sun e15020 Ahn, Myung-Ju 7565, 8014, 8029, 8034, TPS8117, 11113, e19041^, e19051, e19128 Ahn, Sei-Hyun 1070, e11512 Ahn, Soo Kyung 551, 1128 Ahn, Sung Gwe e12005 Ahn, Sunyoung e13017 Ahn, Tae Sung 11030, e22199 Ahrar, Kamran 4516 Ahrendt, Gretchen M. 1098, 9643 Ahrens, Will e21504 Ahsan, Habibul 1548 Ahsan, Samira 1557 Ahuja, Nita 3539 Ai, Junmei 11114 Ai, Yq 3049 Aiba, Keisuke e20576 Aida, Toshiaki 4056 Aiello, Maria TPS7131 Aiello, Rosa Anna e11527 Aieta, Michele 4136^, LBA8005, 9614, e15615 Aigelsreiter, Ariane e15064 Aihara, Satomi 5537 Ailles, Laurie 4568 Aina, Olatunji Francis e20675 Ainslie, Jill 9001 Aintouri, Rachide Jamil e20500 Airoldi, Mario 2084, 6038, 6039 Aishima, Shinichi 1056 Aishvarrya, S 6624 Aisner, Dara L. 8023, e18032 Aisner, Dara 3545, 8024, 8085 Aisner, Joseph 2553, e19145 Aissat, Nasredine 6036, 9511 Aitchison, Michael 4508 Aizer, Ayal A. 5051, e16026 Ajaikumar, Basavalinga S. 6624 Ajani, Jaffer A. 4078, 4083, 4085, 4113, e15013, e15053 Ajavon, Yves 3606 Akabori, Hiroya 4092, e12014 Akagi, Yoshito e14633, e14684 Akahoho, Eugene e14517 Akakura, Nobuaki e14604 Akamatsu, Hiroaki 7572, 7582, 7599, e18556, e19050, e19074 Akamine, Shinji e19016 Akan, Hamdi 7038, e18009 Akande, Taiwo 2569 Akard, Luke Paul 7066, 7073, 7088

Akarolo-Anthony, Sally Nneoma 1576 Akashi, Yusaku 3072 Akasu, Takayuki e14555 Akazawa, Kohei 1029, 3638 Akbari, Mohammad R. 5072 Akbari, Stephanie e22117 Akbashev, Mikhail Y. e15617 Akbulut, Hakan e11511, e15191, e20006, e20655 Akcali, Zafer e19127 Aker, Fugen Vardar e12037 Akers, Stacey 5574 Akgun, Nalan e15191 Akhtar, Mateen e20550 Akhtar, Naveed Hassan 11081, e15600 Akimoto, Etsushi 11111, e22113 Akimov, Mikhail 2561^ Akinci, Muhammed Bulent e15540 Akita, Hirotoshi 7550 Akiyama, Futoshi e11587, e22190 Akiyama, Shoko e14597 Akman, Tulay e11559 Ako, Maiko 10539 Akoulitchev, Alexandre 6063 Akpeng, Belinda 6013 Aksahin, Arzu e14662 Akshintala, Srivandana 2554 Aksnes, Anne-Kirsti 5021, 5038 Aksoy, Sercan e11537, e11544, e11545, e11553, e11554, e11593, e12521, e12563, e14662, e15110, e15175, e20614 Aktas, Aynur 9638, e20572, e20597 Aktas, Bahriye 1082, TPS1141, 5575, e11516 Aktas, Bilge e14660 Aktas, Sedef H. e15191 Akyurek, Serap e17019 Al Ali, Najla 7113 Al Bahrani, Bassim J. e22099 Al Barrak, Jasem e11522 Al Dhaybi, Omar e16012 Al Farsi, Abdulaziz Mohammed e14630 Al Haddad, Seham e11582 Al Hajj, Rima e17583 Al Husaini, Hamed Homoud e19035 Al Mubarak, Mustafa Mohammed e11613 Al Otaibi, Shabab e11518 Al Sakiani, Moahmmed e17528 Al Saleh, Khalid e17008 Al Ustwani, Omar e18018 Al Zahrani, Ahmad e14664 Al-Ajmi, Adel e22099 Al-Ameri, Ali e18011 Al-Barrak, Jasem e15153 Al-Batran, Salah-Eddin LBA3506, 4079, 4080, 4086, 4095, 4100, TPS4153, TPS4158 Al-Gahmi, Aboelkhair e20613 Al-Hadabi, Ibrahim e22099 Al-hajeili, Marwan R. e15077 Al-Hamadani, Mohammed 8580, e17583 Al-Ibraheem, Akram e16500 Al-Kali, Aref 7064, 7094

Al-Khanbashi, Manal e22099 Al-khudari, Samer 6061 Al-Kofahi, Yousef e18502 Al-Lozi, Rawan 1572 Al-Moundhri, Mansour S. e22099 Al-Mubarak, Mustafa 539, e22000 Al-muderis, Omar 10569 Al-Mujtaba, Maryam 1576 Al-Rajabi, Raed Moh’d Taiseer e15171 Al-Saleh, Khalid A. e20501 Al-Shahrour, Fatima 2511 Al-Shamsi, Humaid O. e14630 Al-Shamsi, Humaid Obaid 3548, e20522 Al-Temimi, Mohammed Hassan Hussain 1582 Al-Zaid, Tariq e20034 Alabiso, Oscar e14557 Alahamdi, Mubarak Salem 8593 Alalawi, Raed 7060, 8591, e18527 Alamanis, Christos 4558 Alameddine, Raafat e12525 Alanyali, Hilmi e11501 Alaparthy, Suresh 8072 Alarhayem, Abdulqader e22184 Alas, Veronica 6546 Alba, Emilio 1031 Albadine, Roula 8096, e22159 Albain, Kathy S. CRA1008 Albani, Fiorenzo 2048 Albany, Costantine 4557, e15584 Albarracin, Constance T. 524, 1131 Alberico, Anthony 2089, e13040 Alberico, Thomas 2089 Albers, Peter 4524, 4539, e16003 Albert, Daniel e17573 Albert, Sebastien 6036, e20032 Albert, Ute-Susann e17544 Alberti, Sara 8502 Albertini, Mark R. CRA9003 Alberts, Steven R. 3510, 3523, 3576, 3618, 3640, 4026, e14526 Albertsen, Peter C. 6532 Albiges, Laurence 5049^, 5075, 5088 Albino, Vittorio 11008 Albrecht, Terrance Lynn 6500, e20646 Albright, Joslyn 9101 Alcaide, Julia e22091, e22131 Alcala-Moreno, Iliana e22151 Alcaraz, Diego e19089 Alcindor, Thierry TPS4157, LBA10507, e15034, e15044 Alcorn, Sara R. 9636 Aldape, Kenneth D. 1, LBA2010, 2019^, 2026, TPS2106, e22081 Alden, Christine M. TPS8118 Alderson, Derek TPS4156 Alderson, Lloyd M. e13015^ Alderuccio, Juan Pablo e12526 Aldridge, Julie 9076 Aldridge, Lynley 6556 Aldrighetti, Luca 4129 Alekseev, Boris Y. 4576 Alekseev, Boris TPS5099^ ABSTRACT AUTHOR INDEX 689s

Alektiar, Kaled M. 9501 Aleman, Berthe M. 4536 Aleman, Karen 10588, TPS10595 Alese, Olatunji Boladale e14612 Aleshin, Alex e15001 Aleshin, Vladimir e15583 Alessandretti, Matheus Bongers e15176 Alessandro, Marina 1101 Alesse, Edoardo e14596 Alessio, Adam e13028 Alex, Alexandra Khichfy e14652 Alexander, Brian Michael 2030, 8069 Alexander, Melissa 11106 Alexandre, Jérôme e17514, e20535, e22029 Alexandrou, Paraskevi e22160 Alexeeva, Yulia 8589 Alexis, Dianne e14612 Alexis, Karenza M. 8092 Alfakara, Dima 7064 Alfakeeh, Ali Hussain e17518 Alfano, Catherine M. 9594 Alfanta, Eduard M. 6063 Alfon, Jose e13526 Alfonso, Saily 3086 Algazi, Alain Patrick 8093, 9005, e20010 Algazy, Kenneth M. 6094 Alger, Beverly 9082 Algotar, Amit Mohan e16060 Algros, Marie-Paule 1122, e11579 Alho, Irina 9634, e22072 Ali’, Greta 11066 Ali, Khaled B. e13030 Alì, Marco e11527 Ali, Muhammad e12033 Ali, Nasim 10568 Ali, Nazim N. e17508 Ali, Sayed Sahanawaz 543, e14640 Ali, Shihab 8550 Ali, Siraj M. 1009, 8020, 10577, 11020, 11068, e15035 Ali, Suhail M. 622, 643, 7553, 9634, e18506 Aliberti, Sandra 10552, 10583 Alibhai, Shabbir M. H. 6543, 7067, 7071, 9518, 9536, 9551, 9555, 9595, e20622 Alickaj, Alberta e20677 Aliev, Mamed e21510 Aliev, Vechaslav e14674 Alifrangis, Constantine 7581 Alikhan, Mir Asif e20722 Alimoghaddam, Kamran 7069 Alimzhanov, Marat TPS6098 Alirhayim, Zaid e22184 Aliste, Luisa e15111 Aliu, Oluseyi 6044 Aliustaoglu, Mehmet e11540, e12037, e15100 Alivon, Maureen e13589 Alkadhimi, Zaid 7084, e18001 Alken, Scheryll Paula e13020, e16550 Alkharabsheh, Omar Abed 6567 Alkharouf, Nawal 3104 Alkhasawneh, Ahmad e15108, e15145

Alkhazna, Ammar Ali e22189 Alkhenizan, Abdullah e12551 Alkis, Necati e18510 Allaf, Mohammad 4566 Allam, Emad S. 6526 Allan, Alison L. 5042 Allard, Aurore 5516 Allegrini, Giacomo 1086, e14574 Allemeersch, Joke 10573 Allen Ziegler, Katie L. 7509 Allen, Andrew R. 2524, 2585, 2586, 4007 Allen, Glenn e14550 Allen, Jeffrey Warren 1068, 7511 Allen, Jill N. 4090, e14636 Allen, John Carson e15002, e15102, e15137 Allen, Kerstin 7070, 8518 Allen, M. Shelly 10060 Allen, Mark S. e19013 Allen, Peter J. 3558, 3609, 4116 Allen, Steven L. 7055 Allen-Auerbach, Martin e16019 Allendorf, Daniel Joseph 7591 Aller, Cynthia Barbara e18007 Alley, Evan W. 6515, e17565 Allgaier, Hermann e13548, e13551 Allgeier, Anouk 2011 Allgood, Sallie 7103 Allison, David 2603 Allison, James TPS3120 Allison, Kimberly H. 559 Allo, Ghassan 6041 Allo, Julio e20581, e20612 Alloul, Karine e16088 Allred, Jacob B 9581 Allred, Randy U. 10547 Allum, William H. TPS4156 Alluri, Krishnam Raju 5610, e13010 Almagro, Elena e19532 Almenar-Cubells, Daniel 4560 Almenara, Jorge e22203 Almhanna, Khaldoun TPS3646 Almodovar, Teresa 8043 Almohamad, Watek e19513 Almotlac, Hamidi 1122 Almotlak, Hamadi e11579 Aloj, Luigi 11008 Alonso, Lorenzo e20007 Alonso, Martina e20007 Alonso, Miriam e15533, e15550, e19105, e19160 Alonso, Teresa e16543 Alonso, Vicente 3604, e15107 Alonso-Basanta, Michelle 9088 Alonso-Jaudenes Curbera, Guillermo 2581 Alonzo, Olivier 1507 Aloraini, Abdullah e15044 Aloshin, Vladimir e15546 Alousi, Amin Majid 7011 Alpaugh, Mary 11076 Alpaugh, R. Katherine 580, 11092 Alperovitch, Annick 1578 Alpert, Tracy E. 9527 Alqalyoobi, Shehabaldin e22184 Alran, Severine 1533 Alsayed, Adher e12551 Alseidi, Adnan 4043 Alsidawi, Samer e22030


Alsina, Maria Alsina, Melissa

4098 8529, 8531, 8608, e19516 Alston, Shani Malia 9543, e20582 Altamirano-Dimas, Manuel e15590 Altavilla, Giuseppe 8047 Alter, Robert TPS4595 Alterovitz, Gil 9535 Althouse, Sandra 2529 Altmann, Bettina 8569 Altomare, Ivy 6506, 6516, 6551 Altomonte, Maresa 9070 Altorki, Nasser K. 7602 Altundag, Kadri e11537, e11544, e11545, e11553, e11554, e11593, e11595, e12521, e12563 Altundag, Ozden e11532, e16526, e16528, e16536 Altuntas, Fevzi e18014 Altwairgi, Abdullah Khalaf e17518 Alumkal, Joshi J. 4511, 5003, 5017, 5076 Alva, Vyshak 1038, 2070, 2096, 9086, e15537 Alvarado, Michael 507 Alvarado, Rolyn e21516 Alvarado-Cabrero, Isabel e16518 Alvarado-luna, Gabriela e22151 Alvarez Fernandez, Carlos e14617, e18513, e19034 Álvarez Gallego, José Valero 608 Alvarez, Delia 3059 Alvarez, Elysia e17504 Alvarez, Gonzalo G. e17563 Alvarez, Inaki e12020 Alvarez, Isabel 608, e12015 Alvarez, JoAnn 1034 Alvarez, Ricardo H. 532, 1118 Alvarez-Gallego, Rafael 3543 Alvarez-Perez, Amy I. e20573 Alvarnas, Joseph C. e17556 Alves, Beatriz da Costa Aguiar e20601 Alves, Fabio Abreu 7037 Alves, Marclesson S. 6017 Alves, Maria Teresa Seixas 10533, 10534 Alves, Michel Fabiano e14652, e20691 Alyasova, Anna 9512 Alyea, Edwin 7034 Amable, Lauren e22008 Amadio, Giulia e16538 Amadori, Alberto e22036 Amadori, Dino 552, TPS649, 3040, 3517, 5594, 11022, e11521, e13579, e14512, e15055, e15529, e15615, e16530, e18561, e22056 Amagai, Kenji e14510 Amaniera, Gloria e16099 Amano, Jun 7548 Amano, Toraji e14604 Amant, Frederic TPS5614 Amantini, Consuelo e15513, e15515 Amaral, Alan Alves e20579 Amarantidis, Kiriakos e15063 Amaravadi, Ravi K. 2504, 3621, 9017, 9066, 9088 Amaria, Rodabe Navroze 9022 Amariglio, Roy 5080

Amato, Robert J. e15544, e15545, e15548, e15551, e15552, e15556 Amatruda, Thomas LBA9008 Amatu, Alessio 3581, 11005 Ambannavar, Ranjana 11018 Ambati, Srikanth R. 3101 Ambavane, Apoorva e15601 Ambinder, Richard F. 7009, e17017 Ambros, Peter F. 10015 Ambros, Tadeu Frantz e11611 Ambrosone, Christine B. TPS9647 Ambrus, Julian L. e18018 Amdur, Robert J. TPS6097 Ame, Shanti e17543 Amelio, Dante e13046 Amen, Furrat 6055 Amengual, Jennifer Effie 8575 Amerigo, Marta e19160 Ameryckx, Sophie e19148 Ames, Matthew M. e17017 Ames, Michael e20038 Ames, Patricia 3587 Ameye, Lieveke 528, e12008 Amidei, Christine 2076 Amiel, Corinne 6079 Amin Al Olama, Ali e16000 Amin, Asim TPS4593, 9041, 9050, TPS9103 Amin, Hesham M. 2506^, 3529 Amin, Shantu e13533 Aminossadati, Behnaz 4030 Amir, Eitan 539, e22000, e22015 Amlag, Joanne O. e12030 Ammannagari, Nischala e14632, e14709 Ammannati, Cristina 3038 Ammendola, Aldo e15088 Ammendola, Michele e22104 Amonkar, Mayur 9040, 9044, e20012 Amor Divino, Paulo Henrique e14691 Amores, Arantxa e22058 Amoroso, Domenico 1086, 8043, e11547, e11550 Amoroso, Loredana 10016 Amos, Keith D. 501, 512 Amparo, Jose Roberto e20696 Ampil, Fred e20600 Amselen, David e22119 Amsellem, Marni 9578 Amstutz, Platte T. 11046 Amundsen, Tore 9562 Amzerin, Mounia e20516, e20624 An, Ming-Wen 6520 An, Shejuan e18547 An, Tongtong 8101, e19061^, e19067, e19091, e19101, e19136 An, Xin 4107, e15047 Ana, Sandoval e12547 Anagnostopoulos, Achilles 8567 Anagnostopoulos, Ioannis e15068 Anak, Ozlem 4504, 4576 Anand, Aseem 5030, 5032, 5083, e16005 Ananthakrishnan, Revathi 2574 Anar, Ceyda e18540 Anastasopoulou, Eleftheria A. 3095 Anastasopoulou, Eleftheria e16037

Anatoliy, Chernobay Valentynovych Ancarani, Valentina Ancell, Kristin Kathleen Anchisi, Sandro Anciaes, Fabiana Sequim Ancukiewicz, Marek

629 3040 e14516 3503 e22176 1065, 4047, 4125 Andel, Johannes 3643 Andelkovic, Vladimir e20662 Anderes, Kenna Lynn 1087, 11044 Andergassen, Ulrich 638, 11042, 11043, e22059, e22075 Anderlini, Paolo 7011 Anders, Carey K. 500, 515 Anders, Robert 3016, e22103 Andersen, Klaus Kaae 4052 Andersen, Mads Hald 3028, 8084 Andersen, Rikke 3028, 8084 Andersen, Solveig Norheim 3607 Anderson, Ann E. e16076 Anderson, Barry Douglas 2518, 9517 Anderson, Elsie e20560 Anderson, Garnet L. 1505 Anderson, Ian LBA509 Anderson, James Robert 10012, 10014, 10554 Anderson, Jeffrey TPS3111, 4133 Anderson, Kari e20605 Anderson, Keaven M. e16544 Anderson, Kenneth Carl 3067, 8532, 8582, 8584, 8588, 8592, 8602, e17570 Anderson, Maria 3000, 3001 Anderson, Mark Daniel 2063, e13039, e13044 Anderson, Mary Ann 7018, 8520 Anderson, Roger F. TPS6097 Anderson, Roger T. 3611, 6558, 6606, e17516, e20537 Anderson, S. Keith 2014, 2046, 2072 Anderson, Stephanie 2566 Anderson, Stephen Todd 2099 Anderson, Steven M. 11070, e22142 Anderson, Stewart J. TPS666, 1000 Anderson, Tara B. 8543 Andersson, Borje 7006, 7010, 7011 Ando’, Sebastiano 579 Ando, Kiyoshi e20609 Ando, Koji e15039, e15173 Ando, Masahiko 4088, 7565, 8006 Ando, Yuichi 3535, 11049, e14552, e14614 Andonegui, Marco Alonso 4555 Andorfer, Cathy A. 1037 Andou, Tomoko e15109 Andra, Vindhya Vasini e14694, e15143 Andrada, Zoe e14517 Andre, Fabrice 505, 511, 556, TPS651, TPS653, 2512, 11061, e17520 Andre, Marc TPS8615, TPS8616 Andre, Pascale TPS3117^ André, Thierry 3515, 3524, 3542, 3562, 3596, 3604, 3617, 3618, LBA4003, 4041 Andre, Valerie 5019, 8051^

Andreadis, Charalambos 8535 Andreadou, Anna 4558 Andreeff, Michael 7022, 7029^ Andreetta, Claudia e11565 Andrei, Adin-Cristian 7554 Andrejeva, Liva TPS1609 Andreoni, Bruno e15147 Andreopoulou, Eleni 560, 1118, 2612 Andres, Raquel e12513 Andresen, Corina 9026, 9058 Andrew, Peter 9550 Andrews, David W. 2100 Andrews, Elizabeth B TPS658 Andrews, Miles Cameron 9016 Andrews, Ryan M. e16025, e22135 Andrews, Steven W. 8023 Andria, Michael L. 3573, e14528, e14576 Andric, Zoran Gojko CRA8007 Andrikou, Kalliopi e15058 Andritsos, Leslie A. 7077 Andtbacka, Robert Hans Ingemar TPS3128, LBA9008 Andueza, Maria Pilar e19112 Anduha, Mary e16055 Aneja, Priya e22015 Anelli, Vincenzo e21517 Anene, Ayanna e22124 Ang, Celina 3609 Ang, Joo Ern 2579 Ang, K. Kian 6007, 6011 Ang, Mei-Kim 8107 Ang, Serena e14520 Ang, Soo Fan 6589, 9506, e15097, e20566 Angelergues, Antoine 5063 Angelini, Valentina e14560 Angelo, Laura S. 11086 Angenendt, Philipp 3512 Angevin, Eric 2512, 7604, 9556 Anghileri, Elena 2074 Angioli, Roberto 5560 Angiuoli, Samuel V. 2511 Angleitner-Boubenizek, Lukas 3052 Anido Herranz, Urbano e16095 Anido, Urbano 7549, e16014 Anjum, Mahraz e14630 Anjum, Rana 10509 Annala, Alexander 2018 Anniciello, Annamaria e20013 Annunziata, Christina M. 2514, 10522 Anraku, Masaki 7526 Anrig, Christopher e12536 Ansari, Jawaher 4518 Ansari, Mohammed Iqbal e20613 Ansell, David 6609 Ansell, Stephen Maxted TPS3113, 7041, 8538, TPS8612 Anserini, Paola e17548 Ansmann, Lena e17550 Anson-Cartwright, Lynn e15510 Antetomaso, James 6503 Anthoney, Alan 2525 Anthony, Carol 1080, e11609, e12034, e14646, e20672, e20697 Anthony, Lowell Brian 4141 Anthony, Stephen Patrick TPS11123

Antic, Vladan TPS8123 Antoine, Eric-Charles 6603 Antoine, Martine 7515, 8100, e19036, e19058 Antolino, Giusy e19527 Antón Aparicio, Luis M. 5055, 5087, e15532, e15542, e15558, e22021, e22171 Anton, Antonio 608, 1031, e21509 Antonacopoulou, Anna G. e18507 Antonarakis, Emmanuel S. 5016, 5021, 5085, TPS5100 Antonescu, Cristina R. 10512, 10580, TPS10592 Antonets, Anna V. e16514 Antoni, Giorgia 603, e20556 Antonia, Scott J. 3002^, 3026, 3069, 3091, TPS3112, TPS7607, 8001, 8008, 8030, 8072, TPS8121 Antoniadou, Anastasia e12524, e20642 Antonini Cappellini, Gian Carlo 9035 Antonio, Heriton M. R. e12007 Antonio, Rodriguez e14559 Antoniotti, Carlotta 3563, 3565, 3566, 3602, 3603, 3613, e14531, e14574, e14577, e22056 Antoniou, Antonis C. 1559, 5054, e20660 Antonuzzo, Andrea 9548, e20711 Antonuzzo, Lorenzo 3615 Antoun, Sami 5088 Antunes, Heliton Spindola 6071 Antunes, Luis Carlos Moreira e15067, e15083 Anum, Emmanuel e19530 Anyang, Bean N. 2571 Anyanwu, Uchechi 622 Aoe, Keisuke e19008 Aogi, Kenjiro 571, 11111 Aoki, Daisuke 5590 Aoki, Manabu e16090 Aoun, Hussein e19009 Aoyama, Toru e15112 Aparicio, Guadalupe 5087, e15532, e15542, e15558, e22021, e22171 Aparicio, Jorge 3589, 4560, e14509, e14648, e20643 Aparicio, Thomas 3585, 3614, e14525 Aparo, Santiago 4093, e13550 Apelian, David TPS3127 Apewokin, Senu 8595 Apfel, Christian e22188 Aplenc, Richard TPS10072 Apolo, Andrea Borghese 4543, TPS4589, TPS5095, TPS5102, e16017 Apostolou, Chryssoula 8567 Apostolou, Panagiotis e14699 Appel, Burton 10000 Appelbaum, Frederick R. 7028 Apperley, Jane 7048 Appiah, Juliet 4546 Applebaum, Mark A. 10045 Appleman, Leonard Joseph 2526, 4521 Aprile, Giuseppe 3563, 4000

Apte, Sachin 10556 Apter, Sara e20039 Apuri, Susmitha 7113, e19516 Aquino, Domenico 2074 Aquino, Luciana Carla Martins de 9589 Ara, Carmen e22119 Ara, Takahide e19507 Aracil Avila, Miguel 5566 Arahira, Satoko e13586 Arai, Gaku e15579 Arai, Yoichi e15570, e15576 Araki, Kazuhiro e11587, e15521 Araki, Toshimitsu e22205 Aramaki, Yuko e13500 Arame, Alex 7602 Arana Yi, Cecilia Ysabel 7074, 7089, 7115 Arance, Ana Maria 9004, 9046, e20007 Aranda, Enrique 1125, 3520, e11530 Aranda, Fuensanta e14648 Aranda, Humberto e15111 Aranda, Sanchia e20536 Arandjelovic, Sandra e22115 Aranguren, Dawn e17019 Arat, Mutlu 7038 Arata, Koji 9621 Araujo, Carlos Manoel 6071 Araujo, Dejka M. 10049, e17508 Araujo, John C. e16038 Araujo, Rodrigo Otavio e14568 Arauz, Gabrielle TPS3115 Aravantinos, Gerasimos 1093 Arber, Nadir 1526 Arbilo, Imma C. e22081 Arce-Lara, Carlos Eduardo 8090, e17594 Archambault, Robert LBA4510 Arcila, Maria E. 8018, 8083 Arcos, Rebecca 2517 Arcuri, Jorge e11538 Arcusa Lanza, Angels e12558 Ardavanis, Alexandros 3095, 5055, 11117 Ardigo, Maria Laura 3086, TPS3123 Arellano, Jorge e12508, e16040, e16046, e16052, e16091 Aren, Osvaldo Rudy 8034 Aren, Osvaldo 5002 Arena, Elizabeth Anne 9101 Arena, Francis P. 505, 557, 558, 4005^, 4058^, 4059^, e15023, e15188^ Arena, Maria Grazia e15065 Arenas-Elliott, Carmen P. 11026 Areses, MC 7549 Aresti, Unai e13000 Arevalo, Estefania e19106, e19112 Arevalo-Araujo, Roberto e20569 Argani, Pedram 11019 Argenta, Peter e22007 Argilés, Guillem 2531, 3636, 3637 Argiris, Athanassios 3099, 6006, 6022, 6043, 6051, TPS6098 Arguello, David 2041 Ariazi, Eric A. e13563 Aribal, Erkin e12545 Arif, Saroosh e19077 Arifi, Samia e21513 ABSTRACT AUTHOR INDEX

691s

Arigela, Ravi Sankar

e18003, e19533 Arik, Zafer e11545, e12521, e20614 Arima, Nobuyuki 1106, 1116, e11557 Aristarco, Valentina 1517 Arita, Adriana 8579 Arita, Takeo e13529 Ariyan, Charlotte Eielson 3003^, 9024, 9033 Ariyaratnam, Priyadharshanan 7544 Arju, Rezina 11106 Arkadopoulos, Nikos e12524 Arkenau, Hendrik-Tobias 2579, 8522, TPS8617, e17532 Arlen, Aimee Ginsburg 6607 Arlen, Philip M. 3070, TPS4589, TPS5104, e16017 Armaghany, Tannaz e17585 Armand, Jean-Pierre e22153 Armand, Philippe TPS3113, 8602 Armbrecht, Eric e20049, e20661 Armenia, Silvia e14611 Armenian, Saro 10004, 10020 Armer, Jane M. e20558 Armitage, James O. 8505, 8572 Armstrong, Andrew J. TPS4590, 5011, 5031, 5034, 5081 Armstrong, Dawn Elizabeth e14715 Armstrong, Deborah Kay 1601 Armstrong, Gregory T. 6544, 10032, 10062 Armstrong, Terri S. 1, 2003, 2004 Arnaldez, Fernanda Irene 10040 Arnaout, Angel 1018, e11574 Arnason, Jon E. 8558 Arndt, Carola A. S. 10012, 10554 Arnedos, Monica 510, 511, 2609 Arnell, Christopher 1544 Arnett, Andrea L. e12030 Arnold, Angela G. 1511 Arnold, Dirk 3604, 3643 Arnold, Florence Pilar M. Plaza e14619 Arnold, Mark e14535 Arnold, Rudolf 4030 Arnoletti, Juan Pablo e14546 Arnoux, Valentin e15593 Arns, Britt-Madeleine e19093 Aronson, Melyssa 5508 Arora, Anurag e20610 Arora, Madan L. 570, 3582, 3583, e14518, e14566 Arora, Neeraj K. 6528 Arora, Ritu e13566 Arpaci, Fikret e15623, e18016 Arpino, Grazia e11528 Arra, Claudio 631 Arrand, John R. 4518 Arranz Arija, Jose Angel 4560, 4587, 5542, e15586, e15609, e16014 Arranz, Juan Luis 11089 Arriaga, Yull Edwin e15200 Arrichiello, Cecilia 11008 Arrieta, Fernanda e11538 Arrieta, Oscar e19068, e22068 Arrighi, Giada 1086 Arrigo, Carmela 8047 Arrington, Jasmine 9609 692s

Arrizabalaga, Olatz 1575 Arrondeau, Jennifer e13553 Arrossi, Andria Valeria 8113 Arrowood, Christy 11036 Arruti, Mikel e13000, e14628, e14712, e20718 Arslan, Cagatay e11545, e11595, e12018, e12521 Arslan, Deniz e14683, e14696, e18517 Arslan, Onder 7038, e18009 Artac, Mehmet e18521 Artal, Angel 11028 Artale, Salvatore e14560 Artama, Miia 1514 Arteaga, Carlos L. TPS650^ Arteta-Bulos, Rafael 1067, e13574 Arthur, Douglas W. TPS666 Artioli, Fabrizio e11515 Artioli, Grazia 5548 Artru, Pascal LBA4003, 4046, 9511 Arun, Banu 1024, e12550 Arveux, Patrick 1114 Arvold, Nils D. 2030 Arzbaecher, Jean 2076 Asadi, Khashayar 3011, 7567 Asahina, Hajime 7530 Asami, Kazuhiro 8006, e18530, e19021 Asano, Tomoko 614 Asao, Tetsuhiko e19043 Asao, Yasufumi e22116 Asari, Takao e17006 Asatiani, Ekatherine 2530 Asayama, Masako e15031 Asche, Carl V. e14658 Asche, Julia 3625, e15088 Ascierto, Paolo Antonio 9027, 9035, 9036, 9046, 9065, 9070, TPS9105^, TPS9106, 9548, e20013, e20031 Asensio Sierra, Nuria Maria LBA5501 Asgharzadeh, Shahab 10039 Asher, Ruth 9068 Ashford, Jason M. 10034 Ashida, Reiko e15150 Ashikaga, Takamaru 1000, e20509 Ashing, Kimlin Tan e20651 Ashizawa, Yshio e15579 Ashkenazi, Karin e22173 Ashki, Negin 3080 Ashley, David M. 10021 Ashton-Prolla, Patricia e12546, e22154 Ashworth, Dira R. e20523 Asiedu, Lisa 9528 Asiedu, Michael 7568, e19013 Asija, Aakanksha e15183, e15563 Asikanius, Elina 7004 Askaa, Jon e22065 Aslaminezad, Aliasghar e22167 Asmane-De la Porte, Irene e17543 Asmann, Yan W. 520 Asmis, Timothy R. 3534, 3633, e14598, e14686, e17563 Assaker, Lama Jaoudat e20500 Assayag, Jonathan 1518 Asselain, Bernard 1094, 1533 Asselh, Jamil e15044

NUMERALS REFER TO ABSTRACT NUMBER

Asselin, Marie-Claude TPS4146 Asselti, Maria Consilia e11502 Assenat, Eric 4028 Assi, Hazem e16082, e16088 Assis, Ronnei J. F. e18548 Assouline, Sarit E. 8535, e19520 Asthana, Saurabh 11004 Astolfi, Annalisa 4048, 10540, e21523 Astor, Daniela 1120 Astorg, Florence e17514 Astrow, Stephanie H. 3527, 11062 Astudillo, Aurora e18513 Ataergin, Selmin e15623 Atagi, Shinji 7518, e18530, e19021 Atalar, Banu e11539 Atalay Basaran, Gul e11539 Atallah, Ehab L. 6586 Ataseven, Beyhan 1121 Atasoy, Ajlan e14662 Atasoy, Beste Melek e14660 Atassi, Bassel e17033 Atay, Memis Hilmi e19500 Atchison, Carolyn e16046 Atenafu, Eshetu G. 5058, e15510 Ater, Joann 10049 Atger, Marc e16021 Athanasas, George e12524 Athanasiadis, Athanasios e22202 Athar, Mohammed Abdul Ahad e15200 Atherton, Pamela J. 2596, 3501 Atienza, Jonessa e19514 Atkins, James Norman 1, LBA2010 Atkins, James 1007, 8044, 9531 Atkins, Johnique T. 1051 Atkins, Michael B. 3002^, 4512, 4514, 4521, 4570, TPS4595, CRA9006^, 9076, 9077 Atkinson, Bradley J. e15594, e15611, e15612 Atkinson, Thomas Michael e16018 Atkinson, Victoria 9081 Atluri, Prashanti 2595 Atmaca, Harika e13578, e13580 Atoria, Coral L. 6594 Atrash, Shebli 8595 Atreya, Chloe Evelyn 3507 Atri, Mostafa 4583 Atta, Maria e20642 Attal, Michel 8513 Attard, Gerhardt 5004, 5052 Attia, Steven 10521 Attie, Kenneth M. TPS4595, TPS6098 Attner, Per 6037 Attwood, Kristopher e15604 Attygalle, Ayoma e19543 Atwood, Mary K. 1060 Atzmon, Gil e14540 Au, Heather-Jane 4053 Aubé, Cécile 1058 Aubin, Francine e15094 Aubry, Karine 6053 Aubry, Marie-Christine 7509, 7568, 11119, e19013 Aucejo, Federico e15015 Aucoin, Nathalie 3515, e16082, e16088 Audebert, Christine 8028

Audeh, M. William 11024 Audet, Marie-Lise 6041, e22159 Audi, Raul e11538 Audi, Viviana e11538 Audigier-Valette, Clarisse 7505, 8081, 8099, e19056 Audisio, Riccardo A. 1109, 9557 Audouin, Marie e16089 Auer, Rebecca Ann C. e14686 Auffermann, William F. 2610 Auger, Nathalie 2512 Augustine, Titto A. e14540 Aulakh, Amardeep 7060, 8591, e18527, e22003, e22052 Aulitzky, Walter 4035 Aulmann, Sebastian 11023 Aung, Kyaw Lwin e22035 Aung, Thin Zar e14520 Aura, Claudia 3012 Aurengo, André 6093 Ausems, Margreet Gem 1502 Ausso, Susanna e14613 Aust, Stefanie e16524 Austin, Peter 5007 Austin, Trevor Clark e15095 Autenrieth, Ingo e20652 Auth, Tanja 3098 Autier, Philippe 1519, 5022, e12507, e12548, e16056 Autio, Karen A. 5073, 5090, e16001 Auz, Carmen Laura 11089, e19000, e19109 Avancha, Kiran Kumar Venkata Raja 6548 Avanessian, Priscilla e17556 Avard, Denise 10066 Aversa, Caterina e11581 Avery, Tiffany P. TPS1135 Avigan, David 8558 Aviles Izquierdo, Jose Antonio e20015 Avino, Robert J. 6526 Avisar, Eli TPS11122 Avisar, Noa e13551, e17572 Avital, Itzhak e14500 Avitia, Miguel Angel Alvarez e17031 Avram, Anca M. e19519 Avril, Marie-Françoise e20032 Avritscher, Rony 532 Awad, Mark M. 8083 Awad, Sameh 3599, 3606 Awada, Ahmad 547, 575, 1049^, 1050^, 1055^, 1087, TPS1136, e12008, e19138 Awais, Omar 7577 Awan, Farrukh Tauseef 7040, 7091, 7105 Awrey, Shannon e15590 Axelrod, Rita 6029 Axilbund, Jennifer E. 1601 Axiotis, Constantine A. e14690, e19522 Axtner, Jan e20710 Ayadi, Mohamed Malek e20721 Ayala, Fabrizio e20013 Ayala, Francisco 585, 3042, e12015 Ayala, Rosa 8511 Ayan, Inci 10043 Aydin, Dincer e11540, e14705, e15100

Aydin, Kubra e11540, e15100 Aydiner, Adnan e11534 Aydogdu, Mustafa 1082 Ayeni, Tina 5596 Ayers, Colby 1560 Ayers, Gregory Dan 9019, e14516 Ayers, Leona W. 7573 Ayez, Ninos e14584 Aygun, Sevda e11544 Ayhan, Ali e16526, e16528, e16536 Ayite, Bee e19146^ Aykan, Nuri Faruk e14594 Aymes, Ana L. e13512 Ayodele, Majekodunmi Lawrence e12553 Ayoub, Jean-Pierre M. e15094 Ayres, Aline Sgnolf e13003 Ayuso Sacido, Angel 1575, e13008 Ayyagari, Santa e13010 Ayyanar, Kanyalakshmi e21000 Ayyappan, Sabarish Ram e19525, e19529 Azad, Abul Kalam 4077, 11057 Azad, Nilofer Saba 3539, e14647 Azami, Hidenori 5046 Azami, Yusuke 6086 Azar, Riad 4051 Azari, Laleh e20673 Azarnia, Nozar 517 Azaro, Analia 2016 Azer, Mary W. F. 9062, e20020 Azevedo, Fernanda e14590 Azevedo, Renata Guise Soares e20680 Azevedo, Sergio Jobim TPS661 Azim, Hamdy A. e19035 Azim, Hatem Abdel 589 Aziz, Noreen 9594 Aziz, Salman 9555 Azizi, Michel 5567, e12504 Azkona, Eider e13000, e14628, e14712, e20718 Aznab, Mozaffar e15195 Azoulay, Laurent 1518 Azria, David 1094, e11607 Azuar, Pierre 566 Azuara, Daniel e14554 Azuma, Haruhito e15588 Azuma, Kanako 9621 Azuma, Koichi e19137, e19165 Azuma, Mizutomo 4070, 4110, 4111, e15009, e15022 Azzarello, Giuseppe 6003 Azzaro, Rosa 8564 Azzouzi, Abdel Rahmene e16089

B B, Chia 1125 B, Rodriguez e14559 Ba, Yi 4109 Baak-Pablo, Renee e22152, e22156 Baas, Jara M e14558, e14586 Baas, Paul 7514, 7528, 7581, 7585, 8029 Baba, Eishi LBA4024 Baba, Hideo 3516, 3519, 11065, e14633, e14665, e20576 Baba, Shinichi 1534 Baba, Yoshifumi 11065

Babacan, Taner

e11544, e11545, e12563

Babatunde, Oluwole Adeyemi e12553 Babiera, Gildy 507, 11060 Babigumira, Joseph 6626 Babington, Scott 9001 Babjuk, Marek e16002 Babu, Arvind 8594 Babwah, Jesse Paul e19032 Baccarani, Michele 7001, 7025, 7048, 7073, 7088, TPS7129 Baccelli, Irene 11012 Bach, Bruce A. 6029 Bach, Ferdinand 4009 Bach, Janice 1557 Bach, Peter 6508 Bacha, Jeffrey A. 2093 Bachanova, Veronika 3023 Bachelot, Thomas Denis 511, 557, 561, TPS653, TPS661, 2599, e11602 Bachelot, Thomas 510, TPS650^, e13519 Bachet, Jean Baptiste 4046 Bachet, Jean-Baptiste 3562 Bachi, Angela LBA8005 Bachmann, Felix 2566 Bachmann, Patrick e17022 Bachovchin, William 3058 Backhus, Leah M. 7535, 7546 Backonja, Miroslav 9635 Badalamenti, Giuseppe 10503, 10551, e19084 Badamo-Dotzis, Julie 8530 Badani, Ketan K. e16044 Badari, Ambuga R. 8562 Badarinath, Suprith 621 Badawy, Abd Al-Rahman e13025 Bader, Peter 10007 Badgwell, Brian D. e20594 Badie, Behnam 2018 Bading, James R. TPS11121 Badman, Philip 5507^ Badri, Nadia 5566 Badve, Sunil S. 7605 Badwe, Rajendra A. 2 Bae, Duk-Soo 5601 Bae, Jeong Mo 3550 Bae, Jooeun 3067 Bae, Kyun-Seop 2565 Bae, Sang-Byung 11030, e22199 Bae, Sanggyu e22010 Bae, Sejong 6559 Bae, Sung Hwa 8521 Bae, Woo Kyun e15121, e15573, e17005 Bae-Jump, Victoria Lin 5519, 5523 Baehner, Frederick L. 520 Baek, Jeong-Heum 3595 Baek, Ji Yeon e14504, e14606 Baek, Moo Jun 11030, e22199 Baeksgaard, Lene e15099 Baena, Jose Manuel e11583 Baer, David M. 9645 Baer, Maria R. 7049, e17584 Baerlocher, Gabriela M. 7051 Baertsch, Robert 5006 Baertschi, Daniela 3503

Baez, Luis e11568 Baez-Revueltas, F. Berenice 634, e11533 Bafaloukos, Dimitris 582, e19048 Bagai, Rajesh Kumar 1038 Bagai, Rakesh K. e22032 Bagal, Bhausaheb Pandurang 7043, e19503 Baggerly, Keith A. 1005, 1569, 4538, e22064 Baggstrom, Maria Quintos 7506 Bagijn, Marloes 9045 Bagley, Rebecca G. e14539 Bagnardi, Vincenzo 617 Bagnoli, Marina 11037 Bagnyukova, Tetyana V. 3058 Bago-Horvath, Zsuzsanna 573, 611, 11088, e22090 Bagriacik, Umit E. e12036 Bagrodia, Aditya 4581 Bahadori, Ronja 9503 Bahar, Babak 7069 Bahary, Jean-Paul 2008, LBA4510 Bahary, Nathan 3539, 4012, 4038, e15089 Bahassi, El Mustapha e13023 Bahcall, Safi R. CRA8007, e19097 Bahceci, Erkut 2602 Bahl, Amit 5055 Bahleda, Rastislav 2512, 2535, 3010, 7604, 9556 Bahleda, Ratislav 4574 Bahlis, Nizar J. 8588 Bahlo, Jasmin 7015 Bahnasy, Abeer e14678 Bahoric, Boris LBA4510 Bai, Hua 8101, e19061^, e19067, e19091, e19101, e19136 Bai, Li 4109 Bai, Li-Yuan 6052 Bai, Xuefeng e22071 Bai, Yu-Xian 4109 Baier, Susanne e13009 Baig, Mahadi Ali e14540 Baiget, Montserrat e14541 Bailen, James 5034 Bailey, Alexandra S. 4521 Bailey, Colleen 4583 Bailey, Dale L 9616 Bailey, Elizabeth A 9616 Bailey, Howard Harry e20565 Bailey, Lisa TPS5614 Bailey, Samuel D 7084 Bailly, Greg 5048 Bailon, Olivier 3065^ Bains, Manjit S. 4501, 4534 Bains, Paramjot e11580 Baio, Gabriella e22132 Baiocchi, Luca e15148 Baird, Kristin 10013, TPS10591 Baize, Nathalie LBA8002 Bajaj, Madhuri e22168 Bajaj, Preeti S. e19001 Bajetta, Emilio 4136^, e15589 Bajorin, Dean F. 4501, 4527^, 4534, 4547^ Bajpai, Jyoti 5554 Bakacs, Tibor e13029 Baker, Amy Louise 9102 Baker, Emily 6527, 9508

Baker, Jennifer L. 11098 Baker, Joffre 11018 Baker, Jonathan C. 10585 Baker, Kevin Scott 9526, 9606 Baker, Laurence H. 10522 Baker, Ryan e20024 Baker, Sharyn D. 10005 Bakhous, Aziz 8595 Bakhshi, Sameer 7081, 7082, 10527, e21506, e21522 Bakkum-Gamez, Jamie Nadine 5577 Bakst, Richard Lorne 6019 Bal, Oznur e15110 Bal-Mahieu, Christine 10525 Balachandran, Dave e20528 Balakrishnan, B e11567 Balakrishnan, Nyla 5580, 5584 Balakrishnar, Bavanthi 543 Balakumaran, Arun 8589, e20514 Balan, Vitaly e22168 Balañá, Carmen 2087, 10529, e13016, e16549 Balasa, Vinod e21000 Balasubramaniam, Sanjeeve 2527, 6074 Balboni, Michael J. 6529 Balboni, Tracy A. 6529, 9519 Baldazzi, Valentina e15615 Baldelli, Elisa 5560, e22155 Baldeyrou, Brigitte 10525 Baldi, Giacomo Giulio 10576 Baldini, Editta 8105 Baldini, Elizabeth H. e19121 Baldini, Luca 8509 Baldock, Anne e13017, e13041 Baldota, Sanjay Zumberlal e12032 Baldotto, Clarissa Serodio e18515 Baldueva, Irina Alexandrovma 3088 Balduyck, Bram 7534 Baldwin, Graham e16016 Baldwin, Megan TPS2619 Baldwin, Ron 8523 Balgouranidou, Ioanna e15063 Baliakas, Panayiotis 8567 Balic, Marija 506, 583 Balise, Raymond R. e15011 Balistreri, Mariangela 3563 Ball, David e14545 Ball, Douglas Wilmot 6090 Ball, Graham 1016 Ball, Howard A. 2602 Ballas, Marc S. 2532, TPS7608 Ballatore, Valentina e16099 Ballatori, Enzo 9614 Balleine, Rosemary L. 543 Ballester, Sandra e12019 Ballinger, Marcus 9010 Ballman, Karla V. 520, 521, 522, 1037 Balmaña, Judith 1509, 11024 Balme, Brigitte 9093 Balogh, Agnes TPS4151, TPS9103 Balsamo, Lyn M. 9584 Balsamo, Teresa 576 Baltes, Nina e14539 Baltzer, Heather 1507 Balukrishna, Sasidharan 11019 ABSTRACT AUTHOR INDEX

693s

Balvan, Ozlem

e11540, e14533, e15100 Bamat, Michael K. e20592 Bamboat, Zubin M. 9033 Bambury, Richard Martin e13020 Bamefleh, Hanaa e19035 Bamias, Aristotelis 4525, 4558, 4578, 4586, 5541, e15619 Banavali, Shripad 5554, e20678 Banchereau, Jacques 3014 Banck, Michaela S. 8093 Bancroft, Elizabeth 5054 Bancroft, Tim e17509 Bandak, Mikkel 4532 Bander, Neil Harrison 11081 Bandiera, Elisabetta 5560 Bando, Hideaki 4074, e13510, e22082 Bandos, Hanna TPS657 Banefelt, Jonas e16066 Banerjee, Nila 1046 Banerjee, Susana N. 5514, e13502 Bang, Soo-Mee 1590, e15129 Bang, Yung-Jue 2565, 3004, 3550, LBA4001, 4013, 4044, TPS4151, TPS4155, TPS4157, 8032, 11031, e13505, e15066 Bangemann, Nikola TPS1141 Bangio, Livnat TPS2102 Banissi, Claire 3065^ Bankfalvi, Agnes e11516 Bankhead, Armand 11017 Bann, Carla 9608 Banna, Giuseppe Luigi e16532 Banner-Voigt, Marie Louise Vorndran Coeln e16540, e16541 Bannister, Wade M e17519 Bannon, Sarah A. 1525, 1546 Bannoo, Selina 5500 Banos, Anne 7002, 8510, 8527, 8528, 8583 Bansal-Travers, Maansi 1603 Banzato, Alberto e15606 Banzi, Maria 3524, 3615 Bao, Ting TPS648, e20574, e22034 Bao, Weichao 11082 Bao, Wen-Jing 1588 Bapat, Urmi e20021 Bar, Jair 8048 Bar-Ad, Voichita e17577 Barabasch, Alexandra 11077 Baracos, Vickie E. e13503 Barakat, Richard R. 1511, 9610 Barash, Steven e13551, e17572 Barbano, Raffaela 576, e14655 Barbara, Cecilia 3615, 11058 Barbareschi, Mattia e11569, e13046 Barbault, Alexandre e15049, e15155 Barber, Beth L. 9045, e20014 Barber, Jim LBA9000 Barbera, Maria Aurelia e15003 Barbera, Santi 8066 Barbie, David Allen 8116 Barbieri, Elena 556, e12021 Barbieri, Fausto e19020 Barbon, Ana e14648 Barbosa, Leandro A e22122 Barbounis, Vasileios e12537 Barco Sanchez, Antonio e22073 Barcos, Maurice P. e18018 694s

Bardelli, Alberto Barden, Julian Bardet, Etienne Bardhan, Pooja Bardia, Aditya

TPS3648, 11005 3094 3560 9603 533, 647, TPS1134, TPS1144 Baresic, Tania 641 Barger, Rachel TPS4595 Bargetzi, Mario 8560 Bargfrede, Michael 2547 Bariani, Giovanni Mendonca e15124 Barile, Carmen 9554, e13514, e15512, e15514 Barinoff, Jana 610, 1577 Barkauskas, Deborah Sim e22158 Barkauskas, Donald A. 10053 Barker, Christine TPS8619 Barker, Kerry B. 612 Barker, William 9080 Barlesi, Fabrice 7505, 8000, 8009, 8014, 8027, 8028, 8059, 8081, e19056 Barletta, Giulia TPS7606, 11063 Barletta, Justine A. 6023, 6054 Barlev, Arie e15046 Barlogie, Bart 8515, 8517, 8539, 8592, 8595, 8603, 8610 Barlow, Carolyn 1520 Barlow, Julianne C. 7588 Barlow, Lamont J. 4552 Barlow, William E. TPS657, CRA1008 Barnadas, Agust 1027, e14541 Barnes, Brie S. e12030 Barnes, Grady 5563 Barnes, Tanganyika e14625, e14661, e14681 Barnett, Anne Elizabeth e20565 Barnett, Anthony H. 1578 Barney, Reed B. e16091 Barnholtz-Sloan, Jill 1527, 6538 Barni, Sandro 3508, 4091, LBA8005, e11547, e11550, e11573, e14611, e19084 Barnoy, Eran 7562, 7566 Barocas, Daniel Ari 6532 Baron, Ari David TPS4161^ Barón, Francisco J. e20708 Baron, Marc 1104 Barone, Carlo 3514, 3636, 3637, e14565, e19138, e20650 Barone, Ines 579 Barouk-Simonet, Emmanuelle TPS1607 Barr, Jennifer e20009 Barr, John e20587 Barr, Ronald e17525 Barrajon, Enrique e20705 Barrajon-Catalan, Enrique e19003 Barretina, Pilar e20704 Barrett, A. John 3104 Barrett, John A 3022 Barrie, Maryline 2024, 2032, 2092 Barrientos, Jacqueline Claudia 7014, 7017, TPS7133, 8500, 8501, TPS8619 Barriere, Jerome 2020 Barrio, Santiago 8511 Barrio-Alonso, M. J. e15169


Barrios, Carlos H. TPS651, TPS662, 4504, 4576, 8034, e12510 Barrios, Enrique e14682 Barriuso, Jorge 4135, e15169 Barron, Richard L. 6608, e17509 Barron, Thomas Ian 5084 Barros e Silva, Milton Jose e20644 Barros, Laryssa Almeida Borges de 5540 Barrueco, Jose LBA8011, 8034, e19126 Barry, Elly 2567 Barry, Mitchel 1112 Barry, Patrick e20550 Barry, William Thomas 1032 Barsoum, Gamal 3500 Bart, Joost e22174 Barta, Johannes 3052 Barta, Stefan K. 8524 Bartashnik, Aleksandra 6508 Bartels, Ute Katharina 10029 Barth, Matthew John 3055 Barthelemy, Philippe e16067, e17543 Bartido, Shirley TPS3115 Bartlett, John M. S. TPS656 Bartlett, John 6578 Bartlett, Nancy 2033, 8505 Bartlett-Pandite, Arundathy N. 3021, 4519, 4569 Bartolini, Stefania 2021 Barton, Darren 4518, LBA5000, 5057 Barton, Debra L. 9513 Barton, Sarah Rachel e19543 Bartrina, Jose Maria e16071 Bartsch, Rupert 573, 611, 11088, 11093, e20693, e22090 Bartunkova, Jirina 3076, e16002, e22129 Barua, Animesh 5579 Baruchel, Sylvain 2538, 10039 Barugel, Mario Edmundo 3511, 3620 Baruzzi, Agostino 2048 Barz, Allison 6575 Barzan, Kathleen 10555 Barzi, Afsaneh 3527, 3567, 3568, 4110, 4111, 6545, 11062, e14543, e14714, e15009, e15022, e17559 Bas, Murat e11532 Basappa, Naveen S. TPS4594, 5042, e15503 Basaran, Mert 5055, e15569 Basch, Ethan M. 5026, 6575, 6583, 6587, 9617, 9618, e16018, e17560 Bascomb, Newell e16062 Baselga, José 503, LBA509, 517, 525, 537, 553, 558, 561, TPS650^, 2016, 2530, 2531, 3012 Basen-Engquist, Karen TPS9650 Baser, Onur 6608, e12010, e14689, e16080, e19122 Bashir, Qaiser 7010 Basik, Mark 531, 1018 Baskan, Mazhar Semih e17529 Baskin-Bey, Edwina 5001 Basolo, Fulvio 3613 Bassan, Franco e13514, e15514 Basse, Linda 8512^

Basset, Dawn 2608 Basset-Seguin, Nicole 9036, 9037 Bassett, Jeffrey C. 4540 Bassett, Roland 7011, 9096, e20034 Bassi, Claudio 4006, 4007 Bassi, Sawsan 9568 Bassini, Anna 641 Basso, Gianpaolo e13046 Basso, Umberto 6593, e15514, e15606, e15615, e16078 Bassullu, Nuray e19127 Bast, Martin 8505, 8572 Bast, Robert C. 1569 Baste, Neus e19159 Basterretxea, Laura e15586 Bastholt, Lars 4 Bastiaannet, Esther e20545 Bastian, Boris C. 9002, 11004 Bastick, Patricia A. 1079 Bastos, Bruno R. 8044 Bastos, Diogo Assed e15517, e16005 Basu, Bristi 2580 Basu, Chinmay Kumar 7083, 7114 Basu, Gargi Dan 2041, 11001 Basu, Partha 5529 Basu, Samar e11552 Basu, Sanjib 5579, e18013, e19113, e19117 Basu, Saumen e21519 Basu, Soumit K. 7058 Bataille, Vincent e20022 Batchelor, Tracy 2013, 2015, 2029, 2054 Bates, Michael e21504 Bates, Susan Elaine 2527, 4585, e22213 Bates, Tom 5 Bathala, Tharakeswara e15611 Bathers, Sarah 5 Bathini, Venu Gopal 4058^, 8097 Batist, Gerald 2542, e14556 Batista, Ana 2056 Batista, Ranyell Spencer Sobreira 10586, e14691, e21507 Batman, Erdogan 595, e14558 Baton, Frederique TPS2622 Batra, Anu e15152 Batra, Kumar Kunnal e12523 Batra, Swati 1099 Batsis, Ioannis 8567 Battaglia, Tracy Ann e12509 Battaglini, Claudio 7119 Battat, Erez e14571 Batteux, F 569 Battista, Marco Johannes 615, 5593 Battley, Jodie Emma e15196 Battmann, Achim 4100 Batty, Anthony J. e20021 Battye, Shane 3011 Batuman, Olcay 8594 Batus, Marta e19113, e19117 Bauchet, Fabienne 2067 Bauchet, Luc 2067 Baudelet, Christine TPS9107^ Baudin, Eric 6092 Baudrin, Laurence 7505, 7515, 8081, e19058

Bauduer, Frederic 8536 Bauer, Emanuel C. A. 11042 Bauer, Kathrin 7015 Bauer, Sebastian 10509, 10510, 10553 Bauer, Stefan 4080 Bauer, Todd Michael 2617, 3004 Bauerfeind, Ingo 1020, e17544 Bauernhofer, Thomas e15064 Baughman, Jan E. 3004 Baulies, Sonia e22119 Baum, Michael 1121 Baum, Sarah 7525 Bauman, Julie E. 6005, 6043, 6051 Baumann, Klaus H. LBA5503, 5531 Baumann, Sybille e20538 Baumann, Walter 6623 Baumeister, Hans 3008 Baumert, Brigitta G 2007 Baumgaertner, Isabelle 3601 Baumgarten, Deborah O. e15617 Baumgartner, Paul e17560 Bauml, Joshua 9613 Bavbek, Sevil E. 4504, 5002, e15569 Baxevanis, Constantin N. 3095, e16037 Baxi, Shrujal S. 6024, 6594 Baxter, Nancy N. 9571 Baxter, Nancy 1002 Bay, Jacques-Olivier 10525, 10582 Bayat, Ali-Ahmad e22198 Bayer, Gerald K. 2006, 2051 Bayet-Robert, Mathilde e16021 Baykara, Meltem e11559 Baylin, Stephen 3539 Baylot, Virginie e16067 Bayo, Juan L. 608, e11577, e11583 Bayoglu, Vedat e22061 Baz, Rachid C. 8532, 8588, 8608, e19516 Bazan, Fernando 1122, e11579 Bazan, Marlon 1558, 11050 Bazhenova, Lyudmila 8031, 8109 Bazin, Igor e14674, e15194 Beadling, Carol 7513, e19141 Beal, Kathryn 2057 Beale, Philip James TPS5612, TPS5614 Bealin, Lisa 1538 Beam, Eric e16073 Beamish, Rose 598 Bean, Gregory R 10526 Beard, Brian C. e13041 Beard, Clair 4561 Beare, Sandy 3532, 4120 Bearss, David 6011 Bearz, Alessandra LBA8005, e15512 Bearzi, Italo 3591, 4123, e15058, e15081 Beasley, Mary Beth 11085 Beatson, Melony A. 3070, TPS5095, e16017 Beatty, Gregory Lawrence 3025 Beatty, J David e22178 Beaty, Karen A. 4134 Beau-Faller, Michele 7515, 8000 Beauchamp, R. Daniel 3555 Beaudry, Guillaume 3639 Beaugrand, Annick 10057, 10065

Beaumont, Hubert e18508 Beaumont, Jennifer L 9574, e20527 Beaunoyer, Mona 10048 Beaver, Julia A. 11019 Becchimanzi, Cristina 8564 Bechstein, Wolf TPS3124^, 3538 Bechter, Oliver Edgar 4138 Beck, J Robert e15559 Beck, J. Thaddeus 553, 557, 4010, 4504, LBA8003 Beck, Joseph Thaddeus e15005 Beck, Julia 1537, 5072, 11013, 11060 Beck, Stephen 4554 Becker, Daniel Jacob 6571, e17566, e17589 Becker, Heather 1007 Becker, Marc e21505 Becker, Shawn e22172 Beckett, Laurel A 8097 Beckett, Laurel e15073, e19147 Beckhove, Philipp 3090 Beckloff, Nicholas 1046 Beckman, Robert A. 2583 Beckmann, Matthias W. 591, 640, 5515, 11042, 11043, e22075 Becouarn, Yves 4028 Bedair, Ahmed e17008 Bedard, Marc 542 Bedard, Philippe L. 2517, 2534, 4503, 11002, 11016, e15510, e17515, e22000 Bedard, Philippe 2561^ Beddow, Emma 7544 Bedell, Cindi 3099 Bedell, Victoria 2018 Bedenne, Laurent 3525^, 3614 Bedikian, Agop Y. 9047, e20036 Bedrosian, Isabelle 11060 Beebe, David J. e22141 Beebe, Kristin e19097 Beech, Bettina 6564 Beech, Derrick e12573 Beeke, Carol 1581, 3592, 6598 Beeker, Aart TPS4591 Beer, Ambros e15042 Beer, David G. 11056 Beer, Tomasz M. 5009, 5017, 5053^, TPS5093, TPS5103 Beeram, Muralidhar 2500, e22088 Beerblock, Karine 569 Beerepoot, Laurens Victor 2001 Beg, Muhammad Shaalan 1560 Begna, Kebede 7094 Begnami, Maria D. 11038, e14691, e15184 Begossi, Giovanni e14599 Begueret, Hugues 8100 Begum, Rubina 3532 Begum, Shahnaz 4566 Behera, Madhusmita 2610, 7560, e19094, e20596 Behjati, Sam 9085 Behrens, Carmen 7552 Behrens, Robert J. 3640, 4026, e14526 Behringer, Dirk M. 1589, 4009, 8112 Behzadi, Asita e20575 Beishuizen, Auke 10028

Beith, Jane McNeil 1053, 1079, 9616, e20533, e20584 Beitler, Jonathan Jay 6083 Beitsch, Peter D. e22117 Bekaii-Saab, Tanios B. 4011, 4014, e14535 Bekaii-Saab, Tanios S. 1556 Beksac, Meral 7038, e18009 Bekyashev, Ali e15546 Belanger, Karl 9032 Belani, Chandra Prakash 7508, 7553, 8095, e13530, e13533, e18552, e19094 Belch, Andrew 8588 Belda-Iniesta, Cristobal 1575, 2087, e13008, e19123 Bele, Vivek e17505 Belev, Nicodim F. 1567, e12543 Belichard, Monique 566 Belin, Catherine 3065^ Belka, Claus 1121, LBA2000 Belkacemi, Yazid e14525 Belkora, Jeffrey 9534 Bell, Chaim 5007 Bell, David 5048 Bell, Jenny 11094 Bell, Maria 2607 Bell, Melanie 6556 Bell, Richard 525 Bell-McGuinn, Katherine M. 2584^, 3077 Bella, Santiago Rafael e13036 Bellamy, Patricia 5008 Bellanger, Sylvie e20535 Bellavance, Emily Catherine TPS648 Belldegrun, Arie S. 4507^ Bellera, Carine A. 10570 Belleville, Erik 591, e11525 Bellew, Kevin M. 8029 Bellezza, Guido e22155 Belli, Carmen e15057 Belli, Franca e15065 Bellile, Emily Light 7044 Bellini, Elisa 2084, 6038, 6039 Bellinvia, Anna e12013 Belliveau, James e14599 Bellmunt, Joaquim LBA4509, 4524, 4525, 4529, 4539, 4550, 5013, 5014, TPS5098^, e16028 Bello, Carlo 2568 Bello, Danielle 9024 Bellobi, Cinta e16539 Bellomo, Fernanda 4136^ Bellon, Jennifer Ruth 1105, 1133 Bellows, Brandon Kyle e11541, e15549, e15555, e20043 Bellu, Luisa 2043 Belmont, Laure e19036 Belon, Joaquin e20015 Belotti, Alessandro 3581 Belounis, Assila 10048 Belsante, Michael 4581 Beltran, Brady Ernesto e20023 Beltran, Himisha TPS5096, e15600 Beltran, Pedro J. 11095, e13525 Belum, Viswanath Reddy e14713 Belyaeva, Olesya e13005 Bemis, Heather 9609 Ben Batalla, Isabel 7027

Ben Hassel, Mohamed 2007 Ben Nasr, Sonia e20721 Ben Yehuda, Dina 8509 Ben, Xiao-song 7537 Ben-Aharon, Irit e20548, e20595 Ben-Ami, Eytan e17536, e20039 Ben-Baruch, Noa e11578 Ben-David, Eliel 4037 Benafif, Sarah 2566 Benaim, Ely 605, 2598 Benakanakere, Indira e22195 Benassi, Maria Serena 10571 Benatsou, Baya e22153 Benavent Viñuales, Marta 3551 Benavides, Manuel e13016 Benboubker, Lotfi 8513, 8530, 8542 Benca, Juraj e22023 Bencardino, Katia 3581 Benchimol, Daniel 3596 Bendell, Johanna C. 2503, 2519, 2530, 2544, 2606, 3508, 3564, TPS4149, e15004 Bender, Ryan P. 2041, 11001, e19006 Bendok, Bernard R. 2083 Benecchi, Luigi e15502 Benecchi, Sara 8047 Benecky, Michael e20038 Benedetti Panici, Pierluigi LBA5501 Benedetti, Antonio 4123 Benedetti, Giovanni e11616 Benedetti, Jacqueline K. TPS4145 Benedetto, Lucia e20031 Benedikova, Andrea e22109 Benekli, Mustafa e14533, e14705 Benelli, Giancarlo e17520 Benepal, Tim 9503 Benevides, Carlos Frederico Lopes e11503 Benezra, Robert e22148 Bengrine-Lefèvre, Leïla 9511 Benhadji, Karim A. 4118 Benichou, Jacques 1578 Benider, Adellatif e20516 Benini, Stefania 10571 Benjamin, Hila e22173 Benlyazid, Adil 6053 Bennati, Chiara 8024 Bennett, Antonia V. e16018 Bennett, Antonia V 6575 Bennett, Barbara Kaye 9602 Bennett, Brian e16052 Bennett, Bridget 6091, e17030 Bennett, Carol J. 4540 Bennett, Charles L. 5091, e22181 Bennett, Kathleen 5084 Bennett, Kelly L. 9050 Bennett, Kelly 9041 Bennett, Lindsay 588 Bennett, Michael William e14519 Bennette, Carrie 7535 Bennicelli, Elisa e14657 Bennis, Hassan e13016 Bennouna, Jaafar 605, 3601, 3604, TPS7609, 8027, 8043, e18532, e19046 Benouaich Amiel, Alexandra 2020, 2032 Bensaadi, Lamia e15593 Bensch, Frederike 2050 ABSTRACT AUTHOR INDEX

695s

Bensinger, William 8514, 8529 Benson, Al B. 3540, e15187 Benson, Al Bowen 4142, 4143, TPS4149, 6500, 6617, e14711, e15010, e22093 Benson, Charlotte 10569, e21516 Benson, Don M. 7003, 8519, 8526 Benson, Mitchell C. 4552 Benstead, Kim 1015 Bentley, James 3030 Bentley, Tanya G. e15104 Benton, Christopher Brent 7112 Bentrem, David J. 10559 Bentzien, Frauke 6090 Bentzon, Neils 1110 Benusiglio, Patrick R. TPS1607 Benveniste, Etty N e13011 Beny, Alexander 3560, e22111 Benzel, Heather 6539 Benzi, Luca e20694 Beohou, Kanean 3585 Bepler, Gerold 7561, 8001, 8051^ Beppu, Takashi 6004 Beppu, Toru e14633 Beq, Stephanie 10013 Beran, Garry 7552 Berardi, Rossana 4091, e15513, e15515, e15529 Berardi, Simona 8560 Berchuck, Andrew 5509 Berdeja, Jesus G. 8502, e22139 Berdel, Wolfgang E. 8548 Berdov, Boris A. 4010, e15005 Berek, Jonathan S. 5522^, e16510^ Berenato, Rosa e19086 Berenberg, Jeffrey L. e17547 Berenberg, Jeffrey 3510 Berenguer-Llergo, Antoni e14613 Berenson, James R. 8514, 8598, 8599, e20044 Berenzon, Dmitriy P. e18002 Beretta, Giordano D. e20650 Berg, Christine D. 1523 Berg, Deborah 8514 Berg, Hendrik Pieter Van Den TPS5099^ Berg, Jennifer 2501 Berg, Stacey L. 10023 Bergamini, Cristiana 6020, 6027, 6046 Bergamo, Francesca 3563, 3602, 3603, 3613, e14531, e14574 Bergasa, Nora V. e12526 Berge, Eamon M 8024 Berge, Yann 2561^ Bergenfeldt, Magnus e14593 Berger, Adam C. TPS1135 Berger, Andreas W. 4034 Berger, Andreas 11032, e11601 Berger, Gerd e15068 Berger, Lars Arne 4559 Berger, Michael F. 4573, 7593, 7600, 8022, 9060, e15017 Berger, Nathan A. 6525, e14634 Berger, Raanan 1503, e15597, e15598, e16023, e16068 Berger, Virginie 3601 Berger, Winfried e14502 Bergethon, Kristin 8032 Bergh, Jonas C. S. e22126 696s

Berghian, Anca 1104 Berghoff, Anna Sophie 573, 611, 2040, 2059, e20693 Bergman, Bengt 7504 Bergman, Jacques J. e15103 Bergmann, Anke 1587 Bergmann, Lothar 4035, e15070 Bergmann, Manuela 7015 Bergnolo, Paola 10572 Bergot, Emmanuel 7515 Bergsland, Emily K. TPS2623, 4142, 4143, e15004 Bergstein, Ivan TPS3105^, 7029^ Bergstrom, Donald A. e14539 Bergstrom, Kimberly A. e14668, e20649 Berhane, Sarah 4029, e15093, e15162 Berinstein, Neil Lorne 3030 Beriwal, Sushil 5585 Berk, Veli e14533, e14672, e14695, e14705, e18516, e19107, e20603 Berkenblit, Anna 4513, 4564 Berking, Carola 9046, 11009 Berkowitz, Alyssa Peri 9610 Berlin, Jordan 2531, 4121, e14516 Berloco, Pasquale 4129 Berman, Abigail T. 7578 Berman, David M. e15616 Berman, David Mark 9052 Berman, Hal K. 11002, e11542 Berman, Nancy 8554 Berman, Nathaniel e14517 Berman, Russell S. 9021, 9023, 9054 Bermejo, Begoña 1027 Bernadou, Guillemette 2599 Bernard, Apexa e13512 Bernard, Paula J e13558, e13562 Bernard, Philip Seth 7576 Bernard, Stephen A. 2595 Bernardi, Daniela e11569 Bernardi, Daniele e15514 Bernardini, Marcus Q. 5543 Bernardini, Marcus 5508, 5561 Bernardo, Lindsay Ann 7555 Bernardo, Sebastian 3014 Bernards, Rene 1010, 3530 Berneman, Zwi N. TPS7133 Bernengo, Maria Grazia 9035, 9065, 9070, 9548 Bernet, Laia e14671 Berney, Dan 2525, 4508 Bernhard, Helga 3586 Bernhardt, Dirk 643 Bernier, Marie-Odile 6093 Berns, Anton 7581 Berns, Els M. J. J. 597, 11045 Bernstam, Elmer Victor 6566, 9576 Bernstein, Donna B. 10013 Bernstein, Inge 6600 Bernstein, Leslie TPS9648 Bernstein, Mark L. LBA10504, 10528 Bernstein, Vanessa 1033 Bernstein, Wendy 10588 Bernthal, Nicholas 10555 Berois, Nora e14682 Beroukhim, Rameen 2013, 2030, 5511


Berriel, Edgardo e14682 Berriel, Luiz Gustavo Sueth e13050 Berriolo-Riedinger, Alina TPS8615, 11007 Berrocal, Alfonso 2087, e20007 Berros Fombella, Jose Pablo e18513, e19034 Berros, Jose Pablo e20007 Berry, Donald A. 500, 501, 1007 Berry, Donna Lynn e20540, e20552 Berry, Elizabeth Gates 9019 Berry, Jarett 1520 Berry, John S. 3005, 3096, 3097, TPS3126 Berry, Lynne D. 8019, 8085 Berry, Narelle 9585 Berry, Scott Michael e22141 Berry, Scott R. 3534, 6552, e16082, e16088 Berry, William 2529 Bertagnolli, Monica M. 1531 Bertani, Emilio e15124, e15147, e22078 Berthet, Pascaline 1528 Berthold, Dominik e17545 Berti, Franco 2043 Bertino, Erin Marie TPS3106 Bertocchi, Paola e15514 Bertola, Giulio 10519 Bertola, Manuela 641 Bertolaso, Laura e13514 Bertolini, Valentina e14536 Bertolone, Salvatore J. e21000 Bertolotti, Monica 5522^, e16510^ Bertolus, Chloë e17023 Berton-Rigaud, Dominique 5569 Bertorelle, Roberta 2043, 3563 Bertotti, Andrea TPS3648, 11005, e14654 Bertotto, Ilaria 10552, 10583 Bertran-Alamillo, Jordi 11029 Bertrand, Marie e20630 Bertrand, Sophie e13021 Bertucci, François 10516, 10542, 10546, 10548, 10563 Bertulli, Rossella 10565, 10576 Besa, Emmanuel C. 7116 Besiroglu, Mehmet e14660 Beslija, Semir 1040 Besova, Nataliya e15156 Bespalov, Vladimir e13005 Bessa, Lyvia Rodrigues da Silva 5540 Bessaoud, Faiza 2067 Bessaoud, Hamid e19513 Besse, Benjamin 7505, 7604, 8059, 8108, TPS8124, e19056, e19138 Besselink, Nicolle 1010 Bessudo, Alberto 2555, 5551, 8598, 8599, e20512 Besterman, Jeffrey M. 8535 Betancourt, Elba e12544 Betaraf, Morteza e22167 Bethel, Kelly 8109 Bethke, Kevin P. e11572 Bettelli, Stefania Raffaella 530, 556 Betticher, Daniel C. 3503, 7503, 8060 Bettis, Claudette 9082 Betz, Andreas 8574

Beumer, Jan Hendrik 2526, 2571 Beuningen, Rinie Van e14629 Beusterien, Kathy 6595 Beuthien-Baumann, Bettina e21518 Beuzeboc, Philippe 5063, 5567, e12504, e16009 Bevan, Graham H. 5082, e16061 Bevan, Paul 508, 4507^ Bevans, Margaret TPS10595 Beveridge, Roy A. 6607, 9604, 9605 Beveridge, Roy 6580 Bevers, Therese Bartholomew 1564 Bex, Axel e15525 Beyer, Joerg 4559 Beyne-Rauzy, Odile 7002 Bezares, Susana 4550 Bezerra, Stephania e11503 Bezzon, Elisabetta e15606 Bhadrasetty, Veerendra 11083 Bhagwat, Medha 3104 Bhakta, Radhe S. e15520 Bhalla, Kapil N. 11107 Bhalla, Sunita e11546 Bhandari, Menal e13034 Bharadwaj, Sushma e17593 Bharani-Dharan, Bharani TPS650^ Bhardwaj, Nina 3014 Bhargava, Pankaj e14528, e14656 Bhargava, Rohit e22017 Bhargava, Shipra 7079 Bhargavi, Dandugundu e15143 Bhatia, Ashmeet 647 Bhatia, Gita 1525 Bhatia, Shailender TPS3109, TPS3112, TPS3114, e20048 Bhatia, Smita 6537, 9570, 10004, 10020 Bhatnagar, Bhavana e20574 Bhatt, Geetika e22084 Bhatt, Madan Lal Brahma e17020 Bhatt, Niraj 3039, e13567 Bhatt, Rupal Satish TPS4595 Bhatt, Vijaya Raj 1570, 8572 Bhattacharya, Manisha e17562 Bhattacharya, Sanjay e20686 Bhattacharya, Sudin e15520 Bhattacharyya, Gouri Shankar 1071, 7085, 10069, e16062, e21519 Bhaumik, Srabani e14663 Bhave, Saurabh Jayant e20686 Bhora, Faiz Y. e17589 Bhosale, Bharatsinha Baburao 5554, 6085, 7043, e12520, e17027, e19119, e20678 Bhosle, Jaishree e19007, e19146^ Bhowmik, Debajyoti 6580, 7096, 9604, 9605 Bhowmik, Kumar Tapash 6084 Bhowmik, Shravanti 2557, 3039 Bhutani, Manisha 8597, e19506 Bhutani, Manoop S. 4078, 4083, 4085, e15013, e15053 Bi, Nan 7522, 7579, 7580 Biagi, James Joseph e14553 Biakhov, Mikhail Yu 517, 4059^ Biala, Michelle 9507 Bianchi, Giulia Valeria e12017 Bianchi, Marco Giorgio e22056

Bianchi, Maria Paola e19527 Bianchini, Diletta 5049^, 5052 Bianchini, Erika e13579 Bianchini, Giampaolo 1014 Bianco, Nadia 4136^ Bianco, Roberto 8066 Bianconi, Maristella 3591, 4123, e14610, e15081, e15536 Biankin, Andrew Victor e15029 Bias, Peter e13552, e13555, e17572 Biasco, Guido 4048, 10540, e15003, e15069, e21511, e21523 Biasini, Claudia 2021 Bibby, David C. 4563, TPS5612 Bibeau, Frederic e14621 Bichat, Helene e20011 Bickel, Hubert 11093 Bickell, Nina A. 6640, e16551, e17592 Bidard, Francois-Clement 1533, 4046, 9057 Bidault, Francois 6079 Bidet, Yannick 1057, 1058 Bidzinski, Mariusz 5520, 5572, e16544 Bie, Li e22193 Bieche, Ivan 511, 2615 Biehl, Thomas A. 4043 Bielack, Stefan S. LBA10504 Bienvenu, Bryan J. e15023 Bienvenu, Jacques e17022 Bierman, Philip Jay 8572 Biermann, J. Sybil 10524 Biernat, Wojciech 604, 11069 Biesmans, Bart 3626 Biganzoli, Laura 555 Bigay-Game, Laurence e19056, e19058 Bigger, Elizabeth 11074 Bighin, Claudia 1036, e17548 Bignell, Graham 7581 Bigner, Darell D. 2094, e13015^ Bignon, Emmanuelle e14514, e14542 Bignon, Yves-Jean 1057, 1058 Bignotti, Eliana 5560 Bigras, Gilbert 8096 Bijelic, Lana 11054 Bijelovic, Milorad 7503 Bikov, Kaloyan A. e14524, e14602, e16034 Bilchik, Anton e14500 Bild, Andrea e13522 Bilen, Mehmet Asim e15575 Bilici, Ahmet e12037, e15117 Bilici, Mehmet e11559 Bilimoria, Karl Y. 10559 Bilitou, Aikaterini e20014 Billan, Salem 6065 Billett, Henny Heisler e19525, e19529 Billingham, Lucinda LBA5000 Billouin-Frazier, Shere S. 9100 Billups, Catherine A. 10021 Bilodeau, Paul A. 2006, 2051 Bilsky, Mark 9501 Bin Sadiq, Bakr M. 9568 Binaschi, Monica 5522^ Binder, Gary e20033 Binder, Mascha 7027

Bines, Jose 9589 Bingham, Catherine 580 Bini, Roberto e20562 Binici, Merve e20503 Binkhorst, Lisette e11548, e13513 Binot, Elke 1589 Biondani, Pamela 3641, 4136^, e14716 Biondo, Sebastiano 3629 Bird, Brian Richard 3627 Bird, Brian 1115 Bird, Shelly 4517 Bird, Steven e16013 Birdee, Gurjeet e20532 Birdsall, Timothy C. e20663 Birgisson, Helgi 3571 Birim, Ozcan 7534 Birnbaum, Ariel E. 8075 Birner, Peter 611 Biro, Katie 1557 Biro, Krisztina e15530 Birrer, Michael J. 2573, 5516, 5524, 5534, 6579 Birse, Charlies E. 7601 Birtle, Alison J. 4535, LBA5000, 5002 Bisagni, Giancarlo 530 Bisanz, Heike e15096 Bischof Delaloye, Angelika 8560 Bischoff, Farideh Z. e22047 Bischoff, Joachim 1082 Biscuola, Michele e19105 Bishop, Justin A. 6013, 6047 Bishop, Kenneth D. 9051 Bisias, Stratos e16037 Biskupiak, Joseph E. e16091 Bismayer, John A. 5513 Biswas, Bivas 7081, 10527, e21522 Biswas, Ghanashyam e16062 Biswas, Jaydip e15520 Biswas, Tithi 1069 Biterman, Arie 1108 Bitran, Jacob D. 7121 Bittenbring, Joerg Thomas 8569 Bitterman, Haim 639, e14571 Bitterman, Pincas 5579 Bitting, Rhonda Lynn 5031 Bittner, Rachel TPS3109, TPS3112 Bitton, Rafael Caparica e20579 Bittoni, Alessandro 3591, 4123, e14610, e15081, e15536 Bitzer, Michael 3098, 3625, e15088 Bivalacqua, Trinity 4523 Bivins, Carol 7029^ Bivol, Adrian 5006 Bivona, Trever Grant 11004, 11010, 11027, 11067 Bixby, Dale 7063 Biyikli, Zeynep 10068 Bizieux-Thaminy, Acya e19046 Bjarnason, Georg A. 4565, 4578, 4582, 4583, 4586, TPS4594 Bjerregaard, Jon K. 4052 Bjoern, Jon 8084 Bjørnslett, Merete 9569 Blachard, Maria Jesus 8511 Black, Dalliah M. 11060 Black, Deborah 9616 Black, Esther P. 541 Black, Peter C. 4542, e15590

Black, Robert C. 619 Blackford, Amanda L. 6519, e14647 Blackhall, Fiona Helen 7514, 8051^, 8068, 8108, 9503 Blackman, Alice Sarah 6001 Blackstein, Martin E. 10503, 10551, TPS10593 Blackwell, Kimberly L. TPS651, 1076 Blade, Joan 8511, 8544, 8545 Bladt, Friedhelm 2506^ Blaeker, Hendrik e15068 Blaes, Anne Hudson 9606 Blagden, Sarah Patricia 2576, 5562 Blagoev, Krastan B. e14592 Blair, Elizabeth A. 6008 Blair, Kelly L e17519 Blair, Scott Cameron 9513 Blais, Normand e22159 Blakaj, Dukagjin 6064 Blakeley, Jaishri O’Neill 2016, 2044, 2065 Blakely, Collin M. 11004 Blakesley, Rick E. TPS8119 Blanc, Ellen 4574 Blanc, Jean-Frédéric 4028 Blanc, Veronique 11006 Blancas, Isabel e11583 Blanchet, Benoit e15592 Blanchet, Jean-Sebastien 5074 Blanchette, Caty 627 Blanchette, Phillip Stanley e17515 Blanco Villalba, Marcelo e11600 Blanco, Esperanza e12020 Blanco, Giusi 4136^ Blanco, Ignacio e12513, e12516 Blanco, Javier G. 2594 Blanco, Remei 10529 Blanco-Codesido, Montserrat e13535, e14592 Blaney, Susan 2036, 2538 Blank, Christian U. 3036, 9013, 9046, 9078, e15525 Blank, Jules Harris e17025 Blank, Patricia Renee e12529 Blank, Stephanie V. 2591 Blanke, Charles Davic 3575, 3590, TPS4145 Blasco, Ana 11073, e22147 Blaseg, Karyl e17533 Blasiak, Elizabeth 6635 Blasinska-Morawiec, Maria 3511 Blaszkowsky, Lawrence Scott 4047, e14636 Blattman, Sara 5018 Blau, Carl Anthony e22178 Blay, Jean-Yves 1562, 6563, 10500, 10501^, 10503, 10506, LBA10507, 10514, 10516, 10517, 10525, 10542, 10546, 10548, 10551, 10563, 10568, 10574, 10575, 10578, 10579, 10582 Blayney, Douglas W. 6581 Blazeby, Jane M. 4023, TPS4156 Blazer, Kathleen R. 1536 Bleam, Maureen R. 3507 Bleeker, Wim 3066 Bleickardt, Eric 8542 Blessing, John A. 5527 Blettner, Maria 1074

Bleuse, Jean-Pierre 4028 Blin, Julien 1528 Blinder, Victoria Susana 9597, e20620, e20677 Bliznukov, Oleg e21510 Block, Anne Marie W. e18018 Block, Mark I. e17540 Block, Norman L. e15596 Blohmer, Jens U. 1004, 1121, TPS1138, 11061 Bloma, Marianne 5021 Blomfield, Penny TPS5614 Blonder, Josip e22180 Blonquist, Traci e20552 Blons, Helene 8000, 8100, e22001 Blonski, Marie 2067 Bloom, Beatrice 9527 Bloomston, Mark 4142, 4143 Bloor, Adrian 7101, TPS8619 Blotner, Steven 10514 Blouin, Marie-Jose e14615 Blowers, David 7552 Blum, Brian TPS3120, e22148 Blum, Joanne Lorraine 590 Blum, Mariela A. 4083, 4085, e15013, e15053 Blumencranz, Peter William TPS11122 Blumenfrucht, Marvin e15561 Blumenschein, George R. 6067, 8027, 8028, 8029, e12002, e22086 Blumenstein, Brent A. TPS5103 Blumenthal, Deborah T. 1, LBA2010 Blumenthal, Gideon Michael 2532 Blumetti, Jennifer e12523 Blunt, Al 2563 Blust, Linda S. 6586 Boafa, Camilla 507 Board, Ruth E. 3018, LBA9000 Boasberg, Peter D. 9010, 9066 Bobba, Ravi Kiran e22195 Bober, Sharon 9644 Bobiak, Sarah 4142, 4143 Bobilev, Dmitri 5049^ Bobin-Dubigeon, Christine e13519 Bobolts, Laura Rose 1080, e11609, e12034, e14646, e19130, e20672, e20697 Boccadoro, Mario 8509, 8517 Bocci, Guido 1086, 3602, 3603, e14577 Boccia, Ralph V. 8500, 8501, 8599, 9626 Boccone, Paola 10552, 10583 Bociek, Gregory 8572 Bock, Carolin e22059 Bock, Jason e13551 Bockhorn, Maximilian 11014 Boddy, Alan V. 10033 Bode, Gerd 3011 Bodmann, Joanna 4087, 6061, e15000 Bodmer, Walter e14544 Bodoky, Gyorgy 3511, 3620, 4021 Bodrogi, Istvan TPS5099^, e15530 Bodurka, Diane C. 5580, 5584, 5608, e13534, e20637 Body, Jean-Jacques 9628, e20514 Boeck, Stefan Hubert 4007 ABSTRACT AUTHOR INDEX

697s

Boegemann, Martin 5074 Boehm, Catrin e22055 Boehm, Daniel 615 Boehm, Markus 2531 Boelke, Edwin 1101, e13035, e13051 Boelle, Emmanuelle 3574 Boerman, Dolf 2001 Boerner, Scott Anthony 6045 Boerner, Scott L. e19032 Boers-Doets, Christine Bettine e20669 Boffetta, Paolo 1594, 10061 Bogaerts, Jan 587, LBA1001, 6520 Bogardus, Alicia 9575 Bogart, Jeffrey 6059, 7501, 7506 Bogerd, Sylvia Perez 7541 Boggess, John 5607 Boggi, Ugo 4062 Boglione, Antonella 10572 Bogner, Paul 4067 Bogner, Wolfgang 11093 Bohac, Gerry C. e20616 Bohanes, Pierre Oliver e15009 Boher, Jean Marie TPS663 Bohn Sarmiento, Uriel 3589, e14509 Bohnsack, Oliver e22161 Boige, Valerie 3599, 4028 Boileau, Jean-Francois 1018, 6585, e17526 Boisdron-Celle, Michele 3601 Boise, Lawrence 8540, 8609 Boisen, Mogens Karsboel 3572, 8103 Boisselier, Blandine 2028 Boissiere, Florence e14621 Boisvert, Marc E. 11054 Boitier, Francoise e20032 Boivin, Jean-Francois 1578 Bojarski, Anna 8096 Bojesen, Anders 6600 Bojesen, Stig Egil 4052 Bojmar, Linda 3597 Bojorquez-Gomez, Ana 11105 Bokemeyer, Carsten 3078, 3537, 4559, 7027, 9553 Bokhari, Raza H. 7574 Bokhyan, Beniamin e21510 Bokil, Kamlesh 6084 Boklage, Susan H. e14658 Boku, Narikazu 3518, 4008, LBA4024, 4096, e14623, e15031, e15116 Boladeras, Ana Maria e15111 Bolanca, Ante e15603 Boland, C. Richard e14631 Boland, Patrick McKay 11092 Bolanos-Meade, Javier 7009 Bolden, Lauren D 1508 Boldyrev, Andrey e13545 Bolejack, Vanessa 4063 Boleti, Ekaterini 4508 Boll, Dorry e16517 Bolla, Michel 3560 Bollag, David T. 5541 Bollard, Catherine M. 8577 Bolli, Geremia e12507 Bollig-Fischer, Aliccia 7561 Bolling, Magnus Frodin 11097 Bologna, Fabrina 9027 Bologna, Serge TPS8615 698s

Bolondi, Luigi e15149, e21511 Bolotin, Ellen 3508 Bols, Alain e14587^ Bolt, Toki Anna 4095 Bolt-de Vries, Joan 11045 Bolton, Damien M. e16016 Boltong, Anna e20536 Bolukbas, Servet e18503 Bolwell, Brian James 7008 Bomalaski, John S. 2569, 10526 Bomfim, Thais 1539 Bompas, Emmanuelle 10505, 10506, 10525, 10542, 10546, 10548, 10563, 10578 Bomprezzi, Chiara e13007 Bona, Eleonora 1086 Bonadies, Danielle C. e12542 Bonadona, Valérie TPS1607 Bonadonna, Gianni 537 Bonaiti, Catherine 1528 Bonanni, Bernardo 1516, 1517, TPS1610 Bonanno, Laura 11029, 11078, e22068 Bonaventura, Antonino 9602 Bonaventura, Marguerite 1098, 9643 Bonavia, Rosa e19003 Bonazzina, Erica 3581 Bonciarelli, Giorgio e15512 Bond, David Alan 9600 Bondanza, Attilio 7007 Bondar, Vladimir 3073 Bondar, Volodymyr 4007 Bondarde, Shailesh Arjun 3039, e13567, e16062 Bondarenko, Igor 3073, 3537, 4506, 5516, CRA8007, LBA8011 Bondarenko, Ihor 4007 Bondaruk, Jolanta E. 4538 Bone, Henry G. 9628 Bonekamp, David 2034 Bonetti, Andrea 3615, 5050, 6003, e17551, e20617 Bonfili, Laura e15513, e15515 Bongiovanni, Alberto 11022 Boni, Corrado 530, 3505, 3615 Boni, Luca 3505, 3615 Boni, Valentina 2600 Bonichon, Francoise 6092 Bonifacio, Daniela 546 Bonini, Chiara 7007 Boniol, Mathieu 5022, e12507, e16056 Bonk, Allison 2550 Bonnefoi, Herve R. 511 Bonnefoi, Herve 529 Bonner, James A. 623, 1012 Bonner, Keisha e15079 Bonner, William 2527 Bonnet, Sophie 8536 Bonnetain, Franck 1114, 3515, 3585, 3614, LBA4003, 9511 Bonneterre, Jacques 536, 544, 592, 593, 596, e11523, e11529, e11535, e11543, e12552, e13519, e20630, e22127 Bonneterre, Marie-Edith Anne 3009, e17586


Bonnette, Pierre e19036 Bono, Petri TPS4592 Bonomi, Marcelo Raul 6078 Bonomi, Maria e17555 Bonomi, Philip D. 8012, e19113, e19117, e19150, e22130 Bonomi, Philip 2031, 8004, 8086, TPS8126, 11114 Bonomo, Guido e15147 Bononi, Antonio 9554, e20541 Bonotto, Marta e11565, e11573 Bonvalot, Sylvie 10570, 10575, 10582 Boohaker, Rebecca J. 3085 Boone, David L. e13532 Boone, Phillip 10526 Boonstra, Philip S. 1542 Booth, Benjamin J. e12519 Booth, Brian 2510 Booth, Christopher M. TPS3647, 6628, e11597, e14553, e15616 Booth, Sue 9585 Boothman, David A. 8088^ Bootle, Douglas 2531 Borad, Mitesh J. TPS2621, 8523 Boral, Anthony 8010 Borate, Uma 7104 Borbath, Ivan LBA4003, 4138, TPS4159 Borchert, Kersten TPS4158 Bordani, Rodolfo 7591 Borden, Ernest C. e13521, e16022, e19012 Borderie, F. 569 Bordessoule, Dominique 7002 Bordignon, Claudio 3038, 7007, 8035, 10568, e13593, e18528, e22145 Bordoli-Trachsela, Eveline TPS2627 Bordonaro, Roberto e14560, e14565 Bordoni, Andrea e20542 Bordoni, Rodolfo 11010 Bordwell, Alexander e19536, e22085 Borg, Christophe 3601, 3604 Borgato, Lucia 5548 Borger, Darrell R. 533, 2029, 4047, 4125, e13564, e14636 Borges, Virginia F. 6507 Borget, Isabelle 6092, 9084 Borghaei, Hossein 3058, 8072, TPS8122, e22163 Borghi, Massimo 9554 Borgia, Jeffrey Allen 11114 Borgia, Jeffrey A e19117 Borgmeier, Astrid e19108 Borgonovo, Karen e11573, e12021 Borgquist, Signe 3579 Borgstein, Niels Geert LBA4509 Borkhardt, Arndt 10007 Borley, Nigel 5054 Borm, George F. e11558, e17549 Bornemann-Kolatzki, Kirsten 1537 Borner, Markus M. 3503 Borodulin, Vladimir Borisovich 3084 Borowicz, Stanley John e22051 Borowitz, Michael J. 10001, 10003 Borquez, David Julian 602

Borràs, Josep Maria e15111 Borre, Michael 5001 Borrego, Christina e22142 Borrelli, Deanna e13529 Borrello, Ivan TPS3113 Borresen, Erica 1558, 11050 Borrow, Jennifer 2585 Borsellino, Nicolo 8071, e11526 Borsu, Laetitia 7120 Borthakur, Gautam 7010, 7024, 7029^, 7074, 7089, 7090 Bortlicek, Zbynek e14622, e15581 Bortolami, Alberto e12028 Bortolato, Diego e20504, e20657 Bortolus, Roberto 5050 Boruban, Cem Melih e19107 Boruban, Melih Cem e14705, e18510, e18521 Boruta, David M. 5604 Borzecki, Ann 6562 Bos, Marc Christiaan Allardt 1589, 8112, e12517 Bos, Monique M. E. M. 1072, TPS4591, e14558, e22106 Bosch, Carlos 3589, e14509 Bosch, Jose Manuel 1543 Bosch, Linda J. W. 3552 Bosch-Barrera, Joaquim e19003, e19089, e19159 Boscoe, Francis P. 6565 Bosl, George J. 4501, 4534 Bosman, Fred 3522, 3526, 3577, e14544 Bosq, Jacques 592, 593, 596, 5602, e11535, e11543, e16548 Bosquée, Lionel 7500 Bosse, Ulrich e18511 Bosserman, Linda D. 5515 Bosset, Jean Francois 3560 Bossevot, Rachel e20519 Bossi, Alberto TPS5093 Bossi, Ilaria 3641 Bossi, Leonardo Da Silveira e11551 Bossi, Paolo 6020, 6027, 6046 Bosso, Davide e21500 Bossuyt, Veerle 619 Bostwick, David G. e16076 Boswell, Erica 8602 Bosworth, Alysia 9570 Bota, Maria e12507 Botargues, Josep Maria e15111 Both, Stefan 7578 Botia, Monica 11025 Botros, Ihab e22185 Botta, Mario e12021 Bottaro, Donald P. 4543, TPS4589, 11083, 11103 Botteri, Edoardo 1061, 1595, e15147, e22078 Botti, Gerardo e20013 Bottini, Alberto 530 Bottino, Dean e13508 Bottomley, Andrew 2005^ Bouabdallah, Reda TPS8615 Boucard, Celine 2024 Bouchahda, Mohamed 3599, 3606, e20519 Bouchal, Jan 1063 Bouchalova, Katerina 1063 Bouchard-Fortier, Antoine 627

Bouche, Olivier 3514, 3562, 3604, 3614, 3636, 3637, LBA4003, 4028, 4046, 10546 Boucher, Eveline 4127 Boucher, Yves 1065, 4047 Bouchet, Juliette 2548, 2549 Bouchoucha, Davina e20519 Boudahna, Lamiae e21513 Boudou-Rouquette, Pascaline e13589, e15592, e17514, e20535, e22029 Boudouresque, Francoise 2024 Boudreaux, J. Philip 4141, e15139 Boue, Francois 8524 Bouffard, Karina J. e20568 Bouffet, Eric 10021, 10029, 10066 Bouga, Georgia e12524 Bouganim, Nathaniel 6595 Boughey, Judy Caroline 502, 507, 526 Bouhier Leporrier, Karine 3601 Bouhla, Anthi e20642 Bouillet, Thierry 1583 Boulaamane, Lamia e15506 Boulanger, Luke 6546 Boulet, Stephanie 1114 Boulmay, Brian C. e17522 Boulos, Fouad e12525 Boulos, Majdi e14553 Bouma, Willem H. LBA1001 Bourayou, Nawel e19148 Bourbouloux, Emmanuelle TPS1607 Bourcier, Anne-Véronique 1057 Bourlon, María Teresa e14703 Bourmaud, Aurelie e13594 Bournakis, Evangelos e22160 Boursi, Ben 1526, 1599, e15597, e15598, e16068 Boussahira, D. 569 Boussen, Hammouda e20721 Boussiotis, Vassiliki 8558 Bouteloup, Corinne e17022 Boutis, Anastasios L. e11576 Boutouyrie, Pierre e13589 Boutros, Celine 7604 Boutros, Paul C. e18559 Boutros, Tanya 2568 Bouvet, Michael e22011, e22012, e22013 Bouzid, Kamel 6075 Boven, Epie 1072 Bover, Isabel LBA8002, 11028 Bowden, Chris J. 8017, e13574 Bowden, Emma 11017 Bowden, Sarah Jane 5 Bowen, Karin 2579, 11024 Bowers, Megan 3504 Bowes, Barbara 5070 Bowes, David 5048 Bowie, Janice 6032 Bowman, Lee e20525 Bowman, Marjorie 9639 Bowser, Andrew e17530 Box, Jessica A. 1515 Boxberger, Frank 3561 Boxler, Silvan e16063 Boyarskih, Ulyana Aleksandrovna e12560 Boycott, Kym 10066

Boyd, Jeff e13563 Boyd, Jenny May TPS1143 Boyd, Kevin 1579, 11057 Boyd, Thomas E. 7017, 8500, 8501 Boyer, Jean-Christophe e13519 Boyer, Julie TPS8118 Boyer, Michael J. e18500, e22175 Boyer-Chamard, Agnes TPS663 Boyett, James M. 2035, 2036 Boyiadzis, Michael 7059 Boyko, Matthew John 6622 Boyle, David TPS11120 Boyle, Frances M. 9602 Boyle, Frances 6556, 9026 Boyle, Helen Jane 4574, e16096 Boyle, Jay 6048 Boyle, Lucy TPS5615 Boyle, Peter 1519, 5022, e12507, e12548, e16056 Boylu, Sukru e17529 Bozcuk, Hakan Sat e14683, e18517 Bozcuk, Hakan e18521 Bozhenko, Vladimir Konstantinovich e13545 Bozhok, Alla 503, 537 Bozkurt, Emir e11501, e13578, e13580 Bozkurt, Mustafa e19127 Bozkurt, Oktay e14672, e14695, e18516 Bozon, Viviana 2528, 2547 Bozovic-Spasojevic, Ivana 528 Bozzarelli, Silvia e14611 Bozzi, Paola e20541 Brabbins, Donald S. 1123, e16008 Bracarda, Sergio e15524, e15589, e16093 Bracco, Oswaldo L. 9628 Brach del Prever, Elena Maria 10572 Brachman, David 1, 2003, 2004, 2008, LBA2010 Brachmann, Ranier K 2540 Brackmann, Stephan 3607 Brackstone, Muriel 1002, 1018, 1605, 6585, e12549, e17526 Bradbury, Angela R. 1506, 1538, 11084 Bradbury, Penelope Ann 518, 7510, 8048, e19033 Bradeen, Heather Appleton 10035 Bradford, Andrea 5608 Bradford, Carol Rossier 9607 Bradford, Leslie Siriya 5604, e13564 Bradford, Miranda 9526 Bradley, Cathy 6604 Bradley, Colm 7101 Bradley, Jeffrey D. 7523 Bradley, Jeffrey D. 7501 Bradley, Robert TPS1136 Brady, Ged e22035 Brady, John C. 4520 Brady, Mary Susan 9033 Brady, William E. 3077, TPS3121, 5534 Braga, Henrique Faria 2060 Braga, Sofia A. D. S. e20632 Braghiroli, Maria Ignez Freitas Melro e15090

Brahmbhatt, Himanshu 7586 Brahmer, Julie R. 3002^, TPS3112, 7598, 8001, 8030, 8046, 8072, TPS8121, TPS8122 Braicu, Elena Ioana 5549, e22102 Brailiou, Eugen e13563 Brailoiu, Gabriela Cristina e13563 Brain, Etienne 516, TPS649 Braiteh, Fadi S. 3622, 8028 Braitman, Leonard E. e17578 Brake, Rachael e13531 Brakenhoff, J. A. C. 595 Bramajo, Marina Paula e11600 Brambilla, Elisabeth 7515, e19058 Brames, Mary J. e15621 Brammer, Melissa G. e17527 Brammer, Melissa 625, 642, 6626, e11603 Brana, Irene 2016, 5518 Branchi, Daniela TPS1610 Brandao, Erika Pereira e15176 Brandao, Guilherme 8096 Brandes, Alba Ariela 2005^, 2007, 2021, 2048, 2061 Brandes, Ariela e19020 Brandes, Johann Christoph 6611 Brandi, Giovanni e15003 Brandi, Mario e22104 Brandl, Christian 3048, 7020 Brandsma, Dieta 2001 Brandstedt, Jenny 3579 Brandt, Mark 7089, 7115 Brandwein, Joseph 7067, 7071, 7078 Brannan, Christine 9590 Brannon, Angela Rose 4522, 4573 Bransfield, Alison 3627 Branstetter, Daniel e22144 Brase, Jan C. e22112 Brassard, Maryse 6092 Brat, Daniel 2033 Braticevic, Cecile e15506 Bratslavsky, Gennady 4584 Brauchli, Peter 3503 Brauer, Matthew J. e14505 Braun, Ada H. 9640 Braun, Ada TPS662, 5079, 8589, 9628, e20512, e20514 Braun, Christian LBA2000 Braun, Denis 7515 Braun, J. J. 1072, 3502 Braun, Jerry 7534 Braun, Thomas 568 Bravaccini, Sara 5594, e16530 Braverman, Albert S. e14690, e19522 Bravin, Eric N. e14709 Bravo, Dalibel 10531 Brawer, Michael K. 5005 Bray, Victoria Jane e19132 Braylan, Raul e19506 Brazelton, Jason D. 623 Brea, Elliott Joseph 3047 Breathnach, Oscar S. 3549, e13019, e13020, e13022, e13049 Breathwaite, Larry 9537 Brechbiel, Martin W. 2583 Breda, Enrico LBA5501 Bredel, Markus 1012 Bredin, Philomena e19157

Breese, Virginia e14637 Brega, Diana e12543 Bregant, Cristina 4575 Bregar, Amy J. 1545 Bregartner, Tom e19104 Bregman, Bruno 9084 Bregni, Marco 3056 Brehmer, Bernhard TPS4591 Breij, Esther C. W. 3066 Breiner, Klaus M. 3090 Breit, Samuel N. e22175 Breitbach, Caroline 3608^, 4122^, TPS4161^ Breitbart, Eyal TPS2102 Bremer, Michael 1121 Bremnes, Roy M. 4562 Brenig, Bertram 1537 Brennan, Bernadette 10031, 10518 Brennan, Cameron W. 2057 Brennan, John J. 2031 Brennan, Kristina 9002 Brennan, Murray F. 4101, 10520, e15079 Brennan, Tina 10513, e22146 Brenner, Adrienne A. e14569 Brenner, Andrew Jacob TPS2102 Brenner, Baruch 3531, TPS4158, e14571, e15078, e22111 Breslin, Susan 620, e11520 Bressac, Brigitte 1528 Bressel, Mathias e17535 Bretcha, Pere 3074 Bretscher, Peter e14619 Brett, Francesca e13020 Brett, Sara 3044 Breunis, Henriette 7067, 7071, 9555, e20622 Brevet, Marie 8100 Brewer, Carmen C. 2554 Brewer, Jerry D. 9073 Brewer, Molly 5517 Breyer, Marie e19093 Brezden, Christine B. 6625, e17557 Brezovich, Ivan e15049 Brhane, Yonathan 11057 Bria, Emilio e15057, e16053, e17555 Brice, Pauline TPS8615 Bridge, Carly e13041 Bridges, Juliette e16019 Bridgewater, John A. 3504, 3525^, 3619^, 4023, 4120 Brierley, James D. e14664 Brierley, Karina L. e12542 Briet, Marie e13589 Briggs, Kathryn Jane 516 Brighenti, Matteo 4112, e15086, e15502 Brilhante, Maria Amelia e20632 Brilliant, Kate E. e14637 Brin, Lauren e14641, e18501 Bringhen, Sara 8517 Bringuier, Pierre Paul 8000 Brinkman, Tara M. 10062 Brisendine, Alan 4121 Bristow, Robert 5573 Britan, Laura 5067 Brixner, Diana I. e11541, e20043 Brizova, Helena e22208 Broadbridge, Vy 6598 ABSTRACT AUTHOR INDEX 699s

Broaddus, Russell

5521, 5524, 5584, 5596 Brocard, Anabelle e20022 Brock, Jane E. 1100, TPS1134 Brock, Marko 9580 Brock, Penelope 10016 Brockman, Bryan 8559 Brockmoeller, Scarlet F. 11112 Brockstedt, Dirk G. 4040^, TPS7607 Broder, Michael S. e15104, e22124 Broderick, Samuel TPS4590 Brodie, Chaya 2073, 3100 Brodowicz, Thomas 1040 Brodsky, Robert A. 7032 Brody, Joshua 8579 Broeckelmann, Mechthild 10017 Broge, Kristine M. 6586 Brogi, Edi TPS3120 Brohawn, Philip e20047 Bromberg, Jacoline E. 2001, 2007 Brombin, Romina e16100 Broniscer, Alberto 10021 Bronowicki, Jean-Pierre 4126 Brooks, Barry Don 6580, 9604, 9605 Brooks, Christopher TPS3105^, 7029^, 8582 Brooks, Claire E TPS5615 Brooks, David G. 2513 Brooks, James D. 5092, 11096 Brooks, John 6542 Brooks, Samira A 4522 Broom, Bradley 3529 Brophy, James e16013 Brose, Marcia S. 4, 6000, e15564, e17009 Brouste, Veronique 3558 Brouwer-Visser, Jurriaan e22009 Brouwers, Barbara 1078 Brower, Stacey L 7532 Brown, Alaina J. 5580, 5584 Brown, Andrew M. K. 11016 Brown, Anna e20048 Brown, Celia 11094 Brown, Chris 2017, 2086 Brown, Christopher D. 5028, 6010 Brown, David A. e22175 Brown, Dennis 2093 Brown, Elissa C. 5092 Brown, Gordon Andrew e16041 Brown, Jacqueline 5019 Brown, Janet Elizabeth LBA5000, 5079, 9640, e20514 Brown, Jason R. 1085 Brown, Jaycen 9545 Brown, Jean K. e20540 Brown, Jennifer R. 7003, TPS7133, 8519, 8526, TPS8619 Brown, Jubilee 5527 Brown, Karen T. e15017 Brown, Loreal E 2030 Brown, Louise TPS3645 Brown, M Catherine 6543, 9536, 9551, 9595 Brown, Marie e19015 Brown, Matthew S. 5026, 7562, 7566, e16019 Brown, Michael Paul 9030, 9046, e20025 Brown, Patrick Andrew 10003

Brown, Paul D. Brown, Peter Brown, Regina J. Brown, Robert E.

1, LBA2010 8507 1558, 11050 e15548, e15552, e15556 4039 TPS658

Brown, Todd D. Brown, Vikki Brown-Glaberman, Ursa Abigail 1089, 1090 Browne, Brigid 632 Browner, Ilene S. e14647 Browning, Eiko Theodora e18032 Brownstein, Carrie M. 2502, 2517, TPS2618 Brozos Vazquez, Elena e16095 Brozos, E. M. 7549 Bruce, Jeffrey N. e13017 Bruce, Justine Yang 2537, 5076 Brucker, Sara 5598 Bruckheimer, Elizabeth 2511 Bruckner, Howard e22095 Bruecher, Bjoern L. D. M. e14500 Bruegel, Melanie 10508 Bruemmendorf, Tim 11077 Bruera, Eduardo 9611, 9642, TPS9650, e20528, e20554, e20559, e20581, e20594, e20612 Bruera, Gemma e14596 Bruetman, Daniel e15557 Brufsky, Adam 523, 565, 594, 600, e22017 Brugal Molina, Javier e22073 Brugarolas, Antonio 3074, e22120 Brugieres, Laurence TPS1607 Brugnara, Sonia e13046 Brugnatelli, Silvia e14560 Bruix, Jordi TPS4159, TPS4163 Bruland, Oyvind S. 5038 Brule, Stephanie Yasmin 3528 Brummendorf, Tim H. 7099 Brundage, Michael Donald 4053 Brundage, Michael TPS3647, 9502 Brundage, William e20509 Brunelle, Serge e15506 Brunelli, Alessandro 7602 Brunello, Antonella 6593, e11573, e15606, e20541 Bruner, Deborah 9525, 9527, 9639 Bruners, Philipp 11077 Brunet, Joan e12516, e19159 Brunetti, Anna Elisabetta 4091 Brunetti, Isa Maura e14531, e20711 Brunetto, Andre Tesainer e20506 Brunetto, Andre 2579 Brunhoeber, Patrick S. 5045 Brunner, Christine 583 Brunner, Marianne M. 10047 Brunnstrom, Hans e14580 Bruno Da Costa, Ligia e15172 Bruno, Margarita e11610, e19510 Bruno, Rene e16047, e19049, e19103 Brunotte, Francois 11007 Brunson, Ann 8049 Brusca, Marisa Isabel e11600 Brusquant, David 3515 Brutsche, Martin H. 8060 Bruzzese, Dario e11528 Bruzzi, Paolo 546, TPS649 Bruzzone, Andrea e12518


Bruzzone, Maria Grazia 2074 Bryant, David 9505 Bryce, Alan H. 8523, e16061, e16065 Bryce, Richard TPS8124 Brydoy, Marianne 4562 Bryla, Christina 2527 Brünner, Nils e14710 Brynychova, Veronika 11051 Brzezniak, Christina E. 8026 Bshara, Wiam 5574 Buadi, Francis 8516, 8541, 8581, 8587, 8600, 8606 Bubalo, Joseph S. e20627^ Bubendorf, Lukas 8060 Bucci, Eraldo e14536 Buchbinder, Aby 5052 Buchbinder, Daniel 6091, e17030 Bucheit, Amanda Dawn e20034 Buchholz, Stefan TPS11124 Buchholz, Thomas A. 1131, 6630 Buchler, Markus W. 4006 Buchler, Tomas e14622, e15581 Buchner, Anton e13552, e13555, e17572 Buck, Jill Y. LBA10507 Buckingham, Lela e19113, e19117, e22130 Buckner, Jan C. 2014, 2025, 2046 Buckstein, Michael 6019 Buckstein, Rena 7067, 7071 Buda, Carmelo 1062 Budach, Volker 6014 Budach, Wilfried 1101, e13035, e13051 Budagov, Temuri e14540 Budakoglu, Burcin e11559, e19107 Budczies, Jan 11112 Budd, G. Thomas CRA1008 Budha, Nageshwar R. 2503 Budi, Laszlo e12022^ Budinska, Eva 3522, e14544 Budman, Daniel R. 7055 Buecher, Bruno 1528 Bueckner, Ute TPS1141 Buendia, Maria J. 9541 Bueno, Coralia e12020 Bueno, Raphael 7588 Buerki, Christine 4542, 5033, e16044 Buesa Arjol, Carlos e13543 Bueso-Ramos, Carlos E. 7030 Buessing, Arndt e20623 Buettner, Arden 8607 Buettner, Reinhard 8112, e12517 Buffet, Renaud TPS3117^ Buganza, Manuela e13046 Bugat, Roland e20654 Buges, Cristina e19088 Buggy, Joseph J. 7014 Buglioni, Simonetta e19052 Bugos, Kelly 9061, e20026 Bui Nguyen, Binh LBA10507 Bui, Binh 10542, 10548, 10563 Bui, Cat N. e16080 Bui, Lynne A. 2557 Buikhuisen, Wieneke A. 7528 Buist, Diana SM 559 Buitrago, Sandra e13561 Bujdak, Peter 4556, e15599

Bulanov, Anatoly e15585, e21510 Bullitt, Elizabeth 513 Bulloch, Kaleigh e20546 Bullock, Andrea J. 4054 Bulone, Linda e12564 Bulotta, Alessandra 3038, LBA8005, e13593, e18528 Bulsara, Max 1110, 1121 Bulteau, Stephane e20030, e20038 Bulusu, Venkata Ramesh 10541, e21503 Bunn, Janice 9591 Bunn, Paul A. 8019, 8024, 8074, 8085, e18032 Bunse, Joerg 3634 Bunskoek, Sophie 2050 Buonadonna, Angela 3505 Buonandi, Pasquale 4136^ Buonerba, Carlo 7603, e18536, e21500 Buono, Donna 6509 Buque, Aitziber e14712, e20718 Burakoff, Steven J. 3014 Burattini, Luciano e15513, e15515, e15529, e15536, e15615 Burdaeva, Olga N. e20593 Burdette-Radoux, Susan e12000 Burdmann, Emmanuel e20579 Burga, Rachel A. 3079 Burge, Matthew E. 2520, TPS4157 Burger, Herman 10573, e11548, e13513 Burger, Jan Andreas 7005, 7102, TPS7130 Burger, Renate 8604 Burghuber, Otto e19093 Burgio, Marco Angelo e18561 Burgio, Salvatore Luca 5050, e15529, e16031 Burgues, Octavio e12019 Burhani, Mansoor 7106, 7108 Burhenne, Juergen 9612 Burian, Linda e22211 Buring, Julie E. 6058 Burkard, Mark E. 2607, e20565 Burke, Elaine 6058 Burke, James F. 6044 Burke, James 3608^, 4122^, TPS4161^ Burke, John M. 2533, 8537, 8565, e19518 Burke, Matthew M. 9012^ Burke, Matthew e11597 Burke, Thomas A. e20580 Burke, Thomas W. 9538, 9539 Burkes, Ronald L. 3511, 3620, e17557, e19077 Burkey, Brian 6035, 6061 Burkhardt, Carmen 3068 Burkholder, Iris 4035 Burkholder, Tiana 2039 Burmeister, Bryan 9001 Burnell, Margot J. TPS4157 Burnett, Alan K. 7012, 7021 Burney, Ikram A. e22099 Burns, Peter N. 4583 Burotto Pichun, Mauricio Emmanuel 4585, e14592 Burrell, Matthew O. e16525

Burrington, Christine M. e14632 Burris, Howard A. LBA509, 557, 558, TPS660, 2093, 2503, 2507, 2530, 2531, 2544, 2585, 2617, TPS2620, 3000, 3004, 3044, 3564, 5513, 8008, 8062, 8091, TPS8120, 11102, e13045 Burroughs, Kevin 7509 Burrows, Jon e19057 Burstein, Harold J. 1006, 1007 Burtness, Barbara 6005, 6006, 6016, 6028, 6081, 6090 Burton, Elizabeth M 532, 7090 Burton, Gary Von CRA1008, e17585, e20600 Burton, Harold e20540 Burton-Chase, Allison Michelle 6566, 9576 Burwinkel, Barbara 11012 Bury, Martin J. 1059 Bury, Martin Joseph 9527 Buryanek, Jamie e15548, e15552 Burzykowski, Tomasz 3030 Busaidy, Naifa 6023, TPS6100, e17016 Busam, Klaus J. 3003^ Busch, Raymonde 7004, 7015 Buschinelli, Caio Timko e14679 Busman, Todd A. 7018, 8520 Busse, Dagmar 3561 Busson, Pierre 6079 Bustin, Frederique 8068 Bustreo, Sara 9614 Butaney, Mohit 8023, 8077 Buter, J. 2001 Butera, Alfredo 11058 Buthut, Thomas e14562 Butler, Brian e13051 Butler, Matthew James 5581 Butler, Rachel 11094 Butler, Robert 7119 Butler, Steven M. 520, 565 Butow, Phyllis Noemi 6556 Butow, Phyllis 1559, e20615, e20660 Butrynski, James E. 10511, TPS10591 Butt, Zeeshan e15187 Butterfass-Bahloul, Trude LBA10504 Butterfield, Lisa H. 3041, CRA9007 Butterfield, Lisa 9507 Buttin, Barbara 5574 Button, Anna M. 8563, e15052 Butts, Charles Andrew 7500, e19031 Buttyan, Ralph e15590 Buturuga, Alexandru e19056 Buxbaum, Sarah G. 1573 Buxton, Emily 2525 Buyse, Marc E. 610, TPS3117^, 3533, LBA4001, LBA4002, TPS8121, TPS8122, e19144 Buyukasik, Yahya e18014 Buyukberber, Suleyman e14533, e14705, e18510, e20006 Buyyounouski, Mark K. 9525 Buzaglo, Joanne S. 6500, 9599, e20618 Buzaid, Antonio C. e13562, e14624

Buzdar, Aman

502, 526, 9538, 9539 Buzyn, Agnes e17567 Bvumbe, Patricia e20030, e20038 Byakhov, Mikhail J. 503, 537 Bychkov, Mark e15546 Büchler, Markus W. 3090 Byers, Lauren Averett 2580, 6011, 8104 Bylow, Kathryn A. 4563 Byrd, John C. 7003, 7014, 7077, 8519, 8526, TPS8619 Byriel, Lene 6600 Byrne, Margaret M 1586, e11611, e12547 Bytautas, Jessica e17515

C C. Roach, Emir e11544, e11545 Caballero, Cristina e16014 Caballero, Dolores TPS8616 Caballero, Miguel 6072, e22200 Caballero, Rosalia e12513, e22112 Cabanas, Maria L 7547 Cabanes, Laure e17514 Cabanillas, Fernando e11610, e19505, e19510 Cabanillas, Maria E. TPS6100, e17016 Cabart, Mathilde e18532 Cabezas, Santiago e11561, e16543 Cabioglu, Neslihan e12545 Cabral, Elida 6071 Cabrera, Miguel Angel 608 Cabrera, Silvia 1509 Cabrita, Fernanda e15172 Cabuk, Devrim e11539, e11585 Caca, Karel 3531 Caceres, Aileen e12514 Cadeddu, Christian 603 Cadoo, Karen Anne 10530, e12533, e13019 Cadranel, Jacques 7505, 8000, 8029, e19036, e19056, e19058 Caeiro, M. 7549 Caffo, Orazio 5050, e16031, e16078 Caggiano, Vincent e12511, e12512 Cagle, Phil T. 11085 Caglevic, Christian 516 Cagossi, Katia 530, TPS1610, e11515 Caguioa, Priscilla B. 629 Cahill, Daniel P. 2029 Cai, Fan e13592 Cai, Jie 3544 Cai, Ju-Fen 7590 Cai, Li 11070, e22142 Cai, Ruigang 2614 Cai, Yiran 7552 Cai, Yue e14704 Caillaud, Jean-Michel 593, 596, 5602, e11535, e11543 Caillot, Denis 7002, 8513 Cain, Suzanne 9047 Caires, Inacelli Queiroz de Souza 2060, 9561 Caires-Lima, Rafael 2060, 9561 Cairo, Giuseppe e11517 Cairo, Mitchell S. 3055

Cajal, Rosana Cakır, F Betul Cakana, Andrew Cakar, Burcu

e11583 10043 8545, e19509 e12018, e13578, e13580 Cakar, Mustafa e15623 Cakir, Betul e18006 Calabrese, Filomena 7603, e18536 Calabrese, Massimo e22132 Calabretta, Francesca e19099 Calabrich, Aknar e12510 Calabro, Anthony 7055 Calabro, Luana 9035, e20040 Calabuig, Silvia 10529, 10532 Calais, Gilles 3560 Calaminus, Carsten e20050 Calaminus, Gabriele LBA10504 Calatayud, Dan 4052 Calculli, Lucia e15069 Caldara, Alessia e11569 Caldas Lopes, Eloisi 3101 Caldas, Carlos 1015, 1016 Calderon, Gabriela e12538 Calderón, Mónica 1041 Calderon, Natalia e12564 Calderoni, Giuseppe e16081 Caldwell, Anne 9012^ Caleffi, Maira e22154 Calera, Lourdes e21509 Calfa, Carmen Julia 521, 522 Califano, Daniela 11037 Califaretti, Nadia 574 Caliolo, Chiara e14605 Calip, Gregory Sampang 554 Calise, Fulvio 4129 Calistri, Daniele e14512, e15055 Calkins, Geoffrey 6579 Callahan, Margaret K. 3003^, 9012^ Callander, Natalie Scott 8592, e19517 Callari, Maurizio 1014 Callata, Hector e11561, e16543 Callegaro Filho, Donato e13003 Callego Perez-Larraya, Jaime 2024 Callejon, Gonzalo e12013 Calles, Antonio 2600 Callies, Sophie 5019, 8051^ Callister, Steven M. 9038 Callonnec, Francoise 1104 Calpona, Sebastiano 11022 Cals, Laurent 1122, e11579 Calukovic, Olivera TPS5096 Calvani, Nicola 618, e14605, e15524, e18545 Calvert, Alan Hilary 2566, 2585 Calvert, Paula e14515, e20550, e20687 Calvert, Valerie 2612 Calvo, Begoña e14628 Calvo, Elena Galve e12020 Calvo, Emiliano 2016, 2600, 4550 Calvo, Fabien M. e17567 Calvo, Isabel e11531, e12015 Calvo, Katherine R. 8597, e19506 Calvo, Lourdes 1027, 1031, e22112 Calvo, Mariona e15111 Calvo, P. 7549 Camaño, Sonia e13535 Camacho, Fabian 6558, e17516 Camacho, Juan C. e15140, e15141

Camacho, Luis H. e15023 Camacho, Maria I. 9541 Camandoni, Vanessa Oliveira 7037 Camara, Juan Carlos e14648 Camara, M Carmen 1027, 1031 Camara, Oumar e22075 Camargo, Vanessa Rosas e15186 Camerini, Andrea 1086, e15615 Cameron, Chris 4015 Cameron, David A. 525, 610, TPS656, TPS667, 1094, TPS1136, 1578 Cameron, John L. 4057, e15028 Cameron, Kenzie A. e11572 Camey, Suzi Alves e22154 Camidge, D. Ross 2524, 8010, 8024, 8031, 8032, 8074, 8105, e18032 Camp, Andrea 1023 Camp, Melissa TPS1144 Campagnaro, Erica Leigh e20633 Campana, Dario 10005 Campanella, Delia 10552 Campani, Daniela 4062 Campayo, Marc 7547 Campbell, Alicyn e20712 Campbell, Amy Frances TPS656 Campbell, Fiona 4006 Campbell, Kerry 3058 Campbell, Michael 3017 Campbell, Toby Christopher 9566, 9635, e18537, e20565 Campeau, Marie-Pierre e15094 Campello, Chantal 2020, 2068 Campenni, Giuseppe e14574 Campian, Jian Li 6068 Campone, Mario LBA509, 511, 557, TPS650^, TPS651, TPS653, TPS663, 2599, 2615 Campos, Marta Carmona e20708 Camps, Carlos LBA8002, 11073, e14671, e22147 Canale, Sandra TPS1607 Canavese, Giuseppe TPS1610 Cance, William G. e13547, e13556, e13561, e22143 Cancel Tassin, Géraldine e16089 Candamio Folgar, Sonia e16095 Candamio, Sonia 5603, e20708 Candeloro, Giampiero e14521 Candido, Juliana 11071 Canela, Mercedes 8070 Canellas, Jaime e13016, e17010 Canevari, Silvana 6027, 11037 Caniglia, Fabio 4062 Canil, Christina M. e15591, e16074 Cankir, Havva Yesil e11559 Canney, Peter TPS656 Cannita, Katia e14596 Cano Garia, Fernando e15186 Cano, Juana Maria e14648 Cano, Maria Teresa e11530 Canoll, Peter e13017 Canon, Jean-Luc Re e14587^ Canon, Jean-Luc 3620, 3631, 8063 Cañon, Rosa 3074 Canonici, Alexandra 632 Canoui-Poitrine, Florence e14525 Cantafio, Nina TPS11123 Cantaloni, Chiara e11569 ABSTRACT AUTHOR INDEX

701s

Cantarini, Mireille Veronique 9004 Cantley, Lewis 5521, 5524 Cantor, Alan 7591, 8057 Cantos, Blanca e15609, e19532 Cantu, David e22151 Canturk, Zafer e17529 Canu, Bastianina 3602, 3603, e14577 Cao, Hui 7110 Cao, Jeffrey Quoc e19120 Cao, Wenming e11589, e12557 Cao, Xueyuan 10005 Cao, Yingming 1084, e12006 Cao, Yue 2052 Cao, Z, Alexander 7111, e13525 Cao, Zhisong 2578 Capanu, Marinela 3609, 4101, TPS4144, e15017, e15133 Caparello, Chiara 4062 Caparrotti, Francesca e15619 Capasso, Immacolata 631, e11556 Capdevila, Jaume 4135, 4140, e15107 Capdevila, Laia e16549, e19088, e19089 Capelan, Marta 2566 Capella, Gabriel 3629, 11056, e12516, e14554, e22057 Capelle, Laurent 2067 Capelletti, Marzia 8023, 8039 Capelli, Laura e15055 Capitain, Olivier 3601 Capizzi, Robert L. TPS8123 Capko, Deborah 1019 Caplan, Elyse S. e20712 Caplen, Natasha 10040 Capobianco, Gaetana 8564 Capone, Marilena e20031 Caponi, Sara 4062 Caponigro, Giordano e13590 Caporaso, Neil 1523 Cappelletti, Vera 1014 Cappelli, Carla 4062 Cappiello, Michelle 2587 Cappuzzo, Federico 8080, 11058, 11066 Capri, Giuseppe 2535, e12017 Capriati, Angela 5522^, e16510^ Capussotti, Lorenzo 4129, e14560 Carabantes, Francisco e11577, e11583 Caraco, Corradina 11008 Caraco, Corrado e20013, e20031 Caragacianu, Diana L. 1132, 1133 Caram, Megan Veresh 7044 Caramella, Caroline 7604 Carames, Cristina 11089, e19000, e19109 Caramuta, Stefano e22099 Carasi, Stefania 11066 Caratu, Ginevra 8070 Caravita, Tommaso 8509 Carayol, Jerome e14600 Carballas, Elvira e16549 Carbonel Luyo, Wilver Federico e14706 Carbonero, Rocio 2563 Carcangiu, Maria Luisa 1014, 6066 Carcano, Flavio Mavignier e11500 702s

Carcano, Flavio LBA4509 Carcereny Costa, Enric 11025, 11027, 11029, e19089 Carcereny, Enric 2581, 11067, e19003, e19088 Cardarella, Stephanie e19125 Cardenal, Felipe 2581, 11056 Cardenes, Higinia Rosa 3546, 5610 Cardia, Roberta 1062 Cardin, Dana Backlund TPS4145, e14516 Cardnell, Robert 6011 Cardona Zorrilla, Andres Felipe 9541, 11010, e22028 Cardona, Diana M. 3016 Cardone, Michael H. 7022 Cardoso Martins, Ana Sofia e13540 Cardoso, Fatima 587, TPS661, 1094 Cardoso, Jaime S. 1110 Cardoso-Filho, Cassio e11551 Carducci, Michael Anthony TPS1144, 2016, 4523, 4566, 5039, 5081, 6519, 11053, e15597, e15598, e16051, e16068 Carella, Angelo Michele 7025 Carelli, Bruno e20680 Carey, George e19057 Carey, Lisa A. 500, 501, 512, 515, 527, 1069, 1077 Carey, Mark 5502 Carillio, Guido e11527 Carimi, Alexis e15139 Cario, Gunnar 10017 Carles, Joan TPS5099^, e16045 Carli, Paolo e22149 Carlin, David A 3004 Carlini, Paolo e16053 Carlo, Victor e11610 Carlomagno, Chiara 3505 Carloni, Federica e18561 Carlotti, Agnes e20032 Carlson, Grant Walter 562 Carlson, Jennifer 2613 Carlson, Josh John e19001 Carlson, Matthew J. 5597 Carlson, Nicole E. 7022 Carlson, Rachel e16061 Carlson, Robert W. 1003 Carlson, Susan E. 1515 Carlsson, Anders 8109, 11047 Carlsson, Göran 3524 Carluccio, Silvia 3056 Carmack, Cindy TPS9650 Carmalt, Hugh 1053 Carmeliet, Peter 2056, 7027 Carmichael, Courtney 4571 Carmichael, James 8522, e15004 Carmichael, Joseph 3578 Carmichael, Lakeesha 2537, 6512 Carmona Bayonas, Alberto 3589, e14509 Carmona Campos, Marta e16095 Carnero, Amancio e22045 Carney, Desmond 10530, e12533, e16550 Carney, Patricia A. 559 Carney, Walter P. 622, 643 Carola, Elisabeth 9511 Caroline, Aryeh 6508


Carolla, Robert L. 4528 Carollo, Carla 2043 Caron, Olivier TPS1607 Carousso, Maryann 4501 Carpano, Silvia e16538, e21517 Carpeggiani, Paolo 2021 Carpenter, Amanda 4090 Carpenter, Christopher 3021, 4519, 4569, 5512 Carpenter, John T. 515 Carpenter, Todd J. 6019 Carpenter, William Ruffin 6555 Carpentier, Antoine F. 2005^, 2024, 2061, 3065^ Carpentieri, Marina 4121 Carpinteyro-Espin, Paulina e14703 Carr, Brian I. e15157 Carr, Peter J.A. e20020 Carranza Montenegro, Zoila Elizabeth e14706 Carranza, Hernan e22028 Carranza, Omar Esteban e19106, e19114 Carraro, Dirce Maria e14688 Carrasco, Estela 1509 Carrasco, Eva Maria 1027, 1031, e12513, e22112 Carrasco, Juan Antonio 10529 Carrasco, Ruben 3067 Carrasquillo, Jean P. e15139 Carrasquillo, Jorge A. 3033, 5021 Carrato, Alfredo 1529 Carraway, Hetty Eileen TPS3105^ Carreca, Ignazio Ugo e20719 Carrera, Sergio e13000, e14628, e14712, e20718 Carret, Anne Sophie 10029 Carretta, Elisa 11022, e11521 Carrez, Chantal 11006 Carrier, Marc e15591 Carrier, Nathalie LBA4510 Carrillo, Diana e15059 Carroll, Andrew J. 10001 Carroll, Mary I. 2564, TPS11121 Carroll, Nicholas 10541 Carroll, Peter 5005 Carroll, William L. 10001, 10002 Carruthers, Scott 9001 Carson, Kenneth Robert 9559, e17546, e22181 Carson, Stanley W. 8009 Carson, William Edgar e20018 Carter, Corey Allan 7513, 8026 Carter, David e11586 Carter, Giovani 7105 Carter, Jeanne 9610 Carter, Julia H. e16033 Carter, Knute D. e19065 Carter, Ronald F. 8096 Carter, Scott L. 9015, 11009 Carturan, Sabrina e13514 Cartwright, Thomas H. 6607 Carus, Andreas 5532 Caruso, Francesco e11527 Caruso, Michele e11526, e11527, e14560 Carvajal, Daniel 11075 Carvajal, Nerea 11089, e19000, e19109 Carvajal, Richard D. 3002^,

CRA9003, CRA9006^, 9019, 9049, 9060, 10558, 10580 Carvajal, Tomas 7124 Carvalho, Antonio e22072 Carvalho, Beatriz 3552 Carvalho, Benilton 6073 Carvalho, Carlos 3599, e20632 Carvalho, Genival Barbosa 6017 Carvalho, Jesus Paula 5540 Casacci, Fabio e14512 Casadei Gardini, Andrea e13579, e15055 Casadei, Riccardo 4048, e15069 Casadei, Silvia CRA1501 Casadei, Virginia 1086 Casado Herraez, Antonio 5569, 5593, 10532, e16543 Casado, Antonio 10523, 10529 Casado, Enrique 3589, e14509 Casado, Victoria e19000 Casagrande, Mariaelena 3563 Casal Rubio, Joaquin 7549 Casales Schorr, Mario e20634 Casali, Paolo Giovanni 10500, 10503, 10516, 10519, 10551, 10565, 10568, 10570, 10576 Casanova, Claudia 6003, e18561 Casanova, Luis Augusto 7072, e19538 Casanovas, Oriol 4139, 4140, e22057 Casas, Maria Isabel 1027, e22112 Casasnovas, Rene-Olivier 8536, TPS8615 Casavant, Benjamin Pun e22141 Casbourne, Daniela 7035, 8540 Cascinu, Stefano 2556, 3591, 4123, e14610, e15058, e15081, e15513, e15515, e15524, e15529, e15536 Cascio, Paolo e18522 Cascione, Luciano 11066 Case, Ashley S. e20648 Case, Doug 2006, 2051, 6564, 9505 Casella, Tiziana e11527 Casetta, Lindsay 6045 Casey, Michelle 9020, 9040, e20012, e20030 Cashen, Amanda F. 8507 Casimiro, Enrique e22147 Casimiro, Sandra 9634, e22072 Casper, Corey 10070 Cass, Carol E. 2546 Cassani, Camilla 6020 Cassel, Brian 6638 Cassiano, Fábio e20632 Cassidy, James 3520 Cassier, Philippe Alexandre 2548, 2549, TPS2625, 8008, 10568, 10579, 10582 Cassinello, Javier e12020 Cassivi, Stephen D. e19013 Casso, Deborah e16035 Cassoni, Anna 10518 Castaigne, Jean-Paul e13013 Castaing, Denis 3599, 3606 Castan, Florence e14621 Castan, Remi 3574 Castañeda, Carlos 1041, e12538 Castanon, Carmen e15107

Castanon, Eduardo

9074, e19106, e19112 Castel, Victoria 10016 Castellani, William J. 7039 Castellano, Daniel E. 4135, 4140, 4550, 4587, 5019, e15586, e15620, e16014 Castellanos-Toledo, Araceli 10056, 10058 Castellino, Sharon M. 10004, 10062 Castellucci, Paolo e15154, e18509 Castellvi, Josep 1509 Castelvetere, Marina 576 Castiel, Mercedes 9610 Castiglione, Gaetano e11527 Castillo, Esmeralda 2049 Castillo, Lesley e22175 Castillo-Tong, Dan Cacsire 5575 Castle, Erik P. 4567, e16065 Castro Hernandez, Clementina e22151 Castro, Clementina 4555 Castro, Elena 5054, e16000 Castro, Gilberto 9561, e20579, e20691 Castro, Januario E. 7124 Castro, J. E. 7549 Castro, Justiniano e18015 Castro, Kathleen M. e17560 Castro, Michael 2041, e19006 Castro-Palomino, Julio e13543 Catala, Stephanie 6603 Catalan, Gustavo 608, e12020 Catalano, Daniela e18518 Catalano, John V. 8544 Catalano, Paul J. e14711 Catalano, Vincenzo 4091 Catalanotti, Federica 9060 Cataldo, Thomas e14637 Catena, Laura 4136^ Catenacci, Daniel Virgil Thomas 4011, 4012 Caterson, Stephanie 1133 Cathomas, Richard 7503, 8060 Catino, Annamaria 8071 Catry-Thomas, Isabelle 2020 Cats, Annemieke 3502 Cattan, Stéphane e15134 Cattry, Deepika TPS3113 Cau, Maria Chiara e20556 Cauchi, Carolina e19099 Cauchin, Estelle 3536 Caudle, Abigail Suzanne 1103 Cauley, Diana H. e15612 Causeret, Sylvain 1114 Cavalcante, Ludimila e11575 Cavali, Carla e20647 Cavalli, Maide 8509 Cavallin-Stahl, Eva 4553 Cavallo, Federica 8509 Cavallo, Michele 2048 Cavallone, Luca 1552 Cavanna, Luigi 530, 3517, 8066 Cavazzini, Giovanna LBA5501 Cavicchioli, Livia tiemi e20631 Cavicchioli, Marcelo e14638 Cavo, Michele 8517, 8544 Cawkwell, Lynn e22123 Caygill, Katie 1087 Cayre, Anne 1057, 1058

Cazacu, Simona 2073 Cazes, Aurelie e19036, e22001 Cazet, Aurelie 1053 Cazzaniga, Marina Elena 1086 Cazzaniga, Massimiliano 1517 Cazzola, Mario 7025 Cease, Kemp Bailey 7522 Cebollero, Ana e21509 Cebon, Jonathan S. 3093^, 9005, 9016, 9066, 11072 Cebotaru, Cristina Ligia 5520 Cecchi, Fabiola 4543, 11083 Cecchini, Luca 3591, 4123, e14610, e15081, e15536 Cecconetto, Lorenzo 552 Cecile, Maud e15506 Cedres, Susana 8070 Cefis, Luca e14615 Celik, Hikmet e19512 Celik, Ismail e20006 Celik, Varol e17529 Cella, David 6612, 6632, 6633, 9520, 9574, 9617, e15187, e20527, e20618 Cellier, Pascal 3560 Cem, Onal e17019 Cenci, Simone e18522 Cengarle, Rita e15514 Cenni, Patrizia e13007 Centeno, Barbara e15115 Cerasoli, Serenella 2021, e13007 Cercek, Andrea 3605, 3609 Cerdá, Sara 2600 Cereda, Stefano e15057 Cereda, Vittore e14581 Ceresoli, Giovanni Luca e20650 Cerezo, Laura e15107 Cerezuela, Pablo e20015 Cerhan, James Robert 5082, 8504, 8563 Ceric, Timur CRA8007 Cerillo, Ivana e11528 Cernea, Dana 2005^ Cerri, Elisa 7018, 8520 Ceruse, Philippe 6053, 6056, e17011, e17012 Ceruti, Roberta e19138 Cerutti, Fulvia e18522 Cervantes, Francisco 7053^ Cervantes-Ruiperez, Andres 2522, 2567, 3551, 5502 Cervera Grau, Jose Manuel 5019 Cervera, Pascale 4069, 4127 Cervera-Grau, JM e20705 Cesas, Alvydas 3575 Cescon, David W. 2534, 7517 Cessot, Anatole e13589, e15592, e20535, e22029 Cesta, Alisia e14521 Cetin, Karynsa e20690 Cetina, Lucely e22028 Cetnar, Jeremy Paul 6512 Cezana, Loureno 6017 Cha, Edward 3020 Cha, Yongjun 2098 Chabaud, Sylvie TPS653, 10542, 10548, 10582, e16096 Chabot, John A. e15074 Chabot, Pierre 2031

Chachoua, Abraham 11109 Chacon Cardona, Jose Arnoby e14692, e14693, e15189, e16102 Chacon, Jose Ignacio e12020, e12558 Chadha, Manpreet 2580, TPS11123 Chadjaa, Mustapha TPS5099^, TPS7609 Chadwick, Dianne 11002 Chae, Yee Soo 3553, e11505, e11594, e14549, e18017 Chae, Young Kwang e13591 Chafai-Fadela, Karima TPS2627 Chaffanet, Max 511 Chaft, Jamie E. 7558, e15079 Chagorova, Tatiana 7004 Chagpar, Anees B. 619, TPS1145, 1574, TPS1609, e17597, e20017, e20546 Chahin, Rehab e20622 Chahwakilian, Anne e17514 Chai, K. 3049 Chai, Xiaoyu 1090, e21502 Chaib, Imane LBA8002, 11028 Chaigneau, Loic 1122, 10546, 10563, e11579 Chaiyachati, Barbara H. 10037 Chakiba, Camille 10578 Chakka, Sirisha 10040 Chakrabarti, Anannya 11072 Chakraborti, Prabir Ranjan LBA5000 Chakraborty, Amitava e15520 Chakraborty, Rajshekhar e12564 Chakraborty, Sayan e12039 Chakrapani, Anupam e20686 Chakravarti, Arnab 1, LBA2010, 7573 Chakravarti, Nitin 9047 Chakravarty, Arijit 2567 Chalabi, Nassera 1057, 1058 Chalasani, Pavani 567 Chalchal, Haji I. 1033 Chaleteix, Carine 8513 Challapalli, Amarnath e22194 Chalmers, Alex 7050 Chalmers, Jeffrey J. 1023 Chamberlain, Lisa J. e17504 Chamberlain, Marc C. 2019^, 2037 Chambers, Mara D. 541 Chamie, Karim 4507^ Chamizo, Cristina 11089, e19000, e19109 Champlin, Richard E. 7010, 7011, 8561 Chamras, Hilda 8598, 8599 Chan, Alexandre 6589, 9506, e13582, e20566, e20580 Chan, Allen K.C. 6015 Chan, Ann 3080 Chan, Anthony T. C. 6015, e15048, e17017, e19525, e19529 Chan, Arlene 628, TPS662, 1079 Chan, Daniel Boon Yeow 586 Chan, Daniel W. 5573 Chan, Edward M. 2500 Chan, Ellie e15108, e15145 Chan, Emily 4011, e14516 Chan, Hungching e17519

Chan, Jennifer A. Chan, Kelvin K.

4090, e15126 3534, 4015, 6041, 6552, 6592, 6625, e17515, e17569 Chan, Kevin e15522 Chan, Matthew 9062, 9547 Chan, Michael D. 9505 Chan, Pierre 4117 Chan, Soa-Yu e15182 Chan, Stephen Lam e15048 Chan, Stephen 1016, 7056 Chan, Steve 1015 Chan, Valorie F. 628 Chand, Vikram K. 2523, 8063 Chandarlapaty, Sarat 606 Chander, Subhash e15138 Chandler, Barbara e22161 Chandler, James 2083 Chandra, Pranil 11102, e22139 Chandra, Sunandana 9063 Chandwani, Kavita Dayal e20520 Chandy, Mammen e20686 Chang, Betty Y. 7014 Chang, David D. e12530 Chang, David K. e15029 Chang, DeLi Tilly e20563 Chang, Eric L. e17588 Chang, Gee-Chen e19041^ Chang, George J. 1546, 3612 Chang, Gregory 9023 Chang, Hee Jin e14504, e14606 Chang, Howard T. e13047, e13048 Chang, Hyun e18553 Chang, Ilsung e14505 Chang, Jian Hua 8082 Chang, Kaity 9610 Chang, Ken 11059 Chang, Kevin 10520 Chang, Li e16516 Chang, Mike e16016 Chang, Myron 6605 Chang, Raymond Y. 3094 Chang, Rui R. 3014 Chang, Susan Marina 2015 Chang, Thomas 3060 Chang, Victor Tsu-Shih e14625, e14661, e14681 Chang, Victor T. 1602, 9567, e15561 Chang, Wenju 3610 Chang, Won Jin 637, 1088 Chang, Yeun-Chung 8055 Chang, Yu-Lin e14561 Chang, Yuchiao 9534 Chang, Yung-Ling 4115 Chantrill, Lorraine A. TPS3649, e15029 Chao, Angel e16537 Chao, Calvin e14526, e14569 Chao, Joseph 3089, 6045 Chao, Samuel T. 2070, 2096, 9086, e15537 Chao, Yee 4018, TPS4161^ Chapin, Brian Francis 5069 Chapman, Erica e19519 Chapman, Hannah Louise e20709 Chapman, Judy-Anne W. 564 Chapman, Julia A. 2558 Chapman, Karen e22083 Chapman, Paul B. CRA9003, 9013, 9049, 9060 ABSTRACT AUTHOR INDEX

703s

Chappell, Bridget 2583 Charalambous, Charalambos Haris e19110 Charalambous, Charis e19110 Charalambous, Elpida e19048 Charbonnel, Bernard 1578 Charehbili, Ayoub 1028, e22106 Charles, Brendan 5561 Charlson, John A. 6642 Charlton, Mary E. 1127 Charnley, Richard M. 4006 Charon-Barra, Celine 11007 Charow, Rebecca 9536, 9551, 9595 Charych, Deborah H. 3060 Chasalow, Scott D. 9052 Chase, Weihong 7077 Chasen, Martin Robert e20598 Chatelut, Etienne 3606, 4574 Chatfield, Mark D. e22175 Chatterjee, Aradeep e15520 Chatterjee, Ashim Kumar e15520 Chatterjee, Devasis e14637 Chatterjee, Indranil e17024 Chatterjee, Sanjoy e12039 Chaturvedi, Anil 1523 Chaturvedi, Pankaj 6085, e12520 Chatziioannou, Marina e14699 Chatzileontiadou, Sofia e11576 Chau, Caroline 4549 Chau, Cindy H. TPS5102 Chau, Ian 3619^, 4000, 4023, e14616, e19543 Chau, Nicole Grace 6088 Chau, Noan-Minh e13582 Chaudhari, Pritee Baburao e15138 Chaudhary, Imran e13550 Chaudhary, Lubna 7040 Chaudhary, Preeti 8554 Chaudhary, Surendra Pal TPS4162 Chaudhury, Prosanto e14556 Chaudry, Aasem 5008 Chauffour, Sophie e17514 Chauhan, Dharminder 8582 Chauhan, Nikhil e20521 Chaukar, D. 6085 Chaumard-Billotey, Natacha e16096 Chauvenet, Laure 569 Chauvin, Franck e13594 Chaux, Alcides 4523 Chavan, Rahul Narayan e20037 Chavarri Guerra, Yanin 628, 634, e11533 Chaves, Aline Lauda Freitas e22122 Chaves, Asuncion 585 Chavez-Mac Gregor, Mariana 532, TPS657, 1022, 6630, e12002 Chawla, Neetu 6521 Chawla, Sant P. 2550, 10506, 10514, 10517, 10587, TPS10591, e15128 Chawla, Shanta 8507 Chawley, Neetu 6604 Chay, Wen Yee 6589, 9506, e20566 Chazal, Maurice 3596 Che Bakri, Amalina 5571 Che, Christian e13013 Cheadle, Jeremy 3509 Cheah, Foong Koon e15102 Cheang, Maggie Chon U. 1077 Chebouti, Issam 5556 704s

Chee, Chit Lai e15097 Cheema, Faisal e17585, e20600 Cheema, Simrin K. e20044 Cheifetz, Rona 3590 Chekerov, Radoslav 5549, e16547, e20688, e20689, e22102 Chelis, Leonidas e15063 Chella, Antonio 8014, 11066, e19020 Chen, Aileen B. e18512, e19121 Chen, Alice P. 1024, 2582, TPS4144 Chen, Alice 2036, 2591 Chen, Allen C. 8072, TPS9107^ Chen, Amy Y. 6083 Chen, Andy I. e20627^ Chen, Ann 9011, 9079 Chen, Annie 9577 Chen, Bihong 2018 Chen, Bingliang 3061 Chen, Bingshu E. 1033, 9032, 9502 Chen, Bo 7590 Chen, Carol 630 Chen, Charles 2533 Chen, Chi-Kuan e22100, e22118 Chen, Chi-Long e15080 Chen, Christina 2075 Chen, Christine 8532, 8588 Chen, Chu 1504 Chen, Clara 7096, e16017 Chen, Connie e15508, e15605 Chen, Cui 4107, e15047 Chen, Daniel S. 3000, 3001, 3622, 8008, 9010, e14505 Chen, David Y. 10526 Chen, David LBA509, 534 Chen, Dawei 3544 Chen, Dianke e14704 Chen, Duan e13542 Chen, Dung-Tsa e15075 Chen, Eric Xueyu 6041, 11002 Chen, Fei 6050 Chen, Frank 5531 Chen, Gongyan 8015 Chen, Guihua e15021 Chen, Guoan 11056 Chen, Guoqing J. 4551 Chen, Hankui 11114 Chen, Heidi 8085 Chen, Helen X. 2534, 4032, 5517, 7508 Chen, Herbert e17025 Chen, Ho-Min 3554 Chen, Hong 3043 Chen, Hsiao-Wang 5510 Chen, Hsuan-Yu 8055 Chen, Jen-Shi 4018 Chen, Jenny Ling-Yu e16503 Chen, Jia 8015 Chen, Jian 5551 Chen, Jianhua 8042 Chen, Jie 538, 4131, e16077, e22026 Chen, Jinfei 4106, 10544 Chen, Jingwen 3610 Chen, Jinying 536, 544 Chen, Jiongjie 8016 Chen, Julianne 7010, 7011 Chen, Juxiang 2022 Chen, Ken e22081 Chen, Kristina S. e12508, e16046 Chen, Kuan-Yu 8055


Chen, Kun 6565 Chen, Lei 7093, 7096 Chen, Leo 3624, 9577, 9588, 9624, 9625, e11522, e14607 Chen, Li-Tzong 4018, e13554, e15032 Chen, Liddy e22161 Chen, Lieping 3015, 3044, 11075 Chen, Lijun e15547 Chen, Lili 9565 Chen, Lin Chi 10514 Chen, Ling 6526, 8537, 8565 Chen, Lu 10000 Chen, Mei Hsuan 11076 Chen, Melanie 606 Chen, Melissa 4527^ Chen, Michael M. e15023 Chen, Miin-Fu e15032 Chen, Min 8532, 8588 Chen, Ming-Hui 5051, e16026 Chen, Pei-Jer e15032 Chen, Pengcheng e15062 Chen, Pengyu e12003 Chen, Peter Y 1123, e16008 Chen, Qixun 4094, e15062 Chen, Ronald C. 5040, 6530, 9592 Chen, Rui e19101 Chen, Selby 2072 Chen, Shang-Hung e19041^ Chen, Si-Yi 4106, 10544 Chen, Stephanie TPS2623 Chen, Steven L. e17542 Chen, Sting 11001 Chen, Timothy 9055 Chen, Tzu-Ting 6052 Chen, Vivien e12501, e17522 Chen, Wei 3023, 4577, 7561, 8001 Chen, Wei-Wu 4099, e15127 Chen, Wei-Yu e15080 Chen, Weisan 3093^ Chen, Wen-Tien 11048 Chen, Wu e13542 Chen, Xi 3555 Chen, Xiao-Ping 4126 Chen, Xiaoxia e19166 Chen, Xuehua e22169 Chen, Yan 10032, e13525 Chen, Yanjun 9575 Chen, Yijiang e13542 Chen, Yingbei 4573 Chen, Yingjia e14570 Chen, Yiyou 3544 Chen, Yongchang 4107 Chen, Yongshun e15125 Chen, Youwei 7103 Chen, Yu 1021 Chen, Yuan e20695 Chen, Yuping e15135 Chen, Zhan-Hong 538, 4131, e11589, e12557, e16077, e22050 Chen, Zhengjia 2610, 6083, 6611, 7560, 7589, 8546, e14579, e14612, e19094 Chen, Zhi-yong e18547 Chen, Zhihong e18547 Chen, Zhijian e15135 Chen, Zhiwei 8015, e19014 Chen, Zhong-Ping 2022, e13037 Chen, Zhuo 7516, 11057 Chen, Zong-Ming e15554

Cheneau, Caroline 2028 Chenevert, Thomas L. TPS5094 Cheng, Aaron 7546 Cheng, Ann-Lii 3554, 4099, 4115, TPS4163, e13554, e14501, e15043, e15127, e15182, e19523 Cheng, Ashley Chi Kin e19041^ Cheng, Christopher J. e15543 Cheng, Dangxiao 4077, 11057 Cheng, Edward 10560 Cheng, Gang 7537, 8015 Cheng, Jason C. 4099, e16503 Cheng, Kit e16546 Cheng, Lee 9538, 9539 Cheng, Lin 1084, e12006 Cheng, Lu 11057 Cheng, M. Jennifer 9636, e20638 Cheng, Michael 9052 Cheng, Qiao-Yuan 7590 Cheng, Shinta e16035 Cheng, Skye H Hong-Chun e12003 Cheng, SuChun 4521 Cheng, Susanna Y. e19077 Cheng, Thomas KC e14530 Cheng, Tiewei 4538 Cheng, Tina 9032 Cheng, Winnie e15541 Cheng, XingXing 647 Cheng, Ying 4025, 4109, 7507, 8015, 8042 Cheng, Yuen Yee 7586 Chengal, Rajani e21503 Chenna, Ahmed 604 Cheong, Jae-Ho 4113, e15144 Cheong, Ye-Whang e11566 Chepeha, Douglas Brian 9607 Cher, Lawrence 2017, 2061 Chera, Bhishamjit S. 6018, TPS6097 Cherala, Ganesh 5017 Cherbavaz, Diana B. 520, 5029 Cherniack, Andrew 5511 Chernovskaya, Tatiana V. e20593 Cherny, Nathan 9560 Cherrick, Irene 10004 Cherry, Carol 1538 Cherubini, Chiara e13579 Chervoneva, Inna 5061 Chesney, Jason 3022, TPS3109, LBA9008 Cheson, Bruce D. 7045 Chetaille, Eric TPS5098^ Chetiyawardana, Shan 5 Chetrì, Maria Concetta e14605 Chetrit, Angela 1599 Cheung, Foon Yiu 4117 Cheung, Kwok-Leung e11567, e11608, e20588 Cheung, Nai-Kong V. 3033 Cheung, Patrick e16070 Cheung, Tan To 4117 Cheung, Winson Y. 3569, 3590, 3593, 3624, 6502, 6504, 9547, 9577, 9588, 9593, 9596, 9598, 9624, 9625, e11522, e14603, e14607, e15153, e20589 Cheung, Yin Ting 6589, 9506, e20566 Chevez-Barrios, Patricia e17573 Chevillard, Sylvie 6055

Cheville, John 4567, e15539 Chevillote, Patrick 1114 Chevreau, Christine LBA4500, 10505, 10516, 10525, 10542, 10548, 10563, 10574, 10575 Chevret, Sylvie 7002 Chew, Anne TPS7132 Chew, Helen K. 621, CRA1008, 1024, 6533, e19147 Chi, Andrew S. 2013, 2015, 2029 Chi, Dennis 1511 Chi, Kim N. 5013, 5039, 5042, TPS5101 Chi, Ping 10512 Chi, Susan N. 10030 Chi, Zhi Hong e20027 Chia, Stephen K. L. 518, 574, 1044, 6041 Chia, Yee Hong e17568 Chia, Yen Lin 1087 Chiadini, Elisa e16530 Chiado Cutin, Simona 10572 Chianese-Bullock, Kimberly A. TPS3118^, TPS3125 Chiang, Ling-Ling e19029 Chiang, Nai-Jung e15032 Chiappa, Antonio e15147, e22078 Chiappetta, Gennaro 11037 Chiappori, Alberto 3091, 8001 Chiara, Gabriele 10552 Chiara, Silvana 3505, 3615, 9614, e14557 Chiaramonte, Raffaella 7060, 8591, e18527, e22003, e22052 Chiarenza, Maurizio e11527 Chiarini, Ramona 6593 Chiarion-Sileni, Vanna 9013, 9035, 9065, 9070, 9548, e20028, e22036 Chibaudel, Benoist 3515, 3520, 3524, 3562, LBA4003, 4046, 6036, 9511 Chibon, Fred 10561 Chico, Isagani M. 8559 Chida, Kingo 8038, e20658 Chien, Amy Jo 2605, 6619, 6620 Chien, Chun-Ru e20604 Chien, Sean S. e22092 Chieng, Wei Shieng 1535 Chikamori, Kenichi e19008 Chilukuri, Ram e17560 Chilukuri, Srinivas e15120 Chin, Bennett 5003 Chin, Keisho 4074, 4108, e15016, e15105 Chin, Kevin M. 9053, 9059 Chin, Suet-Feung 1015 Chin, Venessa T. e15029 Chin-Yee, Nicolas J. 6625 Chinen, Ludmilla T. D. 11038 Chinen, Ludmilla Thome e13050, e17032 Chinn, Derek CRA6510, 6518 Chinnaiyan, Prakash 2047 Chino, Fumiko 6506, 6516 Chinot, Oliver L. 2002^, 2005^, 2020, 2023^, 2024, 2032, 2061, 2092 Chinratanalab, Wichai 8605, e19539

Chintagumpala, Murali M. 10009, 10021, 10023, e17573 Chintapatla, Rangaswamy e17589 Chiofalo, Giuseppe e19086 Chioffi, Franco e13046 Chionh, Fiona J. M. 3545, 11072 Chiorean, E. Gabriela 2502, 2529, 3007, 3059, 3546, 4005^, 4058^, 4059^, e15188^ Chiosea, Simion I. 6051 Chiosis, Gabriela 3101, 11076 Chirgwin, Jacqueline H. e20536 Chirinos, Luis e21512 Chiriva-Internati, Maurizio 7060, 8591, e18527, e22003, e22052 Chirivella, Isabel e15620 Chiron, Marielle e14539 Chishima, Takashi 1047, e22011, e22012 Chisholm, Gary B. 9611, e20554, e20581, e20612 Chisholm, Julia C. TPS9104 Chism, David D. e15595 Chisti, Mohammad Muhsin 1541 Chitale, Dhananjay 11085 Chitnis, Shripad D. 2567 Chittawatanarat, Kaweesak e11508 Chittoor, Sreenivas 8052 Chittoria, Namita 4515, 4565 Chiu, April E. 7120 Chiu, Chang-Fang 1600, 4018, 6052 Chiu, Wing K. e16529 Chiuri, Vincenzo Emanuele e11517, e15615 Chiuzan, Cody e20019 Chiyoda, Tatsuyuki 5590 Chkadua, George Z. e20042 Chkourko, Halina 8579 Chlebowski, Rowan T. 1504, 1524, 3594 Chllamma, Muralidharan 5058 Chlosta, Piotr 5019 Chmael, Susan 2587 Chmielowska, Ewa 5541 Chmielowski, Bartosz 9026, TPS9105^ Cho, Angela 3022 Cho, BC John 7526 Cho, Byoung Chul 8027, 8028 Cho, Chi Heum 5568 Cho, Daniel C. TPS2627, 4505, 4512, 9076 Cho, Eun Kyung 3595, e19129 Cho, Goon Jae 8521 Cho, Haruhiko e15112 Cho, Hyun Min e14563 Cho, Jae Yong 4000, 4013, 4113, e15132 CHO, Jangho e15132 Cho, Jonathan K. CRA1008 Cho, Kyung-Ja e15051 Cho, Michael e15561 Cho, Mong 4122^ Cho, Nam-Yun 3550 Cho, Sang-Hee e15121, e17005, e20621 Cho, Sanghee LBA4024 Cho, Steve Y. 5021

Cho, Yo Han 9633 Cho, Yong Kwan e15020 Cho, Yoonjin 8526 Cho, Yukiko e14510 Choi, Byung Se 2098 Choi, Chang-Min e19079 Choi, Cheuk Wai e14530 Choi, Dae Ro e17026 Choi, Eun Yong 4017 Choi, Gyu Seog e14549 Choi, Hyo Seong e14504, e14606 Choi, Ji Soo e11584 Choi, Jin-Hyuk e15020 Choi, Junsung 9500 Choi, L. Mi Rim 3575 Choi, Michael Y. 7124 Choi, Mihee 4114 Choi, Minsig e15077 Choi, Moon Ki 637, 1088, e15613 Choi, Sang Il e15129 Choi, Sangbum e18537 Choi, Seung Hong 2098 Choi, Seungtaek 5069 Choi, Walter e17589 Choi, Won-young e15121, e17005, e20621 Choi, Woonyoung 4538 Choi, Yoo-Duk e17005 Choi, Yoon Ji e19079, e22025 Choi, Yoon-La 637, e19041^ Choi, Younak 4044, e15066 Choi, Younjeong 2507 Chollet, Philippe J. M. e11615, e16021 Chollet, Philippe 1057, 1058 Cholujova, Dana e15599 Chon, Hong Jae e15144 Chondros, Dimitrios e14505 Chone, Carlos Takahiro 6073 Chong, Clayton D e17513 Chong, Curtis Robert e18512 Chong, Dawn QQ e13027 Chong, Geoffrey 2583 Choo, Su Pin 4117, 6618 Choo, SuPin 9509, e15137 Choong, Peter 10567 Chopra, Rajesh 2606, 8522, e15004 Choquet, Sylvain 2032 Choquette, Linda E. 9620 Choschzick, Matthias e16535 Choti, Michael A. 4142, 4143 Chottiner, Elaine G. 8543 Chou, Angela e15029 Chou, Joanne F. 3609, 10019 Chou, Wen-Chi e15151 Chouahnia, Kader 1583 Chouaid, Christos 8014, 8081 Chouaki, Nadia 8068 Choudhury, Ananya e16069 Choueiri, Michel e15562 Choueiri, Toni K. 4512, 4514, 4519, 4524, 4530, 4539, 4565, 4569, 4570, 4572, 4578, 4586, TPS4588^, e15518, e15624 Chougnet, Cecile 6092 Chouinard, Edmond Emilien 553, 558 Chouitar, Jouhara e13529 Chovanec, Michal 4556, e15599 Chow, Chi-Wan 2601

Chow, Edward Chow, Katherine Chow, Laura Quan Man

9502 6015 TPS3112, 8010, 8072, TPS8121, TPS8122 Chow, Lilian e15002 Chow, Pierce K. H. e15102, e15137 Chowbay, Balram 2588, 8107 Chowdhary, Aneel A. 2089, e13040 Chowdhury, Simon 4508, 4525 Chowhan, Amit Kumar e15143 Chowhan, Naveed Mahfooz LBA8003 Choy, Edwin LBA10507, 10511 Choy, Hak 2100, 7501, 7523, 8074 Choyke, Peter L. TPS4589, 11083, e15177 Chrétien, Anne-Sophie e11560 Chrischilles, Elizabeth A. 6602, e15052, e19065 Chrisment Di Lucca, Julie e20032 Chrisofos, Michael 4558, e15619 Christakidis, Evagelos e15063 Christensen, Bernd TPS1137 Christensen, Ib Jarle 4532, e14710 Christiani, David C. 4125, e19080, e19081 Christians, Kathleen K. TPS4147, e15082 Christie, Alan 5571 Christie, Hayden e20706 Christinat, Alexandra e13502 Christodoulou, Christos 582, 1093 Christodoulou, Marianna e12524 Christopherson, Kala 7105 Christophyllakis, Charalampos 1045 Christos, Paul J. 4011, TPS5096, 11081, e20549 Chronister, Nicole e16055 Chrystal, Kathryn F. 5536 Chu, Benjamin F. 7542 Chu, CM e15048 Chu, Emily Y. 9017 Chu, Esther Dawn 8602 Chu, Gregory H. e16019 Chu, Jackson 3593 Chu, Ka Wah 6015 Chu, Laura TPS658, e15185 Chu, Melinda Bernabe e20049, e20661 Chu, Michael Patvin e13503 Chu, Peiguo 3089 Chu, Quincy S. 2523 Chu, Quyen 6533, e20600 Chu, Xiang-Yang 1547 Chua, Clarinda Wei Ling e14520, e15002 Chua, Eu Tiong e13027 Chua, Melvin 11116 Chua, Sue e19543 Chua, Victoria S 2550 Chuah, Benjamin e14507 Chuah, Charles 7048, 7066 Chuang, Ellen 2591, e20641 Chubenko, Viacheslav TPS7609, e13005 Chue, Xiu Ping e13582 Chugh, Rashmi 2540, 2580, 10524, 10584 ABSTRACT AUTHOR INDEX

705s

Chui, Wai Keung Chuma, Stacey Chumsri, Saranya

9506 8602 TPS648, e20574, e22034 Chun, Eun Ju e15129 Chun, Guinevere TPS5102 Chun, Hoo Geun 4013 Chun, Sang Hoon 1540 Chun, Yoon S. 1133 Chung, Amy T 2082 Chung, Carmen e19031 Chung, Caroline e11542 Chung, Chi-Li e19029, e19030 Chung, Christine H. 6005, 6007, 6016, 6028, 6047 Chung, Chung Taik 6059 Chung, Doo Hyun e18555 Chung, Gina G. 619, 2587 Chung, Hans T. e16070 Chung, Hsing-wen 7065 Chung, Hsingwen 7096 Chung, Hyun Cheol 4089 Chung, Hyun Cheol e15098, e15144 Chung, Hyun Hoon e20530 Chung, Hyun-Chul LBA4001 Chung, Ik-Joo e14501, e15121, e17005, e20621 Chung, Jeanenne TPS8612 Chung, Jin-haeng e18553 Chung, John Woojune 4 Chung, Karen e20665 Chung, Peter W. M. 4503, e15510 Chung, Suyoun e13569 Chung, Vincent M. 2564, 3089, TPS4145 Churchman, Michael 9068 Churpek, Jane E. CRA1501 Churpek, Matthew CRA1501 Chute, Deborah 6061 Chuzel, Joelle 9511 Chyjek, Anna e17531 Chyla, Brenda J. 8520 Chyla, Brenda 2036 Ciamporcero, Eric 4582 Cianfrocca, Mary E. 1091 Ciardiello, Fortunato TPS3648, TPS3649, e14565, e19031 Cibula, David 5516 Ciccarese, Chiara e16053 Ciccarese, Federica e15069 Ciccarese, Mariangela 618, e11517, e12021 Ciccolini, Joseph 7117 Ciccone, Giovannino 8509, 8517 Ciceri, Fabio 7007 Cicero, Sherri 8533, 8534 Cicinelli, Ettore 5559 Ciftci, Rumeysa e11592, e14594, e20016 Ciga Lozano, Miguel Angel e14589 Cigler, Tessa 1024, e20641 Cihan, Sener e14662 Cihon, Frank 3514, 3636, 3637 Cikalo, Maria e11602 Cilingir, Fatih Mehmet e11506 Cillan, Elena 4560, e16049 Cillien, Nicole 3094 Cillo, Umberto e15088 Ciltas, Aydin e14705, e18510 Cimino-Mathews, Ashley TPS1144 706s

Cinar, Caner Cinar, Pelin Cinciripini, Paul M. Cinefra, Margherita

e20502 4055 1564 618, e14605, e18545 Cinieri, Saverio 618, 4091, 8066, 8071, e14565, e14605, e18545 Cioe, Alex e12518 Cioffi Lavina, Maureen e19140 Cioffi, Giovanni 631, e11556 Ciombor, Kristen Keon 3555, e14516 Ciorra, Alida Armida e19099 Cipani, Tiziana 6003 Cipolla, Carlo Maria 1061 Cipollari, Chiara e15148 Cipollini, Giovanna e13009 Cipresso, Clemente 631, e11556 Cipriano, Toni Marie 9581 Ciprotti, Marika 2520, 2583 Cirino, Crescenzo e19099 Cirkel, Geert A. e20653 Cirrincione, Constance T. 1007, 1076 Cirrincione, Constance 500, 501, 1032, 9515, 9581 Cirrito, Thomas TPS3105^, 7029^ Ciruelos Gil, Eva Maria 600 Ciruelos, Eva M. e11561 Ciruelos, Eva 503, 608, TPS650^, 1041, 9641 Cisak, Kamila e12523 Cislo, Paul e15601 Cisneros-Soberanis, Fernanda e22151 Citron, Marc L. 1032 Citterio, Giovanni 8035 Ciuffreda, Libero 3505, 8043, e14557 Ciuleanu, Tudor-Eliade 7500, CRA8007, 8080, TPS8126 Ciurea, Stefan O. 7010, 7011 Civelek, Ali Cahid e22084 Civelli, Enrico M. 6020 Civriz Bozdag, Sinem e18014 Clack, Glen 4511, e22035 Clackson, Tim 7001, 7063, TPS7129, 8031 Claeys, Alisa J. 2518 Clamon, Gerald H. 9090 Clamp, Andrew 5514 Clancy, Thomas E. 3639 Clapton, Genevieve Sian e20014 Claret, Laurent e19049, e19103 Clarisse, Benedicte 9510 Clark, Amy Sanders 519 Clark, Emma 600 Clark, Jason 3025 Clark, Jeffrey W. 4047, 4125, 8032, e14636 Clark, Jennifer 9066 Clark, Joseph 4521, 9050 Clark, Kellie N. 10034 Clark, Leslie Horn 5523 Clark, Mary Beth 2587 Clark, Melissa 6590, e20543 Clark, Noel D 4541 Clark, Rachel Marie 5604, e13564 Clark, Richard E. 7052^ Clark, William B. 6533 Clark-Garvey, Sean 8575 Clark-Swanson, Kamala e13017


Clarke, Blaise 5508, 11002 Clarke, Christine 5602, e16548 Clarke, Kathryn 567 Clarke, Noel W. 5012, e16069 Clarke, Stephen John e14582, e17541 Clary, Douglas O. 6000 Classe, Jean Marc e11607 Classe, Jean-Marc 566 Classen, Carl Friedrich e13053 Clatot, Florian 1104 Claude, Line 10518 Claude-Desroches, Mederic 6092 Claudio, Pier Paolo 2089, e13040 Clauditz, Till e17003 Clausen, Ole Petter Fraas 3607 Clauser, Steven B. 6536 Clauw, Daniel A. 9615 Clavere, Pierre 3560 Claxton, David e19502 Clayman, Marla L. e11572 Cleary, James F. 9635, e20565 Cleary, James M. 2553 Cleary, Sean P. e14573, e15087 Cleeland, Charles S. 7574, 9618, 9646, e17508, e17588, e20514 Clemens, Michael R. 548, TPS1141, 11043 Clemens, Pamela L. TPS3109 Clement, Jessica Mary 4546 Clementi, Laura 2556 Clementi, Regina 8537, 8565 Clements, Arthur e20025 Clemmer, Joel 5604 Clemons, Mark J. 542, 574, 6595, e16074 Clemons, Mark 531, 6597, e11574, e11597, e19024 Clerico, Mario 9614 Cleven, Arjen e14503 Cleverly, Ann 2016, 2039, 2061, 2563, 4118 Cliby, William 5510 Clifton, Guy T. 3005, 3096, 3097, TPS3126 Clifton-Bligh, Philip e20533 Climent Duran, Miguel Angel 4587, e15586, e16014, e16028 Climent, Miguel Angel 503 Cline-Burkhardt, Vivian Jean M. 3616 Clingan, Philip R. 4058^ Clisant, Stephanie 2548, 2549, 10525 Cloke, Vicky 11094 Closa, Adria e14613 Clough-Gorr, Kerri e20542 Cloughesy, Jonathan N. 2055 Cloughesy, Timothy F. 2055 Cloughesy, Timothy Francis 2002^, 2005^, 2012, 2015, 2023^, 2044, 2606, e13017 Clow, Fong 7057, TPS7130 Clynes, Martin e11536 Clynes, Raphael 521, 522 Cmelak, Anthony 6005, e20531 Coate, Linda E. 1579 Coate, Linda 1591 Coates, Alan S. 529 Coberly, Suzanne K. 2071, 11095

Cobham, Marta E. e20641 Cobleigh, Melody A. 610, TPS666 Cobo, Manuel LBA8002, 8043 Cobos, Everardo 7060, 8591, e18527, e22003, e22052 Coburn, Natalie G. e14573 Cocciolo, Alessandro e20681 Cochet, Alexandre 11007 Cochrane, Brandy 574 Cockburn, Myles e17573 Cockerill, Alyson e20010 Coco, Michelina 576, e14655 Cocorocchio, Emilia 9548 Codreanu, Ion e19514 Cody, Hiram S. 1019 Coëtmeur, Daniel e19078 Coffey, Greg 8574 Coffin, Cheryl M. 10513 Coffin, Robert LBA9008 Cognetti, Francesco 9035, 9065, 9548, e15057, e21517, e22206 Cogoni, Alessio Aligi e15524 Cogswell, Janet e14661 Cogswell, John 3016 Cohain, Ariella 3014 Cohen, Adam D. TPS3113, 8576 Cohen, Adam Louis e13522 Cohen, Deirdre Jill 3587, 4011, 4012, 4040^ Cohen, Evan N. 9646 Cohen, Ezra E. W. 6000, 6001, 6008, 6010, 6022, 6030, 6065, 6066, 6090, TPS6098, e13532 Cohen, Harvey Jay 9515 Cohen, Jonathan E. e21508 Cohen, Kenneth J. 10030 Cohen, Kenneth Stuart e19542 Cohen, Lewis J. TPS3107, TPS3108, TPS3109, TPS3112 Cohen, Lorenzo 9642 Cohen, Monique 566 Cohen, Pascale 511 Cohen, Patrick 2535, 10506 Cohen, Roger B. 6090, 6094, TPS6098 Cohen, Romain e22153 Cohen, Steven J. 9546, e14545, e15089 Cohen, Yael TPS2102 Cohen, Zvi R e13002 Cohn, Allen Lee 3616 Cohn, Michael e14545 Cohn, Richard J. 10021 Cohn, Susan Lerner 10015, 10039 Cohn-Cedermark, Gabriella 4503, 4553 Coiffier, Bertrand TPS7133, TPS8616 Coil, Douglas 2578 Coimbra, Felipe José Fernandez e15184 Coindre, Jean-Michel 10542, 10548, 10561, 10582 Coit, Daniel G. 4082, 4101, 9033 Cojocarasu, Oana 3601 Coker, Courtney e22148 Colak, Dilsen e14662 Colarusso, Enzo e13046 Colcher, David TPS11121 Colditz, Graham A. 9559

Coldwell, Douglas M. e14545 Cole, Sarah 2501 Coleman, Ilsa e22212 Coleman, Jonathan A. e12527 Coleman, Matthew 10060 Coleman, Morton 8555 Coleman, Niamh e13019, e13022, e13049 Coleman, Robert E. TPS662 Coleman, Robert L. 2611, 5521, 5524, 5602, e16548 Coleman, Roger e22212 Coles, Charlotte e20526 Colevas, A. Dimitrios 3015, 6005 Colgan, Marta N. 9049 Colin, Paul Emile e11549 Colins, Brendan 4132 Coll, Jean-Luc e19058 Collado, Victor e19112 Collard, Olivier 10563 Collaud, Stephane e18503 Collée, Margriet 1502 Colleoni, Marco 529, 589 Collette, Laurence 3525^, 3560 Collette, Sandra 4529 Colley, James 3509 Colli, Leandro Machado e15190 Collichio, Frances A. LBA9008, 9050 Colligan, Bruce e16033 Collignon, Joelle 8536, e11549 Collins, Chelsea Lee 10006 Collins, Denis 1066 Collins, Helen e16046 Collins, Ian M. 1559, e20660 Collins, LaTonya R. 7053^ Collins, Linda 9068 Collins, Michael 6500 Collins, Stuart I. LBA5000 Collovà, Elena e11547, e11550, e11573 Colman, Howard 1, LBA2010, 2015, 2026 Colman, Roos 7541 Colomban, Olivier 5547, e13594, e16050, e19515 Colombi, Chiara 4112, e15086 Colombi, Scialini e18528 Colombino, Maria e20013 Colombo, Michela 7060, 8591, e18527, e22003, e22052 Colombo, Nicoletta LBA5503, 5516, 5541, e16547 Colomer, Ramon 11033 Colon, Virgilio e16521 Colonna, Sarah V. 1034 Colonna, Valentina 9092 Colote, Soudhir 3524 Colozza, Marian 537 Coltelli, Luigi 1086 Colten, Mary Ellen 6518 Colucci, Giuseppe 618, 8071, e14565 Colussi, Orianne e22121 Colvin, Gerald e22172 Comandone, Alessandro 10572 Combe, Kristell e11552 Combemale, Patrick 10579 Comber, Harry e14515 Combest, Austin J. 3009

Combest, Austin James e17586 Combier, Jean-Philibert 1114 Come, Steven E. 630, 6507, e20508 Comelli, Simone e20562 Comen, Elizabeth Anne 606, e22148 Comenzo, Raymond 8545 Comito, Francesca e19084 Commo, Frederic 511 Comoglio, Paolo M. TPS3648, 11005 Compas, Bruce 9609 Compton, Carolyn C. 1592 Compton, Kathryn 4543 Comstock, Christopher TPS3120 Concepcion, Raoul S. 5034 Concert, Catherine 6091, e17030 Concin, Nicole e16524 Conde, Esther e19123 Conde, Veronica e11583 Conde-Sanchez, Jose Manuel e15533, e15550 Condon, Carolyn H TPS6098 Condori, Elizabeth e13000, e20718 Condy, Mercedes M. 10512, 10558, TPS10592, TPS10594 Cong, Xiangyu TPS1609 Cong, Xiuyu Julie 6001 Cong, Ze e20665 Congregado-Ruiz, Belen e15533, e15550 Coniglio, Arianna e15148 Conill, Carles e15107 Conklin, Dylan 1054 Conklin, Heather M. 10034 Conkling, Paul 8008, e15089 Conley, Anthony Paul 10545, 10556, e21514, e21515 Conley, Christine 9076 Conley, Claire 9572 Conlon, Anna S.C. 9615 Connell, Louise Catherine e14666 Connell, Nathan Theodore 6574 Conner, Joe 10047 Conner, Nalini e20523 Connery, Cliff P. e17589 Connor, Carol Sue 1026 Connors, Joseph M. 8552, TPS8612 Conrad, Bettina TPS1141 Conrad, Charles A. 2019^, 2042, TPS2106 Conrad, Ernest U. e21502 Conrad, Peggy 1530 Conrads, Thomas P. 6051 Conry, Robert Martin 9038 Constantinides, Constantinos A. e15619 Constantinou, Maria 619 Constenla Figueiras, Manuel e14706 Constenla, Manuel e14648, e15609 Constine, Louis S. 10000, e20667 Conte, Bruno e20640 Conte, Pier Franco 530, 556, e19138 Conter, Henry Jacob 10049 Contini, Mariapaola e16510^ Contractor, Kaiyumars B. e22194 Contreras, Diana e16546 Conzen, Suzanne D. 11101

Cook, Natalie 4023 Cook, Richard J. e14630 Cook, Robert W. 7605, 9022 Cooke, Jeff e14698 Cooke, Laurence 7062 Cooksey, Jennifer 2505 Cookson, Michael S. 4540 Cooley, Sarah A. TPS3106 Cools-Lartigue, Jonathan e15034 Coombes, Kevin R. 6011, TPS8118 Coombes, R. Charles 635, e22194 Coombs, Catherine Callaghan 7118 Coombs, John H. e15511 Cooney, Kathleen A. TPS5094 Cooney, Matthew M. e16022 Coons, Stephen 2008 Cooper, Brenda W. 7058 Cooper, Joseph 6553, 6629, e17579, e17581, e17582 Cooper, Kumarasen e15106 Cooper, Maureen A. 7116 Cooper, Pamela e14506 Cooper, R. Seth e22139 Cooper, Todd Michael 10007 Cooper, Wendy e18500 Cooper, William 9626, e20518, e20569 Cooper, Zachary A. 9015 Cooperberg, Matthew R. 5005, 5024, 5034, 5092 Cooray, Prasad 4081 Copelan, Edward Alan 7008 Copelan, Edward 7028 Copeland, Amanda 8535 Copetti, Massimiliano 576, 6593 Copin, Marie-Christine 8100 Coppa, Christopher e15015 Coppola, Carmela 631, e11556 Coppola, Domenico e15115 Copur, Mehmet Sitki 6539 Coras, Natalia e20023 Corazzelli, Gaetano 8564 Corbacioglu, Selim 10017 Corbelli, Jodi e15003 Corben, Adriana 1019 Corbett, Richard e22020 Corchuelo-Maillo, Carolina e15533 Corcoran, Claire 620, e11520 Corcoran, Ryan Bruce 3507 Corcoran, Stacie 8571 Cordeiro, Eivete e22176 Cordero, David e14613 Cordio, Stefano Sergio 11058 Corfield, Emily 6063 Coriat, Romain 3536 Corica, Tammy 1110 Corines, Marina 1552, 1555, e12527, e12536 Corkhill, Andrea 3500 Corless, Christopher L. 7513, 10511, e19141 Corman, John M. 5016, 5053^ Cormier, Janice N. 9047, e20558 Cormio, Gennaro LBA5501 Corn, Benjamin W. 2047, e21521 Corn, Paul Gettys 4517, 5026, 5076, e15594, e15611, e15612, e16038 Corn, Tim 7097 Cornelio, Gerardo H. e14501 Cornic, Marie 1104

Corominas-Faja, Bruna

e19003, e19159

Corona-Villalobos, Celia Pamela 4124 Coronado, Pluvio e16543 Corradetti, Michael Nino 5609 Corral Jaime, Jesus e19160 Corral, Jesus e19105, e22045 Corral, Norberto e18513 Corre, Romain 7505 Correa, Arlene M. 4085 Corrie, Philippa 3018, LBA4004, LBA9000, 9031, e15085 Corrigan-Cummins, Meghan 8597 Corso, Giovanni e22037 Corso, Simona 11005 Cortegoso Mosquera, Alexandra Sabela e16095 Cortelazzi, Barbara 6020, 6027 Cortes Semperes, Maria 1575, e19123 Cortes, Javier 517, 524, 547, 555, TPS649, TPS650^, TPS651, TPS665, 1011, 1049^, 1050^, 1055^, 1131, TPS1136, 2561^ Cortes, Jorge E. 7001, 7012, 7021, 7023, 7024, 7029^, 7030, 7048, 7063, 7066, 7068, 7073, 7074, 7088, 7089, 7090, 7099, 7100, 7112, 7115, TPS7129 Cortes, Ulrich 3513 Cortes-Funes, Hernan 537, 555, 1041, 9641, e12020 Cortesi, Enrico e14574 Cortesi, Laura TPS1610 Cortet, Bernard e12552 Cortez, Javier 1087 Cortot, Alexis B. e19056 Corvez, Maria Margarita 8559 Corwin, Alex e19536 Corwin, David e13017, e13018 Cosaert, Jan 6030 Cosby, Roxanne 3534 Coscas, Yvan 1562, 6563, 6603 Cosenza, Carol 6518 Cosgriff, Thomas 4504 Cosgrove, David 4124, e14647 Coskun, Belgin e18009 Coskun, Hasan Senol e14683, e14696, e18517 Coskun, Ugur e14533, e14705 Cosman, Rasha 2086 Coss, Christopher e16015 Cossio, Silvia Liliana e12546 Cossio-Poblete, Maria e22009 Cossor, Furha Iram 1580 Cossu Rocca, Maria 6003, 6027 Cossu, Antonio e20013 Cossu, Laura e15147 Costa e Silva, Veronica Torres e20579 Costa, Alberto e17545 Costa, Carlota 11010, 11025, 11027, 11067, 11078, e22068, e22119 Costa, Daniel Botelho 8050, 8116 Costa, Felipe D’Almeida e11503, e15184 Costa, Frederico e14590, e15049, e15155 Costa, Luis 5079, 9634, e22072 ABSTRACT AUTHOR INDEX

707s

Costa, Marcos André e15176 Costa, Maria Eduarda Ferro 9589 Costa, Marília Sampaio Lemos e12562 Costa, Sandra e19069 Costa, Serban Dan TPS1138 Costa, Wilson Luiz da 10586 Costa, Wilson Luiz e15184 Costa-Gurgel, Maria Salete e11551 Costantino, Joseph P. 1000, TPS1139 Costanzo, Raffaele 8066 Coste, J. 569 Costello, Brian Addis 5082, e16061 Costello, Regis 7117 Costello, Rene 8597, e19506 Costentin, Charlotte 4118 Cote, Andre 2044 Cote, Julie e17517 Cote, Michele L 1504, 7561 Cotter, Finbarr E. TPS7131 Cottler-Fox, Michele 8610 Cottu, Paul H. 569, 5515 Cottura, Ewa 2561^ Couch, Fergus J. TPS11120 Coudert, Bruno P. e11529 Coukos, George 3077 Coulter, Sally 543 Coupland, Sarah E 9031 Couriel, Daniel R. 7044, 8543 Courneya, Kerry S. TPS3647 Cournoyer, Sonia 10048 Courtin, Ryan 4014 Cousillas Castineiras, Antia e14706 Cousin, Philippe 10563 Coutant, Charles 1114, 11007 Coutlee, Francois 6041 Coutre, Steven E. 7003, 7005, 7017, TPS7133, 8500, 8501, 8519, 8526, 8531 Couturaud, Benoit e20032 Couture, Christian 8096 Couvillon, Anna TPS5095, TPS5104, e16017 Cova, Agata 9092 Coveler, Andrew L. 7074 Covelli, Andrea Marie 9571 Covello, Kelly L. TPS3110 Covello, Renato e21517 Coveney, John 9585 Coventry, Brendon J. 9001 Covey, Joseph M 11103 Cowall, David Eric e20628 Coward, Jermaine I. G. e19007 Cowens, John W. 506 Cowey, Charles Lance 4563, 9026 Cowley, Mark e15029 Cowzer, Darren e15196 Cox, Charles E. TPS11122 Cox, David 563 Cox, Donna S. 8027 Cox, James D. 7574 Cox, Karen e20588 Cox, Nancy J. 534 Cox, Teresa Mary 11099 Cox, Trevor F. LBA4004, 4006 Coxon, Fareeda Y. LBA4004, 4023, TPS4156 Coy, Catherine M. e22178 Coyle, Doug 4015 Coyle, Mariann 11021 708s

Coyle, Seamus e14515 Coyne, Joseph W. e20663 Coyne, Patrick J. 6638 Cozzolino, Camille e15134 Crabb, Simon J. 4508, 4525, 4549 Crabtree, Gerald R. 10515 Craciunescu, Oana I. e15560 Craddock, Kenneth J. 11002 Craddock, Kenneth 8096 Craft, A. W. 10031 Crager, Michael e14569 Crago, Aimee Marie 10512 Craig, Adam 7066, 7073, 7088 Craig, Michael 7040, 7058, 8537, 8557, 8565, e19518 Cramer, Paula TPS7133 Crane, Jason 2044 Cranmer, Lee D. 9102, 10581 Craven, Renatta 5607 Craver, Randall 2085 Crawford, Donna 2586 Crawford, Forrest 6076 Crawford, Jeffrey 6534, 7506, 8039, e19100, e20564, e22166 Crawly, Freya 6595 Credi, Marc e19002 Creemers, Geert-Jan 3502 Creighton, Terrance e15604 Cremolini, Chiara 3505, 3563, 3565, 3568, 3602, 3603, 3613, 3615, e14531, e14574, e14577 Cremonini, Anna Maria 2048, e13007 Crepaldi, Giorgio 9554, e13514 Crescentini, Robert M. 9603 Crespo, Carmen 608, 1027, e22112 Crespo, Guillermo e15169 Crespo, Mateus 4511, 5052 Cress, Rosemary 6606, 8049, e14570 Cress, W. Douglas e22155 Cressman, Sonya 6550 Cresta, Sara 3008, e12017 Cresti, Nicola 2586 Cretella, Elisabetta e12021, e13009, e20541 Creutzberg, Carien L. 8568 Crevenna, Richard 2078 Crew, Katherine D. 560 Crews, Kristine Radomski 10005 Crickx, Beatrice e20032 Crimaldi, Anthony Joseph e21504 Crinò, Lucio 6003, 8024, TPS8121, TPS8122, e19020, e22155 Cripe, Timothy P. 10047 Crippa, Claudia 8509 Crippa, Flavio 10565 Crippa, Stefano e14536 Cripps, M. Christine 3633 Crisan, Anamaria 4542, 5033, 5089 Criscitiello, Carmen 617, 1595, 11003 Crisi, Girolamo 2048 Cristal-Luna, Gloria R. e20696 Cristea, Mihaela C. 2526, 2564, 2584^ Cristina, Goso e16510^ Cristina, Morales 1125 Cristofanilli, Massimo 531, 580,


1009, 11092 e22149 7573, 11066 TPS3111, 3600, 4040^ Crocker, Ian R. 2003, 2004 Croitoru, Adina 3575 Croley, Jessica Jones 541 Crombet Ramos, Tania 3013 Crombet, Tania 3086, TPS3123 Cronier, Damien 2500 Cronin, Angel 6547, 7128, e19121 Cronin, Maureen T. 9002, e22146 Cronk, Michelle F. TPS4157 Cropet, Claire 510, 10516 Cropper, Stephen J. TPS8620 Cros, Sara e16549, e19088 Crosara Alves Texeira, Marcela e14652 Crosby, Thomas TPS4156 Crosse, Barbara 7595 Crotty, Joseph F. 4017 Croughs, Therese 10013 Crowe, Joseph P. 1508 Crowell, Brynne TPS2621 Crowley, Janeen e20677 Crowley, John 8515, 8539 Crown, John 548, 598, 620, 632, 1054, 1066, e11520, e11536 Croxford, Matthew e14608 Crozier, Jennifer A. 1037 Cruciani, Giorgio TPS1610 Crump, Barbara 1602, 9567, e14681, e15561 Crump, Michael 8535 Cruz Abrahao, Manuel e14590 Cruz, Cristina TPS3646, 8008 Cruz, Felipe Melo e20524, e20601, e20680 Cruz, Felipe LBA4509 Cruz, Josefina 10532 Cruz, Juan J. e22058 Cruz, Juan Jose e11531 Cruz, Marcelo Rocha e15176 Cryer, Sarah K 8069 Cseh, Jozsef e12022^ Csõszi, Tibor 558, 561 Cuaia, Ornella e20040 Cuatrecasas, Miriam e14588 Cubas-Cordova, Miguel 7027 Cubedo, Ricardo 10523, 10529, 10532 Cubero, Daniel de Iracema Gomes e20524 Cubero, Daniel Iracema e20601 Cubillo, Antonio 2600, 3543 Cubukcu, Erdem e11559 Cucherousset, Nahla e19513 Cuddy, Amanda 1525, 1546 Cueva, Juan Fernando 5603 Cuff, Katharine 1079 Cuffe, Sinead 1579, 4077, 6543, 11057 Cufi, Silvia e19003, e19159 Cui, Chuan Liang e20027 Cui, Jiuwei 3031, e15198, e18550 Cui, Ri 7573 Cui, Yan 4097 Cui, Yuqi e22071 Cuicchi, Dajana e15154 Crivellari, Diana Croce, Carlo M. Crocenzi, Todd S.

Culakova, Eva Culine, Stephane

6534, e20667 LBA4500, e16009 Cullen, Kevin J. 6022, 6032 Cullen, Michael H. 7595 Culliney, Bruce 6091, e17030 Culotta, Kirk Salvatore 2611 Culver, Kenneth W. e15500, e15504, e15538 Cummings, Craig 3020 Cummings, K. Michael 1561, 1566, 1603 Cummings, Natalie Dawn e13546 Cummins, Robert 3549 Cumpston, Aaron 7040 Cuneo, Antonio 7025, 7045 Cunha, Isabela Werneck 10586, e21507 Cunliffe, Heather 1037 Cunniff, Elizabeth Grace Carideo e13529 Cunningham, David TPS2626, 3504, 3511, 3521, 3532, 3620, LBA4004, 4020, 4023, TPS4153, TPS4155, TPS4156, e14616, e19543 Cunningham, Diana E. 3041, 7059, e22017 Cuorvo, Lucia Veronica e11569 Cupissol, Didier 6001, 10505, 10506, 10542, 10548 Cupit, Lisa 3636, 3637 Cuppini, Lucia 2074 Curda, Michael 11088 Cure, Herve e16021 Curiel Garcia, Maria Teresa 5603 Curiel, Clara N. 9102 Curigliano, Giuseppe 617, 1595, 9582 Curley, Brendan F. 8557 Curley, Kathleen F. 9620 Curran, John 11020, e22146 Curran, Michael A. 3003^ Curran, Tom 2035 Curran, Walter J. 7589, 8546 Curran, Walter John 7501 Currie, Jean-Christophe e13013 Currier, Mark 10047 Currow, David 9560, TPS9649, e20584 Curry, Jonathan L. e20034 Curry, Marjorie Adams e11582 Cursons, Ray T. e13583 Curti, Alessandra 4112, e15086 Curti, Brendan D. TPS3109, 4521 Curtin, John Patrick 2591 Curtin, Leslie e13561 Curtin, Nicola J. 2580 Curtis, C. Martin 8009 Curtis, Kelly Kevelin TPS2621, 10521 Curtis, Kristen Rebecca e16005 Curtis, Lesley H. 6504, 6631 Curtis, Wendy 3019 Curtit, Elsa 1122, e11579 Curvietto, Marcello e20031 Cushen, Samantha e15566 Cushman, Stephanie 11011 Cusido, Maria Teresa e22119 Cusimano, Maria Christine e19033 Cussenot, Olivier e16089

Custers, Jose A. E. 10549 Custodio, Ana B. 3589, e15169 Cutter, Kathy e19528 Cutz, Jean-Claude 8096 Cuzick, Jack M. 506, 575, 1559, 5005, e20660 Cvancarova, Milada 4562 Cwajna, Slawa 5048 Cwiertka, Karel e22109 Cwikla, Jaroslaw e15045 Cyanam, Dinesh 11017 Cykert, Sam 6584 Cykowski, Lori 9053, 9059 Cynober, Luc e20535 Cyprien, Lori A. 9083 Cyriac, Sunu Lazar 7081, 7082 Czapiewski, Piotr 11069 Czartoryska-Arlukowicz, Bogumila 604 Czaykowski, Piotr e16082, e16088 Czerniak, Bogdan 4538 Czerwinski, Debra 3015 Czibere, Akos Gabor 2609 Czuczman, Myron Stefan TPS8618

D D’ Amico, Maria e14605 D’Agata, Gabriella e16532 D’Aiuto, Giuseppe TPS1610 D’Alessandro, Roberto 2048 D’Alicandro, Valerio e19052 D’Alimonte, Laura e16070 D’Alonzo, Alessia 1036, e17548 D’Ambra, Marielda 4048 D’Ambrosio, Consuelo 6003 D’Ambrosio, Lorenzo 10552, 10583 D’Amico, Anthony Victor 5024, 5051, e16026 D’Amico, Cosimo TPS1610 D’Amora, Paulo e13562 D’Andrea, Gabriella 606 D’Andrea, Kurt P 1510 D’Angelica, Michael Ian 3558, 3609, 4116 D’Angelica, Michael e15079 D’Angelo, Alessandro e16078 D’Angelo, Sandra P. 9060, TPS9105^, 10512, 10558, 10580, TPS10592 D’Apuzzo, Massimo 2018 d’Ario, Giovanni 3526, 3577 D’Assoro, Antonino e13516 D’Avella, Domenico 2043 D’Chuna, Nicholas e22052 D’cruz, Anil K e12520 D’hondt, Veronique e12008 D’Hoore, Andre 3588 D’Incecco, Armida 11066 D’Souza, Gypsyamber CRA6031, 6032 D’Urso, Leonardo e16099 D’Urso, Susanne e22114 Da Corte, Donatella e20541 da Costa, Alexandre Andre Balieiro Anastacio 11038, e11503, e13050, e17032 da Silva, Antonio 3075 Da Silva, Guedes e15172 da Silva, Juliana Ribeiro 5540

Dabakuyo, Tienhan Sandrine 1094, 1114 Daban, Alain 3560 Dabbous, Firas M. e12519 Daber, Robert 1510 Dabir, Snehal e18526 Dacic, Sanja 11085 Dada, Reyad e20613 Dadaev, Tokhir 5054, e16000 Dadia, Solomon e21521 Dadu, Ramona e17016 Daenen, Laura G.M. e20653 Daeninck, Paul Joseph e17596 Dafni, Urania 7514 Daga, Haruko 7529, 8056, e14551 Dagdas, Simten e15623 Dagher, Lucy 4126 Dago, Angel E 11047 Dagrada, Gianpaolo 10565 Dahal, Arati e11541, e15549, e15555, e20043 Dahan, Laetitia 4028 Daher, Alain e20500 Dahiya, Saurabh 2070, 2096, 9086, e13031, e15537 Dahl, Alv A. 5533, 9569 Dahl, Gary V. H. 7097 Dahl, Olav 4553, 4562 Dahlberg, Suzanne Eleanor TPS1606, 7508, 7510, 8046, 8106, e19125 Dahlrot, Rikke Hedegaard 2088 Dahut, William L. 4543, TPS4589, TPS5095, TPS5102, TPS5104, e16017 Dai, Donghai 5597 Dai, Feng e17597 Dai, Guanghai e14501 Dai, Minghan e17561 Dai, Shuqin 4107 Daidone, Maria Grazia 1014 Daignault, Stephanie 4545, TPS5094 Daigo, Yataro 3092, 11104 Daiko, Hiroyuki TPS4152 Daily, Karen Colleen 6605 Daimon, Takashi 6576, e16090 Daireaux, Aurélie 9510 Daisne, Jean-Francois 3531 Dakhil, Shaker R. LBA509, 553, 1003, 3501, 3640, 5034, 6029, 7509, TPS8119, 9572, TPS9647, e14526 Dakhil, Shaker 3616 Dal Bello, Maria Giovanna TPS7606, 11063 Dal Canton, Orietta 10572 Dal Lago, Lissandra e12008 Dal Molin, Graziela Zibetti e20644 Dalagiorgou, Geena e11513 Dalchow, Carsten e17003 Dale, David C. 6534, 6608 Dale, William 9545, e16006 Dalenc, Florence 511, e11529, e11607 Dalesio, Otilia 3502 Daley, John 3067 Dalgleish, Angus 3018 Dalia, Samir 10556 Dall’Agata, Monia e13007 Dall, Peter e17544

Dalla Palma, Maurizia Dallabona, Monica Dallabrida, Susan M.

5548 e13046 e16079, e17558 Dalle, Stephane 9093 Dalton, James T. e16015, e19100 Dalton, Susanne O. 4533, 6570 Dalvi, Tapashi e11570, e11571, e18543 Daly, Barbara J. e20633 Daly, Benedict 7502, 7524 Daly, Mary Beryl 1538 Daly, Norma e14666 Damaraju, Vijaya L. 2546, e13503 Damask, Amy LBA509 Damazo, Amilcar Sabino e22150 Dambach, Donna 645 Damber, Jan-Erik 5081 Damian, Silvia 2535, e12017 Damiano, Vincenzo 7603, e18536 Damião, Ronaldo 9628 Damm, Robert e22040 Damon, Lloyd Earl e19541 Damore, Michael A. 2071 Damrauer, Jeffrey S. e15595 Damyanov, Danail I e20514 Danaei, Mahmoud e22201 Dancey, Janet 9032, 11016 Dancour, Alan 4037 Dane, Faysal e14533, e14660, e14662, e14705 Danel, Claire 8100 Danese, Mark 625 Danesh Manesh, Amir Hossein 7087 Daneshmand, Maryam 3103 Daneshmand, Siamak 4531, 4542 Daneshmanesh, Amir Hossein e22198 Danesi, Romano 3603, 11058, e22056 Dang, Chau T. 606, 630, 6527, 9508 Dang, Long H. 4563 Dang, Nam H. 2574 Dangi, Uma Bhaskar e18004, e19503 Danhauer, Suzanne 6564, e20532 Dani, Carla 10519 Daniel, Catherine e12504 Daniel, Davey B. 8091 Daniel, Speiser E. e20011 Danielczyk, Antje 3008 Daniele, Bruno TPS4159 Daniele, Gennaro 8066, 11008 Danielli, Riccardo 9548 Daniels, Dianne e13002 Daniels, Gilbert H. 6025 Daniels, Gregory A. TPS3128 Daniëls, Laurien Aletta 8568 Danielsen, Haavard E 3607 Danila, Daniel Costin 5020, 5030, 5032, 5052, 5083, 5090, TPS5096, e16005 Danilov, Alexey Olegovich 3088 Danilova, Anna Borisovna 3088 Dank, Magdolna e12022^ Dannenberg, Andrew J. 6048 Danner, Bettina 4034 Danner, Omar e12573

Danova, Marco e20647 Dansey, Roger D. 7003, 7005, 7017, TPS7131, TPS7133, 8500, 8501, 8519, 8526, TPS8617, TPS8618 Dansin, Eric 8043, 8059, e19056 Dansky Ullmann, Claudio 605 Danso, Michael A. TPS664 Danson, Sarah 3018, 8051^, LBA9000, 9031, 9068 Dao, Tao 3047 Dao, Thao-Vi e20018 Dar, Mohammed 3021 Darbonne, Walter C. 2503 Darden, David E. 7018, 8520 Darendeliler, Emin e15569 Dareng, Eileen O. 1576 Darling, Gail 4077, 7516 Darlix, Amelie 2067 Dartevelle, Philippe e18503 Dartigues, Peggy TPS8615 Darvin, Maxim E. e20688, e20689 Darvishian, Farbod 9023, 9054, 9091, 11106 Darwish, Oussama M. 4581 Darzi, Ara W e14620 Das, Dipmala e20686 Das, Mayukh 8051^ Das, Prasenjit e19524 Das, Saroj 6089 Das, Satya 8546 Das, Shiva K. e22166 Das, Soma 2570 Das, Sudeep e13014 Dasanu, Constantin e19514 Dasappa, Lokanatha 517 Dasari, Arvind 3512, e14567 Dascola, Isabella 2021 Dasgupta, Swati 7083, 7114 Dasilva, Marcelo C 7588 Daskalaki, Emily e19048 Dasu, Sriram 6545 Date, Yuko e12035 Datko, Farrah Mikhail 606 Dauba, Jérôme 3515 Daud, Adil TPS2623, 3507, 9005, 9009, 9016, 9066, 9094, TPS9105^, e20010 Daugaard, Gedske 4502, 4503, 4529, 4533, 5059, TPS5098^, e20561 Daugherty, Christopher 6612, 9520, e17511 Daugherty, James P. 621 Daum, Severin e15068 Daunton, Adam LBA5000 Dauplat, Marie-Mélanie 1057 Dauplat, Marie-Melanie 1058 Daurelle, Micky 1582 Davar, Diwakar 9075 Dave, Harish P. 9027 Dave, Manish J. 7106, 7108 Dave, Sandeep S. 7107 Daver, Naval Guastad 7068, 7074 Davicioni, Elai 4542, 5033, 5089, e16044 David, Alice K. TPS664 David, Marc e15044 Davidenko, Irina 4007, TPS4153, 5541 ABSTRACT AUTHOR INDEX

709s

Davidoff, Amy J. e17584 Davidovics, Sarah A. 1601 Davids, Matthew Steven 7018, 8520 Davidson, Brian 3504 Davidson, Darin J. e21502 Davidson, Ian R e20008 Davidson, Nancy E. 520 Davidson, Neville LBA9000 Davies, Andrew John 2574, TPS8617 Davies, Andrew 636 Davies, Angela M. e19147 Davies, Diane L. 7555 Davies, Janine Marie 2595 Davies, Lauren e17506 Davies, Michael A. TPS6100, 9096, e20034, e20036, e22081 Davies, Sue 11116 Davila, Jessica e17501 Davis, Darren W. 1087, 11044 Davis, Elizabeth J. 10524 Davis, Evan D. 7103 Davis, Glen e20584 Davis, Ian D. 3093^ Davis, John W. 5069 Davis, Keith L. e11570, e11571 Davis, Mary L. 9032 Davis, Matthew M. 6517 Davis, Mitzie-Ann 6636 Davis, Rachel 9579 Davis, Roger B. 6058 Davis, Samantha 1042 Davis, Sharon 1080, e11609, e12034, e14646, e19130, e20672, e20697 Davis, Suzanne E. TPS8118 Davison, Jon M. 4103 Davison, Timothy S. TPS11120 Davison, Timothy 7532 Davite, Cristina e15061, e19138 Daw, Hamed 1038, 6577 Dawood, Shaheenah S. 524, 1131 Dawson, Keith L. e17561 Dawson, Nancy Ann 5047^, e16017 Dawson, Philip 5587 Dawson-Athey, Linda 5514 Day, Fiona 3598 Day, Kathleen C. 4545 Day, Mark L. 4545 Dayen, Charles e19078 Dayton, Martin e22114 Dayyani, Farshid e16038 Dazzi, Claudio 2021, e18561 Dcruz, A. K. 6085 de Aguirre, Itziar e19088 de Andrade, Jurandyr Moreira e12007 De Angelis, Carmine e11528 De Angelis, Verena e16093 De Azambuja, Evandro 525, 528, 575, e12008, e12515 De Baere, Thierry 2512, 3599, e22040 De Barros E. Silva, Milton Jose e15184, e20640 De Benedictis, Elena e12017 De Benedittis, Daniela e19527 de Bock, G. 9557 De Boer, Christopher 6578 De Boer, J. P. 6057 710s

De Boer, Maaike e11558, e17549 De Boer, Richard H. TPS660, 8045, 9628, 9640 De Bono, Johann Sebastian 2513, 2579, 2580, 2608, 3062, LBA4509, 4511, 5004, 5009, 5010, 5011, 5012, 5013, 5014, 5026, 5049^, 5052, 5065, TPS5099^, e16010 De Braud, Filippo G. 2556, 3641, 4121, 9092, e14716, e22056 De Brot, Marina 507 de Bruijn, Peter e11548, e13513 de Bruïne, Adriaan P e14503 de Castria, Tiago Biachi e20579 De Castro, Javier 1575, e13008, e19123 De Cecco, Loris 6027, 11037 De Celis Ferrari, Anezka Carvalho Rubin e14652 De Censi, Andrea 1516, 1517, TPS1610, 5541 de Charry, Félicité e16050 De Clercq, Beatrice e13519 De Conti, Ronald C. 9011, 9056^ de Craen, Anton J. M. e20545 De Dosso, Sara 3008, 4009, e14536 De Filippi, Rosaria 8564 De Flon, Caroline e15553 De Fusco, Andre 11040 De Galitiis, Federica 9065, 9548 De Geest, Koen 5597 De Giorgi, Ugo 4525, e15529, e15615 De Giorgi, Vincenzo e20013 de Goeij, Bart 3066 de Gooyer, Domingo 1072 De Gournay, Emmanuel 1114 De Gouveia, Paulo e22000 de Graaf, Hiltje 1072 de Graaf, Michiel A. 8568 de Graan, Anne-Joy M. 2597 de Gramont, Aimery 3515, 3520, 3524, 3533, 9511 De Gregorio, Nikolaus 5531, 5542 De Gregorio, Veronica 3613 De Greve, Jacques 8063 De Groot, Jan Willem 3036 De Groot, John Frederick 2019^, 2042, 2063, TPS2106, e22081 de Groot, Steffen M. 1072 de Gruijl, Tanja D. 3029 de Haas, Richard R. 1072 De Jesus-Acosta, Ana 4039, 4057, 4063, e14647, e15028 de Jong, Martin 6057 De Jonge, Maja J. 2522, 2579, e19138 de Jongh, Felix E. 3502, 11045 De Juan, Ana 540, 10523 de la Cruz Merino, Luis e11583 De La Cruz-Merino, Luis e11577, e22073 de la Fouchardière, Arnaud 10579 de la Fouchardiere, Christelle 4, 4127, 6092 De La Fuente, Sebastian G. e14546 De La Garza, Jaime G. e17031 de la Haba-Rodriguez, Juan 1125, e11530, e14559 de La Ménardière, Hélène e17514 de la Morena, Pilar 3042, 8070


De La Motte Rouge, Thibault 5063 De La Pena, Lorena 517, TPS665 De La Rochefordiere, Anne 1533 De La Serna Torroba, Javier 7004 de la Torre, Martha e19068 de Lama, Eugenia e15111 De Las Penas, Ramon LBA8002, 10523 De Laurentiis, Michelino TPS650^, e11528, e11556 De Lemos, Mario Law e15541 De Leon, Maria B. 5610, e16522 De Lima, Marcos J. G. 7006 De Lima, Marcos 7010, 7011 De Lio, Nelide 4062 De Los Santos, Jennifer F. 527, 1052 De Lutio, Elisabetta 11008 De Maglio, Giovanna 3563 De Manzoni, Giovanni e15148 De Marinis, Filippo LBA8005, 8066 De Martino, Iolanda e20694 De Marzo, Angelo 5027 De Mattos-Arruda, Leticia 2561^ De Mello, Ramon Andrade e19069 De Miguel, Bernardo 10517 De Minicis, Samuele 4123 De Mones del Pujol, Erwan 6053 de Morrée, Ellen S. 5064 de Oliveira, Claire 6033 De Oliveira, Julia Andrade 2060, 9561 De Paoli, Antonino 10519 De Parseval, Laure A. 9028, 9029 De Pas, Tommaso M. 8035 De Pas, Tommaso 2556, LBA8005, 8010, 8029, e19020 de Perrot, Marc 7516, 7526, 11109, e18503 De Piaggio, Marina e20705 De Placido, Sabino e11528, e18536 de Portugal, Teresa e15609 de Pril, Veerle TPS7608 De Renzis, Benoit 7002 De Richter, Pieter e22136, e22157 de Ridder, Jannemarie e14584 de Roos, Albert 8568 De Roover, Joke 5569 De Rosa, Francesco 3040, 9065 De Rycke, Yann 1533 De Salvo, Gian Luca e20028 De Santana, Iuri Amorim 2060, e13003 De Santis, Maria 4529, TPS4591 de Schultz, Wito 5055 De Schutter, Jef 3626 De Shields, Teresa e20520 De Simone, Daria e22003 de Simone, Valeria e16093 De Sloover, Daniel 1510 De Smet, Marina 2521 De Snoo, Femke 11090, TPS11122, e22117 De Souza, Carmino 7053^ De Souza, Jonas A. 6612 De Souza, Paul L. 5009, e22005 de Torres, Ines 10529, 10532, e16045 De Velasco, Guillermo e15609, e15620

De Vicente, Emilio 3543 De Vincenzo, Fabio e15615, e22145 De Vincenzo, Rosa Pasqualina e16538 De Vita, Fernando 4091 De Vos, Filip Yves Francine Leon 2001 De Vos, Sven 7017, 8500, 8501, 8559, TPS8618 de Vries, Elisabeth G. E. 2050 de Vries, Hilda 7581 de Vries, Ronald 8502 de Wijn, Rik e14629 de Wilt, Johannes H. W. 10549 de Wilt, Johannes e14584 de Wit, Djoeke 2592, 10547 De Wit, Maike 4559 De Wit, Ronald LBA4509, 4529, 5023, 5064, e16059 de’Liguori Carino, Nicola 9557 De, Pradip 2613, e13570 Dea, Katherine 7093 Deabreu, Andrea e16070 Deady, Sandra e14515 Deal, Allison Mary 515, 1077, 2595, 6501, 9543, e14522, e20582 Dealis, Cristina e13009 Dean-Colomb, Windy Marie e13566 Deane, Natasha G. 3555 DeAngelis, Lisa Marie 2015, 2095 DeAngelo, Daniel J. 7048 Dearden, Claire E. TPS8619, e19543 Dearnaley, David Paul 5012 Deasy, Joseph 3549 Deaton, Laurel 3512, e14567 Deb, Partha e16551 Deb, Siddhartha 11072 Debarbieux, Sebastien 9093 Debatin, Klaus-Michael 10017 DeBenedetto, Robert TPS8123 Debiec-Rychter, Maria e13528, e22046 Debieuvre, Didier 7515, 8000, e19078 DeBraganca, Kevin 2086 Debruyne, Philip R. 6029 Debus, Juergen e15574 Decaestecker, Jochen 3575 DeCamp, Malcolm M. 7553, 7554, e18506, e18552 Decarli, Nicola L e13046 deCastro, Carlos 7118 Decatris, Marios P. e19110 Decaulne, Virginie e14600 Decedue, Charles J. 2558 Dechowdhury, Roopa 2532 Decker, David A. e11590 Decker, Paul A. 2025, 2072 Decker, Thomas 591, LBA3506, 3586, e11525, e22075 Decleves, Xavier 569 Decordova, Shaun 2608 DeCristofaro, Alison H. e22124 Decroisette, Chantal 8099 Dede, Isa e11511, e18521 DeDelva, Pierre e20009 Dedieu, Jean-François 2560 Dedousi-Huebner, Vaia 7573 Deeken, John F. 2616, TPS2624 Deen, Keith C. 4519, 4569

Dees, Elizabeth Claire

605, 3026, e13574 Deeter, Robert e11570, e11571, e18543 DeFina, Laura 1520 Degiuli, Maurizio 4027 DeGore, Lori 9643 deGraffenried, Linda A. 1515 Degtiar, Irina e22172 Deguchi, Tomohiro e14552 Degun, Ravi e17520 Deharo, Steve TPS11120 Dehaspe, Luc 3552 Dehette, Stephanie e19078 Dehlendorff, Christian 3572, 4052 Dehler, Silvia e20542 Dehner, Louis P. 10024 Dei Rossi, Andrew 11018 Dei Tos, Angelo Paolo 10500, 10519, 10565 Deidda, Martino 603 Deininger, Michael W. N. 7001, 7063, TPS7129 DeJesus, Yvette A. 9538, 9539 Dekker, Henk 11087 del Barco, Sonia 1027, e13016 Del Bianco, Paola e20028 del Boca, Carlo e15502 Del Bue, Serena 3056 del Buono, Sabrina e16093 Del Campo, Jose Maria 1011, LBA5503, 5504 del Carmen, Marcela G. 5604 Del Conte, Alessandro 641 Del Conte, Gianluca 2535 Del Fabbro, Egidio 6638, e20559 del Giglio, Adriana Braz e20631, e20680 Del Giglio, Auro e16030, e16058, e20524, e20601, e20631, e20680 Del Mastro, Lucia 1036, e17548 Del Piano, Francesco 1057 del Pino, Marta e22200 Del Prete, Michela 3591, 4123, e14610, e15081, e15536 Del Prete, Salvatore 618 Del Priore, Giuseppe 5610, e16522, e16554, e22095 Del Re, Marzia 11058, e22056 Del Valle, Luis 2085 Del Vecchio, Michele 9027, 9030, 9035, 9046, 9065, 9070, 9548, e20025 dela Rosa, Corazon P. 5047^, 5053^ Delain, Martine 8530 DeLair, Deborah 5545, 5595 Delaloge, Suzette 547, 2599 Delamarre, Estelle 3588 Delaney, Joseph e16013 Delaney, Shannon e13541 DeLaney, Thomas F. 4047, 10520 Delannes, Martine 10570 Delanty, Laurie TPS3111 Delarue, Richard TPS8616 Delattre, Jean-Yves 2020, 2028 Delattre, Olivier 2615 Delaunay, Jacques 7002 Delbaldo, Catherine 3542 Delbrook, Cindy 10008

Delcambre, Corinne 10563, 10574, 10575, 10582 DelCorso, Lisette e12518 Delcuratolo, Sabina e14565 Delea, Thomas E. e20665 deLeon, Maria Creselda e16554 Deleporte, Amélie 9517 Deleu, Ines LBA509, 561 Delforge, Michel 8510, 8527, 8528, 8544, 8583 Delfrate, Roberto 4112 Delgado, Mayte e11583 Delgado-Guay, Marvin Omar e20559, e20612 Deliveliotis, Charalambos e15619 Della Puppa, Alessandro 2043 della Valle, Alberto 3056 Dellas, Kathrin 6077 Dellasala, Sara 7090 Dellinger, Thanh Hue 5599 Delman, Keith A. LBA9008, 9022 Delmar, Paul 3035 Delmas Marsalet, Beatrice e19513 Delord, Jean-Pierre 2548, 2549, 2561^, 2606, 2615, 3035, 4505, 6036, 8028, 8522, 9028, e19138 Delorenzi, Mauro 3522, 3526, 3577, e14544, e14561 Delouya, Guila e15094 Delpech, Yann 1013 Delpero, Jean-Robert 3596 Delrio, Paolo 11008 DeLuca, Amy N. 6619, 6620 Delva, Remy LBA4500 Delvenne, Philippe e11549 Delwail, Vincent 2032 Demanse, David 2531 Demant, Angela 8548 Demant, Peter e13549 Demarchi, Martin e14671 Demaria, Sandra TPS3122 DeMario, Mark e18514 DeMatteo, Ronald P. 3558, 3609, 4116, 10538 Demers, Christine e17517 Demetri, George D. 10501^, LBA10502, 10503, 10506, 10510, 10511, 10517, 10547, 10551 Demetter, Pieter 3524, 3562 Demeule, Michel e13013 Demeure, Michael J. 4038 Demey, Wim e14587^ Demian, Gerges Attia e12023 DeMicco, Michael 2568 DeMichele, Angela 519, 6560, 9639 Demichelis, Francesca 1554 Demidov, Lev V. 9013, 9020, e20042 Demir, Gokhan e19127, e20006 Demir, Mevlut e20614 Demircan, Orhan e17529 Demirci Alanyali, Senem e11501 Demirci, Abdullah Fatih e11537 Demirci, Umut e11559, e12036, e14533, e14662, e15540, e19107 Demirhan, Salih e20502 Demirkazik, Ahmet 8034, e18521, e20655 Demiroz, Candan e17019 Demko, Suzanne 2510 Demmy, Todd L. 4067

Dempsey, Paul W. 580, 11040 Demurjian, Mike e22095 Demuynck, Hilde 8536 den Hartigh, Jan 595, 2592 den Hollander, Margret 2592 den Hollander, Martha W. 2050 Den, Robert Benjamin e17577 Denda, Tadamichi 3516 Denduluri, Neelima 9604, 9605 Deng, Changchun 8575 Deng, Jie 6040, e20558 Deng, Wei 8542 Deng, Yanhong e14704, e20546 Deng, Youping 11114 Dengel, Lynn 1019, TPS3118^ Dengler, Jolanta 7051 Denicoff, Andrea 1596 Denis, Marc G. 8000, e19046, e19151 Denis, Olivier e20652 DeNittis, Albert S. 9527 Deniz, Kemal e14672, e14695 Denizot-Guillemaut, Severine 10516 Denkert, Carsten TPS1138, 4016, 11061, 11112 Denlinger, Crystal Shereen 2609, 3587, 4121 Denning, Krista L. 2089 Dennis, Constance S. e22081 Dennis, Phillip A. 2532 Denniston, Kyle A. 1127 DeNoble, Sarah 9076 Denouel, Amelie e14621 Denq, William 6051 Denslow, Sheri 5589 Densmore, John e18005 Dent, Rebecca Alexandra 574, 6589, 9506, e20566 Dent, Rebecca 524, 1131 Dent, Susan Faye 542, 6595 Denvir, James 2089 Deo, S. V. S. TPS4162, 10527, e12539, e15138, e21506, e21522 Deodhar, Kedar 5554 Depenni, Roberta 2021 Deplanque, Gael 3614 Der, Sandy 11057 Deray, Gilbert 5567, e12504 Derbel, Olfa 10579 Dercksen, Wouter 1028, e17549 Dering, Judy 5510 Derks, Sarah e14503 Derleth, Christina Louise 6532 Dermeche, Slimane e15506 Derom, Eric 7541 Derome, Andrew e20030, e20038 Derosa, Lisa e15524 DeRouen, Mindy C. 5605 Derrien-Colemyn, Alexandrine 4577 Dervan, Peter Brendan e13588 Dervenis, Christos 4006 Deryal, Mustafa TPS1137 Des Guetz, Gaetan 1583, 3536 Desai, Arati Suvas 6094 Desai, Avni Mukund 560 Desai, Bhardwaj 2065 Desai, Jayesh TPS2619, 3573, 3598, TPS3649, LBA10507, 10567, 11015, e14608

Desai, Krupali 9613 Desai, Madhuri 2519 Desai, Manisha 1504 Desai, Pankaj B. e13518 Desai, Rupal 3001 Desai, Sunil J. 10004 Desaiah, Durisala 2016, 2039, 2061, 2563, 4118, LBA8003 Desauw, Christophe e15134 Deschamps, Claude e19013 Deschamps, Frederic 2512 Deschamps, Lydia e20032 Deschenes, Jean 8096 Descotes, Jean Luc e15593 Deserti, Marzia e15003 DeShazo, Mollie 8057 Deshmukh, Chetan Dilip 3039, e13567 Deshpande, Hari Anant 6076 Deshpande, Rahul TPS4146 Deshpande, Vikram 4047, 4125 Desideri, Giovambattista e14521 Desideri, Serena 2044, 2065, TPS2105 DeSilvio, Michelle 516, 621, TPS664 DeSimone, Dennis C. e13563 Desjardins, Annick 2035, 2039, 2090, 2094, e13015^ Desjardins, Laurence 9057 Desjardins, Leandra 9609 Desmoulins, Isabelle 2548, 2549, 11007 Desnoyers, Luc Roland e22183 Desolneux, Gregoire 3558 DeSouza, Nandita 5054 Despain, Darrin 2586 Desrichard, Alexis 1058 Dessain, Scott K. e22163 Desseigne, Francoise 4046 Dessi, Mariele 603, e20556 Destro, Annarita e14611 Detre, Simone 535 Detterbeck, Frank C. 7602 Dettino, Aldo A. e14638, e20640 Detty, Tammi 2529 Detweiler-Short, Kristen 8543 Deudon, Stephanie TPS651 Deuña-Flores, Armando 10056 Deutsch, Eric 9556 Dev, Rony e20559 Devarajan, Karthik 9546 Devarakonda, Siddhartha 7563, 8076 Devaux, Yves e16096 Devenport, Martin 3044 Devereux, Stephen TPS8619 Devidas, Alain 8536 Devidas, Meenakshi 10001, 10002, 10003 Devine, Catherine E. 4516, 6023, e17016 Devoe, Craig E. 4010, 7055, e15005 Devogelaere, Benoit 11086 DeVries, Catharina 573 DeVries, Todd 4527^, 4547^, 5047^ Devriese, Lot A. 2536 Dewar, John A. 5 Dewaraja, Yuni e19519 ABSTRACT AUTHOR INDEX

711s

Dewdney, Alice e14616 DeWeese, Theodore L. 9636 Dewhirst, Mark W. e15560, e22166 Dewhirst, Mark 5509 Dey, Nandini 2613, e13570 Dezentje, Vincent O. 595, 597 Dhabhar, Firdaus S. 9504 Dhakal, Sughosh e20667 Dhall, Girish 2049 Dhanda, Rahul 7065, 7096, e19139 Dhani, Neesha C. 4049, TPS10593, 11002 Dhar, Arindam TPS4593 Dhar, Vikrom K. 570, 3582, 3583, e14518, e14566 Dhesy-Thind, Sukhbinder K. e20522 Dhillon, Haryana M. TPS3647, e14582 Dhimolea, Eugen 11039 Dhodapkar, Madhav V. 8515 Dholakia, Avani Satish 4039, 4057, e15028 Di Bacco, Alessandra 8514 di Bari, Maria-Giovana e14581 Di Bartolomeo, Maria 3641, e14716 Di Blasio, Anna e14521 Di Buduo, Eleonora 1014 Di Cataldo, Andrea 10015 Di Cecilia, Marialuisa e20031 Di Cocco, Barbara e19099 Di Costanzo, Francesco 3615, 4091, e14557 Di Desidero, Teresa 3602, 3603, e14577 Di Donato, Samantha 11058 Di Fabio, Francesca e14557, e14717, e15154 Di Filippo, Franco e21517 Di Fiore, Frédéric 3585 Di Giacomo, Anna Maria 9065 Di Giacomo, Daniela e14596 Di Girolamo, Stefania e15003 Di Guardo, Lorenza 9035, 9070, 9092 Di Iulio, Julianna 9001 Di Lauro, Luigi e15065 Di Lauro, Vincenzo e22149 Di Leo, Angelo 610, TPS650^ Di Lorenzo, Giuseppe 4539, 5050, 5055, 7603, e16031, e16093, e18536, e21500 Di Lullo, Gloria A. e20671 di Maggio, Antonio e12534 Di Maggio, Gabriele e14655 Di Maio, Massimo 8066, 11008, e12021, e19031 Di Marco, Anna Maria e11568 Di Marco, Mariacristina 4048, e15069 Di Marco, Rosanna e11527 Di Mari, Anna Maria e11526 Di Meglio, Giovanni e13009 Di Monta, Gianluca e20031 Di Narzo, Antonio Fabio 3526 Di Nicolantonio, Federica 11005 Di Palma, Mario 5075, 5088 Di Pietro Paolo, Marzia e11573 Di Raimondo, Francesco 7025, 8509 712s

Di Rocco, Roberta e15124 Di Scala, Lilla 2522, 3035 Di Scioscio, Valerio e21511 Di Stefano, Anna Luisa 2024, 2028, 2074 Di Tomaso, Emmanuelle TPS650^ Di Valentin, Tanya e14686 Diab, Adi TPS3120 Diaconescu, Razvan e19115 Diallo, Abou 3558, 6582 Diallo, Alhassane 9057 Diamantopoulos, Nikolaos e11576 Diamond, Don J. 3089 Diamond, Eli L. 7120 Diamond, Jennifer Robinson 2502, 2557 Dian, Darius 3064 Diao, Lixia 6011 Dias, Fernando Luiz 6071 Dias-Oliveira, Indhira 10535 Dias-Santagata, Dora 533, 2029, 7555, 8083 Diasio, Robert B. 3510, 4071 Diaz Garcia, Vanesa 9641 Diaz Rubio, Eduardo e11561, e16543 Diaz, Angelica 7601 Diaz, Berta 1509 Diaz, Jose 9574 Diaz, Luis A. 2511, 4039, 11005, e14647, e15028 Diaz, Monica 2569 Diaz, Roberto 2552, e14618 Díaz-Chávez, José 4555 Diaz-Padilla, Ivan 2534, 2600, LBA5503, e22000 Diaz-Rubio, Eduardo 3533 Dibaj, Shiva 1561 DiBella, Nicholas J. 7122, 8559 DiBella, Nicholas 7096 Dicato, Mario A. e14591 Dichmann, Robert 8599 DiCioccio, A Thomas 2502, 2517 Dicker, Adam 2100, e17577 Dickinson, Andrew 4511 Dickinson, Peter D. e16069 Dickinson, Shohreh I. 4541 Dickler, Maura N. 606, 9610 Dickow, Brenda 4577, 5041 Dickson, Diana L. 5563 Dickson, Elizabeth Louise e20571, e22007 Dickson, Erica 1558, 11050 Dickson, Holli 8017 Dickson, Mark Andrew CRA9003, 9060, 10512, 10558, 10580, TPS10594 Diebold, Anne E. 4141 Diebold, Marie Danielle 3562 Dieci, Maria Vittoria 556 Dieckmann, Karin 2078 Diefes, Kristin 2026 Diego, Emilia 1098, 9643 Diehl, Frank 3512 Diehl, Joseph W. e20044 Diehl, Nancy N. 7047 Diekstra, Meta 4580 Diel, Ingo J. 9640 Dieli-Conwright, Christina Marie TPS9648 Dienstmann, Rodrigo 3551, 9029


Dieras, Veronique 511, TPS652, TPS663, 2599, e13519 Dierschke, Nicole A. e15171 Dietel, Manfred 4016, 11112, e15071, e19060, e22042 Dietrich, Bruno 3008 Dietrich, Daniel 3503 Dietrich, Jorg TPS2104 Dietrich, Mary S. 6040, 6049, e20531, e20555, e20558, e20599 Dietrich, Pierre-Yves e15619 Dietz, Albert J. e20539 Dietz, Allan B. e20037 Dietz, Andreas 6002, e17021 Dietz, Donny e14690 Dieudonné, Anne-Sophie 595, 1078 Diez, Juan Jose 4140 Diez, Marc e17010 Díez, Orland 1509 Dif, Nicolas 2007 DiFeo, Analisa 3014 DiFurio, Megan J. 5519 Diggs, Brian S. 4073 DiGiovanna, Michael 619, 1085, 2587 DiGloria, Celeste M 5578, e13564 Dignam, James 1, LBA2010 Dignan, Mark e14673 Digregorio, Jocelyn e20627^ Digumarti, Raghunadharao 7061, 7080, e18000, e18003, e19533, e20684 Dikilitas, Mustafa e20603 Dikshit, Rajesh 2 Dileo, Palma 10516 Dilhuydy, Marie-Sarah 7004 Diller, Lisa 6544, 10071 Dillon, Deborah 1132 Dillon, Patrick Michael 6021, e11596, e18005 Dillon, Stacey 3019 Dilts, David M. 1596, 6524 Dilworth-Anderson, Peggye 6584 Dim, Daniel e22189 DiMaio, Daniel 1574 Dimas, Konstantinos e16083 Dimassi, Hani e12525 Dimitrakopoulos, Fotinos-Ioannis D. e18507 Dimitri, Lucia e18518 Dimitriadi, Sergey N. e15602 Dimitriadi, Ylija Nikolaevna e12560 Dimitroulakos, Jim 8048 Dimitrova, Nevenka 1046 Dimopoulos, Meletios A. 582, 1093, 4558, 8510, 8517, 8527, 8528, 8544, 8583, e15619 Dimopoulos, Nektaria 3093^ Dimou, Anastasios e22049 Dina, Roberto 5562 Dinan, Michaela A. 6504, 6554, 6631 Dinc, Nur e11540, e15100 Dincaslan, Handan 10068 Dinda, Amit e19526 Ding, Beiying TPS662 Ding, Jianmin e15040 Ding, Keyue 7510, 8048, e19033 Ding, Lieming e19161 Ding, Lu 1588

Ding, Pei Ni e19132 Ding, Xiaosheng e19067 Ding, Xiaoyan 2614 Ding, Yan 10004 Ding, Zhenyu e19055 Dingemans, Anne-Marie C. 7514 Dingli, David 8516, 8541, 8581, 8587, 8600, 8606 Dinh, Hillary 2550, e13572, e15128 Dinh, Vy Thuy e22062 Dinis, Jose 6065 Diniz, Alessandro Landskron e15184 Diniz, Ana Carolina Sigolo Levy e13050, e20640 Diniz, Paulo Henrique Costa e15199 Dinn, Sean 2097 Dinney, Colin P. N. 4538 Dinniwell, Robert Edward 6585, e17526 Diodoro, Maria G. e22206 Dion, Patrick 9511 Diorio, Caroline 627 DiPaola, Robert S. 2553, 2582 DiPasquale, Maria Chiara e11569, e13046 DiPersio, John F. 7048 DiPetrillo, Thomas A. 2047, 7502, 7524 DiPetro, Renee e15029 DiPippo, Vincent A. e16007 Dipiro, Pamela 1105 DiRaddo, Ann Marie 2557 Directo, Michael 6545 DiRenzo, Jennifer 10030 Dirix, Luc Yves 11045 Dirksen, Uta 10031, 10518 Dirrichs, Tim 11077 Disalvatore, Davide 617 DiSimone, Christopher 2533 Dispenzieri, Angela 8516, 8541, 8581, 8587, 8600, 8606 Dito, Elizabeth 4014 Dito, Gennaro 3019 DiTomaso, Emmanuelle 2015 Dittmar, Ashley J. e13549 Dittmer, Christine 1577 Dittrich, Christian 549, e19145 Dittus, Kim 9591, e12000 Dive, Caroline e22035 Divekar, Ganesh Harishchandra 2557 Divekar, Ganesh 3039, e13567, e19119 Diwakar, Ravi 8053 Diximier, Adrien e19078 Dixit, Payal 11076 Dixon, Samara Ann 9543, e20582 Dizdar, Omer e11532, e16526, e16528, e16536 Dizon, Don S. TPS3121, 6579, 6590, e20543 Djulbegovic, Benjamin e19516 Djurisic, Igor e14676 Dnistrian, Ann M. 9610 do Amaral, Nayra Soares e15199 Do, Ingu 637 Do, Kim-Anh 4517 Do, Kinh G. TPS4144 Do, Richard Kinh Gian 4116

Dobbs, Nicola A. 2525 Dobbs, Stephen 5500 Doberstein, Stephen K. 3060 Dobson Amato, Katharine Ann 1603 Dobson Amato, Katharine 1566 Docao, Christine 6092 Doctor, Stephanie 5015 Dodbiba, Lorin 4077 Dodd, Anna e14582 Dodge, Jason Esli 5561 Doebele, Robert Charles 2524, 3545, 8023, 8024, 8074 Doerste, Ulrike e16535 Dogan, Erkan e11537, e14533 Dogan, Oner 10043 Doglioni, Claudio LBA8005 Dogru, Atalay e11585 Dogu, Mehmet Hilmi e18014 Dogusoy, Gulen Bulbul e19127 Dohan, Daniel Paul 4055 Dohany, Lindsay 1541, 1557 Doherty, Glen 3549 Doherty, Lisa M. 2030 Doherty, Mark e15142, e15196 Dohner, Hartmut 7012, 7015, 7023 Dohollou, Nadine 6603 Doi, Takako 1047 Doi, Toshihiko 11031, e13500, e13510 Doisneau-Sixou, Sophie F. e22059 Doki, Yuichiro e15016 Dokiya, Takushi e16090 Dolan, James P. 4073 Dolan, M. Eileen e13541 Dolasik, Ilhan e11585 Dolecek, Therese A. 2069, 2099 Doleman, Susan LBA9008 Doll, Corinne M. e12505 Doll, Helen A. e20537 Doll, Kemi M. 5589 Dollinger, Matthias M. e15088 Dollman, James 9585 Domb, Avi 4037 Dombi, Eva 10522 Dombret, Hervé TPS3117^, 7012, 7021 Domchek, Susan M. 519, 1510, 11024 Dome, Jeffrey 10014 Domenech, Carles e13526 Domenech, Montserrat e16014 Domine, Manuel LBA8002, 11089, e19000, e19109 Dominguez, Maria Ester 1073, 11118 Dominguez-Hormaetxe, Saioa 540 Dominici, Laura Stewart 1100, 1117, 1133 Dommach, M. 4009 Domont, Julien 10548, 10568 Domschke, Christoph Wolfram 11012 Donald, Emma 8045 Donatangelo, Silvio e22176 Donath, David e15094 Donath, Elie e13539, e19155 Donati, Donatella e15514 Donati, Giovanni e18522 Donato, Giuseppe e22104 Donehower, Ross C. 3539, e14647 Donelan, Karen 6544 Dong, Dan Feng e22096 Dong, Haidong 3037

Dong, Hua TPS4149 Dong, Huang 11048 Dong, Jun 6029 Dong, Mei 8525 Dong, Min 538, e16077, e19504 Dong, Ruifen 5535 Dong, XinXin 6520 Dong, Ying 8088^ Donia, Marco 3028 Donington, Jessica S. 11109 Donini, Annibale e15148 Donini, Maddalena 4112, e15086, e15502, e16078 Donizetti, Tiago e22074 Donker, Mila LBA1001 Donnarumma, Daniela 8564 Donnellan, Eoin 1115 Donnellan, Paul P. e20008, e20505 Donnellan, William Bruce 7104 Donner, Davide e13046 Donohue, Kathleen 6501 Donovan, Diana e20641 Donovan, Jenny TPS656 Donskov, Frede 4565, 4578, 4586, 5532, e15518 Dookeran, Keith A. e12519 Doolan, Padraig e11536 Doolin, Elizabeth E. 4563, TPS5612 Dooms, Christophe 7514 Doorduijn, Jeanette 8507 Doosti, Mohammad e22079 Doot, Robert K 5003 Dorent, Richard 5567, e12504 Dorer, David J. 8031 Dores, Graca 4536 Dorff, Tanya B. 4501, 4531, 5062, 9632, 11040, 11047, e16073 Dorff, Tanya B e16020 Doria-Rose, Paul 6522 Dorjsuren, Dorjbal 1016 Dormady, Shane e22124 Dorman, Naoise Maria e12565 Dorn, Christiane 10562 Doros, Leslie Ann 10024 Doroshow, James H. 11103, e22080 Dorr, Andrew 2580 Dorroh, Scott Alan 7597 Dort, Joseph C. e12505 Dorval, Etienne 3614 Dos Anjos, Carlos Henrique 5540 Dos Santos Aguiar, Simone 10536 Dos Santos, Lisa A. e16546 dos Santos, Lucas Vieira 4000, e11500, e18534, e20506 Dossul, Tehseen e20608 Dotan, Efrat 9546, e15559 Doty, Shaun 11048 Dou, Gui-Fang e19075 Doubek, Michael 7101 Doucette, John 6062, 8555 Doufexis, Dimitrios e22202 Dougall, Bill e22144 Dougenis, Dimitrios e18507 Dougherty, Brian 5505 Dougherty, David W. 9537 Dougherty, Jeffrey e13538 Dougherty, Thomas 2089, e13040 Doughty, Julie C. 588 Douglas, Pamela S. 1520 Douglass, Larry E. e16033

Douillard, Jean Yves LBA8011 Douillard, Jean-Yves 3511, 3520, 3533, 3542, 3620, 4118, e19046 Douka, Vassiliki 8567 Douma, Shyanne 505 Doumit, Elias e19516 Doupe, Malcolm e17596 Dourthe, Louis-Marie e17543 Douura, Hideki e13504 Dowdy, Sean Christopher 5510, 5577, 5593 Dowell, Johnathan 8074 Dowell, Jonathan 8088^ Dowlati, Afshin 8114, e13521, e18526 Downes, Michelle R. 5070 Downie, Louise 635 Downing, Sean 1009, 11020, e22146 Dowsett, Mitchell 506, 525, 535, 575 Dowsett, Robert J. 9620 Doyle, Austin 4517, 6524 Doyle, L. Austin 2564, 5517, 5524, 8026 Doyle, Teresa e13049 Doyle-Gundlach, Kerry 1558 Dozin, Beatrice 1036 Drabick, Joseph J. 4517, e19502 Drach, Johannes W. 8533, 8534 Drago, Francesco 3040 Draht, Muriel X. G. e14503 Drake, Charles G. 3002^, TPS3112, 4514, 5016 Dralle, Sarah 2516^, e18002 Dranitsaris, George 6595 Dranoff, Glen 3067 Drapkin, Ronny 5524 Drappatz, Jan 2013 Drazer, Michael e16006 Dreicer, Robert LBA4509, 4515, e15534, e16022 Dreno, Brigitte 9036, e20022 Dreosti, Lydia Mary 531 Dresemann, Antje e13565 Dresemann, Gregor Paul e13004, e13565 Dresler, Carolyn 1561 Dressler, Lynn G. 6501 Drevs, Joachim e22114 Drevyanko, Timothy F. 4026 Drew, Philip e22123 Drew, Yvette 2586 Dreyer, Chantal 6036 Dreyer, Nicholas J 6058 Dreyer, Zoann 7097, 10004 Dreyfus, Francois 7002 Dreyling, Martin H. TPS8613^, TPS8618 Driessen, Chantal 6057 Drill, Esther N. 7558 Drilon, Alexander Edward Dela Cruz 7570, 8067 Driscoll, James e22030 Drobish, Amy 1077 Drobner, Igor 9512 Dromain, Clarisse e11607 Dronca, Roxana Stefania 5082, 9009, 9016, 9048, 9073, e16061, e20024 Drooz, Alain e14545 Dror, Ygael e22111

Droz, Jean-Pierre e16096 Drozdov, Ignat 4137 Drozdowskyj, Ana 11027 Drucker, Arik Marc 5048 Druker, Brian J. 7063 Drukker, Caroline 587 Druy, Alexander 10055 Dry, Sarah M. 10555 Dsouza, Philomena Charlotte e22099 Du Bois, Andreas 1577, LBA5503, 5553 du Mortier, Catherine e17514 Du, Lingling 2070, 2096, 9086, e15537, e19012, e19025 Du, Nan 5558, e19044 Du, Wenmin e15185 Du, Xiang 8547, e14667, e14685 Du, Zedong TPS4154, e14645 Du, Zhi e15040, e15050 Dua, Divyanshu 6541 Duan, Fenghai 5003 Duan, Jianchun 8101, e19061^, e19067, e19091, e19101, e19136 Duan, Zhigang e17501 Duan-Porter, Wei 7103 Duarte, Maritza 3074 Dubbink, Hendrikus J. 2011 Dubensky, Thomas 4040^, TPS7607 Dubergé, Thomas 10582 Dubey, Sarita TPS4153 DuBois, Steven G. 10026, 10027, 10045, 10060 Dubowy, Ronald L. 7005, TPS7131 Dubray-Longeras, Pascale 1057, e11615 Dubrovsky, Leonid 3047 Dubrowskaja, Natalia e22076 Dubsky, Peter Christian 573, 11088, 11093, e11601, e22090 Duchemann, Boris 7604 Duchnowska, Renata 604 Ducimetiere, Francoise 10563 Duckworth, Lizette Vila e15108, e15145 Duclos, Brigitte e17543 Duclos, Marie LBA4510 Ducoulombier, Agnes 536, 544 Ducray, Francois 2028 Ducreux, Michel 3599 Duda, Dan G. 1065, 4047, 4125 Duda, Gabriel Dan 2056 Duddalwar, Vinay 8554 Dudek, Arkadiusz 9048 Dudley, B. Stephens 5513 Dudley, Matthew W. 2584^ Dudney, Sean 10530 Dueck, Amylou C. 520, 6587, e16065 Dueland, Svein 3547 Duewell, Peter 3064 Duez, Nicole J. LBA1001 Duff, Erin 1076 Duff, Jennifer Michelle 6605 Duffau, Hugues 2067 Duffaud, Florence 10505, 10516, 10542, 10546, 10548, 10563 Duffield, Emily TPS8118 Duffy, Austin G. e15177 ABSTRACT AUTHOR INDEX

713s

Duffy, Danielle 5061 Duffy, Michael J. 1054, 1066 Duffy, Regan M. 7513, e19141 Duffy, Steven e11602 Dugast, Catherine TPS1607 Duhoux, Francois P. 1533 Duivenvoorden, Wilhelmina e16011 Dukleska, Katerina 10520 Dumais, Valerie e12522 Duman, Berna Bozkurt 9587 Dumanli, Esra e17529 Dumas, Olivier e17517 Dumitru, Filip 4000 Dummer, Reinhard 9004, 9020, 9025, 9028, 9071, TPS9105^, e20028, e20050 Dumont, Aurelie 536, 544, e22127 Dumont, Patrick e19078 Dumoulin, Daphne e18562 Dunavin, Neil 9600 Dunbar, Joi 8518 Dunbar, Martin 2584^ Duncan, James S. 512 Duncavage, Eric James 11099 Dundar, Ebru e19071 Dunetz, Bryant TPS11123 Dunkel, Ira J. 10019, 10030 Dunleavy, Kieron 8524 Dunn, Barbara k 1516 Dunn, Ian F. 2030 Dunn, Janet A. TPS656, TPS667, 1015, 4023, LBA9000 Dunn, Kelli B. e20573 Dunn, Keren e17507 Dunn, Lara 9610 Dunning, Mark 1015 Dunphy, Frank 8029 Dunphy, Mark 11076 Dunst, Juergen 6077 Duong, Hien Kim 7008, 8585^ Duong, Vu 7049, e17584 Dupin, Nicolas e20032 Dupont, Jakob 2540 Duprat, Joao 9001 Dupre, Aurelien 10579 Dupuis, Olivier 3515, 3542 Dupuy, Danielle 6609 Duque, Lourdes 9567 Duquette, Debra 1557 Duquette, Mark e17014 Durack, Jeremy C. TPS3120 Duran Martinez, Ignacio 5019 Duran, Ayse Ocak e14672, e14695, e15110, e18516 Duran, Christine 8554 Duran, Ignacio 4140, 4587, e15533, e15550, e16028 Durand, Jean-Bernard e20664 Durand, Jean-Philippe e13589, e15592, e17514, e20535, e22029 Durando, Xavier e11615, e16021 Durango, Isabel Cristina e12571 Durante, Emilia e15514, e17551, e20617 Durany, Robert 5550 Durazo-Arvizu, Ramon e14578 Durecki, Diane E. 8543 Duret, Aude 10582 Durie, Brian G. 8586, 8596 Durnali, Ayse e14662, e19107 714s

Dursun, Polat

e16526, e16528, e16536 Duru, Gerard 9093 Duruisseaux, Michael e19036 Durusoy, Raika e12509 Dusek, Ladislav e14622 Dusetzina, Stacie 6572 Dusmet, Michael 7544 Duster, Sarah M. e17511 Dutcher, Janice P. 4520, 4521, e12527 Dutcus, Corina 1049^, 1050^, 1 055^ Dutia, Mrinal P. 2569 Dutra-Clarke, Ana Virginia Calogeras 7558 Dutta, Pinaki R. 6034 Dutton, Susan J. TPS5615, 9503 Duval, Alex 3524 Duval, Vincent TPS650^ Duvvuri, Uma 6043 Duyster, Justus 10508 Dvadnenko, Konstantin V. e16514 Dwernychuck, Lynn e14619 Dwivedi, Pankaj e20678 Dworan, Nina e19093 Dy, Grace K. 2528, 2557, 2609, 7509 Dy, Sydney Morss 9636 Dyal, Herman e22184 Dyer, Richard 4555 Dygai-Cochet, Inna 11007 Dylke, Elizabeth S 9616 Dymond, Angela 4511 Dyson, Gregory e15077 Dytfeld, Dominik 8543 Dzhabarov, Farhad e20005 Dzhandzhugazyan, Karina e12024 Dziadziuszko, Rafal e22092 Dzienis, Marcin Radoslaw 9081 Dziewirski, Wirginiusz 10564 Dörken, Bernd 4016 Dørum, Anne 9569

E E, Aranda E, Damodaran S E, Fuentes Ea, Roth Eaddy, Michael Eads, Jennifer Rachel

e14559 e19118 1125 TPS2623 10590 6500, e20633 Eagle, Ralph e17573 Eakle, J F 558, 561 Eapen, Mary 10006 Eapen, Sara e16025, e22135 Earl, Helena Margaret 5, TPS667, 1015, 5514, 10541, e21503 Earl, Julie 1529, 4140 Earle, Craig 6625, 9523, 9537 Earles, Kristofer 6547 Early, Dayna S 4051 Earp, Shelton 512 Easaw, Jacob C. 2053 Easton, Douglas e16000 Eastwood, Daniel 8505 Eatock, Martin McKinlay 2586, e15085 Eaton, Anne 1021, e13509


Eaton, Bree Ruppert 7589 Ebata, Tomoki 4119 Ebbinghaus, Scot 9009 Eberhard, David e22187 Eberhard, Jakob 3579, e14580 Eberhardt, John 9089, e14500 Eberhardt, Wilfried Ernst Erich e19138 Eberhardt, Wilfried e19060 Ebert, Matthias Philip 4009 Ebert, Matthias e14702 Ebi, Noriyuki e19016 Ebrahim, Jalal 6585, e17526 Eby, Jonathan M. e22170 Eccher, Claudio e11569 Eccles, Diana 5507^ Echarri, Maria Jose e12558 Echenique, Miguel M. e11610 Echeveste, Jose Ignacio e19027 Echeveste, Jose 9074 Echt, Katharina V. 5067 Eck, Steven 7045 Eckardt, Jeffrey 10555 Eckardt, John R. 8559 Eckart, Michael 7015 Eckel-Passow, Jeanette 2072, 4567, e15539 Eckert, Eleanor e15034 Eckert, Karl 7014 Eckhardt, S. Gail 2557, 3587 Eckloff, Bruce W. 7568 Economopoulou, Christina e20642 Economy, Katherine E. 1117, 1133 Ecsedy, Jeffrey 2598 Ecstein-Fraisse, Evelyne Brana 5023 Eddings, Courtney e15073 Eddy, Sean 11017 Edelheit, Simone 1046 Edeline, Veronique TPS8615 Edell, Eric e19013 Edelman, Gerald 9094 Edelman, Martin J. 2515, 7523, 8039, TPS8125, e20574 Eden, James 11094 Edenbrandt, Lars 5081 Edenfield, William Jeffery 2051 Edenfield, William J. 2006 Edge, Stephen B. 1006 Edil, Barish H. 4057 Edington, Howard 9043 Edmondson, Richard J. TPS5614 Edmundowicz, Steven Alphonse 4051 Edwards, Joanne 588 Edwards, Lloyd 6584 Eeast, James e22034 Eeles, Ros A. 5054, e16000 Efebera, Yvonne Adeduni 8584 Effenberger, Katharina E. 11014 Effinger, Karen Elizabeth 10046 Efird, Jimmy 1069 Efstathiades, Thomas e19093 Efstathiou, Eleni LBA4509, 4558, 5014, e15619 Egan, Kathleen e20545 Egberts, Friederike 11009 Egerdie, Blair e20514 Egerer, Gerlinde 9612

Egevad, Lars 11097 Eggener, Scott E. 6513, e16006 Egger, Matthias 4079 Eggermont, Alexander M. 2512, e20035 Egleston, Brian 1538, 6500 Egloff, Ann Marie 6006 Egorova, Natalia 6640, e16551 Eguchi, Keisuke 7536 Eguchi, Kenji e12541, e20609 Eguchi, Susumu e14633 Eguchi, Takashi 7548 Ehlert, Karoline 10017 Ehmann, W. Christopher e19502 Ehninger, Gerhard e21518 Ehrenwald, Edward e14545 Ehrlich, Peter 10000 Ehrnrooth, Eva 6001 Eichhorst, Barbara 7015 Eichstaedt, Martina 8112 Eickhoff, Jens C. 2537, 2607, 9566, 9635, e20565 Eid, Rouba e20500 Eid, Samir-Shehata M. e15505 Eidtmann, Holger TPS1138, 3012 Eiermann, Wolfgang 503, 537, 1014, TPS1138 Eigentler, Thomas K. e20050 Eil, Robert 4073 Eilber, Frederick C. 10555 Eilber, Frederick R. 10555 Eilers, Grant 10509, 10510 Ein-Gal, Shlomit Y. 9082 Einhorn, Jan 9567, e14661 Einhorn, Lawrence H. 4554, 4557, e15584, e15621 Einsele, Hermann e15193 Einstein, Mark H. 5517, 5592 Eiriksson, Lua R. 5508, 5543 Eisa, Heba El-Sayed e12023 Eisbruch, Avraham 9607 Eisen, Andrea 1550, e17515 Eisen, Hannah M. 7588 Eisen, Tim 3073, 4506, 4513, TPS4590 Eisenberg, Marcia e22142 Eisenberger, Andrew 7031 Eisenberger, Mario A. 5023, TPS5099^, TPS5100, e15597, e15598, e16051, e16068 Eisenbruch, Maurice 6556 Eisenhauer, Elizabeth A. 518, 2053, 5042, 5502 Eisenstat, David Daniel 2053 Eisinger, François 1562, TPS1607, 6563, 6603 Eisner, Florian e15064 Eissa, Yasmine 3083 Eisterer, Wolfgang e15041 Ejlertsen, Bent 529, TPS660 Ekenel, Meltem e14594 Eklund, John W. 9087 El Ashry, Mohamed e18505 El Bastawisy, Ahmed El Saied e14678 El Fakir, Samira e20516 El Gammal, Mosaad 7013 El Ghali, Ilham e22201 el Ghissassi, Brahim e16527 El Hader, Carlos e11568

El Hariry, Iman TPS1136 El Kadi, Abir e20516 El Karak, Fadi e20534 El Khodary, Dalia Abd-Elghany e11599 El Kouri, Claude 8068, e19046 EL Lathy, Hala Ahmed e17013 El Mekkeoui, Zineb Benbrahim e21513 El Mesbahi, Omar e21513 El Osta, Badi Edmond 3103 El Osta, Lana e20534 El Sayed, Ali e18005 El Solh, Hassan M. B. 10052 El-Assal, Shaaban 1075 El-Deiry, Mark 6083 El-Gazzaz, Galal e15015 El-Haddad, Mostafa S. e13025 El-Haddad, Shawky e13025 El-hajj, Ghada e12525 El-Hariry, Iman CRA8007, TPS8126 El-Hashimy, Mona 505, 557 El-Khoueiry, Anthony B. 2501, 2564, 3539, 3567, 3568, 4110, 4111, 4128, e14543, e14714, e15009, e15022 El-Khoueiry, Rita Elie 3565, 3566, 3567, 3568, 4110, 4111, e14543, e14714, e15009, e15022 El-Modir, Ahmed e16048 El-Naggar, Adel K. 6009 El-Nashar, Amr 10044 El-Rayes, Bassel F. 6611, e14579, e14612, e14618, e15033, e15140 El-Refai, Sherif e13030, e19009 El-Sadda, Wael e12004, e18505 El-Serag, Hashem e17501 El-Sherify, Mustafa e12023, e17008 El-Tamer, Mahmoud 1019 El-Zeiny, Amany e14678 Elachy, Samar 3083, e22204 Elaidi, Reza-Thierry 5063 Elaschoff, Michael 7022 ELBolkainy, Tarek 4537 Elbouazzaoui, Samira 2597 Elder, David 9017 Eleftheraki, Anastasia G. e19048 Elegbede, Olusegun Elijah e12553 Elenitsas, Rosalie 9017 Elens, Laure 2597 Eleuteri, Anna Maria e15513, e15515 Elez, Elena e19002 Elfiky, Aymen 5016 Elgeioushi, Nairouz 7045 Elhaddad, Alaa 10044 Elia, Loredana 7025 Elia, Manana 1026 Elias, Adriana del Carmen e11538 Elias, Anthony D. LBA10507 Elias, Dominique 3642, e14534 Elias, E. George e20052 Elias, Ileana 9030 Elias, Ilena e20025 Elias, Laurence e15014 Elisei, Rossella 4, 6000 Elit, Lorraine 5515, 5586 Elizalde-Velazquez, Susana 10056 Elkhanany, Ahmed 7094 Elkin, Elena B. 6594 Elkiran, Emin Tamer e18560

Elkiran, Tamer e14705, e19107 Ellard, Susan 518, 5042 Ellchuk, Tasha 7596 Ellebaek, Eva 3028, 8084 Elledge, Richard M. 541 Ellenhorn, Joshua D.I. 3089 Ellershaw, John E. 9563 Ellingson, Benjamin M. 2055 Elliott, Catherine 564 Elliott, Michelle A. 7064 Elliott, Robert Lange 3087 Elliott, Tony 4511, 5002, e16069 Ellis, Carla 4523 Ellis, Catherine Elizabeth TPS664 Ellis, Georgiana Kehr 1090 Ellis, Ian O. 1016, e11608 Ellis, Leslie R. 2516^, e18002 Ellis, Matthew James 502, 526 Ellis, Peter G. 6643 Ellis, Peter Michael e19077 Ellis, Sarah Gabrielle 3018 Ellisen, Leif William 533, 2029 Ellison, David W. 2035 Ellison, Gillian e22035 Ellsworth, Susannah G. 4057, 9636, e15028 Ellwanger, Kristina 3068 Ellwood-Thompson, Rhianedd 11094 Elmashad, Nehal Mohammed e18505 Elmesidy, Salah Eldeen e11614 Elmore, Joann G 559 Elmquist, William F. 9048 Elser, Christine 1521 Elserafy, Mostafa M. e14624 Elshaikh, Mohamed A. e16552 Elsherief, Wessam e11614 Elson, Diane F e17025 Elson, Paul 2070, 2096, 4515, 7008, 8113, 9086, e13030, e13521, e15534, e15537, e16022, e19012, e19025 Elsoueidi, Raymond e14673 Eltaher, Ahmed M. e15505 Elter, Thomas 7015 Elting, Linda S. 6630, 6634 Elvin, Paul 8045 Elzinga, Grace 2082 Emadi, Ashkan 7049 Emami, Marjan 11057 Emanuel, Ezekiel J. CRA6510, 6518 Emery, Jon 1559, e20584, e20660 Emery, Lyndsey 1510 Emi, Akiko 11111, e22113 Emi, Yasunori e14633, e15158 Emile, George Adly e17514 Emile, George e15592, e20535, e22029 Emile, Jean Francois 3525^ Emile, Jean-François 10542, 10548 Emiloju, Oluwadunni 2576 Emmanouilides, Christos E. e15607 Emmert, Amy 7034 Emons, Guenter TPS11124 Emori, Fabiano e13003 Emoto, Shigenobu e15027 Emuron, Dennis Omoding e20685 Enane, Francis e15097 Encarnacion, Tiffany e11590 Enders, Sabine 3064

Endo, Itaru 1047, e22011, e22012 Endo, Masahiro 7572, 7582, 7599, e18556, e19050, e19074 Endo, Tateo 8006 Endo, Yumi 614 Endoh, Masaaki e15179 Enero, Catherine 3033 Enevold, Gina 6564 Eng, Cathy 3508, 3512, 3529, 3632, 4134, e22081 Eng, Charis 1527 Eng, Christine M. 10023 Eng, Kurt e13529 Eng, Lawson 4077, 9536, 9551, 9595 Eng-Wong, Jennifer TPS4150 Engel, Joerg TPS11124 Engel, Juergen 5062, e15596 Engel-Riedel, Walburga 8013 Engelhard, Herbert H. 2080, e13038 Engelhardt, Brian G. 8605, e19539 Engelhardt, John 3061, 9055 Engelhardt, Marc 2566 Engelke, Anja 7004 Engell-Noerregaard, Lotte 8084 Engelman, Jeffrey A. 8010, 8032, 8083 Engelstaedter, Verena 3064 Engenhart- Cabilic, Rita 6077 Engert, Andreas e13552, e13555 Englesbe, Michael 7044 English, Patricia A. 6041 Enjo, Kentaro 5046 Enk, Alexander e20028 Ennis, Marguerite 550 Enny, Christopher 8545, e19509 Enokida, Tomohiro e13586 Enomoto, Yasunori e19054 Enright, Katherine 6628, e17503 Enschede, Sari H. 7018, 8520 Ensor, Joe 601 Ensslin, Courtney J. e13571 Enting, Roelien H. 2050 Enzinger, Andrea Catherine 6529, 9519 Enzinger, Peter C. 4090 EO, Wankyu e15036 Eoli, Marica 2074 Eom, Bang Wool e15056 Epelman, Sidnei 10057, 10065 Epenetos, Agamemnon A. 2539 Epner, Elliot E. e18012, e19502 Eppink, Berina e13540 Epstein, Andrew S. TPS4144, 6508, e20586 Epstein, Joel Brian 6040, e20669 Epstein, Mara Meyer 5086 Epstein, Melinda 3527 Eradat, Herbert Aaron TPS7133 Erba, Harry P. 7028, 7104, 7126 Erban, John Kalil TPS1136 Erber, Ramona 1092 Ercolani, Cristiana e19052 Ercoli, Alfredo 5548 Erdal, Selnur B. 7542 Erdem, Dilek e11506, e14697 Erdem, Gokhan e15623, e18016 Erdem, Lale 2011 Erdkamp, Frans 557, 3502, e14586

Erdmann, Robert 7027 Eren, Tulay e14533, e15110, e15175, e18546, e20614 Erfán, Jozsef e12022^ Ergin, Melek e19512 Erho, Nicholas 4542, 5033, 5089 Erickson, Beth TPS4147, 5588, e15082 Erickson, Bradley J. 2014 Erickson, Heidi S. 8079, e19057 Erickson, Kelly e15001 Erickson, Nicholette 2006, 2051 Ericson, Solveig 7096 Eriksson, Barbro 4031 Eriksson, Mikael LBA10504 Erjavec, Zoran 3502 Erkol, Burcak e12037, e22061 Erlander, Mark G. 594, 4133, e11504, e15006, e15104, e15130, e19072 Erlichman, Charles 2551, 2562, 3539, 4032, 5517, 6587 Ermani, Mario 2021, 2048 Ermolenko, Natalya Aleksandrovna e12560 Ernst, David J. e19102 Ernstoff, Marc S. 4521, TPS4593 Erol, Edibe 5553 Eroles, Pilar e12019 Erridge, Sara LBA2009 Errihani, Hassan e15506, e16527, e20516, e20624 Errington, Julie 10033 Erskine, Courtney L. 521, 522 Ersoy, Ugur e11559 Ervin, Thomas J. 4005^, 4058^, 4059^ Esaki, Taito 3082, LBA4024, e15170 Esbah, Onur e15110 Escalante, Carmelita P. e20664 Escalante, Carmen 9642 Escalante, Lorena 7072 Escalon, Juliet e14517 Escara-Wilke, June TPS5094 Escherich, Gabriele 10017 Escobar, Elizabeth e15131 Escobia, Verula B. e14517 Escudero, Maria Jose e12513 Escudero, Pilar 3589, 4140, e14509 Escudier, Bernard J. TPS2622, 4574, 5075, 5088 Eser, Markus 3068 Eser, Mithat e18016 Esfandbod, Mohsen 7069 Eshaghian, Shahrooz 8598, 8599 Esiashvili, Natia 8546 Esin, E. C. E. e12563 Eslam pia, Kiumars e15195 Esler, Claire e21516 Esmailpour, Taraneh 7601 Espadaler, Jordi e13526 Esparaz, Benjamin 3600, TPS9651 Espat, Joseph 10538 Espat, N. Joseph 3079 Espenschied, Carin 1536 Espenschied, Jonathan R. 3089, 9575 Espie, Marc 547 Espin-Garcia, Osvaldo 1579, 9551, 9595 ABSTRACT AUTHOR INDEX

715s

Espinal Dominguez, Edward e14592 Espindle, Derek 9617, 9618 Espino, Guillermo 2547 Espino, Marc e16071 Espinosa Aunion, Ruth e12558 Espinosa, Enrique 608 Espinoza Venegas, Macarena Paz e20705 Espinoza-Delgado, Igor 2571 Espirito, Janet L. 9604, 9605 Esplin, Brandt L. e19096 Esposito, Assunta e20031 Esposito, Jason 7122 Esquerdo, Gaspar e20705 Essa, Hoda H. e15505 Essapen, Sharadah 5500 Esseltine, Dixie 8545, 8559, e19509 Esser, Regina 3630 Esserman, Laura 587, 3017, 6619, 6620 Essig, Stefan 10032 Essler, James e19015 Esteban, Emilio e15586, e18513, e19034 Esteller, Manel 2064, 3581, e14609 Esterni, Benjamin 566, TPS663 Estes, Judith e19519 Esteva, Francisco J. 601, 622 Esteve-Puig, Rosaura 9002 Esteves, Brooke 4513, 4564 Esteves, Jorge e15172 Estevez, Laura G. e11531 Estevez-Diz, Maria Del Pilar 5540 Estey, Elihu 7012, 7021, 7074 Estfan, Bassam N. e20572 Estiarte, Angels e13543 Estrada, John e12501 Estrada, Juan 11095 Estrada-Tejedor, Roger 11027 Esumi, Hiroyasu 2559, 7512, e19076, e22082 Etienne-Grimaldi, Marie-Christine 3596, 3606, e13519 Etminan, Mahyar e16013 Eto, Masatoshi 4526, 9623, e15588 Ettinger, David S. 7598 Ettl, Johannes 581, e20623 Ettrich, Thomas Jens 4034 Etxaniz, Olatz e13016 Etzioni, David 9034 Etzioni, Ruth D 1505 Etzl, Michael Matthew 10030 Eun, Jinny 1090 Eustache, Francis 9510 Evan, Caroline e16032 Evangelista, Andrea 8517 Evangelista, Rebecca e12531 Evans, Andrew 4568, e17589 Evans, Barrie David 5536 Evans, Colleen 4090 Evans, D. Gareth 5507^ Evans, Douglas B. TPS4147, e15082 Evans, Mark e15106 Evans, Matthew Stephen 622 Evans, Shelley TPS8617, TPS8618 716s

Evans, Steven S e13558 Evans, Steven e13562 Evans, T. R. Jeffry 2586, 4007, 9026, 9031, e11586 Evans, Tracey L. TPS7609, 9613 Evans, William K. 6550, e17531 Even, Caroline 10563 Eveno, Clarisse 3642 Evens, Andrew M. 8576 Everett, Jessica 1557 Evers, Stefan 3035 Everson, Richard Bernard 3639, e22211 Evgenyeva, Elena e14671 Evrard, Serge 3558 Ewer, Michael 526 Ewing, Amy L 7532 Exman, Pedro e13003 Exner, Ruth e11601 Extermann, Martine 9603, e20545 Extra, Jean-Marc TPS663 Extremera, Sonia 547 Eymard, Jean-Christophe LBA4500, 5075, e16021 Eysmans, Cabell 9011, 9056^ Ezendam, Nicole P. M. e16517 Ezzalfani, Monia 2577 Ezzeddine, Rana TPS8122

F Fabbri, Maria Agnese e12031 Fabbro, Michel 2020, 2067 Fabi, Alessandra 9614, e19052 Fabian, Carol J. 1026, 1515 Fabián-Morales, Eunice 4555 Fabiani, Bettina 8536 Fabre, Elizabeth e22001 Fabregas, Rafael e22119 Fabregat, Joan 4139 Fabrey, Robyn e13529, e13531 Facchinetti, Antonella e22036 Facchini, Gaetano 5050, e16031 Facchini, Thomas 6603, e11607 Facciabene, Andrea 3077 Fackenthal, James CRA1501 Facon, Thierry 8513, 8530, 8542, 8589 Factor, Rachel e13522 Fadel, Elie e18503 Faderl, Stefan 7024, 7074, 7089, 7092, 7095, 7102 Faedi, Marina 2048, e13007 Faez Garcia, Laura e14617 Fagin, James A. 6024 Fagundes, Marcio 7578 Fagundes, Renato Borges e15067, e15083 Faham, Malek 3020, 8511, 8601 Fahey, Thomas J. e14517 Fahlbusch, Melanie e16003 Faia, Kerrie 7070 Fain, Olivier 8536 Fainardi, Enrico 2048 Fairbrother, Wayne J. 2503 Fairfield, Kathleen 6536 Faivre, Sandrine J. TPS2622, 4118, 4127, 6036 Faivre, Thea 4041


Fakhrejahani, Elham e22116 Fakhry, Carole 6032 Fakih, Marwan 3089 Falato, Claudette e22126 Falchi, Lorenzo 7098 Falchook, Aaron David 5040 Falchook, Gerald Steven 1051, 2506^, 2598, 2604, 2611, TPS2619, 3103, 3507, 11086, e13575, e13591, e22086 Falchuk, Steven Charles 2006, 2051 Falci, Cristina 6593, e20541 Falcini, Fabio TPS1610 Falco, Esther 4098 Falcon, Silvia 4504 Falcone, Alfredo 1086, 3505, 3514, 3533, 3563, 3602, 3603, 3613, 3615, 3636, 3637, 4062, 11058, e14531, e14574, e14577, e20711, e22056 Falcone, John 1098 Falcone, Katherine L. 5563 Falconi, Adam 8040 Falcou, Marie-Christine 1533 Falge, Christiane 7051 Falk, Martin H. 7500 Falk, Stephen 3504, 4023, TPS4156 Falkowski, Slawomir e22046 Fall, Barbara 4507^ Falla, Juan Camilo e15123 Fallica, Giuseppina e11527 Fallowfield, Lesley e20514 Faloppi, Luca 3591, 4123, e14610, e15058, e15081, e15536 Faluyi, Olusola Olusesan 4077 Falzarano, Sara Moscovita 5029 Famooto, Oluranti Ayotunde 1576 Fan, Bingjie e15197, e18551 Fan, Boli e22159 Fan, Cheng 1011 Fan, Gilbert 9506, e20566 Fan, Jean 5520, 5591 Fan, Jia 3610, e22103, e22133 Fan, Kang-Hsien 6532 Fan, Katherine Y. 4039, e15028 Fan, Sheung Tat 4117 Fan, Xiaolin 7052^, 7054^ Fan, XinJuan 538 Fan, Ying 2614 Fan, You Hong 6011, 8104 Fan, Yun 8525 Fan, Zhongyi 5558 Fanale, Michelle A. 7045 Fanciullino, Raphaelle 7117 Fanelli, Marcello Ferretti e14638, e11503, e15184, e20640, e20644 Fanelli, Marcelo e14688 Fanetti, Giuseppe 3641, e14716 Fang, Fang 5038, 5060, 5080 Fang, Jens e12024 Fang, Lei 2536 Fang, Liang 644 Fang, Qin 7519 Fang, Sally 6619, 6620 Fang, Weijia e14530, e22192 Fangusaro, Jason R. 2101 Fanti, Stefano e15154, e18509 Fanton, Christie 7111 Faoro, Leonardo TPS1142^

Farace, Françoise Farag, Ahmad Farag, Kamel Faragher, Ian Faraj, Shiela F. Farasatpour, Michael Farber, Charles Michael

2535 e13025 4537 3598 4523 e17506 7086, TPS7133 Farber, James 1554 Fardanesh, Reza 6062 Fareau, Gilbert G. e17025 Fares, Basem e12029 Fares, Fuad e12029 Farfariello, Valerio e15513, e15515 Farges, Marie-Chantal e11552 Farhadfar, Nosha 599 Farhangfar, Carol J. e22081 Faria, Flavia Watusi e21001 Faria, Luciana Costa e15199 Faria, Luiza Dib e15090 Faria, Mariana 9634 Faricy-Anderson, Katherine E. 6574 Farid, Samar e14678 Faries, Mark B. 9101 Farina, Gabriella e12021 Farina, Patrizia 2043, e15606 Farinella, Eriberto 9557 Farioli, Andrea e15003 Faris, Jason Edward 4125 Farjah, Farhood 7546 Farley, John H. 5534 Farlow, Deborah Norman 9015, 11009 Farmakis, Dimitrios e18542 Farolfi, Alberto e11521 Farooq, Umar 3639, e22211 Faroux, Roger 3542, 3601 Farran, Leandre e15111 Farrant, Hannah 7595 Farrar, John T. 6560, 9639 Farre, Jose e22120 Farrell, Michael Anthony e13020 Farrell, Michael P. 1542, e12565 Farrell, Nicholas John TPS8119 Farrell, Steve 1520 Farrow, Katherine 5085 Farrugia, David e15085 Fartoux, Laetitia 4127, TPS4160 Faruki, Hawazin 11070 Farver, Carol 8113, 11091 Fasanmade, Adedigbo TPS3646, 10028 Fasano, Julie 606 Fasce, Hebe Margot 1073, 11118 Fasching, Peter A. 591, 640, 11042, 11043, 11061, e11525, e22075 Fasciolo, Antonella e20694 Fasola, Gianpiero 3631, e11565 Fassunke, Jana 1589 Fathallah, Hassana e13518 Fathi, Amir Tahmasb 3104 Fatigoni, Sonia 9614 Fattoruso, Silvia Ileana e15065 Faucette, Stephanie 2528, 2547 Faucheron, Jean-Luc 3596 Faure, Christelle 566 Fauster, Yvonne TPS1137 Fausti, Valentina e11573 Fauth, Florian W. B. 3531

Favaretto, Adolfo G.

8043, 11029, 11078 Favaretto, Adolfo e19148 Favier, Bertrand e16096 Favre, Veronique 2548, 2549 Favrel, Veronique e17011, e17012 Fawole, Adewale 6577 Fawunmi, David 1119, 1568 Fawzy, Ehab Esmat 9568 Fawzy, Maria R. e17560 Fayad, Luis 8523 Fayaz, Mohamed Salah e12023 Fayette, Jerome 6001, 6036, 6056, e17011, e17012 Fazio, Nicola 4136^, e15124, e15147 Fazio, Vito Michele 576, e14655 Fazli, Ladan e15590 Featherstone, D’Andra 10524 Febbo, Phillip G. 4520, 5003, 5006, 11053 Febbraro, Antonio 8071, e14565 Febbraro, Michela e17563 Febbraro, Terri 1545 Fechina, Larisa 10055 Feddersen, Isa 10017 Fede, Angelo Bezerra de Sousa 5540 Fedele, Palma 618, e14605, e18545 Federico, Federica e14605 Federico, Piera 7603, e18536, e21500 Federico, Sara Michele 10027 Federman, Noah TPS10591 Fedor, Helen L. 5027 Fedyanin, Mikhail e14674, e15583, e15585, e16509, e21510 Fee-Schroeder, Kelliann C. e17538 Feely, William 3003^, TPS3111, 9012^ Feeney, Amanda 5514 Fegely, Maryellen 5563 Feher, Olavo 2060, e13003 Fehm, Tanja N. 638, 640, 1030, 5598, e22075 Fehm, Tanja N. 591, 1020 Fehn, Karen 1118 Fehrenbacher, Louis TPS1139, 3501 Fehse, Boris 7027 Fei, Luo e22066 Fei, Zhou e19059 Feibelmann, Sandra 9534 Feigen, Malcolm e18559 Feigenberg, Steven J. TPS648, e22034 Feijoo, Margarita e12015 Feiler, Monica e13518 Fein, Daniel 8594 Fein, Luis e15610 Feinberg, Bruce A. 6553, 6629, e17579, e17581, e17582 Feinn, Richard S. 9620 Feisel, Gabriele 1082 Fekrazad, M. Houman e15136 Felch, Natalie 11047 Feld, Jordan J. 6592 Feld, Ronald 1579, 7526, e19031 Feldhamer, Ilan 639 Feldman, Arthur M. 6094 Feldman, Darren Richard 4501, 4534, e15517

Feldman, Eric Jay 7100 Feldman, Michael D 519, 1510 Feldman, Rachel 9609 Feldman, Tatyana A. TPS8612 Feldman-Moreno, Rebecca Anne 2041 Feldstain, Andrea e20598 Feldt-Rasmussen, Bo e20561 Felici, Alessandra e15524 Feliciano, Josephine Louella 2515 Felip, Enriqueta 1011, 2581, 4135, CRA8007, 8010, 8070, TPS8119, 11027, 11029, 11067 Felipe, Aledson Vitor e22074 Felismino, Tiago Cordeiro e20644 Feliu Batlle, Jaime e14648 Feliu, Jaime 3589, e14509, e15107 Feliubadalo, Lidia e12516 Felix, Gabriela Espirito Santo 1539 Feliz, Luis R 6072 Fellman, Bryan 6566, e16556 Fenaux, Pierre 7002 Fend, Falko 3098 Feng, Allen 4124 Feng, Amy 8589 Feng, Felix Yi-Chung 1025, 5033, 5089 Feng, Ji Feng 4109, 8016, 8061 Feng, Ji-Feng 8525 Feng, Jianguo e18520 Feng, Jifeng 1064, 7507 Feng, Mary Uan-Sian 10524 Feng, Ping bo e15030 Feng, Runhua e22169 Feng, Tao 9545 Feng, Weineng 8042 Feng, Yan 11091 Feng, Yang 10511, e14711 Feng, Yin-Hsun e17018 Feng, Zhenqing e22169 Feng, Ziding 5092 Fennell, Dean Anthony TPS8126 Fennell, Dean 7585, CRA8007 Fenner, Martin e16024, e16064 Fennessy, Fiona M. 9500 Fenske, Timothy S. 6586, 8505 Fenton, Mary Anne 619 Fenwick, Stephen W. 4132 Ferguson, Chad e21504 Ferguson, Daniel 2594 Ferguson, Mark K. 7535 Ferguson, Michelle 5571 Ferguson, Sarah E. 5508 Ferguson, Sarah E. 5543, 5561 Ferguson, Tomas e17547 Fergusson, Dean 6597 Ferlay, Celine 4574 Fermand, Jean-Paul 8545 Ferme, Christophe TPS8615 Fermer, Christian 5563 Fernandes, Donald J. e11588 Fernandes, Gabriela Carvalho e22154 Fernandes, Kimberley 1002 Fernandez Calvo, Ovidio e15620, e16014 Fernandez de Lascoiti, Angela e14589 Fernandez Montes, Ana 540 Fernandez Parra, Eva 4098, e16014

Fernandez Ribeiro, Francisca e14706 Fernandez, Anna 3629 Fernandez, Antonio e12020 Fernandez, Aranzazu e22200 Fernandez, Conrad Vincent 10066 Fernandez, Gustavo L. e15596 Fernandez, Marianna 3010 Fernandez-del Castillo, Carlos 4047 Fernandez-Landazuri, Sara 9074 Fernandez-Morejon, Francisco J. e22120 Fernandez-Serra, Antonio 1543 Fernando, Hiran Chrishantha 7502, 7524 Fernando, Indrajit Nalinika 5 Ferrajoli, Alessandra 7098, 7102 Ferraldeschi, Roberta 5052 Ferrand, Christophe e13519 Ferrand, Francois-Regis 6079 Ferrandina, Gabriella LBA5501, e16538 Ferrante, Pasquale 3056 Ferrara, Pasqualinda e14605 Ferrara, Raimondo e14557 Ferraresi, Virginia 9070, 9548, 10516, e21517, e22206 Ferrari, Alessia e11515 Ferrari, Andrea TPS9104 Ferrari, Daris 6003, e14557 Ferrari, Stefano 10568, 10571 Ferrari, Teresa Cristina de Abreu e15199 Ferrari, Vittorio D. e15148, e15524, e15615 Ferrario, Cristiano e11521 Ferraris, Gustavo Alberto e13036 Ferraro, Danielle Angela 4081 Ferraro, Giuseppa 1062 Ferraú, Francesco e11526, e19084 Ferreira, Arlindo 9634 Ferreira, Carlos G. M. 6071, e14568 Ferreira, Carlos Gil Moreira 1587, e18515 Ferreira, Elza Maria de Sa 6071 Ferreira, Iza e22085 Ferreira, Monica e19069 Ferrero, Jean-Marc 510, e13519 Ferretti, Benedetta e11616 Ferretti, Vincent 11016 Ferri, Lorenzo e15034, e15044 Ferris, Andrea Stern e20618 Ferris, Robert L. 3099, 6005, 6043, 6051 Ferro, Antonella 1086, e11569 Ferroni, Fabio e15069 Ferroni, Patrizia e14581 Ferru, Aurelie 3513, 3536 Ferrucci, Leah M. e20017 Ferrucci, Pier Francesco 9035, 9070, e20025 Ferry, David 3500, 3573, 4000 Ferry-Galow, Katherine V. e22080 Ferte, Charles 3010 Ferzi, Antonella e19084 Fesl, Christian 506 Fesler, Mark e20049, e20661 Festa, Joanne e20701 Fetterly, Gerald J. 2557, 2594, e13505

Fetzer, Dominique 1538 Feusner, James Henry 10037 Feyer, Petra C. 1121 Fiacchi, Paola e13579 Fiala, Mark 9559 Fiala, Ondrej e15581 Fialova, Anna e16002, e22129 Fiammenghi, Laura 3040 Ficarra, Guido 530, 556 Fichtenholtz, Alex e22146 Ficorella, Corrado e14596 Fidias, Panos 2524 Fidler, Mary J. e19113, e19117, e22130 Fiduccia, Pasquale 5548, 6593, e15606 Fiederlein, Barbara e20641 Fiedler, Walter M. 7027 Fiedler, Walter 3008 Fiehn, Oliver 11112 Field, Amanda 10024 Field, Kathryn Maree 2017, e14608 Field, Kathryn M. 3584, e14583, e14640 Field, Megan 6063 Fielding, Anitra 4013, 5505, 11024 Fields, Alan P. 2551 Fiets, W. Edward 3036 Fife, Kate 7595, 9503 Figarella-Branger, Dominique 2067 Figg, William Douglas 2527, 4543, TPS4589, TPS5095, TPS5102, 10588, TPS10595, e15177, e16017 Figlin, Robert A. 4571, e17507 Figueiredo, Jose Marcio Barros e15190 Figueredo, Alvaro Tell 3548 Figueroa Carbajal, Jose de Jesus 10056, 10058 Figueroa, Angelica e15532, e22021 Figueroa, Barbara e20640 Figueroa, David J. 3021 Figueroa, Jose A. 7060, 8591, e18527, e22003, e22052 Figueroa, Juan D. e12571 Figueroa, Santiago e22147 Filali, Taha e19063 Filardi, Bruno e15190 File, Danielle M. 8090, e17594 Filho, Elias Abdo 5540 Filiberti, Rosangela e12518 Filicko, Joanne e17577 Filidei, Elena e14531 Filidei, Mario 1086 Filipenko, Maxim Leonidovich e12560 Filipits, Martin 506 Filipovic, Lana e22115 Filippetti, Massimo e19052 Filkins, Richard e18539 Finch, Clarence 9611 Finch-Jones, Meg 3504 Finckenstein, Friedrich Graf TPS8121 Fine, Bernard M. 5020 Fine, Gregg Daniel 3000, 3001, 3622, 4505, 8008 Fine, Robert Lance 4040^ Fine, Samson 5027 ABSTRACT AUTHOR INDEX

717s

Fineberg, Susan 1118 Finelli, Antonio 4568, 5070 Fingert, Howard 2598 Fink, Anna-Maria 7015 Finkel, Kevin e15551 Finkelman, Brian S. e17591 Finkelman, Richard D. 4511 Finkelstein, Dianne M. 628, TPS662 Finkelstein, Steven E. 5034 Finkenzeller, Charlotte e22059 Finkler, Neil TPS5616 Finlay, Esme 6529, e20606 Finlay, Jonathan L. 2049 Finley, David J. 7570 Finn, Laura Elizabeth 7047 Finn, Richard S. TPS652, 1054, TPS4159, TPS4163 Finnes, Heidi D. 2596, e20024 Finney, Joseph D 9559 Finnigan, Helen 4506 Finniss, Susan 2073 Finocchiaro, Gaetano 2074 Fioravanti, Anna 3602, 3603, e14577 Fioravanti, Suzanne 2532, e15177 Fiore, Francesco e15061 Fiore, Louis 6562 Fiore, Marco 10519 Firouzbakht, Aryan e14607 Firvida, Jl 7549 Fisch, Karin e22112 Fisch, Michael 3600, e20520 Fischbach, Neal A. 4084 Fischer von Weikersthal, Ludwig LBA3506 Fischer, Andrew e17014 Fischer, Anja 10007 Fischer, Jurgen R. 8001 Fischer, Kersten e22055 Fischer, Kirsten 7004, 7015 Fischer, Patricia 4534 Fisher, Barbara Jean 2008, 2033 Fisher, Brenda 2518 Fisher, Cyril 10569 Fisher, David 3509, TPS3645, 9080 Fisher, Gabrielle 5005 Fisher, George A. 3622 Fisher, Jennifer C 4522 Fisher, Joy D. 2044, TPS2105 Fisher, Kate 3644, 10556 Fisher, Micah 7035 Fisher, Michael J. 10021 Fisher, Paul Graham 10046 Fisher, Richard I. 8562 Fisher, Richard 9001 Fishkin, Paul A. S. e17590 Fishman, Elliot K. 4039, 4057 Fishman, Marc L. 1080, e11609, e12034, e14646, e19130, e20672, e20697 Fishman, Paul Arthur 6018 Fishman, Val 1080, e11609, e12034, e14646, e19130, e20672, e20697 Fiskus, Warren 11107 Fitch, Margaret 9571 Fitchett, George 9573 Fite, Charlotte e20032 Fitz, Anne 9638 Fitzal, Florian 573, e11601 718s

Fitzgerald, Natalie 6550 Fitzgerald, Timothy Louis e14635 Fitzpatrick, Frances e15566 Fizazi, Karim LBA4500, LBA4509, 5002, 5009, 5010, 5013, 5037, 5049^, 5065, 5075, 5079, 5088, TPS5093, TPS5097, TPS5098^, TPS5103, 9628, 9640 Flacco, Antonella e22155 Flahavan, Evelyn M 5084 Flaherty, Amber Lea 4541, e15544 Flaherty, Keith 533, 2500, 9005, 9010, 9015, 9016, 9020, 9026, 9028, 9029, 9058, 9064, 9066, 9076, 9094, e15564, e17570, e20050 Flaherty, Lawrence E. CRA1008, TPS9103 Flaig, Thomas W. 4504, 5059, e16055, e17510 Flamiatos, Jason Frederick 5017 Flamm, Anne Lederman 6500 Flanagan, William M. 6550 Flanders, Aaron W. 8597, e19506 Flanders, Vincent e14698 Flatmark, Kjersti 3547 Flauti, Giuseppe e22037 Flavin, Marisa 9019 Flechl, Birgit 2078 Flechon, Aude LBA4500, 5002, 5063, e16096 Fleck, Ullrich e14513 Fleckenstein, Jochen 1121, 8566 Fleige, Barbara 1020 Fleisher, Linda 6500 Fleisher, Martin 5030, 5032, 5083, 5550, 7508, e16005 Fleishman, Stewart Barry e20607 Fleitas, Tania 2522 Flejou, Jean-François 3524 Fleming, Gini F. 1024, 2584^, 5517, 5534, 11101 Fleming, Jason B. e22012 Fleming, Margaret E. 3044 Fleming, Mark T. 5018, 5066 Fleming, Martin D. 9042 Fleming, Nathaniel H. 9021, 9023, 9054, 9067 Fleming, Nicole Dierschke 5596 Fleming, Steven 6558, 6606 Fleming, Timothy 633 Flensburg, Mimi F 3551, 6002 Fleshner, Neil Eric 4568, 5007, 5070 Fletcher, Jonathan A. 10509, 10510 Fletcher, Kalen Michele 9521 Fletcher, Robert H. e19065 Fleten, Karianne Giller 3547 Flickinger, John Charles 7553, e18506, e18552 Flinn, Ian 7003, 7005, 7017, 7063, 7070, 7086, TPS7131, 8500, 8501, 8502, 8518, 8519, 8526, 8537, 8559, 8565, e19518 Flint, Melanie S 6051 Flood, William A. 6515, e17565 Floquet, Anne LBA5503, 10505 Florea, Ana-Maria 2081 Florence, Lachenal e19515 Florendo, Erika Ocampo e20549


Flores Gutierrez, Juan Pablo e14708 Flores Stella, Rebecca e17507 Flores, Aurea M. e15596 Flores, Claudio J. e12566, e12570, e19538, e22165 Flores, Claudio J. e12538 Flores, Eileen 9018 Flores, Jacklyn J. e20645 Flores, Ludmila 6088 Flores, Raymundo e12538 Flores, Ronald A. 9622 Florescu, Marie e22159 Florián Gericó, Jesús e12015 Floriani, Irene 6003, LBA8005, e14611 Floris, Giuseppe 10573, e13528 Flowers, Christopher 7035, 7086, 8546, 8559, 8609 Flowers, Dale 6094 Flyger, Henrik 1110 Flynn, Joseph M. 7077 Flynn, Michael 2566, 2585 Flynn, Patrick J. 2014, 3539, CRA9003, 9533 Foa, Paolo 6003 Foa, Robin 7025 Focan, C. N. J. 3599, 3606 Foekens, John A. 11045, e22106 Foerster, Frank Gerhard 602 Foerster, Robert e15574 Fogelman, David R. 4031, 4064 Fojo, Antonio Tito 2527, TPS3127, 6074, e14592, e17555 Fojo, Tito 4585, TPS5104, e22213 Folbrecht, Jeanelle 9575 Folch, Erik 8050 Folio, Les TPS4589 Folkert, Michael Ryan 9501 Follows, Sarah 2609 Folprecht, Gunnar 3525^, 3538 Foltran, Luisa 641 Fong, Lawrence 3020, 5077 Fong, Peter C. C. 5536 Fong, Yuman 3558, 3609, 4116 Fonseca, Emilio e22058 Fonseca, Fernando Affonso e20601 Fonseca, Fernando L. A. e16030, e16058 Fonseca, Leonardo Gomes e20691 Fonseca, Rafael e19517 Font, Albert TPS5099^ Fontaine, Karine e14600 Fontaine-Bisson, Benedicte e12522 Fontana, Andrea 576, 1086, 6593 Fontana, Annalisa 3517 Fontana, David TPS3109, TPS3112 Fontana, Valeria e17548 Fontana, Vincenzo 11063 Fontanals-Cirera, Barbara 9091 Fontanini, Gabriella 3563, 3613, 11066 Fonte, Joseph M. e17574 Fontein, Duveken e22152 Fontenay, Michaela 7002 Fontes Jardim, Denis Leonardo 2509 Fontes-Borts, Lucia e15095 Foo, Yu Lee 6589 Foote, Robert Leonard 6095

Foran, James M. 7046, 7047, 7104 Forastiere, Arlene A. 6006, 6016, 6028, 6081, 6515, e17565 Forbes, John F. 529 Force, Seth 2610 Force, Thomas 5061 Forcignano, Rosachiara e11517 Ford, Daniel LBA5000, TPS5099^, e16048 Ford, Hugo 4023 Ford, James M. 1003 Ford, Jennifer 10019 Ford, Jo-Ann e15084 Ford, Laurie Ann e18018 Ford, Leslie 1516 Forde, Patrick M. 7598 Foreman, Nicholas K. 10030 Forenza, Salvatore 517 Forer, David 5065, 5066 Forero, Andres 623, 3057, 7045 Forero-Torres, Andres 527, 1052 Forestieri, Valeria e11528 Formaker, Carl 5077 Forman, Andrea 1538 Forman, Stephen J. TPS3105^, 8556 Formenti, Silvia TPS3122 Formenti, Sylvia 1042 Formento, Jean-Louis 3596 Formento, Patricia 3596 Formica, Vincenzo e14581 Formiga, Maria Nirvana Cruz e14638 Fornara, Paolo e22055 Fornarini, Giuseppe e15615 Fornaro, Lorenzo 3615 Fornecker, Luc e17543 Fornier, Monica Nancy 606 Forones, Nora Manoukian e22074 Foroughi, Nasim e20578 Fors, Darron H e20044 Forsberg, Goran 3073, 5081 Forschner, Andrea e20050 Forslund, Ann 8530 Forstbauer, Helmut 640, TPS1137 Forster, Kenneth 7501 Forster, Martin 2566 Forsyth, Peter A. J. 2039, e13024, e13026 Forsythe, Laura Pence 9594 Forte, Carla 2589 Fortenbery, Nicole e13024 Fortin, Bernard e19115 Fosko, Scott e20049, e20661 Foss, Francine M. 7070, 8507, 8518 Fossa, Sophie D. 4536, 4562 Fossaa, Sophie D. 5533 Fossella, Frank V. TPS8118, 11044 Foster, Nathan R. 2562, 7510, 11119 Foster, Richard 4554 Foster, Rosemary 5578, e13564 Foster, Tanina e20646 Foszczynska-Kloda, Malgorzata 604 Foti, Silvia LBA8005 Fotiou, Chariklia e11576 Fotopoulou, Christina 5553, 5562, 5593 Fotuño, Maria Antonia e19112 Fouad, Mona 6559 Fougeray, Ronan 4524, 4539 Foukakis, Theodoros e22126

Fouladi, Maryam 2035, 2036 Foulkes, William 1552 Foulon, Stephanie 10518 Fountas, Leanne M. 8036 Fountzilas, George 582, 1093, LBA4509, 4558, 6012, e19048 Fouret, Pierre 7515 Fourneau, Nele 8502, 8530 Fournel, Pierre e19060 Fournier, Charles 10525 Fournier, Keith F. 4134 Fourrier-Réglat, Annie e14514, e14542 Fowler, Ashley 1123 Fowler, Floyd Jackson 6518 Fowler, Nathan Hale 7017, 8500, 8501, 8523 Fowler, Sarah 4584 Fox, Bernard A. TPS3110 Fox, Edward A. TPS2627 Fox, Gerard B. 2520 Fox, Jennifer e20646 Fox, Josef J. 5073, 5090 Fox, Kevin R. 519 Fox, Nicholas 522 Fox, Patricia S. 9096 Fox, Peter 543 Fox, Richard e15093 Fox, Susan 8535 Foy, Patrick C. 6586 Fra, Joaquin 10523, e18513 Fraboulet, Gislaine e19078 Fracasso, Paula M. 3077, TPS3121, 6021 Fraccon, Anna Paola 9554, e13514, e15512, e15514, e16078 Fradet, Yves 3639, 5009 Fradique, Antonio Caldeira e15172 Fragou, Archontoula e12524 Fraisse, Jean 1114 Fralick, Michael e11597 Fram, Robert J. TPS4148 Frampton, Garrett Michael e22146 Frampton, Jonathan Mark e22164 Franasiak, Jason 5523 Franceschetti, Benvenuto e20647 Franceschi, Enrico 2021, 2048 Francesco, Michelle 7014 Francescutti, Valerie e20573 Franchina, Tindara 1062, e19086 Francia di Celle, Paola 2084 Francis, Adele TPS656 Francis, Jennifer e15123 Francis, Prudence A. e20536 Francisco, Federico R e13558 Francisco, Federico e13562 Francisco, Liton 9570 Franckena, Martine e16504 Francl, Mia Ivy 1102, 9542 Franco, Daniela e12031 Franco, Fernando e19532 Franco, Rebeca 6640, e16551, e17592 Franco, Renato 11037 Franco, Silvia 1509 Francois, Eric 3601, e14514, e14542 Frank, Elizabeth S. e17574 Frank, Joseph 2018 Frank, Russell e14615 Frank, Stephen Jay e16023

Frank, Steven J. 5069 Franke, Fabio A. 10506 Frankel, Arthur E. TPS3105^, 7029^ Frankel, Eitan S. 6610 Frankel, Paul Henry 1024, 2018, 2526, 2564, 4571 Frankfurt, Olga TPS3105^ Franklin, Wilbur A. 8019, 8085, e18032 Franko, Jan e17599, e20714 Frantal, Sophie 9024 Frantsiyants, Yelena e13042, e20005, e22022 Frappaz, Didier 2020, 10026 Fraser, Alison M 1582 Fraser, Danyelle 9507 Fraser, Graeme A e17525 Fraser, James W 3104 Fraser, Lindsay 5507^ Frassineti, Giovanni Luca 3517, e14512, e15055 Frassoldati, Antonio 530, e11547, e11550, e14557 Frati, Paola 9092 Fratino, Lucia e16078 Frattini, Mark G. e15059 Frattini, Milo e14536 Frauchiger, Anna L. 9025 Fraumeni, Joseph F. 4536 Frazee, Diane 6094 Frazier, A. Lindsay 10010, 10011, 10036, 10054, 10061 Frébourg, Thierry 1528, TPS1607, e14596 Frechen, Sebastian 8112 Frederick, Dennie T. 9015 Frederick, Peter J. 5574 Fredlund, Paul TPS2621 Fredman, Elisha T. e15015 Freedland, Stephen J. 5005 Freedman, Amy e14656 Freedman, Andrew N 6562 Freedman, Matthew 4570 Freedman, Rachel A. 513, 616 Freedy, Shoaib 11081 Freeman, Arnold e13029 Frega, Giorgio e15003 Frei, Karl 2081 Freiberger, Anja 9612 Freier, Eva e15055 Freire, Javier 540 Freire, Joäo Geraldes e15118 Freitas, Daniela 5540, e14590 Freitas, Helano C. e15184, e20640, e20644 French, Jena TPS6100 French, Pim 2011 Frenkel, Eugene P. 8088^ Frenken, Bettina e22201 Freshwater, Tomoko 5518 Freter, Carl e22195 Freudensprung, Ulrich 5541, 5542, 5544 Frey, Noelle V. TPS7132 Freyer, David Robert 10020 Freyer, Gilles TPS2625, 5547, e13594 Frezza, Anna Maria e21516 Friard, Sylvie e19058 Friberg, Gregory R. 2071 Friberg, Lena E. 2597

Friccius-Quecke, Hilke 3078, 5582 Frick, Kevin D. 6515, e17565 Frickhofen, Norbert e17021 Fridman, Evgeniya e21508 Fridrik, Michael A. e15041 Fried, Georgeta 11024 Friedberg, Jonathan W. 8502 Friedenreich, Christine TPS3647 Friedl, Thomas W. P. 638, 11042, 11043, e22059, e22075 Friedlander, Michael LBA5503, 5505, 5542, TPS5614, 9602, 11024 Friedlander, Philip 3014, 9080 Friedlander, Terence W. TPS2623, 5077, 11048 Friedman, Allan H. 2094, e13015^ Friedman, Danielle Novetsky 10019 Friedman, Debra L. 9609, e20523 Friedman, Eitan 1552 Friedman, Ellen 7125 Friedman, Henry S. 2090, 2094, e13015^ Friedman, Lori 2613, e13528, e13570 Friedman, Paula N. 6501, 11053 Friedmann, Alison M. 10001, 10002 Friedrich, Franziska LBA2000 Friedrich, Katja 591 Friedrich, Tobias 3090 Friedrich-Medina, Paola 10011 Friend, John TPS9649 Friend, Julia C. 4584 Frierson, Ethel Linda e20677 Friese, Christopher Ryan e20511 Friese, Klaus 638, 1121 Friess, Martina 7587 Frigeri, Ferdinando 8564 Frigerio, Simona 9092 Frisbee-Hume, Susan 9611, 9642, e20528, e20581 Fritsch, Cornelius 3075 Fritschel, Elyse e12010, e14689, e19122 Frizziero, Melissa e15057 Frolova, Mona e12027 Froment, Marie-Anne 5605 Frueh, Martin 3503, 7503, 8060 Fruehauf, John 9082 Fruehwald, Michael 10017 Frumovitz, Michael M. e16556 Fruth, Briant 5517 Fry, Dennis G. 1087 Frye, Carla B 6627 Fu, Binyu e16520 Fu, Haian 2610 Fu, Jack Brian e20626 Fu, Jianhua e15135 Fu, Mei R. e20558 Fu, PingFu 7036, 8114 Fu, Robert 2610 Fu, Rochelle e13001 Fu, Siqing 2506^, 2545, 2611, TPS2619, 9544, 11086, e13534, e13575, e13591, e22086 Fu, Tommy 8533, 8534 Fu, Xiang-Ning 1547 Fu, Yali 8063 Fu, Yan 5558, e19044 Fu, Zheng e13052, e15197 Fucek, Ivica 3068

Fuchs, Charles S. 1531, 3533, 4000, 4022 Fuchs, Ephraim Joseph 7009 Fuchs, Eva-Maria 622 Fuchsmann, Carine e17011, e17012 Fucikova, Jitka 3076, e16002 Fuente, Natalia e13000, e14628, e14712 Fuentes, Maria Belen e21512, e22060 Fuereder, Thorsten e16042, e20693 Fuerst, Sophie 5531 Fuertes, Carmen TPS3111 Fuhr, Uwe 8112 Fujibayashi, Mariko e12026 Fujieda, Shinji e14510 Fujii, Masato 6004 Fujii, Masazumi e13012 Fujii, Satoshi 1113 Fujii, Takeo 9629 Fujii, Tsutomu e14614 Fujii, Yoshitaka 614 Fujimori, Masamoto 2501 Fujimoto, Chinatsu e15170 Fujimoto, Daichi 8098, e19045 Fujimoto, Hiroshi 1097 Fujimoto, Hiroyuki 4526 Fujimoto, Junya 2601, 8104 Fujimoto, Noriko 8111 Fujioka, Hikaru e11605 Fujioka, Hiroya TPS1140 Fujioka, Rumi 2559 Fujisaka, Yasuhito e13501, e20004 Fujisawa, Masato e15588 Fujisawa, Tomomi TPS654, 6588 Fujisue, Mamiko e11557, e13536 Fujita, Masami 5538 Fujita, Shin e14555 Fujita, Shiro 8098, e19017, e19045 Fujita, Takashi e12001 Fujitani, Kazumasa e15016 Fujitani, Sumiaki e13500 Fujiwara, Hiroshi 8506 Fujiwara, Hiroyuki 5552 Fujiwara, Keiichi LBA5503, 5506, 5593, 5602, e16548 Fujiwara, Kimiko 9621 Fujiwara, Kiyoshi 5528 Fujiwara, Michitaka 4088 Fujiwara, Toshiyoshi e13577, e15161 Fujiwara, Yasuhiro e20557 Fujiwara, Yoshiro e19023 Fujiwara, Yutaka 7540, 8064, e13511 Fukada, Ippei e11587 Fukuda, Haruhiko 4104, TPS4152, 5537 Fukuda, Masaaki 8006 Fukuda, Minoru e19016 Fukuda, Takeshi e20676 Fukuda, Yasushi e19040 Fukuhara, Suguru 8551 Fukui, Motonari 11041 Fukumoto, Shinichi e19142 Fukumura, Dai 2056 Fukunaga, Masao e20510 Fukunaga, Mutsumi e14551 Fukuoka, Junya 7529 Fukuoka, Kazuya 7583 Fukuoka, Masahiro e20682 ABSTRACT AUTHOR INDEX

719s

Fukushima, Hiraku

3638, e14527, e14604 Fukushima, Hirofumi e17006 Fukushima, Masanori e16090 Fukushima, Masaori 6004 Fukushima, Nobuaki e13520 Fukushima, Norimasa 4072, 4104 Fukushima, Ryoji LBA4002 Fukutake, Nobuyasu e15150 Fukutomi, Akira 4008, e14623, e15031, e15116 Fukuzaki, Tomoharu 8551 Fulcher, Gingi e20651 Fulk, Monica TPS11123 Fuller, Alice 3500 Fuller, Courtney 6539 Fuller, Greg 2063 Fuller, Gregory N e13044 Fuller, Timothy e14641, e18501 Fuloria, Jyotsna 9513 Fulp, William J. 6531, e15075 Fumagalli, Debora 3012, 11003 Fumagalli, Elena 10500, 10576 Fumagalli, Luca 617, 1595 Fumagalli, Monica 589 Fumarulo, Valeria Vincenza 5559 Fumoleau, Pierre 11007, e11529 Funahashi, Yasuhiro 5520, 5591, 9058 Funakoshi, Taro e14623 Funakoshi, Tomohiro e15580 Funel, Niccola 4062 Funez, Rafael e22091, e22131 Fung, Christina e11597 Fung, Chunkit 9549 Fung, Gordon TPS2623 Fung, Henry C. e18013 Fung, Sharon 6550 Funke, Jennifer M. 2529 Funke, Roel Peter 4505, e14505 Fuqua, Suzanne A. W. 579, 592, 593, 596, e11535, e11543 Furet, Jean Pierre e14525 Furini, Lara e17551, e20617 Furlong, Terry 7006 Furman, Richard R. 7003, 7014, 7017, 8500, 8519, 8526, TPS8619 Furness, Andrew James Scott 3036 Furniss, Debra TPS4156 Furukawa, Hiroshi 4072, e14551, e14601 Furukawa, Hiroyuki 3006 Furukawa, Katsunori 4056 Furuse, Junji 4120, 4126, e15031, e15116, e20004, e20576 Furuta, Akihiko e12532 Furuta, Koh 7540 Furutani, Takashi 5046 Furuya, Kenichi e16519, e21520 Fury, Matthew G. 6024, 6034, 6048 Fusayasu, Hideo e16098 Fusco, Juan Pablo e19106, e19114 Fusco, Vittorio e14657, e20694 Fuse, Nozomu 4075, e13500, e13510, e14527 Fuster, Jose 4140, e13016 Futagawa, Shunji e14651 720s

Futreal, Andrew Fuwa, Nobukazu Fuxius, Stefan

10577 6086 4035

G G, Pulido e14559 Gaafar, Rabab Mohamed 7584, 7585, e19035 Gaba, Colette e12016 Gaba, Lydia e14588, e17580 Gaboury, Louis 1018, 4060 Gabra, Hani 2576, 5562 Gabrail, Nashat Y. 7109, 7110, e15014, e20518 Gabram, Sheryl G. A. 562 Gabriel, Stacey B. 9015, 11009 Gabrielson, Edward TPS1144 Gabrilove, Janice Lynn 7126, 8579, e20570 Gabrin, Michael J 7532 Gadaleta, Cosimo e11502 Gadaleta, Cosmo D. e15061 Gadaleta, Cosmo Damiano e22104 Gadaleta-Caldarola, Gennaro e15061 Gade, Stephan 11061 Gadea, Neus 1509 Gadgeel, Shirish M. 2524, 7561, 8001, 8105, 8114, 11109, e13030, e19009 Gadi, Vijayakrishna K. 1090 Gadinsky, Naomi e12503 Gaffey, Sarah C. 2013, TPS2104 Gaffney, David K 5588, e16091 Gaffory, Cécile e16089 Gafter-Gvili, Anat e20595 Gage, Brian e17546 Gagliato, Debora De Melo 1022 Gagne, Havaleh Marie e20509 Gagnier, Paul TPS5093 Gagnon, Dennis D. 9617 Gagnon, Dennis 9618 Gagnon, Robert C. 3021, 4042 Gahramanov, Seymur e13001 Gaiger, Alexander 2078 Gaillard, Isabelle TPS8615 Gainor, Justin F. 8083 Gaion, Fernando e15512 Gaiter, Timo e14702 Gajate, Pablo e16543 Gajavelli, Srikanth 8097 Gajewski, Thomas 3025, TPS3110, TPS3114, CRA9003 Gajjar, Amar J. 2035, 10021 Gajra, Ajeet 6059, 7538, 7539, 9545 Gajria, Devika 606, 11076 Gal, Anthony A 2610, 7560 Galais, Marie-Pierre 3601 Galán, Maica 4098, e15111 Galani, Eleni P. 4558 Galanis, Evanthia 2014, 2046, e13516 Galanos, Anthony N. e20674 Galateau-Salle, Francoise 7515, 8100 Galbán, Craig J. TPS5094 Galdermans, Daniella 8063 Galdon, Guillermo e16071 Galetta, Domenico 8071


Galiauskas, Raimundas 3627 Galibert, Virginie 1528 Galicier, Lionel 8524 Galimberti, Viviana 589 Galimi, Francesco 11005 Galinski, Ilene 7050 Galizia, Danilo 10552, 10583 Gallach, Sandra 11073, e22147 Gallagher, Christopher J. 1015 Gallagher, David J. 1542, e12565 Gallagher, Jacqueline 5595 Gallagher, Loretto e20550 Gallagher, Maryann 519 Gallagher, Meghan e15046 Gallagher, Olive e20505 Gallagher, Sarah A. e15595 Gallamini, Andrea TPS8612 Gallani, Maria Laura e13579 Gallardo Martin, Elena e14706 Gallardo, Enrique 4550, 4560 Galle, Peter Robert TPS3124^, 4086 Gallego Perez-Larraya, Jaime 2028 Gallego, Javier 4098 Gallego, Oscar 2087 Gallegos Sancho, Isabel e12020 Gallegos, Marc 11056 Gallenstein, Donna 9011 Galli, Andrea 3056 Galli, Luca 9065, e20711 Galliano, Marco e14657 Gallick, Gary E. e16038 Gallie, Brenda L. 4568 Galligioni, Enzo 5050, e11569, e13046, e15524, e16031, e16078 Gallinger, Steven 4049, 5508, e14573, e15087 Gallmeier, Eike e13540 Gallo, Ciro LBA5501, 8066, e19031 Gallo, Giacomo e20562 Gallo-Stampino, Corrado 4121, 11031 Galmarini, Carlos 5566 Galrisa Neto, Isabel e20708 Galsky, Matt D. 4524, 4525, 4539, 4551, 4563, 5015, 6540, 6613, e15549, e15555, e15580, e16032 Galun, Eithan 4037 Galuppo, Sara 2043 Galuska, Stefan 11059 Galvan Salazar, Gabriel e15186 Galvan, Patricia 1011 Galvin, James M. 7523 Galvin, Katherine e13529 Galvin, Shelley L e20648 Gambacorta, Marcello TPS3648, 11005 Gambacorti-Passerini, Carlo 7048, 7099 Gambara, Guido 5560 Gambaro, Alessandra 3581 Gambarotti, Marco 10571 Gamberi, Gabriella 10571 Gambhir, Sanjiv Sam 11006 Gambino, Abbondanza e11517 Gamble, S. Ellen 10042 Gamblin, T. Clark 9507 Gamboa-Dominguez, Armando e14703, e15186

Gamboni, Alessandro 2021 Gambotti, Laetitia e17023 Gamelin, Erick 3601 Gámez-Pozo, Angelo 608 Gammaitoni, Loretta e14654 Gammon, Guy 7012, 7021, 7023 Gamucci, Teresa 4091, 5050, e12021, e12031, e16031, e20619 Gamulin, Marija e15509 Gan, Hui Kong 2520, 2583 Ganchev, Boian 2588 Gandara, David R. 1024, 2526, 2564, 2569, 5517, 7510, 7511, 7527, 8026, 8027, 8028, 8049, 8097, 8110, e19147 Gandhi, Ajeet K e13014, e13034 Gandhi, Arpita 1602 Gandhi, Arun e15120 Gandhi, Jitendra G. e15014 Gandhi, Leena 2500, 2530, 8008, 8030, 8116, TPS8124 Gandhi, Sonal 6585, e17526 Gandini, Sara 1061, 1516, e20634 Gane, Ed 4118 Ganee, Laurence e20030, e20038 Ganem, Gerard 6603 Ganesan, Arun Kumar e17002 Ganesan, Prasanth 2604, e17554 Ganesan, Shridar 1091 Ganev, Tosho 3073 Gang, Wu 6026 Gangadhar, Tara C. 2571, TPS3107, 9009, 9088 Gangadharan, Sidharta P. 8050 Gangoli, Vinay e17560 Gangolli, Esha A. 2528, 2547, 2567 Gangopadhyay, Sudeshna 7085, e16542 Ganguli, Sushila 2566 Ganguly, Arupa e15563 Ganguly, Manomoy 1099 Ganini, Carlo 4575 Ganji, Purnachandra Nagaraju e14618 Ganju, Vinod 4059^, 4081, 5079 Gann, Claudia-Nanette e19126 gannard Pechin, Elsa 1122 Ganser, Arnold 7027, e16024, e16064 Gansert, Jennifer L. e13525 Ganta, Ranga Raman e18003, e19533 Ganten, Tom M. e15088 Ganti, Apar Kishor 1570, 7538, 7539, 7571, e22048 Gany, Francesca 9597, e20620 Ganz, Patricia A. TPS657, TPS1139, 6528, 9594 Gao, Ang 1520 Gao, Bo 543, 2517 Gao, Chan 4571 Gao, Feng 4051, 7563, 8041, 8076, 9559 Gao, Guanghui e19166 Gao, Guozhi 7109 Gao, Hui e14567 Gao, Jennifer 6579 Gao, Jianjun 3043 Gao, Jianpeng e22169 Gao, Jing 4097

Gao, Jingjing 2552 Gao, Limin e17537 Gao, Lina 5017 Gao, Wei 9627 Gao, Ya Ning e14556 Gao, Yingtang e15050 Gao, Yun e12557 Gao, Yuying 646 Gao, Zhenhua e15167 Gara, Rishi Kumar e17020 Garau Llinas, Isabel e12558 Garavelli, Silvia 7060 Garaventa, Alberto 10016 Garay, MIguel e22165 Garbarino, Daniela 3615 Garbay, Jean-Remy 566 Garbe, Claus 9020, 9037, 9046, TPS9106, e20050 Garber, Judy Ellen 1531, TPS1606, 10071 Garber, Judy 9644 Garbo, Lawrence E. 3622, 7122 Garces, Alvaro Henrique Ingles 9589 Garces, Yolanda I. 6095, 7501 Garcia Alfonso, Pilar 3619^, 4098 Garcia Arroyo, Francisco Ramon e14706 García Campelo, Rosario 2581, 11028 Garcia Carbonero, Iciar e16028 Garcia del Muro, Xavier LBA10507, 10523, e15586 García Domínguez, Rocio e15609 Garcia Gerardi, Carlos Fernando 6596, e17539, e20636, e20656 Garcia Lopez, Maria Jose e12020 Garcia Marco, Jose Antonio TPS7131 Garcia Saenz, José Ángel e11561, e12015, e12558 Garcia Sebastian, Cristina e21512 Garcia, Agustin A. 5520, 9632 Garcia, Agustin 1024, TPS5616 Garcia, Angel 1509 Garcia, Beatriz 3013 Garcia, Cristina e22060 García, Elena 3543, 11033 Garcia, Eliane e19060 Garcia, Elizabeth 1531 Garcia, Joaquin J. 6016, 6028, 6095 Garcia, Joe G. N. e22051 Garcia, Jorge A. 4515, TPS4590, e15534, e16022 Garcia, Jose A. e13526 Garcia, Josep 2023^ Garcia, Khristofer e13529 Garcia, Marcio Ricardo Taveira e13003 Garcia, Richard 3019 Garcia, Salvador Ricardo e13539, e19155 Garcia, Stéphane 8100 Garcia, Teresa 585 Garcia-Aguilar, Julio 3605 Garcia-Albeniz, Xabier e14588 Garcia-Alfonso, Pilar e14592 Garcia-Berbel, Lucia 540

Garcia-Campelo, M. Rosario TPS8119, 11027, 11029, 11067 Garcia-Carbonero, Rocio 3551, 4041, 4140, e14561, e15107, e22045 Garcia-Casado, Zaida 1543 García-Donas, Jesús 4140, 4587, e15586, e16028 Garcia-Filho, Reynaldo Jesus 10533, 10534 Garcia-Foncillas, Jesus 11089, e19000, e19109 Garcia-Garre, Elisa 585, 3042, e12558 García-Girón, Carlos 3589, e14509 Garcia-Manero, Guillermo 7010, 7024, 7029^, 7089, 7116, 7122 Garcia-Martin, Rosa 1041 Garcia-Martinez, Elena 585, 3042 Garcia-Molleva, David 3629 Garcia-Palomo, Andres e12020 Garcia-Sanz, Ramon 8511 Garcia-Vargas, Jose E. 5060, 5068, 5080 Garcia-Velasco, Adelaida e19159 Garciarena, Pedro e13044 Garde, Javier LBA8002, e14671 Garden, Adam S. 6087 Gardikas, Nicolas e20642 Gardin, Claude TPS3117^ Gardini, Giorgio 2021 Gardizi, Masyar 1589, 8112, e12517 Gardner, Faithlore Patrice e15539 Gardner, Lawrence 9067 Gardner, Olivia S. 8027, 8028 Gardner, Thomas A. 5047^ Gardner-Thorpe, James 3504 Gareen, Ilana F. 1563, 7525 Garetto, Ferdinando 10572 Garey, Jody S. 6580 Garg, Madhur 4093, 6064 Garg, Naveen 4064 Garicochea, Bernardo 1539 Garin Chesa, Pilar 5504 Garin, August 4007, e14674, e15194, e15585 Garin, Avgust e15583 Garje, Rohan 2070, 2096, 9086, e15537 Garland, Elizabeth e20570 Garland, Sheila N. 9613 Garlipp, Benjamin e22040 Garmey, Edward Graeme TPS7610 Garner, Andrew P 10509 Garner, Elizabeth 4006 Garner, William J. 2093 Garnett, Mathew 7581 Garofalo, Amanda TPS664 Garon, Edward B. 2524, 8004, 8012, 8019, 8085, 8086, e19150 Garralda, Elena 2511, 2600 Garraway, Levi A. 1531, 6023, 9015, 10536, 11009 Garrett, Andrew e17587 Garrett, Chris R. 3512 Garrett, Michelle 2608 Garrido, Jose Manuel Tello 5059 Garrido, Maria e15609

Garris, Rebecca S. 7024 Garrison, Jill e16044 Garrison, Louis 6626 Garrone, Ornella 9614 Gartemann, Juliane e11507 Gartner, Elaina M. 548 Garufi, Carlo e15057, e22206 Garusi, Cristina e20634 Gary, Kristen 4017, e20586 Gary, Sarah Tressel e16079, e17558 Garza, Miguel 11044 Garza, Racheal 4517 Garzaro, Massimiliano 6038, 6039 Gaschler-Markefski, Birgit LBA8011, 8034, e19126 Gasco, Amaya 11025, 11029, e22119 Gascon, Pedro e17580 Gasmelseed, Ahmed e11518, e17528, e19035 Gasmi, Mohamed 4046 Gaspar, Laurie E. 8074 Gaspar, Nathalie 10031, 10518 Gasparetto, Cristina 8531, 8586, 8596 Gasparini, Giampietro 610, 3588 Gasparini, Pierluigi 11066 Gasparro, Donatello e15524, e16078 Gass, Margery 1524 Gassent, Juan Manuel e14671 Gastanaga, Victor M. 9083 Gastier-Foster, Julie M 10001 Gataa, Ithar e20535, e22029 Gatalica, Zoran 2041, 11001, e19006 Gatineau, Michel 6036 Gatolliat, charles-Henry 6079 Gatsos, George e20635 Gatt, Elyse 6546 Gatti, Marco 10583 Gatto, Lidia 10540, e21511, e21523 Gaub, Marie-Pierre 3596 Gaudernack, Gustav 3053 Gaudin, Anne-Francoise 9084 Gaudy, Allison 2594, e13505 Gaulard, Philippe TPS8616 Gaule, Patricia Brid 1066 Gauler, Thomas Christoph 4559, 6002, 6065, e17015, e17021, e19138 Gaur, Rakesh 9531 Gautam, Shiva 2080 Gauthier, Eric Roland TPS652 Gauthier, Geneviève 642, 10545, e11603, e21514, e21515 Gauthier, Mélanie 9511, 11007, e11529 Gauthier-Villars, Marion TPS1607 Gautier-Felizot, Laure 7505 Gautschi, Oliver 7503, 8060 Gava, Alessandro 6003 Gavila, Joaquin 1031 Gavoille, Celine 2615 Gavrilovic, Igor T. 2095 Gawande, Jayant Shankar 7043 Gay, Francesca Maria 8509 Gayat, Etienne 3642 Gayer, Christopher 9599, e20618 Gayle, Arlene Angela e14550 Gayo, Javier e22021 Gazdar, Adi 8088^ Gaziel-Sovran, Avital 9091

Gazzah, Anas 2512, 7604, 9556 Ge, Di 7537 Ge, Yingzi 3090 Geater, Sarayut Lucien 8016, 8061, e19002, e19041^ Geay, Maria e20032 Gebauer, Kai e22076 Gebauer, Mathias 11006 Gebbia, Vittorio 8066, 8071, e11526 Geberth, M. 558 Gebhardt, Frank 2508 Gebregziabher, Netsanet 3546 Gebski, Val 543, TPS3649, 4081, TPS5614, e19132 Gebuijs, Elizabeth e13549 Gecmez, Gizem e11537, e11544, e11545 Geczi, Lajos 5059, e15530 Geddie, William R. e19032 Gedske Daugaard, Kirsten 4532 Gedye, Craig 4568 Geel, Robin Van 2531 Geffen, David Barry e22069 Geh, Ian 3532 Gehlert, Sarah J. 9581 Geho, David 10514, e13508, e18514 Gehrig, Paola A. 5519, 5523, 5589, 5607, e16529 Gehrmann, Mathias e22112 Geier, Larry 1026 Geiger, Xochiquetzal 1037, 1059 Geiges, Goetz 1571 Geijsen, Debby e15103 Geisel, Juergen 8569 Geisler, Christian 7101 Geissler, Michael TPS3124^, 4034 Geist, Thomas 1589, 8112 Gelao, Lucia 617, 1595 Gelber, Richard D. 525, 529, 575 Gelber, Shari I. 6507 Gelber, Shari e20508 Gelblum, Daphna Y. 6034 Geldart, Thomas R. 4549 Gelderblom, Hans 595, 597, 2592, 4580, 6057, 7534, 10503, LBA10504, 10516, 10547, 10551, e14558, e14586, e20669, e22152, e22156 Gelehrter, Sarah 10020 Gelfond, Mark Lvovich 3088 Gelibter, Alain e15057, e22206 Gelin, Aurore 6079 Geller, Berta M 559 Geller, David A. 9507 Geller, James I. 10047 Geller, Melissa Ann e22007 Gelman, Rebecca Sue 513, TPS1134 Gelmon, Karen A. 518, 564, TPS652, 1033, 1102, 1585, 2534, e22020 Gelsomino, Fabio e14560 Gemignani, Mary 1019 Genden, Eric Michael 6019 Genden, Eric 6062 General, Rosale e15575 Generali, Daniele Giulio 530, e11573 Genestreti, Giovenzio e18561 Geng, Jianhao 10557, e15166 Geng, Qian Qian e22096 Genin, Berengere e14600 ABSTRACT AUTHOR INDEX

721s

Gennari, Alessandra

546, 552, TPS649, 5594 Gennatas, Constantine G. e15114 Gennatas, Spyridon e19146^ Genome Atlas Reseach Network, The Cancer 6011 Genova, Carlo TPS7606, 11063 Genovesi, Dario e14531 Gentien, David 511, 2615 Gentilcore, Giusy e20031 Gentilini, Fabiana 8509 Gentilini, Oreste Davide 589, 1517 Gentzler, Ryan D. e13568 Geoerger, Birgit 10026, 10027 Geoffrois, Lionnel LBA4500 Georgantas, Robert W. e20047 George, Ben e15082 George, Benjamin Jacob e17575 George, Daniel J. 2593, 4520, TPS4590, 5026, 5031, 5059, 5076, 6631, e15500, e15504, e15508, e15605 George, Marina e20664 George, Melissa 7039 George, Saby e15604 George, Steve 3500 George, Suzanne 10510, 10511 George, Thomas J. e15108, e15145 George, Thomas e12023 George, Timothy 9072 Georgiou, Georgia e12537 Georgopoulou, Urania e11513 Georgoulias, Vassilis 1045, 7594, e14639, e22101, e22105 Gerami, Pedram 9022 Gerard, Mary 2013 Gerardi, Chiara e14611 Gerber, Bernd TPS1138 Gerber, David E. 2507, 8046, 8072, 8074, 8088^, 8095 Gercovich, Daniela e20504, e20636, e20656, e20657 Gercovich, Felipe G. 6596, e17539, e20636, e20656 Gercovich, Natasha 6596, e20656 Gerdes, Michael e14663 Gerecitano, John F. 7018, 8520, 8571, 11076 Geredeli, Caglayan e18510, e18521, e19107 Gerger, Armin 4110, 4111, e15009 Gergich, Kevin 9009 Gerhardt, Axel 1120 Germa, Caroline TPS650^ Germa-Lluch, Jose R. 4560, e16014 Germann, Julie N. 10064 Germann, Nathalie TPS5098^ Germer, Christoph T. e15193 Gernone, Angela e15524, e16081 Gerratana, Lorenzo e11565 Gerrits, Johan e20653 Gerritse, Frank L. e16059 Gerritsen, Winald R. 3053, 5055, TPS5093 Gerry, Arianna Aldridge 9061, 9504, 9532, e20026 Gerschpacher, Marion e16042 Gershenson, David Marc 5534 Gershenwald, Jeffrey E. 9047 Gerster, Sarah e14561 722s

Gerstner, Elizabeth Robins 2054 Gertler, Stan Z. 6595 Gertz, Morie A. 8592 Gertz, Morie 8516, 8541, 8581, 8587, 8600, 8606 Gerunda, Giorgio Enrico 4129 Gervais, Radj 8014, 8043, 11010, 11029, e19058 Geschwind, Jean-Francois 4124, 4126 Geschwindt, Ryan 10026, 10027 Gesierich, Anja 9037 Geskin, Albert 9043 Geslin, Catherine e14539 Gettinger, Scott N. 3001, 3002^, 8008, 8030, 8031, 8072, 8105, TPS8118, TPS8121, 11075 Getz, Gad 9015, 10536, 11009 Getzenberg, Robert H. e16015 Geuna, Elena e11581 Geva, Ravit 1526, e22111 Gevorgyan, Arpine 3641, e14716 Gewirtz, Alexandra N. 3609 Gey, Aurelia e20041 Geyer, Charles E. TPS1139 Geyer, Mark B 3055 Geyer, Susan Michelle 1023 Geynisman, Daniel M. e17511 Gez, Eliahu e16023 Ghadessi, Mercedeh 4542, 5033, 5089, e16044 Ghadge, Meera e18004 Ghadjar, Pirus e17019 Ghadyalpatil, Nikhil e15120 Ghaemimanesh, Fatemeh e22198 Ghaffar, Abdul e12033 Ghaffari, Seyed Hamidolah 7069 Ghai, Vikas e18012 Ghalib, Mohammad Haroon e13550 Ghamande, Sharad A. TPS5613 Ghaneh, Paula 4006 Ghanem, Hamdy M. 1075 Ghanem, Ismael 1041, e11561, e12558 Ghanem, Sassine e20534 Ghannam, Mohammed 6628 Ghanouni, Pejman 9500, 9565 Gharami, Firoj Hossain 7083, 7114 Ghatage, Prafull 5502, 5541 Ghavamzadeh, Ardeshir 7069 Ghazal, Hassan H. TPS8117 Ghazalpour, Anatole 2041, e19006 Ghazaly, Essam Ahmed 2576 Ghenev, Peter e14669 Ghesquieres, Herve 2032, 8504 Ghi, Maria Grazia 6003 Ghia, Paolo 7101, TPS7130, TPS7133 Ghiani, Massimo 603 Ghias, Kulsoom e14680 Ghielmini, Michele E. G. 8560, e14536 Ghimire, Krishna Bilas 8606, e14627, e17598, e20529 Ghio, Domenico e18528 Ghiorghiu, Serban 531 Ghiotto, Cristina 5548, e13514 Ghirelli, Cristina 11071 Ghiringhelli, François 2020 Ghiuzeli, Cristina Maria 7055


Ghobrial, Irene M.

620, 6088, 8602, TPS8620 Ghoddusi, Majid e13590 Ghosh, Indranil e12039 Ghosh, Jaya 5554, e20678 Ghosh, Joydeep e18004 Ghosh, Monalisa Ghosh 7104 Ghosh, Sunita e14575, e14595, e14715 Ghosn, Marwan e20534 Giaccone, Giuseppe 2527, 3004, 6524, 7513, 8019, 8026, 11034, 11085 Giacobbo, Maria e12028 Giacomazzi, Juliana e22154 Giacomini, Elisa e22206 Giaginis, Constantinos e22160 Giamarellou, Helen e12524 Giampaglia, Marianna e20681 Giampaolo, Maria Anna e12031 Giampieri, Riccardo 3591, 4123, e14610, e15081, e15536 Gian, Victor G. 5513, e22139 Gianfelice, David 9500 Giannakakou, Paraskevi TPS5100 Giannarelli, Diana e11517, e16053, e17555, e21517 Giannelli, Gianluigi 4118 Gianni, Luca 503, 505, 525, 537, 1014, 2535, 3008 Giannikopoulos, Petros 11010, 11027, 11067 Giannini, Caterina 2014, 2025, 2046 Giannini, Edoardo G. e15088 Giannini, Massimo e15055 Giannini, Riccardo 3613 Giannobile, William 568 Giantonio, Bruce J. 2536, e14711 Giaquinta, Stefania e14717, e15154, e18509 Giard, Sylvia 566 Giardina, Giovanni TPS1610 Giardino, Felicetta 9092 Giashuddin, Shah 11106 Gibbon, Darlene 2553 Gibbons, David 3549 Gibbons, Don Lynn 8104 Gibbons, Jackie 5066 Gibbs, Peter 3575, 3584, 3598, 11015, e14583, e14608, e14640 Gibbs, Richard A. 8577, 10023 Gibney, Geoffrey Thomas TPS3106, 9011, 9056^, 9066, 9079 Gibson, Jeffrey B. 7569 Gibson, Jessica TPS11122, e22117 Gibson, Michael K. 4011, 4103, 6043 Gielissen, Marieke F. M. 10549 Giese, Klaus 2508 Giessen, Clemens Albrecht 3630 Gietema, Jourik A. 2050 Giever, Thomas A. 6586 Giffard, Benedicte 9510 Giger-Pabst, Urs e16523 Giglio, Pierre 2019^ Giguere, Jeffrey K. 2006, 2051 Giguere-Duval, Philippe 642, e11603 Gil Deza, Ernesto 6596, e17539, e20504, e20636, e20656, e20657 Gil Gil, Miguel J. e12558, e13016

Gil, Antonio Gil, Miquel Gil, Thierry Gil-Arnaiz, Irene Gil-Bazo, Ignacio

1509 2087 4529, 5002 e20015 e19106, e19112, e19114 Gil-Martin, Marta e16539 Giladi, Moshe e22125, e22134, e22138 Giladi, Nissim 2073 Gilam, Avital 578 Gilbert, Christopher 7553, e18552 Gilbert, Elizabeth 11048 Gilbert, Ethel S. 4536 Gilbert, Houston 5020 Gilbert, Jill 6016, 6022, 6047, 6049, e20531 Gilbert, Lucy TPS5613 Gilbert, Mark J. TPS2621 Gilbert, Mark R. 1, 2003, 2004, LBA2010, 2015, 2019^, 2042, TPS2106, e13044 Gilbertson, Richard J. 2035 Gildener-Leapman, Neil 3099 Giles, Francis J. TPS7131 Giles, Stephen e13001 Gill, Devinder Singh TPS8619 Gill, Donal e20505 Gill, Navkiranjit K. 7059 Gill, Sharlene 3569, 3590, 3639, TPS3647, 4050, 6502 Gillaizeau, Florence e16009 Gillaspie, Erin e14632 Gillbanks, Angela TPS2626 Gillen, Gerry 2589 Gillen, Peter 3549 Gilles, Barthelemy e11535 Gilles, Erard M. 592, 593, 596, 5602, e11535, e11543, e16548 Gillespie, John Williams 4577 Gillespie, Theresa Wicklin 1130, 5067, 6523 Gillies, Kim TPS5614 Gilligan, Timothy D. 4515 Gillison, Maura L. 6005, 6007, CRA6031 Gilly, Francois-Noel 3596 Gilman, Paul e17565 Gilmer, Tona M. 11026 Gilmore, Hannah L. 1046 Gilmore, Joan TPS7132 Gilmore, Katherine R. e20645 Gilmore, Steven e20574 Gimbergues, Pierre 566 Gimenez Capitan, Ana 11025, 11027, 11078, e22068 Gimsing, Peter 8512^ Ginestà, Mireia M. e22057 Gingerich, Joel Roger e17596 Gino, Giancarlo 10572 Ginocchi, Laura 4062, e20711 Ginsberg, Lawrence E. 6067, e13035 Ginther, Charles 5510 Ginty, Fiona 2097, e14663, e16033, e18539, e22085 Giobbie-Hurder, Anita 529 Giombelli, Ermanno 2048 Giordano, Aldo Victor e14596 Giordano, Heidi 2585, 2586 Giordano, Pasqualina 8066, 11008

Giordano, Sharon Hermes

1022, 6630 Giordano, Silvia 11005 Giorgadze, Davit 8095 Giorgetti, Assuero e14531 Giotis, Angie 6552 Giotta, Francesco 618, 631, e11502 Giovanella, Beppino C. 2578 Giovannucci, Edward L. 5078, 5086 Giovino, Gary 1603 Giralt, Jordi 3560 Giranda, Vincent L. 2036, 2065, 2584^ Girard, Nicolas e19036 Girard, Pascal e13594 Giraudet, Anne Laure 6092 Giraudi, Sara 1036, e17548 Giraudo, Enrico e14654 Girda, Eugenia 5592 Girgin, Sadullah e17529 Girgis, Afaf 9602 Giri, Nagdeep 2568 Giri, Uma 6011 Girish, Sandhya 644, 645, 646 Girkas, Constantinos e20642 Giron, Cathy e17543 Girones, Regina 4560, e20643 Giroux, Julie e13589, e17514 Girvan, Allicia C e20525, e20629 Gitlitz, Barbara Jennifer 7511, 8026 Gittleman, Mark e22117 Giubellino, Elena 10572 Giuffrida, Dario e11526 Giuliani, Francesco e14565 Giuliani, Jacopo e17551, e20617 Giulini, Stefano Maria 4129 Giulino, Lisa B. 3055 Giusti, Ruthann Marie 2510 Giusto, Mauro e15512 Gladieff, Laurence 5544 Gladkov, Oleg 548, 3073, 3508, 4010, e11586, e15005, e17572 Gladstone, Douglas 7009, 7045 Gladwin, Amanda 8045 Glaholm, John e16048 Glanville, Julie e11602 Glare, Paul A. e20677 Glas, Martin LBA2000 Glaspy, John A. 5515 Glass, Bertram 8566 Glass, Jon 2033 Glass, Katherine e14535 Glasser, Michael e20722 Glasspool, Rosalind Margaret 5571 Glatzle, Joerg 3098 Glaudemans, Andor W. J. M. 2050 Glazer, Jenna e20712 Gleason, Charise 7035, 8540 Glehen, Olivier 3642 Gleich, Lyon L. TPS9649 Glen, Hiliary 9027 Glezerman, Ilya 4534, e20512 Glied, Sherry A. 6505, 6509 Gligich, Oleg e19525, e19529 Gligorov, Joseph 1058, 5567, e12504 Glimelius, Bengt 3571, 3597, LBA4003, 4006, e14710 Glisson, Bonnie S. 6030 Glode, L. Michael 5053^, e16055

Glogowska, Oliwia Anna e18529 Glogowski, Emily e12536 Glogowski, Maciej e18529 Glomb, Patricia 2556, e19126 Glória, Igor e20632 Glorius, Pia 8604 Glover, Jason Michael 10053 Glover, Katrina Y. 3600 Gluck, Stefan 6548, 11090, TPS11124 Gluz, Oleg TPS655^, 1092 Gluzman, Alexander e22111 Glynne-Jones, Robert 3532 Gnant, Michael 506, 553, 557, 558, 561, 573, e11601, e14537, e20693 Gnoni, Antonio e11517, e20681 Go, Ronald S. 8580, 9038 Go, Se-Il e18555 Go, William Y. 3616, 3631 Gobburu, Joga 2515 Gocke, Christopher D 7009 Gocze, Peter 5541 Godara, Amandeep e20048 Godbold, James H. 5015, 6540 Goddard, Emma TPS3647 Goddard, Karen e20589 Godfrey, Wayne R. 8500, 8501, 8519, 8526, TPS8617, TPS8618 Godley, Paul Alphonso 6530 Godoy, Antonio Carlos e15190 Godwin, Andrew K. 1026, e22048 Godwin, John E. TPS3108 Godwin, Thomas 11054 Goebel, Georg 583 Goebel, Wiebke 3094 Goede, Valentin 7004 Goedegebuure, Peter S e16508 Goehler, Thomas TPS1137, e14532 Goel, Ajay e14631 Goel, Gaurav e20686 Goel, Madhu Mati e17020 Goel, Rakesh 3633 Goel, Sanjay e13550, e14540, e19145 Goel, Shom 1065 Goeman, Sara e19519 Goéré, Diane 3642 Goergen, Krista M. 5546 Goerlich, Dennis 1020 Goertz, Hans-Peter 6546, e17561, e19001 Goessling, Wolfram 4090 Goette, Heiko 4021 Goetz, Eva M. 9015 Goetz, Matthew P. 1024, 2562, 2596 Goff, Laura Williams e14516 Goffin, John R. 6550 Goffredo, Veronica e22104 Gogarty, Darragh S e12565 Gogas, Helen 582, 1093, 11009, e18542, e20028 Goggin, Timothy K. 2531 Gogia, Ajay e12539, e19524 Gogineni, Keerthi 519, CRA6510, 6518 Gogna, Apoorva 8107 Gogoi, Radhika 5581 Gogov, Sven 4504, 4576 Goguen, Laura A. 6058 Gogula, Venkata Ramana 7080

Goh, Anthony e15102, e15137 Goh, Boon C. 6063, e14507, e17017 Goh, Brian e15102 Goh, Chee Leng e16000 Goh, Jeffrey C. TPS5612 Goh, Vicky e15608 Goji, Takahiro 4075 Gojon, Helene 1119, 1568 Gok Durnali, Ayse e18510 Gokarn, Anant 7043 Goker, Erdem 4009 Goker, Hakan e18014 Gokmen, Erhan e20006 Gokmen-Polar, Yesim 7605 Goksu, Sema Sezgin e14683, e14696, e18517 Goktepe, Ozge 3593, 6502, 8552 Golan, Talia 4037, TPS4144 Golant, Mitch 9599, e20618 Golchin, Ava 6019 Gold, Heather Taffet 6549 Gold, Heidi L. 9054, 9067 Gold, Kathryn A. 6087, 8102, 8104 Gold, Philip Jordan 3587 Goldbarg, Veronica e17543 Goldberg, Gary L. 5592 Goldberg, John M. TPS10591 Goldberg, Judith D. 1042 Goldberg, Judith D TPS3122, 11106 Goldberg, Richard M. 1556, 2595, 3510, 3514, 3520, 3523, 3533, 3636, 3637, e14535 Goldberg, Stacie M. TPS3107, TPS3108 Goldberg, Stuart L. 7052^, 7093, 7100 Goldberg, Terri Robin TPS4159 Goldberg, Zelanna TPS8123 Goldbrunner, Roland LBA2000, TPS2103 Goldenberg, David M. e14508, e15089 Goldes, Yuri 4037 Goldfarb, Ronald H. 517 Goldfarb, Shari Beth 606, 9610 Goldfinger, Mendel 8524 Goldhirsch, Aron 529, 589, 617, 1061, 1595 Goldim, Jose Roberto e22154 Goldin, Jonathan 5026, 7562, 7566, e16019 Goldin, Robert D e14620 Goldinger, Simone M. 9025, 9071, 11009 Goldkorn, Amir 11040 Goldman, Cecilia e20680 Goldman, Charles David e17599, e20714 Goldman, Jehudit 1108 Goldman, John M. 7001 Goldman, Jonathan Wade 2500, 2524, 2540, TPS2619, 3059, 8072, 8093 Goldman, Stanton 3055 Goldman, Stewart 2035, 2036, 10522 Goldrich, Adam 8594 Goldschmidt, Emma e19513 Goldschmidt, Hartmut 8510, 8527, 8528, 8583, 8590, 9612

Goldsmith, Stanley J. 11081 Goldstein, David P. 9536 Goldstein, David LBA4003, 4005^, 4053, 4058^, 4059^, TPS4157, 6556, 9602, e15188^ Goldstein, Lori J. 508, 1003 Goldstein, Matthew 3015 Goldstein, Michael 8050 Goldstein, Robert 2566 Goldstein, Theodore C. 5006 Goldwasser, Francois 5567, e12504, e13589, e15592, e17514, e20535, e22029 Goldwasser, Meredith 8010 Goletz, Steffen 3008 Golfinos, John e13033 Gollerkeri, Ashwin 2533 Gollnow, Angelika e17531 Golmard, Jean-Louis e15592 Gologan, Olguta 6041 Goloubeva, Olga G. e20574 Golshan, Mehra 501, 1100, 1132 Golshayan, Ali Reza 4525 Golub, Todd 10536 Golubovskaya, Vita e13547, e13556, e13561 Gombos, Andrea e12008 Gomella, Leonard G. 4547^, 5061 Gomes Da Silva, Maria TPS8616 Gomes DaGama, Erica 11076 Gomez De Liano Lista, Alfonso e16049 Gomez Dorronsoro, Maria Luisa e14589 Gomez Izquierdo, Lourdes e19105 Gomez, Daniel Richard 7521, 7574 Gomez, Gonzalo 11033 Gomez, Henry Leonidas e12538 Gomez, Henry 628, e12570, e22165 Gomez, Ivan 3052 Gomez, Joseline X. e17511 Gomez, M.Auxiliadora e11530, e14559, e14648 Gomez, Maria Carmen e16549 Gomez, Nerea e19027 Gomez, Roberto E. 3086, TPS3123 Gomez, Rosa Maria Sanchez 10529 Gomez, Scarlett Lin 1083, 1504, 5605 Gomez-Martin, Carlos 2600 Gomez-Roca, Carlos Alberto 2548, 2549, 8027, 10514 Gomez-Roca, Carlos 9028 Gomez-Roman, Javier 540 Gomez-Vega, Maria J. 11021 Gomez-Veiga, Francisco 5087, e22171 Gomi, Daisuke e14670 Gomi, Naoya e11587, e22190 Goncalves, Anthony 511, 566, TPS663, 2615, e11607, e13519 Goncalves, Priscila Hermont 6045 Goncalves-Mendes, Nicolas e11552, e17022 Gonda, Kenji 3063 Gonen, Can e22061 Gonen, Mithat 507, 4116, 6539 Gong, Gyungyub 1070 Gong, I-Yeh 2569, e14570, e15073 Gong, Jifang 4097, e15174 ABSTRACT AUTHOR INDEX

723s

Gong, Jing e19004 Gong, Lei e15062, e19073 Gong, Sylvia J. 2583 Gonsalves, Wilson I. 8587, 8600 Gonsky, Jason Parker 8594 Gonullu, Guzin e11506, e14697 Gonzales-Gomez, Pilar 9091 Gonzalez Cao, Maria e20015, e22119 Gonzalez Dacal, Jose 5087 Gonzalez de Castro, David 11094 Gonzalez de la Peña, Miriam e19105, e19160 Gonzalez de Sande, Luis Miguel 10529, 10532 Gonzalez del Alba, Aranzazu e15586 Gonzalez Flores, Encarnacion e11583 Gonzalez Florez, Hector Alirio e22207 Gonzalez Guerrero, Juan Francisco e14708 Gonzalez Palacios, Carlos e11600 Gonzalez Patino, Ezequiel 5603 Gonzalez, Adriana e11538 Gonzalez, Alberto 2032 Gonzalez, Alvaro 9074 Gonzalez, Anneliese e15556 Gonzalez, Diego e11538 González, Encarnación 4098 Gonzalez, Germaine 3091 Gonzalez, Gisela 3013 Gonzalez, Jorge 3013 Gonzalez, Luis e12571 Gonzalez, Melanie L. 1602, 9567, e14625, e14661, e15561 Gonzalez, Michael 2566, 2580 Gonzalez, Paula e12558 Gonzalez, Rene 9005, 9016, 9022, 9026, 9066 Gonzalez, Ricardo Jorge 10556 Gonzalez, Sara 3629 Gonzalez, Sonia 1027 Gonzalez, Xavier 608 Gonzalez-Angulo, Ana M. 524, 532, 598, 601, TPS657, 1005, 1006, 1022, 1131, 2531, e12002, e22064, e22081 Gonzalez-Arenas, Maria Carmen 2581 González-Barrios, Rodrigo 4555 Gonzalez-Billalabeitia, Enrique 585, 3042, 4560 Gonzalez-Garay, Alejandro G. 3050 Gonzalez-Grajera, Belen e15620 Gonzalez-Larriba, Jose-Luis e11561, e15609 Gonzalez-Manzano, Ramon e22120 Gonzalez-Martin, Antonio 5541, 5544, 5569, e12015 Gonzalez-Mella, Pablo TPS8117 Gonzalez-Pisano, David 11033 Gonzalez-Ribbon, Nilda 4523 Gonzalez-Santiago, Santiago e12513 Gooch, Michael e22211 Goodall, John e22164 Goode, Ellen L. 5510 Gooding, William E. 6051 Goodman, Andrew 9031 724s

Goodman, Annekathryn 5604 Goodman, Ben 3546 Goodman, Elizabeth L. 9570 Goodman, Karyn A. 3605, 9524 Goodman, Michael 1130, 5067, 6532 Goodman, Stacey 8605, e19539 Goodman, Vicki L. 8009, 9013 Goodspeed, Wendy J. 2554 Goodwin, Anne 2554 Goodwin, Gail e22095 Goodwin, Neal 8110 Goodwin, Pamela Jean 550, 1033, 1521, TPS1608 Goodwin, Rachel Anne 3528, 3633, e14553 Goonewardena, Madusha LBA9000 Gooptu, Mahasweta e17578 Gooskens, Saskia e20035 Gopal, Ajay K. TPS8614^ Gopal, Arun 9622 Gopalakrishna, Prashanth e19145 Gopalakrishnan, Vancheswaran 10049 Goparaju, Chandra 11109 Gopinathan, Anil e14507 Gorak, Edward J. 8592 Gorbunova, Tatiana e13042 Gorbunova, Vera A. 4021, 8014, e15156 Gorbunova, Vera e15546 Gordeev, Sergey e14674 Gordon, Brittaney-Belle Elizabeth 9543, e20582 Gordon, Leo I. 8576, TPS8613^ Gordon, Michael S. 2507, 2533, 2567, 3000, 3059, TPS3109, TPS3112, 3622, 4505, 5551, 8008, 8027, 9094 Gordon, Noa e15078 Gordon, Ruth Ann 9012^ Gordon, Sarah e17547 Gordu, Zulfukar 10068 Gordy, Anna Lina-Karin e15621 Gore, Elizabeth 7523, e17594 Gore, John L. 4540 Gore, Lia 10007, 10026, 10028, 10030 Gore, Martin Eric 3036, 3073, TPS4592, 5544, LBA9000, e15624 Gore, Steven 7126, e17584 Gorelick, Jeremy 1563, 5003, 7525 Goren, Eran e22173 Gorender, Ethel 10057, 10065 Gorguc, Ipek 1016 Gorgun, Omer 10043 Gori, Stefania e11556, e11573 Gorin, Brian e16025, e22135 Gorini, Alessandra 9582 Gorlia, Thierry 2007, LBA2009, 2011 Gorlick, Richard Greg 10053, LBA10504, 10528 Gorlov, Ivan e15575, e22047 Gornet, Jean-Marc 3585 Goroshinskaya, Irina Aleksandrovna 3084, e16515, e22002 Gorritz, Magdaliz e15511 Gorritz-Kindu, Magdaliz e14576 Gorska, Isabelle e15094, e22159 Goryca, Krzysztof 11069


Goss, Glenwood D. CRA8007, 8048, TPS8126, 11016, e19033, e19066 Goss, Paul E. 564, 628, TPS662, 6557 Goswami, Chanchal 4000, 8053 Goswami, Meghali 3104 Goswami, Srikanta e18537 Goswami, Trishna 7045 Gota, Vikram 7079, e19118 Goteke, Vamshi Krishna Reddy 7061, e18003, e19533 Gotera, Gustavo e21512 Gothard, Lone 11116 Gotink, Kristy 11087 Gotlieb, Vladimir e17537 Goto, Koichi 7512, 7557, 8056, 8078, 9621, e19076 Goto, Tomoko e16519 Goto, Yasushi 8058 Gotoh, Mitsukazu e19162 Gotoh, Yukiko e13536 Gottfried, Maya LBA8011, e15597, e15598, e16051, e16068 Gotthardt, Susan TPS2627 Goubar, Aicha 556 Goudot, Patrick e17023 Gougeon, Francois e22159 Gough, Karla e20536 Goukassian, David e22010 Gould Rothberg, Bonnie 6042, 6076, 7033 Goulet, Dan 512 Gounder, Mrinal M. 10512, 10558, 10580, e13509 Gounder, Murugesan 2582 Goupil, Francois 7505 Gourdin, Theodore Stewart 7049 Gourgou, Sophie 1094 Gourgoulianis, Konstantinos e22202 Gourley, Charlie 5505, 5571, TPS5615 Gouttefangeas, Cecile 8084 Gouw, Launce G. 10514, 10517 Gouw, Launce 10587 Gouy, Sebastien 1114 Govind Babu, Kanaka 1071, 8053 Govind, Eriat e19092 Govindan, Ramaswamy 7563, LBA8003, 8004, 8012, 8041, 8076, 8086, e19150, e19158 Govindan, Serengulam V. e14508 Govindarajan, Rangaswamy 7597, e15152 Govindasami, Koveela e16000 Gowda, Krishne e13533 Gowdra Halappa, Vivek 4124 Goy, Andre 8522, 8533, 8534, TPS8613^ Goyal, Abhishek e15037 Goyal, Gautam 5554 Goyal, Lipika 4090, 4125 Gozde, Yazici e17019 Graas, Marie-Pascale 8063 Grabek, Daniel e20610 Grabelsky, Stephen A. 4054 Grabowski, Eric 10018 Grabowsky, Jennifer A. 1095, 2605, TPS2623 Grabsch, Heike TPS4156

Gracia, Jose Manuel e18513 Gracova, Kristina e22057 Gradishar, William John 626, TPS661, 1032, 1091, 6617, e22093 Gradishar, William 6533 Graef, Suzanne 4029 Graefen, Markus 5043 Graeven, Ullrich TPS4158 Graf von der Schulenburg, J.- Mathias e19060 Graf, Claudine e21505 Grafe, Andrea 602 Graff, Jeremy Richard 2097, e16033 Graff, John 6615, 9601, e20511 Graff, Julie Nicole 5017 Grah, Christian e20710 Graham, Alex e16040 Graham, Alison M. 7018, 8520 Graham, Anne Marie TPS661 Graham, Dinny 5602, e16548 Graham, Donna M. TPS2618, 6033, e12533 Graham, Janet TPS4160, 4511 Graham, Martin 2504, 3621 Graham, Nadine A. 542 Graiff, Claudio e13009 Gralla, Richard J. 8087, 8092, 9512, e19100, e20716 Gralow, Julie 520, CRA1008, 1090, 9515 Gramatzki, Martin 8604 Gramza, Ann Wild TPS3127, 6074 Grana, Chiara e15147 Grana, Generosa 1091 Granados-Garcia, Martin e17031 Granata, Roberta 6020, 6027, 6046 Granato, Anna Maria 3040 Granato, Felice 7544 Grande, Carolyn Marie e17009 Grande, Enrique 4135, 4140, e15169, e15532 Grande, Roberta e20619 Grandinetti, Jose e11600 Grandis, Jennifer R. 6009, 6043, 6051 Grandjouan, Sophie 1528 Grane, Ronald e19012 Granetto, Cristina 3615 Grange, Florent 9069 Granger, Meaghan 10039 Granier, Muriel 6036 Granito, Alessandro e15149 Granot, Zvika e22148 Grant, Stefan C. 7591, 8057, e19143 Grasela, Dennis M. TPS3111 Grassi, Angela e22036 Grassi, Elisa 4048, e15069 Grasso, Salvatore A 5579 Gratama, Jan-Willem 11045, e22106 Gratias, Eric J. 10014 Grau, Juan J. 6072 Grau, Montse 1543 Graudenz, Marcia S. e22154 Graupera, Mariona e22057 Gravalos Castro, Cristina e14648 Gravalos, Cristina 9641 Gravelle, Debbie e20598 Gravenor, Donald 8599

Gravis, Gwenaelle LBA4500, 5002, 5063, e15506, e16067 Gray, Alastair 3500 Gray, Heidi J. 2584^ Gray, Jhanelle Elaine 3091, 8001 Gray, Kathryn P. 4561, 4570, e16032 Gray, Mike J. 609, e13515 Gray, Phillip J. 8069 Gray, Richard G. 5 Gray, Richard J. 9034 Gray, Stacy W. 1553, 6547 Graziano, Stephen L. 6059, 7506 Graziosi, Luigina e15148 Grazziutti, Monica 8539, 8595 Greally, Megan e13019, e13022, e13049 Greathouse, Amy 2518 Grebe, Nadine e21505 Grecea, Daniela 629 Greco, Angela 6066 Greco, Carlo 4062 Greco, F. Anthony 2544, 8062, 8091, TPS8120, 11080, e15006, e15501, e19062 Greco, Filippo e17551, e20541, e20617 Greco, Raffaella 7007 Greco, Ralph Steven 9061, e20026 Green, Adam L. 10011, e17573 Green, Anders e19157 Green, Andrew J. 1542, e12565 Green, Andrew R. e11608 Green, Dan e22151 Green, Daniel M. 10021 Green, Esther e20507 Green, Mark R. 7046, 8607, 10590 Greenberg, David 6621 Greenberg, Jonathan 2583 Greenberg, Mark L. 10032 Greenberg, Peter 7126 Greenberg, Richard Evan 9525 Greenberg-Dotan, Sari 639, e14571 Greenblatt, David Y e14550 Greene, Michael W e14632 Greengold, Richard H. 5053^ Greenhalf, William LBA4004, 4006 Greenlaw, Roger e20698 Greenlee, Heather 560 Greeno, Edward e15188^ Greenwood, Amy 7544 Greer, John P. 8605, e19539 Greer, Joseph A. e20551 Greer, Wenda 8096 Gregg, Richard William 5042 Gregorc, Vanesa 3038, LBA8005, 8035, e13593, e18528 Greig, Paul David e14573, e15087 Greil, Richard 506, 1040, TPS3124^, 3604, TPS4158, e14537, e15041 Greillier, Laurent 7584 Greinemann, Jasmin 602 Greipp, Philip R. e19517 Greisinger, Anthony 9022 Grellety, Thomas 6582 Grenache, David G. 5555 Grenacher, Lars 3090 Grendahl, Darryl e17538, e20605

Grenga, Italia Gresham, Gillian

e14581 3624, 4050, 9547 Greskovich, John 4087, 6035, 6061 Gress, Thomas M. 4034 Gress, Thomas Mathias 4030 Gressick, Lori A. 7018, 8520 Gressin, Remy 2032 Greten, Tim F. 4040^, 4127, e15177 Gretler, Daniel D. 8574 Grever, Michael R. 1023, 1043 Grewal, Iqbal S. 3024 Grewal, Satkiran S. 10035 Grgic, Mislav e15509 Gribben, John G. 2576 Gribbin, Thomas Edward 4038 Grice, Jessica Houston 3044 Gridelli, Cesare 8066, 8068, e19031 Grieve, Robert 5 Grifalchi, Federico 11058 Griffin, Ann C. 1083 Griffin, Michael TPS4156 Griffin, Thomas W. 5004, 5009, 5010, 5037 Griffioen, Arjan W. 7528 Griffith, Diana 10509 Griffith, Elizabeth e11590 Griffith, Kent A. 8543, 9601, 9615, e19519 Griffiths, Elizabeth A. e18018 Griffiths, Michael 11094 Griggs, Jennifer J. 7044, e20511 Grigioni, Walter Franco TPS3648 Grignani, Giovanni 10519, 10552, 10583 Grignol, Valerie P e20018 Grigorenko, Alexander 6508 Grigorieva, Julia 4061, 5575, LBA8005 Grilley-Olson, Juneko E. 6094, TPS6097, 7576 Grills, Inga S. 1123 Grimaldi, Antonio M. 9065, e20031 Grimaldi-Bensouda, Lamiae 1578 Grimer, Robert 10518 Grimm, Christoph e16524 Grimm, Donata e16535 Grimm, Marc-Oliver TPS4591 Grimm, Sean Aaron 2013, 2019^ Grimm, Shawna e17599, e20714 Grimminger, Peter Philipp 3527, 11062 Grimmond, Sean e15029 Grinblatt, David L. 7086 Griner, Paula L. 8091 Gringeri, Enrico 3563 Grinspan, Jessica 6595 Grischke, Eva-Maria 591, e11525 Grisell, David 9505 Grisham, Rachel N. 5545 Gristina, Valerio e20647 Gritz, Ellen R. 1561 Grivas, Petros 4545, TPS5094 Grivaux, Michel e19078 Grizzle, William E. 623 Grob, Jean Jacques 9013, 9036 Grober, Yuval e13002 Grobmyer, Stephen R. 1508

Groen, Harry J. M.

8014, TPS8119, 11025 Groeneweg, Jolijn W. 5578, e13564 Grogan, Thomas M. 3576 Grogan, William 3549, e13019, e13020, e13022, e13049 Groisberg, Roman 6076 Groman, Adrienne 4067, e20573 Gromeier, Matthias 2094 Gromisch, Christopher M. e15017 Gronchi, Alessandro 10500, 10519, 10565 Grondin, Yohann e22016 Gronesova, Paulina 4556, e15599, e22023 Gronkowski, Martina 9612 Groome, Patricia A. 1592 Gropper, Adrienne 1117 Gros, Thomas e22177 Grosh, William W. TPS3118^, TPS3125 Groshen, Susan G. 3587, 4531, 5062, 8554, 9632, e16020, e16073 Gross, Amy L. 1601 Gross, Andrew e15562 Gross, Cary Philip 1522, 6511, 6549, 9545, 10063 Gross, Howard M. 1059, 9572, TPS9647 Gross, Mitchell E. 11047, e16020 Gross, Neil D. 3099, CRA6031, 6051 Gross, Thomas G. 3055 Grossbard, Michael L. 6571, e17566 Grosse Lackmann, Kirsten 581 Grosse Perdekamp, Maria T. TPS10592 Grosse-Hovest, Ludger 3054 Grosshans, David 10009 Grossi, Francesco TPS7606, LBA8005, 8035, 8051^, 11063 Grossman, Robert L. 5028 Grossman, Steven R. e22203 Grossman, Stuart A. 2034, 2044, 2054, 2065, TPS2105, 6068 Grossmann, Kenneth F. TPS6098 Grossmann, Kenneth TPS9105^ Grosso, Federica e14657 Grosso, Joseph 3003^, 3016, 3019, TPS3109, TPS3112 Grote, Deanna 8538 Grote, Hans Juergen 3537 Grothey, Axel 3501, 3514, 3533, 3618, 3636, 3637, 6520, 11119, e14564 Grous, John J. 4040^, TPS7607 Grover, Surbhi 5609 Groves, Morris D. 2019^, TPS2106, e13039 Growdon, Whitfield Board 5578, 5604, e13564 Grubbs, Stephen S. 3611 Gruber, Deborah Beth e13033 Gruber, Ines 1030 Gruber, Michael L. e13033 Gruellich, Carsten e15574 Gruenberger, Birgit e15041 Gruenberger, Thomas 3538, 3619^ Gruenwald, Viktor 2038, 2077, e15624, e17021

Gruhn, Bernd 10017 Grujicic, Danica LBA2009 Grumett, Simon Aird 3018 Grun, Delphine 610 Grunberg, Steven M. e20509 Grunberg, Steven LBA9514 Grundy, Paul Edward 10014 Grunwald, Michael Richard 7026 Grupp, Stephan A. TPS10072 Grushko, Tatyana A. 11021 Grutsch, James F. e17502 Gruttadauria, Salvatore 4129 Grünwald, Viktor e16024, e16064, e22076 Grzankowski, Kassondra S e16553 Grzeda, Lukasz 531 Grønberg, Bjørn Henning 9562 Gschwantler-Kaulich, Daphne e11606 Gschwend, Juergen TPS4591 Gu, Aiqin e19161 Gu, Dongying 4106 Gu, Fei 7533 Gu, Jessie 7005, 8519 Gu, Jian 1532 Gu, Lin 7506, 8039 Gu, Yu 2523 Gu, Zheng e14656 Guadagni, Fiorella e14581 Guan, Zhongzhen 4025, e14501 Guaraldi, Monica 6003 Guardino, Ellie 644, e20712 Guardiola Amado, Victor Daniel e15007 Guarino, Michael J. e14528, e15089 Guarneri, Valentina 530, 556 Guastalla, Jean Paul e16547 Guba, Susan C. LBA8003, 8004, 8012, 8086, e19150 Gubens, Matthew A. 11004 Gucalp, Ayca 6508 Gucalp, Rasim A. e20512 Gucalp, Rasim 8097 Guchelaar, Henk-jan 595, 597, 2592, 10547, e14558, e14586, e22152, e22156 Guckert, Mary E. 9013 Guddati, Achuta Kumar 7127, 9558, e18008, e22179 Gudin, Amelie e14621 Gudipudi, Deleep Kumar 5610 Gudipudi, Deleep e16554 Guduru, Sridhar 7016 Guenthner-Biller, Maria Margarete 3064 Gueorguieva, Ivelina 2016, 2039, 2563, 4118 Guerci-Bresler, Agnès 7066 Guercy-Bresler, Agnes 7002 Guérin, Annie 642, 7093, 10545, e11603, e21514, e21515 Guerin, Mathilde e16067 Guerin-Meyer, Veronique 3542, 3601 Gueron, Beatrice 9084, e20021 Guerra, Jhon 2049 Guerra, Raquel Bezerra 9561 Guerra, Silvia e19159 Guerrera, Francesco 7602 Guerrero, Carmen T. 1529 ABSTRACT AUTHOR INDEX

725s

Guerrero, David e14589 Guerrero-Zotano, Angel e12513 Guerrieri-Gonzaga, Aliana 1517, TPS1610 Guettier, Catherine e19513 Guetz, Sylvia e19108 Guez, David e13002 Guggenheim, Douglas Eric e20549 Guglielmelli, Tommasina 8509 Guglielmi, Alfredo 4129 Guglielmini, Pamela Francesca e14657, e20694 Guha, Chandan 4093 Guha, Udayan 7513, 8026 Guida, Francesco Maria e15528 Guida, Michele 9035, 9065, 9070, 9548, e20028 Guido, Alessandra e15154 Guidoboni, Massimo 3040, 9035 Guiducci, Graziano e13007 Guiel, Thomas e19057 Guigay, Joel 6055, 6079 Guijarro, Maria V 9091 Guijarro, Ricardo 11073 Guilhot, Francois 7001, TPS7129 Guillamo, Jean Sebastien 2020, 3065^ Guillem, Jose G. 1555, 3605 Guillem, Vicente 537, 1014 Guillemeau, Claire TPS1607 Guillemet, Cecile 10505, 10563, e11529 Guillen-Ponce, Carmen 1529 Guillot, Aline 5063, e15607 Guimaraes, Andrea Paiva e17032 Guimbaud, Rosine 1528, 3599 Guinan, Patrick 2590, e16085 Guindalini, Rodrigo Santa Cruz 1506, 1530, 11021, 11084, e20691 Guirguis, Alfred S. 5579 Guise, Theresa e22072 Guitton, Jerome TPS2625, e13594 Guiu, Séverine 11007, e11529 Guix, Benjamin e16071 Guix, Ines e16071 Guix, Marta 4587 Guix, Teresa e16071 Gujral, Sumeet e19503 Gul, Zartash 7084, e18001 Gulati, Amit e17003 Guldberg, Per e12024 Gulden, Cassandra 1530 Guler, Emine Nilufer e11553 Guler, Tunc e15110, e18521 Gulesserian, Melina e19093 Gulino, Sara 6094 Gulisano, Marcella TPS1610 Gulley, James L. TPS3127, 4543, TPS4589, TPS5095, TPS5102, TPS5104, e16017, e16036 Gullipalli, Muralidhar e18000, e18003, e19533, e20684 Gullu, Ibrahim Halil e11553, e11595 Gulmi, Frederick e16101 Gultekin, David H. 4116, e16001 Gulzar, Zulfiqar 11096 Gulzow, Mary 6539 Gumbrecht, Walter 591 Guminski, Alexander David 9046 726s

Guminski, Alexander 9062 Gummadi, Tulasi 9048 Gump, William e21000 Gumurdulu, Yuksel 9587 Gumus, Mahmut e11540, e14533, e14705, e15100, e15117, e19107 Gumus, Yusuf e19513 Gumussoy, Ozge e19107 Gumz, Brenda Pires e15155 Gunaldi, Meral 9587 Gunapala, Ranga e19007 Gunasagar, C. e19092 Gundabolu, Krishna 7125 Gundeti, Sadashivudu 7061, e18000, e18003, e19533, e20684 Gundgaard, Maria Gry 4502, 4533, e20561 Gunduz, Seyda e14683, e14696, e18517 Gunn, Shelly e22088 Gunter, Marc J. e22009 Guntinas-Lichius, Orlando e17021 guo Wei, Zhang e19085 Guo, Cheng-cheng 8503, 8573, e13037 Guo, Chengcheng 8508 Guo, Fang e15582 Guo, Huiqin e19080, e19081 Guo, Jiajia 1084, e12006 Guo, Jun e15622, e20027 Guo, Shan e15552 Guo, Sheng 3544 Guo, Wei jian e14644 Guo, Wei CRA8007, TPS8126, e19097 Guo, Xin e13531 Guo, Ying e20626 Guo, Yong-Jun 1588 Guo, Zeng-qing 4025 Guollo, Andre 7037 Gupta, Abha A. 10554, TPS10593 Gupta, Arun e14566 Gupta, Ashok Kumar 3002^, 3003^, 3016, TPS3106, TPS3110, TPS3111, TPS3113, 4514, 8030, CRA9006^, 9012^ Gupta, Avinash 2586, 3018, 9068 Gupta, Digant 5036, e17502 Gupta, Manish TPS3114 Gupta, Natasha 5564 Gupta, Neel Kamel e19541 Gupta, Neeraj 2555, 8514 Gupta, Niraj K. e14698 Gupta, Rajnish K. 1591 Gupta, Ritu 7081, 7082, e19524, e19526, e22098 Gupta, Sanjay 8104 Gupta, Shilpa e15115 Gupta, Shweta e12523 Gupta, Subhadra 2 Gupta, Subhash e13043, e20679 Gupta, Sudeep 524, 629, 1131, 5554, e20678 Gupta, Vikas 7067, 7071, 7078 Gupta, Vinay 2058, 8587, 8600 Gupta, Vishal 6019, 6062 Gurell, Daniel e22095 Guren, Tormod Kyrre 3571, 3573, 3597, e14710


Gurleyik, Gunay Gurman, Gunhan

e12037 7038, e18009, e18010 Gurney, Howard 543, 4580 Gurpide, Alfonso e19027, e19106, e19114 Gursoy, Pinar e12018, e13578 Gururangan, Sridharan 2035, 10021 Gusakova, Irena e22069 Gusella, Milena 9554, e13514, e20541 Gusso, Giuseppina 641 Gust, Kilian e15590 Gustafson, Eric e14599 Gustafson, Gary S. e16008 Gustafson, Michael P e20037 Gustavsen, Gary e11504 Gutheil, John 7074 Guthrie, Troy H. TPS9103 Gutierrez Restrepo, Eduardo e18513 Gutierrez, Andres A. TPS3106, 4514 Gutierrez, Antonio 10529 Gutierrez, Benjamin e16035 Gutierrez, Eddy Isabel e14628, e14712 Gutierrez, Martin TPS3113, 8522, 10514 Gutierrez-Barrera, Angelica M. e12550 Gutin, Alexander 5005, 5043 Gutin, Philip H. 2057 Gutzmer, Ralf 9004, 9013, 11009 Guven Mert, Aslihan e15100 Guven, Aslihan e11540 Guy, Gery P. 1130 Guy, Laurent e16021 Guy, Michelle e16000 Guyman, Laura e13041 Guyomard, Aurelie 1114 Gwede, Clement K. e12556 Gwin, William Rayford e13517 Gyan, Emmanuel 2032 Gyergyay, Fruzsina Eva e15530 Günther, Andreas 8604 Gyorffy, Balazs e11564

H Haag, Georg Martin 4079 Haaland, Benjamin 524, e11591 Haan, Josien 3552 Haanen, John B. A. G. 3036, 9078, 9085, e15525 Haas, Christian J. 9098 Haas, Julia 8023 Haas-Kogan, Daphne A. 10060 Haase, Oliver e15068 Haasjes, Janny G. 3502 Haba, Reiji e22108 Habben, Kai 2092 Habbous, Steven 6033 Habeebu-Adeyemi, Fatima Murtazha e11612 Haber, Susan G. 6514 Haberal, Nihan e16526, e16528, e16536 Haberl, Hannes 2038 Haberle, Beate 10037

Habermann, Anika 5531 Habermann, Thomas Matthew 8504, 8533, 8563 Habersetzer, Francois TPS4161^ Habets, Leo e22201 Habib, Nagy A 2576, 5562 Habibi, Mehran TPS1144 Habibian, Muriel LBA4500 Habra, Mouhammed Amir TPS6100, e17016 Habte-Gabr, Eyassu 6567 Hack, Stephen Paul TPS4155 Hacker-Prietz, Amy 4039, 4057, e15028 Hackl, Bettina 7019 Hackman, Trevor TPS6097 Hackmann, John TPS1141 Hadaschik, Boris e16063 Haddad, Abdo S. 1038 Haddad, Dana 9034 Haddad, Elie 10048 Haddad, Mojgan 604 Haddad, Robert I. 1594, 6023, 6030, CRA6031, 6054, 6058, 6088, 9530 Haddad, Tyler C 6023, 6058 Haddad, Zaid 4542 Hade, Erinn e20018 Hadenfeldt, Rebecca 6539 Hadengue, Alexandra 6036 Hadfield, Matthew TPS2627 Hadid, Tarik H. 7075 Hadji, Peyman 591, e11525, e11601 Hadley, Alison Maree TPS5614 Hadley, Terence J. 8062 Hadwin, Richard 5507^ Hadzikadic Gusic, Lejla 1098 Haeberle, Lothar 591, 640, 11042 Haefeli, Walter E. 3090 Haenebalcke, Christel 7541 Haenel, Mathias 8566 Haese, Alexander 5043 Haferkamp, Bonnie e14707 Hafner, Shria 9023 Hagel, Christian 7027 Hageman, Lindsey 10004 Hagemann, Ian S. 11099 Hagemann, Thorsten 11071 Hagemeister, Fredrick B. 8523 Hagenbeck, Carsten 640 Hager, Henrik 5532 Hagerman, Linda 518, 9032 Haggag, Rasha Mohamed 4537 Haggstrom, David 6536, 9594 Hagiwara, May e20665 Hahn, Markus 1030 Hahn, Noah M. 4563, TPS4588^, TPS5101 Hahn, Seung Shin 6059 Hahn, Stephen M. 7578 Hahn, William C 1531 Haider, Kamal 3580 Haigentz, Missak 6047, 6064, 8097 Haigis, Robert e22177 Hainaut, Pierre e22154 Haince, Jean-Francois 3639 Hainsworth, John D. 5513, 8062, 8091, TPS8120, 9026, 11080, 11102, e13045, e15006, e15501, e19062

Hainsworth, John D. 5009 Haj Mohammad, Nadia e15103 Hajduch, Marian 1063, e22109 Hajek, Roman 8517, 8544 Hajj, Carla 3605 Hakamada, Kenichi e15179 Hakendorf, Paul 3592 Hakimi, A. Ari 4573, e12527 Halabi, Susan 1592, 4520, TPS4590, 5011, 5031, 11053 Halama, Niels 3035 Halamkova, Jana e14622 Hale, Diane F. 3005, 3097, TPS3126 Hales, Gill 5542 Hales, Russell K. 9636 Haley, Barbara B. 1003 Haley, Sherri 11036 Halfdanarson, Thorvardur Ragnar 6542, e19065 Halford, Sarah E. R. 2525 Hall, Anthony 3029 Hall, Brett 8502 Hall, Geoff 5514 Hall, Lawrence 3014 Hall, Louise e20588 Hall, Marcia TPS5615 Hall, Merryn 4081 Hall, Nathan 1023 Hall, Per 4536 Hall, Peter TPS656 Hall, Simon J. 6613 Halle, Martin e20623 Hallek, Michael J. TPS7133 Hallek, Michael 7004, 7015 Haller, Nairmeen Awad e18011 Hallman, Doreen M. 8537, 8565, e19518 Hallmeyer, Sigrun TPS3128 Hallquist, Allan e16525, e18538 Halmos, Balazs 8114 Halpenny, Barbara e20552 Halperin, Daniel M. 4036 Halpern, Michael T. 6514 Haluska, Frank G. 7001, 7063, TPS7129, 8031 Haluska, Paul 1052, 5510, 5515 Halwani, Ahmad Sami TPS3113 Halytskyy, Oleksandr 9536, 9551, 9595 Ham Guo, Maung Shwe 6589, 9506, e20566 Hamadani, Mehdi 7040, 7045, 7058, 8557, TPS8612 Hamaguchi, Tetsuya 3559 Hamaloglu, Erhan e15168 Hamamoto, Yasuo e14527 Hamann, Heidi A. 6601, 8017 Hamauchi, Satoshi 4074, e14623 Hamberg, Paul 11045, e11548, e13513 Hamblett, Kevin J. 11095 Hamburg, Solomon I. TPS2621 Hamburger, Tamar e20039 Hamdan, Alhafidz 2075 Hamdy, Ahmed M. e15014 Hamdy, Nayera 10044 Hamdy, Neveen A. T. 1028 Hamed, Alaa e12554 Hameed, M 10558

Hamid, Omid 3000, 3001, 3022, 3507, 3622, 4505, 4531, 9005, 9009, 9010, 9016, 9026, 9032, 9037, 9041, 9053, 9058, 9059, 9066, TPS9105^, e13574 Hamidi, Habib 5510 Hamilton, Ann S. 6532, 6615, 9601, e20511, e20532 Hamilton, Betty Ky 7008 Hamilton, Erika Paige 1076, e17562 Hamilton, Garth 11115 Hamilton, Jackson e13035, e13044, e13051 Hamilton, Nicola 606 Hamilton, Robert 4568 Hamilton, Ronald L. e22017 Hamlin, Paul A. 8571 Hamm, Alexander 3588 Hammad, Nazik 1593, 3534 Hammam, Walid e11614 Hammel, Pascal LBA4003, 4041, 4046 Hammerman, Ariel 639, e14571 Hammerman, Peter S. 6008, 6010 Hammers, Hans J. 4566, TPS4593, 5021, 5076, e15597, e15598, e16051, e16068 Hammerschmid, Nicole 549 Hammerstingl, Renate e15061 Hammond, Samantha 2013 Hampel, Heather 1530, 1556 Hampshire, Margaret K. e20671 Hamulak, John e19012 Hamza, Mohamed Ali 2042 Hamzaj, Alketa e16093 Han, Baohui 7507, e19018 Han, Chun e15030 Han, Dolly 6585, e17526 Han, Ernest Soyoung 5599 Han, HQ 2541 Han, Hyo S. 1118, 3026, 3069 Han, Jae Young 7555 Han, Ji-Youn 8105, 8108, e19019 Han, Kelong 2603, e14505 Han, Lei 8048, e19033 Han, May e19002 Han, Paul 6536 Han, Sae Won 3550 Han, Sae-Won 551, 2565, 4044, e15066 Han, Sang Uk e15020 Han, Shi Rong e13506 Han, Wonshik 551, 1039, 1128, e22063 Han, Xiao-Hong e19075 Han, Xuesong 6569 Hanamoto, Atsushi 6082 Hanamure, Yutaka 6004 Hanaoka, Takuya e20585 Hancock, Michael L. e16015, e19100 Handgretinger, Rupert 10007 Handisides, Damian 8602 Handley, Kelly 5 Handorf, Charles e22033 Haney, Patricia 9013 Hanfstein, Benjamin 7051 Hang, Evelyn 5077 Hangauer, David G. e13505

Hanker, Lars Christian 602, 5531 Hankonarson, Hakon 10004 Hanley, Amy E. 6533 Hanley, Michael J. 2555 Hanlon, Courtney 8602 Hanlon, Katherine 8579 Hann, Christine L. 7598 Hanna, Diana L. 3527, 11062 Hanna, Ehab Y. 9047 Hanna, Glenn J. 6023, 6054, 9530 Hanna, Mina Samir Erian e17566 Hanna, Nader e14524, e14602 Hanna, Nasser H. 1561, 4557, 8029, 8034, e15584, e19126 Hanna, Nasser 8106, TPS8125 Hanna, Rabbie Kriakoss e16552 Hannah, Alison L. 1087, 2566 Hannah, Alison 5066 Hanniford, Douglas 9089, 9091 Hannig, Carla 3531 Hannon, Breffni e20639 Hannouf, Malek Bassam 1605, e12549 Hanocq, Florence e11549 Hanrick, Marian e14519 Hanse, Monique 2001 Hansen, Aaron Richard 6045, 11002, 11016 Hansen, Anker e22065 Hansen, Daniel 2518 Hansen, Joergen 3572 Hansen, Katrine Urth 6600 Hansen, Lissi e20702 Hansen, Nora M. e11572 Hansen, Olfred 7504 Hansen, Ryan N e17527 Hansen, Steinbjorn 2088 Hansen, Tine Plato 6600, e15099 Hansen, Torben 3572 Hanson, John e13503 Hanson, Nana 8079 Hansra, Damien Mikael 1586, e11611, e19140 Hansson, Arne G. 612 Hansson, Johan 9036 Hanusch, Claus TPS1138 Hao, Desiree e12505 Hao, Xuezhi 7507 Hao, Yanni 9617, 9618 Hapfelmeier, Alexander 581, e15042 Happe, Antje e20710 Haqq, Christopher M. 2541 Haque, Sofia 6024, 6034 Har-Zahav, Gil 9630 Hara, Akinori LBA4002 Hara, Hidehiko e15527 Hara, Hiroki 4074, e15031 Hara, Isao e16092 Harada, Akiko e13511 Harada, Hideyuki 7556 Harada, Masao 7530, 8033, e19142, e20609 Harada, Taishi 8111, 11055 Harada, Toshiyuki e19142 Haraldsdottir, Sigurdis 1556, e14535 Harari, Alexander e20011 Harari, Paul M. 6007, TPS6099 Harats, Dror TPS2102 Harb, Wael A. 557, 2609, e13502

Harbeck, Nadia 508, TPS649, TPS652, TPS655^, 1092 Harbison, Christopher 8072 Harcharik, Sara 3014, 9080 Hardacre, Jeffrey M. 3007 Hardan, Izhar 8509 Hardcastle, Emily 9609 Harden, Robert Norm 3540 Harden, Susan 7595 Hardenbergh, Patricia H. 6641 Hardesty, Rosemarie A. 2616 Hardin, James W. 8596 Hardin, James 5091, 8586 Harding, James J. 9060 Harding, Kimberly TPS2627 Hardt-Madsen, Michael 6600 Hardwick, Fred e22052 Hardwick, Nicola 3089 Hardwick, Richard 10541, e21503 Hardy, Kristina K. 10034 Hardy-Bessard, Anne-Claire TPS5099^ Hargrave, Darren R. 10027 Hari, Parameswaran 6586 Harker, W. Graydon 4504 Harkin, D. Paul TPS11120 Harkness, Cameron Blair e20648 Harlan Fleischut, Megan e12536 Harland, Stephen John 4535 Harle, Alexandre e11560 Harleaux, Dina 3103 Harlos, Craig Henry 1597 Harlow, Seth P. 1000 Harmankaya, Kaan 9024, 9053, 9059 Harmenberg, Ulrika e15553 Harmer, Victoria TPS656 Harmon, Jocelyn 4038 Harnicek, Dominique e13540 Harning, Ronald 2557 Harold, Nancy TPS5095, 8094, e16017 Haroldson, Sylvia e19015 Harper, Felicity W. K. e20646 Harper, Jamie e17590 Harputluoglu, Hakan e18560 Harrell, Robyn K. 6580, 6607, 9604, 9605 Harrelson, Robin 2516^ Harries, Mark LBA9000 Harrington, Jennifer 9590 Harrington, Kevin J. 3062 Harris, Dean Laurence TPS4157 Harris, Deborah 4528 Harris, Faye R. 7568 Harris, Gordon J. 513 Harris, Jonathan 6007 Harris, Kathleen R. e22204 Harris, Lyndsay 500, 619, 1046, 2587 Harris, Marion 4005^, e15188^ Harris, Pamela Jo 2553, 9517 Harris, Rebecca 3509 Harris, Robert J. 2055 Harris, Samuel John 11072, e18559 Harris, Wayne e15617 Harris, William Proctor 4010, e15005 Harrison, David A. 9573 Harrison, Deb e20668 ABSTRACT AUTHOR INDEX

727s

Harrison, Lauren Harrison, Louis Benjamin

3055 6091, e17030 Harrison, Michael Roger e15508, e15605 Harrison, Michelle L. e20584 Harshman, Keith 9014 Harshman, Lauren Christine 4525, 4586, e15518 Hart, Charles P. e13527 Hart, Eric M 8036 Hart, Lowell L. 3508, 3564, e13045 Hart, Lowell 558 Harte, Steven 9615 Harter, Philipp 1577, LBA5503, 5505, 5531 Hartfeil, Donna M. 5003 Hartkopf, Andreas D. 1030, 5598, 11012 Hartlapp, Ingo e15193 Hartley, Dylan 645 Hartley, Eliza TPS10592 Hartman, Anne-Renee 1544 Hartman, Christina TPS3113 Hartmann, Arndt 1092 Hartmann, Christian 2007, 2027 Hartmann, Joerg Thomas 3538 Hartmann, Lynn C. 5510, 5546 Hartsell, William F. 7578, 9502 Hartung, Gernot Georg 4035 Hartzema, Abraham e16013 Haruki, Tomohiro 7557 Harun, Nusrat 6030, 7552, 8102 Haruta, Rumi e22113 Harvey, Allison 9578 Harvey, Becca 9084 Harvey, Donald 6083 Harvey, Harold A. 1024 Harvey, R Donald 3026, e20596, e20608 Harvey, Vernon J. 628 Harvey-Berino, Jean 9591 Harza, Mihai 3073, 4564 Harzman, Alan e14535 Harzstark, Andrea Lynne TPS2623, 5077 Hasan, Baktiar 7584, 7585 Hasanein, Hassan e20036 Hasanovic, Adnan 8022, 8067 Hasegawa, Dave 11044 Hasegawa, Hiroko e14551 Hasegawa, Hiromi 2559 Hasegawa, Seiki 7583, e18557 Hasegawa, Takeo e19162 Hasegawa, Yasuhisa 6004 Hasegawa, Yoshie 613, 1029, 6588 Hasenbach, Kathy 2081 Hasford, Joerg 7051 Hashemi Sadraei, Nooshin e19012, e19025 Hashemi-Sadraei, Neda e13031 Hashibe, Mia 1582, 1594 Hashiguchi, Yasunori e20676 Hashim, Nurul Asykin 3627 Hashim, Yassar e16508 Hashimoto, Hironobu 9621 Hashimoto, Masaki e18557 Hashimoto, Shiho 5590 Hashimoto, Yasuhiro e15565 Hashizume, Masahiro 7548 728s

Hashizume, Toshinori 7536 Hashmi, Salman 11106 Hashmi, Sharukh 7064, 7094 Hasky, Noa e20548 Hasrouni, Edy 7008 Hass, Peter 6077 Hassall, Timothy E. 10021 Hassan, Andrew Bassim 10516 Hassan, Khaled Aref 7522 Hassan, Maha e17557 Hassan, Manal 4064 Hassan, Raffit TPS7607 Hassan, Shazia 6552 Hassan, Syed e22184 Hassanein, Hala 10044 Hassanein, Mohamed K. e22011 Hassel, Jessica Cecile 9020, 9027, 11009 Hasselblatt, Martin 2056 Hassett, Michael J. 6565 Hassett, Michael 6562 Hassoun, Hani 8545 Hasturk, Serap e19071 Hata, Akito 8098, e19017, e19045 Hata, Taishi 3516, e14551 Hata, Yasuhiro e14527 Hata, Yoshinobu 11052 Hatabu, Hiroto e19125 Hatahet, Kamel 9546 Hatake, Kiyohiko e20576, e22190 Hatakeyama, Shingo e15565 Hatanaka, Kazuteru e14604 Hatano, Takashi e15527 Hatcher, Helen 10541, e21503, e21516 Hatse, Sigrid 1078 Hattori, Akinori e11604, e12026 Hattori, Masaya e12001 Hatzidaki, Eleana e16083 Hau, Peter LBA2000, LBA2009, TPS2103 Haubold, Kathrin e22055 Hauch, Siegfried e14567 Haugnes, Hege Sagstuen 4553, 4562 Hauke, Ralph J. 4563 Hauke, Ralph 2533 Hauns, Bernhard 3625, e15088 Haupt, Eric C. 5073, 5090, e16001 Hauptmann, Michael 4536 Haura, Eric B. 3091, 8001, 8019, 8085, e22155 Hauschild, Axel 9013, 9025, 9026, 9030, 9036, 9046, 9058, TPS9104, TPS9106, e20025, e20028 Hausman, Diana Felice 2053, 5042 Haustermans, Karin 3531 Hautmann, Matthias 6077 Hautzel, Hubertus e16003 Hauzenberger, Tanja TPS1141 Havel, Libor 605, 7500, 8043 Haverstad, Rune 7504 Havlat, Luiza 8505 Havrilesky, Laura Jean 5523, e16529 Hawes, Debra e16020 Hawes, Susan 2573 Hawety, Amr e13025 Hawkes, Eliza Anne e19543 Hawkins, Cynthia 10029 Hawkins, Douglas S. 10012, 10554


Hawkins, Michael J. TPS4149 Hawkins, Robert E. 3073, TPS4590 Hawkins, Tim E. 8537, 8565 Hawkins, William G. e16508 Hawkins-Daarud, Andrea e13028, e13041 Hawley, Sarah T. 6615, 9579, 9601, e20511 Hawryluk, Matthew J. 11100 Hawthorne, Ben e22031 Haxel, Boris e17021 Hay, Kevin A. 8552 Hayakawa, Kazushige 4070 Hayanga, Jeremiah William e17534 Hayase, Ryouji 5526 Hayashi, Hidetoshi e13501, e19023, e19165 Hayashi, Katsumi 10543 Hayashi, Kazuhiko TPS4152 Hayashi, Mitsuhiro 1029 Hayashi, Naoki 1126, e11524, e20683, e22064 Hayashi, Naomi e14552, e14614 Hayashi, Narihiko e16098 Hayashi, Nobuya e13501 Hayashi, Shin-ichi e22019 Hayashi, Tetsutaro e15590 Hayashi, Toshinobu 9621 Hayashi, Tsutomu e15112 Hayashida, Tetsu e11598 Hayat, Henry e15597, e15598, e16023 Haybaeck, Johannes e15064 Haydar, Mazen e19513 Hayden, Jill 9615 Haydon, Andrew Mark 3093^, TPS3649 Haydu, Lauren 9062, e20020 Hayenga, Jon e22031 Hayes, Christi e16546 Hayes, Daniel F. 1052, 9615 Hayes, David N. 6009, 6022, 6047, 6094, TPS6097, 7576 Hayes, Ellen e20687 Hayes, Jad 6580 Hayes, James E. 1554 Hayes, Monica Prasad e16551 Hayes-Lattin, Brandon M. e20627^ Hayman, Anne e13035 Hayman, James 7522 Hayman, Suzanne R. 8516, 8541, 8581, 8587, 8600, 8606 Haynes, Debbie 11102 Hays, John L. 2514 Hayslip, John W. 7084, e18001 Hayward, Larry 10517 Hayward, Rodney A. 6044 Haz-Conde, Mar e15532, e22021 Hazama, Shoichi 3006 Hazard, Sebastien e19022 He, Aiwu Ruth 2616, TPS2624, TPS4159 He, Chao sheng e15567 He, Jie 9002, 11100, e22146 He, Jintao e19161 He, Kuanglin 5563 He, Mengye e22094 He, Qingqing e22089 He, Suqin e19097 He, Wei e22186

He, Xia 2543 He, Xiaofeng TPS4154, e14645 He, Xiaping 512 He, Yayi e19166, e22070 He, Yi 1049^, 1050^, 1055^ He, Yong e19026 He, Zhao hui e15567 Head, Bobbie 1003 Head, Jonathan F. 3087 Head, Julia 4549 Healy, Patrick 5031 Heard, Bridgette e17590 Heath, Elisabeth I. 5041, 5085, e22168 Heathcock, Lindsey 2026 Heaton, Robert B. e19057 Hebart, Holger Frithjof 4034 Hebbar, Mohamed 3599, e15134 Hechmati, Guy e16052 Hecht, J. Randolph 3520, 3533, 3616, LBA4001 Heckel, Dirk e20030, e20038 Heckler, Charles E. TPS9647, TPS9651, e20526 Heckler, Charles E. 9572 Heckman, Michael 7047 Heckman-Stoddard, Brandy M. 1516 Hedley, David W. 2534, 4049 Hedlund, Gunnar Eric 3073 Heemskerk, Bianca 3036, 9078, 9085 Heemskerk-Gerritsen, Bernadette Anna Maria 1502 Heerdt, Alexandra S. 1019 Heerema, Nyla A. 10001 Heerma van Voss, Marise R. e22174 Heery, Christopher Ryan TPS3127, TPS5104, e16036 Heese, Scott 1042 Heetfeld, Maximilian e15071 Heffner, Leonard T. 8540 Heffner, Leonard 8545 Heflin, Lara 6619, 6620 Hegde, John e16026 Hegde, Upendra P. 9620 Hege, Kristen 2606, 8522, e15004 Hegenbart, Ute 8545 Hegerova, Livia 8581 Hegewisch-Becker, Susanna TPS3124^, 4086 Hegg, Roberto 531, 5541 Hegi, Monika E. 2007, LBA2009 Hehlmann, Rüdiger 7051 Heidecke, Claus Dieter e16534 Heidecke, Cordula Nicole 11027, 11067 Heideman, Danielle 8065 Heideman, Jennifer 2537, 2607 Heidemann, Danielle e22184 Heidenreich, Axel 5001, 5055, TPS5098^ Heijndijk, Marianne e14587^ Heijns, Joan Barbara 1028, e22106 Heike, Michael TPS3124^, 4079 Heil, Daniel S. 8578 Heil, Gerhard 4035 Heil, Joerg 11012 Heilbrun, Lance K. 5041, 5085, 6045, e22168 Heim, Jennifer e22009

Heinemann, Volker TPS3124^, LBA3506, 3630, 4007 Heinrich, Bernhard 508, TPS1141, 5019 Heinrich, Georg 11043, e22075 Heinrich, Michael C. 10509, 10510, 10511 Heintges, Tobias LBA3506 Heiss, Markus M. 3078 Heist, Rebecca Suk 2530, 4090 Heitjan, Daniel 519 Heitmann, Jonas S. 7019 Heitz, Florian 1577 Hejna, Michael e15041 Helbich, Thomas 11088, 11093, e22090 Helbig, Ulrike 4080 Held, Gerhard 8566, 8569, 8570 Helene, Charytansky 566 Helenowski, Irene B. 2083, 3540, 5574 Helfgott, Daniel e15192 Helft, Paul R. 3546 Helgason, Thorunn 2531 Helissey, Carole 9556 Helle, Svein Inge 5068 Hellemans, Peter 8502, 8530 Heller, Glenn 5032, 5083 Heller, Wolfgang H. e20610 Hellman, Maria 5563 Hellmann, Andrzej 7066 Hellmann, Matthew David 7559, 8018 Hellwig, Karsten e14513, e14562 Helman, Joseph 9607 Helman, Lee J. 10025, 10040, 10522, TPS10591 Helms, Gisela 1020 Helton, Joan e20592 Helton, Scott 4043 Helvaci, Kaan e14533, e15110 Helwig, Christoph 7500 Helzner, Elizabeth 8594 Hembrough, Todd A. e19057 Hemperly, Stephen e20046 Hemphill, Michael Brian 2544 Henao Carrasco, Fernan e22073 Hendershot, Kristopher A. e20608 Henderson, Aaron e17575 Henderson, Dave e19536 Henderson, Les 4012 Henderson, Michael A. 9001 Henderson, Michael T. 1504 Hendifar, Andrew Eugene 10517 Hendlisz, Alain 3588 Hendrick, Franklin e17584 Hendricks, Ryan 6540, 6613 Hendriks, Jeroen M.H. 7534 Hendrix, Laura H. 5040, 6530, 9592 Henegan, Clark 1548 Heng, Daniel Yick Chin 558, 4565, 4578, 4586, TPS4593, TPS4594, 6622, 9596, e15518 Heng, Jennifer C. TPS1606, 8077, 8116 Hengst, Willem Den 7534 Hengstler, Jan G. 615 Henin, Emilie TPS2625, 5547, e13594

Henke, Michael Henkel, Thomas Hennecke, Silvia Henner, William David

6002 e12517 1537 e22033, e22172 Hennessy, Bryan 3549, e13022 Hennessy, Meliessa G. TPS7610 Hennessy, Sean 6560 Henning, Karla 9055 Henning, Stefan W. 3625, e15088 Hennings, Leah J. e15152 Henriksen, Jonathan 10560 Henriksson, Roger 2002^, 2005^, 2023^ Henry, Christophe e14539 Henry, David H. 9628, 9640 Henry, Norah Lynn 500, 501, 9615 Hens, Angela 540 Henshall, Susan M. e22175 Henshaw, Joshua W. 2580 Hensing, Thomas A. TPS7610, e19113, e19117 Hensley, Martee Leigh 5550, 5595, e13509 Hentrich, Marcus 4559 Hentsch, Bernd 3625, e15088 Hentschel, Bettina 2027, 2045 Heo, Dae Seog 1590, 2098, 6069, 6614, 8521, e18555 Heo, Jeong 4122^, TPS4161^ Heon, Narre e16018 Heong, Valerie e14608 Hepp, Philip Gm e22075 Herbein, Lindsay 8544 Herbolsheimer, Pia Maarit 11054 Herbst, Ronald 7045 Herbst, Roy S. 1561, 3000, 8008, 8045, TPS8118, 11075 Hercbergs, Aleck e22077 Herchenhorn, Daniel 6071 Herkal, Amrita 5032, e16005 Herman, Ben 5003 Herman, James Gordon 3539, 3552, e14503 Herman, Joseph M. 4039, 4057, 6519, e15028 Hermann, Kirstine e14593 Hermann, Robert C. TPS659, 7560, 8012, 8086, e19150 Hermansen, Simon Kjaer 2088 Hermes, Kerstin 6623 Hermine, Olivier TPS8613^ Hernan, Hilary R e17025 Hernandez Garcia, Alba e21509 Hernandez, Ana Banos e20580 Hernandez, Ana 4560 Hernández, Carlos Alberto 4555 Hernandez, E. 7549 Hernandez, Irene e14589 Hernandez, Jesus Maria e22058 Hernandez, Juan Luis e22058 Hernandez, Maria Angeles e22058 Hernandez, Mike e17016, e20568 Hernandez, Rohini Khorana e12508, e16066, e20690 Hernandez, Tatiana 11089, e19000, e19109 Hernandez-Losa, Javier 7514, e16045

Hernando, Cristina 11073, e20007, e22147 Hernando, Eva 9089, 9091 Hernando, Ovidio 3543 Hernando-Monge, Eva 9067 Hernberg, Micaela TPS9106 Herndon, Betty e22189 Herndon, James Emmett 2094, e13015^ Hero, Barabara 10015 Herod, Jonathan 5500 Heron, Dwight Earl 6043, 7502, 7524 Herrel, Lindsey Allison 5067 Herrera, Claudia 10020 Herrera, Luis A. 4555, e22151 Herrick, James L. 10531 Herrin, Jeph 6511 Herrlinger, Ulrich LBA2000, TPS2103 Herrmann, Ken e15042 Herrmann, Michael 3094 Herrmann, Richard 3503 Herschorn, Sally D. 1512 Hersey, Peter 9009, 9020, 9026 Hersh, Evan 9030, 9102, e20025, e20033 Hershberg, Robert Mark 3077 Hershman, Dawn L. 560, 1033, 1118, 2591, 6505, 6509, e15074 Hertz, Daniel Louis 11053 Hertzberg, Mark S. TPS8616 Hertzberg, Mark 8537, 8565 Herwig, Uwe e16535 Herz, Susanne e16533 Herz, Thomas e15088 Herzog, Cynthia E. TPS9104 Herzog, Thomas J. 5566, 5593, 5602, e16548 Hescot, Segolene e22029 Heske, Christine 10025 Heskel, Marina 5609 Hesketh, Paul Joseph 9512 Heslop, Helen E. 8577 Hespanhol, Venceslau e19069 Hess, Allan 3104 Hess, Georg 8507, TPS8614^ Hess, Jordan e17577 Hess, Kenneth R. TPS2106, 2509, 2545, 9544, e22086 Hess, Viviane 3503 Hesse, Thomas e16534 Hesse, Tobias 602 Hessing, Trees 595, 2592 Heth, Jason 2052 Hetzel, David J. e20648 Heuberger, Adam 11050 Heubner, Martin Leonhard 584, e11516 Heukamp, Lukas Carl 1589, 8112, e12517 Heurteau-Foulon, Stephanie 4127 Heuser, Michael 7027 Heutte, Natacha 9510 Hewish, Madeleine e19146^ Hewitt, Chris 9590 Hewitt, Stephen M. 2532 Heymach, John 4042, 6011, TPS8118, 11044

Hibshoosh, Hanina 560 Hicking, Christine LBA2009 Hickingbottom, Barbara 8602, e15557 Hickish, Tamas 3504, 3524, e20713 Hickman, Theresa 4122^, TPS4161^ Hicks, James B. 5030, 11047 Hicks, Lisa K 6592 Hicks, Rodney J. 10567 Hida, Naoya 8054 Hida, Toyoaki 8033, 8105 Hidaka, Brandon H 1515 Hidalgo, Manuel 2511, 2600, 3543, 4005^, 4017, 4041, e11531 Hielscher, Carsten 602 Hielscher, Joerg LBA3506 Hierro, Cinta e17010 Higaki, Kenji 1048^, 6588 Higaki, Yuichiro 6004 Higano, Celestia S. 5003, 5020, 5026, 5034, e16025 Higgins, Ashantice K. 1034 Higgins, Brian Patrick e19077 Higgins, Brian 10514 Higgins, Helen B. TPS656, TPS667 Higgins, Kristin 6083, 7589, e18506 Higgins, Michaela Jane 11019 Higgins, Philip C 6573 Higginson, Irene 9627 Higgs, Brandon W e20047 Higuchi, Katsuhiko 4070, e15113, e15122 Hihara, Jun e22053 Hijazi, Youssef 3048, 3051, 7020 Hijiya, Nobuko 7097 Hikosaka, Tomomi e14623 Hilferty, Rebecca A 8115 Hilfrich, Joern TPS1138 Hilger, Crystal e20605 Hilger, James D. 8598, 8599, e20044 Hilhorst, Riet e14629, e14702 Hill, Arnold D. 1112 Hill, Brian Thomas 7008 Hill, Christopher R 10033 Hill, D Ashley 10024 Hill, John S. 2071, 11095 Hill, Laura A. TPS11120 Hill, Paula e20523 Hill, Sam 635 Hill-Kayser, Christine e20671 Hillejan, Ludger e18511 Hillemanns, Peter 5531 Hillen, Travis 10585 Hillengass, Jens 8590 Hiller, Louise TPS667, 1015 Hillerdal, Gunnar N e19148 Hillman, David W. 1059 Hillman, Shauna L 7502 Hillmen, Peter TPS7133, TPS8619 Hills, Margaret 535 Hilpert, Felix 5531, 5542 Hils, Rita 1577 Hilsenbeck, Susan G. 10023 Hilton, John Frederick 2585, TPS2627 Hilton, Magalie 2002^, 2005^, 2023^ Hilton, Tracy W. e15539 ABSTRACT AUTHOR INDEX

729s

Hindenburg, Hans-Joachim 5569 Hindmarsh, Pamela TPS4146 Hingorani, Sunil R. 4010, 4059^, e15005 Hinson, James M 2617 Hintzman, Patricia F. 2520 Hinzmann, Bernd 3634 Hirabayashi, Masataka 11041 Hirabayashi, Naoki e15112 Hirai, Fumihiko 7529, e19165 Hirakawa, Akihiro e20557 Hirakawa, Kosei 3006 Hirakawa, Masahiro e15060 Hirama, Hiromi e16054 Hirano, Akira e11604, e12026 Hirano, Kenji e15146 Hirano, Satoshi 3638, 4008 Hirano, Teiichi e19507 Hirao, Motohiro TPS4152 Hirao, Yoshihiko 4526 Hirashima, Noboru e15159 Hirashima, Tomonori e19021 Hirashima, Yasuyuki e16507 Hirashima, Yoshinori e14527, e20585 Hirata, Eiji 5526, 11049 Hirata, Kazuto 7564, e18530, e19053 Hirata, Koichi e15060, e20576 Hirata, Toshiki 11041 Hirayama, Michiaki e15060 Hiret, Sandrine 8028 Hirmand, Mohammad 5065 Hirohashi, Tomoko 11031 Hironaka, Shuichi 4076, TPS4152, e15016 Hirose, Hajime 9095 Hirose, Takashi e19164 Hiroshi, Nakanishi 7573 Hiroshima, Yukihiko e13576, e13577, e22011, e22012 Hirota, Makoto 6060 Hirota, Seiichi 10539 Hirsch, Bradford Richard e15508, e15572, e15605 Hirsch, Fred R. 1067, 8106, e22042 Hirsch, Michelle S. 4561, 5056, e16026 Hirschberg, Sandra 635 Hirsh, Vera CRA8007, 8108, TPS8126, e19037 Hirshaut, Yashar e15192 Hirshfield-Bartek, Judith 1105 Hirte, Hal W. 2523, 2534, 11016, e13502 Hirte, Hal 5517 Hirway, Priay 10035 Hirzel, Alicia e11575 Hisamatsu, Kazufumi 571 Hisamoto, Akiko 7530 Hishiki, Tomoro 10038 Hishima, Tsunekazu e18524 Hishinuma, Shoichi 4008 Histed, Stephanie 11083 Hitier, Simon 5055 Hitron, Matthew J. 2542 Hitschold, Thomas 602 Hitt, Ricardo 1575, e13008, e19123 Hitzler, Johann 10032 Hixson, Douglas e14637 730s

Hiyama, Eiso 10038 Hjelde, Harald Harris 9562 Hjort, Lars 10031 Hlavata, Zuzana e22023 Hlavsa, Jan 11051 Hlubocky, Fay J. 6612, 9520, e17511 Ho, Alan Loh 6024, 10558 Ho, Alice Y. 1021 Ho, Anthony D. 8590, 9612 Ho, Baotran e13547 Ho, Cheryl 7551, e19039, e19131, e19147, e22020 Ho, Ching-Liang 4018 Ho, Garrett CL e14530 Ho, Han Kiat 9506, e13582, e20566 Ho, Jingshan 586 Ho, Judy e16019 Ho, Patty PY e14530 Ho, Thai Huu 4567, e16065 Ho, Timmy-Tai A e17590 Ho, Viet 7113 Ho, Wing Ming e15048 Ho-pun-cheung, Alexandre e14621 Hoang, Catherine 6093 Hoang, Khang 7016 Hoang, Tien 2607, 9566, e18537 Hoang-Xuan, Khê 2005^, 2007, 2032, 3065^ Hobday, Timothy J. CRA1008, 1033, 4032, e20605 Hoberman, Kenneth 7029^ Hobor, Sebastijan 11005 Hoch, Jeffrey S. 6033, e19031 Hoch, Ute 1087, 3060 Hochhaus, Andreas 7001, 7051, 7052^, 7054^, TPS7129 Hochmair, Maximilian J. e19093 Hochman, Tsivia 11106 Hochster, Howard S. 3587, 4011, 4084 Hochwald, Steven N. e13547, e13556 Hocke, Julia TPS4160 Hockett, Richard e22139 Hoda, M.Raschid e22055 Hodge, Jeff Paul 9027 Hodgin, Mary 4039 Hodgkinson, Victoria e22123 Hodgson, David C. 10000 Hodgson, Nicole 1002 Hodi, F. Stephen 3000, 3001, 3002^, TPS3106, TPS3107, TPS3110, TPS3114, CRA9006^, CRA9007, 9009, 9010, 9041, 9076, TPS9103, TPS9105^, TPS9107^ Hodin, Richard e17014 Hodis, Eran 9015, 11009 Hoe, Nicholas 3626 Hoeffken, Gert 8013, e19148 Hoeffkes, Heinz-Gert 1082, TPS1137 Hoefler, Heinz 581 Hoegdall, Estrid Vilma Solyom 3572, e14593 Hoehler, Thomas 3586, e14502 Hoekstra, Harald J. 9001 Hoekstra, Otto S. e22128 Hoeller, Christoph 9024, 9025 Hoelzer, Karen L. e20526 Hoering, Antje 4063, 8515, 8603 Hoff, Paulo M. LBA4001, 9561, e14590, e14652, e20579


Hoff, Paulo Marcelo 3520, TPS4150, e15090, e20691 Hoffman, Heather J. 11106 Hoffman, Karen Elizabeth 5069 Hoffman, Mark Allan e16546 Hoffman, Richard M. 6532 Hoffman, Robert M. e13576, e13577, e22011, e22012, e22013, e22014, e22209, e22210 Hoffman, Steve e22095 Hoffman-Censits, Jean H. 4527^, 5061 Hoffmann, Chen e13002 Hoffmann, Isabell 1074 Hoffmann, Thomas 3586 Hoffmeyer, Anna 6530 Hofheinz, Ralf Dieter 4009, 4079, 4095 Hofheinz, Ralf 3531, 3561, TPS4158 Hofland, Kenneth e15099 Hofman, Paul 8100, e19046 Hofman, Veronique 8100 Hofmann, Daniel TPS655^ Hofmann, Inga 10054 Hofmeister, Craig C. 8532, 8584, 8588 Hofree, Matan e15562 Hofstatter, Erin Wysong 1565, TPS1609, 2587, 6635 Hofstetter, Gerda e16524 Hofstetter, Wayne Lewis 4078, 4083, 4085, e15013, e15053 Hofstädter, Ferdinand e20517 Hogan, William J. 7041, 7064, 7094 Hogendoorn, Pancras C. W. LBA10504 Hogeveen, Sophie 6585, e17526 Hogg, David TPS10593 Hogge, Donna 7029^, 7100 Hoh, Carl 11098 Hohenberger, Peter 10500, 10503, 10551, 10566 Hohenberger, Ralph 10566 Hohenberger, Werner 3561 Hohenfellner, Markus e16063 Hohl, Raymond J. 2575 Hohmann, Nicolas 3090 Hohn, Gabriela e20701 Hohneker, John A. 2610 Hoimes, Christopher J. e15543 Hojat Farsangi, Mohammad 7087, e22198 Holash, Jocelyn 7111 Holcombe, Randall F. 4010, e15005, e20570 Holdai, Veera e20628 Holden, Sylvia A. TPS2627 Holden, Viran R. LBA8003 Holdgaard, Paw Christian e19163 Holdhoff, Matthias 2016, 2034, TPS2105 Holdren, Matthew 3019 Hole, Knut Hakon 3547 Holen, Kyle D. 2520 Holes, Leanne 7005, 7017, 8500, 8501 Holgado, Esther 1575, e13008, e19123 Holgado, Silvia e11538 Holguin, Francia e19159

Holland, Eric C. 2095 Holland, Jack e17515 Holland, William S. 8110 Hollander, Abby e17553 Hollander, Niels Henrik 3572, 4052 Hollebecque, Antoine 2512, 3010, 4505, 4574, 7604, 9556 Hollen, Patricia J 8087, 8092 Hollenbach, Stanley 8574 Hollenbeck, Brent K. 5044 Hollenhorst, Helmut 5048 Hollerbach, Stephan 3531 Holley, Veronica R. 11086 Holliday, Laura e17587 Hollingshead, Melinda G. 11103 Hollis, Donna 6501 Hollman, Travis 3003^ Hollman- Hewgley, Denise e18539, e19536 Holloway, Claire 1018 Holloway, Melanie e14516 Hollowell, Courtney M. P. 2590, e16085 Hollywood, Ellen TPS4144 Holm, Bente 8084, 8103 Holm, Niels Vilstrup 4502, 4533 Holman, Laura L. 1569, 5596, e16556 Holmes, Chris E. e12000 Holmes, Elaine e14620 Holmes, Frankie Ann 590 Holmes, Holly Michelle 4064 Holmes, Jarrod P. TPS3126 Holowaty, Eric J. 4536 Holsinger, F. Christopher TPS6100 Holstein, Sarah Abigail 2575 Holtzman, Matthew Peter 9043 Homann, Nils 4079, 4095 Homel, Peter e20607 Homerin, Michel TPS4161^ Homicsko, Krisztian TPS2103 Homma, Sakae 11052 Homma, Shigenori e14548, e15038 Hommel-Fontaine, Juliette TPS2625 Homsi, Alaeddin 2593 Hon, Henrique 6543 Hon, Jeremy K. 4059^ Honda, Hiroshi e15008 Honda, Kazufumi e15080 Honda, Kord 7036 Honda, Tatsuya TPS3116 Honecker, Friedemann 4559, 9553 Honegger, Juergen Bernd e20050 Honeywell, Richard 11087 Hong, Angela 9001 Hong, Bum-Sik e15519 Hong, Dae Sik 11030, e22199 Hong, David S. 1051, 2506^, 2509, 2545, 2611, 6090, 8523, 9544, 11086, e13534, e13575, e13591, e22086 Hong, Fangxin e20552 Hong, Huang Ming 8503, 8508, 8573 Hong, Ji Hyung e14563 Hong, Jin Hwa 5539 Hong, Jun Hyuk e15516, e15519 Hong, Jung Yong 637, 1088, e15613 Hong, Junshik 3595

Hong, Junsik e19129 Hong, Quan 3003^, 9012^ Hong, S. Peter 10042 Hong, Seung-Hyun e19019 Hong, Sook Hee 1540, e15164 Hong, Sung-Hyeok 10042 Hong, Susan 1506, 11084 Hong, Theodore S. 4047, e14636 Hong, Waun Ki 8079, TPS8118 Hong, Xiao-Nan 8525 Hong, Ye 4577 Hong, Yong Kil LBA2009 Hong, Yong Sang 3570, 3628, 10589 Hong, Young Seon e15164 Hongo, Fumiya e15526, e15531 Honkoop, Aafke H. 1072 Honkoop, Aafke 2001 Honma, Rio 7550 Honma, Yoshitaka 3559, 4074 Honma, Yuichiro e19043 Honnorat, Jerôme 2020 Honsova, Eva 11051 Hood, Brian L 6051 Hoogstraat, Marlous L. 1010 Hook, Jane 5500, LBA10504 Hooker, Craig M. 7598 Hoon, Dave S. B. 9095 Hooning, Maartje 1502 Hope, Kirsty e16040 Hopfinger, Georg 7015 Hopkins, Jenny R. 1596 Hopkins, Judith O. 4520 Hopkins, Tom 2576 Hopkins, Wendie 2583, 3093^ Hopman, Wilma e14553, e17518 Hopmans, Sarah e16011 Hopper, John L. 1559, e20660 Hoque, Ehteshamul e19501 Hoque, Mohammad 4566 Horai, Takeshi 7556 Horak, Christine E. 3003^, 3016, TPS3114, 9012^ Horak, Ivan David 3551, 6002 Horak, Peter e16042 Horan, Anastasia e20550 Horan, Gail e21503 Hord, Norman e13047 Horenblas, Simon e15525 Horgan, Anne M. e14515, e20550, e20687 Horgan, Anne M. 4130 Horgan, Paul G. 588 Horiba, Margit Naomi 4012 Horie, Shigeo e15527 Horiguchi, Jun 1029, e20510, e22019 Horii, Rie e11587, e22190 Horiike, Atsushi 7556, e13504 Horinouchi, Hidehito 7540, 8064, e13504 Horio, Akiyo e12001 Horio, Hidetoshi e18524 Horio, Hirotoshi 7536 Hormigo, Gloria e15111 Horn, Brenda 6094 Horn, Leora 6533, 8008, 8030, 8105, e22092 Hornberger, John C. 3640, e16044, e17561, e22172

Hornbrook, Mark Christopher 6018 Hornbuckle, Joanne 3504 Horndler, Carlos 10529 Horne, Heather e15089 Hornedo, Javier e12015 Hornick, Jason L. 10511 Hornuss, Cyrill e22188 Hornyak, Thomas J. 2532 Horobin, Joanna e13523 Horowitz, Neil S. 5524, 5588 Horowitz, Nina Ruth TPS1145, TPS1609, e20546 Horsman, Melissa J. e14632 Hortobagyi, Gabriel N. LBA509, 532, 553, 558, 561, 601, TPS657, 1005, CRA1008, 1017, 1022, e22064 Horton, Terzah M. 10003 Horton, Wendy M e17595 Horvai, Andrew 10045 Horvath, Lisa e18500, e22175 Horvath, Peter e20540 Horwich, Alan e19543 Horwitz, Steven M. 7070, 8507, 8518 Horwitz, Susan Band 2612 Hosaka, Takashi e20590 Hoschar, Aaron P. 6061 Hoshino, Tomoaki e19134, e19137 Hosing, Chitra 7011, 8561 Hoskin, Peter 9502 Hoskins, Paul 5502 Hosoda, Kei e15113, e15122 Hosoda, Mitsuchika 613, e20510 Hosokawa, Ayumu 4076 Hosomi, Yukio e18524, e19133 Hosono, Ako 1113, 10050 Hosono, Masako Hosono 7564 Hospers, Geke A. 3036 Hospitel, Marie 2535 Hossain, Dewan Md Sakib 4571 Hotko, Yevhen 3575 Hotta, Katsuyuki e19008, e19023, e19040, e19124, e19167 Hotte, Sebastien J. 2523, 2534, TPS4594, 5039, 5042, 5059, TPS5103, 6041, 11016 Hou, Hui Ying 622 Hou, Jeannie 9037 Hou, Jing-Zhou 7059 Hou, Kevin 7030 Hou, Mei 7507, 8016, 8061 Hou, Ming-Mou e13534 Hou, Yafei 3020 Hou, Yijuan e13550 Houck, Kevin 6503, 6551 Houck, William A. TPS664 Houdoyer, Claude 1528 Houe, Vincent 5515 Houillier, Caroline 2032 Houle, Emilie e13013 Houlgatte, Alain 5074 Houot, Roch 3015 Hourigan, Christopher Simon 3104 Houry, Sydney 3596 House, Larry 2570 Houston, Nicole D. 2514 Houston, Stephen LBA9000 Hout, David Richard 1067 Houterman, Saskia e18562 Houthuijzen, Julia M. e20653

Houtkamp, Mischa 3066 Houts, Arthur C. TPS659 Houtsma, Danny e22152 Houvenaeghel, Gilles 566 Hoverman, J. Russell 6580, 6607, 9604, 9605, e20668 Hovey, Elizabeth J. 2017 Hovick, Shelly Renee Anstey 6566, 9576 Howard, David H. 6514 Howard, Dianna S. 7084, e18001 Howard, Jason 6016 Howard, Nicole TPS11122 Howard, Penny e20588 Howard, Scott C. e20521 Howard, Wu e16522 Howe, James R. e15052 Howell, Carrie R 10022 Howell, David D. 6616, e20625 Howell, Doris 9536, 9551, 9595 Howell, Elizabeth A. e16551 Howell, Eric 7535 Howell, Jahna 2558 Howell, Josh 6580 Hozumi, Yasuo 3082, e20510 Hrdina, Astrid 3052 Hricak, Hedvig 5073, e16001 Hromadkova, Hana e16002 Hruban, Ralph H. 4039, 4057, e15028 Hrushesky, William J. 1080, e11609, e14646, e19130, e20672, e20697 Hrushesky, William John Michael e12034 Hsia, Te-Chun 8087, 8092, e19041^ Hsiang, Jack 3527, 11062 Hsiao, Chao e15076 Hsiao, Chin-Fu e15032 Hsiao, Franny 6508 Hsiao, Shih-Hsin e19029, e19030 Hsiao, Susan Jean e14659 Hsiao, Wayland e15617 Hsiao, Wendy C. e15104 Hsieh, Andrew Caleb 5077 Hsieh, Ching-Yun 6052 Hsieh, James 4573 Hsieh, Min-Shu 4115 Hsieh, Ruey Kuen e20580 Hsieh, Susie 6632, 6633 Hsieh, Te-Chun 6052 Hsieh, Wen Son 6063, e17017 Hsu, Charles C. 4039 Hsu, Cheng-Pang e19103 Hsu, Chih-Hung 3554, 4099, 4115, e15043, e15127, e15182, e19523 Hsu, Ching 3508 Hsu, Chiu-Hsieh e16060 Hsu, Chiun 4018, e15043 Hsu, Christine Cho-Shing e15037 Hsu, Jack 6059 Hsu, Karl 2530 Hsu, Limin 1017 Hsu, Ta-Wen e15127 Hsu, Tina 1044, 9577 Hsu, Wei-Hsun e19523 Hsu, Yanzhi 4000 Hsueh, Eddy C. e20049, e20661 Hu, Adriana e12502 Hu, Bo e22103

Hu, Chaosu Hu, Chen Hu, Cheng-Ping Hu, Chengping Hu, Eddie Hu, Guohong Hu, Guoqing Hu, Huabin Hu, James Hu, Jennifer J. Hu, Jethro Lisien HU, Jian Hu, Jim C. Hu, Kaiweng Hu, Kenneth Hu, Li-ya Hu, Man Hu, Melody Hu, Mimi I-Nan

6026 2008 8016, 8061 7507 e12502 5535 6026 e14704 4501, 4531 6564 2019^ 1547 6513, 9529 3027 6091, e17030 e20695 e15197, e18551 TPS648 TPS6100, e17016, e20512 Hu, Qiancheng e14645 Hu, Simin 7063 Hu, Tianle 2500 Hu, Xi-Chun 1064 Hu, Xiao-hua 4025 Hu, Xing-Sheng e19075 Hu, Xuejun e19004 Hu, Yi e15135 Hu, Zhihuang 8015 Hua, Li e17000 Hua, Ye 8584 Huang, Ahong e12010 Huang, Alan LBA509, e13525 Huang, Alex Yee-Chen e22158 Huang, Chao H. e22048 Huang, Chao-Yuan e16503 Huang, Cheng 8015 Huang, Chung-Yi 4115 Huang, David C.S. 7018 Huang, Furong e17508 Huang, Gloria S. e22009 Huang, He 8503, 8508, 8525, 8573 Huang, Helen J. 11086 Huang, Hsin-Hui 6052 Huang, Hui 7065 Huang, Hui-Qiang 8525 Huang, Jerry M. 4031, e15126 Huang, Jia Jia 8503 Huang, Jian e12500 Huang, Jianming e16531 Huang, Jin 1604 Huang, Kitty 7520 Huang, Longlong e12505 Huang, Maosheng 1532 Huang, Marilyn 5580, 5584, e20637 Huang, Mary S. 10035 Huang, Meijuan 8015 Huang, Minzhou e22163 Huang, Miriam 4067 Huang, Peng TPS1144, 4057, 5023 Huang, Raymond 2075 Huang, Sharon 9095 Huang, Shiu-Feng 4018 Huang, Shuguang 7532 Huang, Sui e22094 Huang, Sujuan 10022 Huang, Ta-Chen 4099, e15127 Huang, Wei e18537 Huang, Weidong 604 ABSTRACT AUTHOR INDEX

731s

Huang, Wenying e22192 Huang, Xin TPS652 Huang, Xuelin 7022 Huang, Yan 6026 Huang, Yi-Ching 1506 Huang, Yi-Ran e15622 Huang, Yingjie 628 Huang, Yunchao 8016, 8061 Huang, Zhiyu e15062, e19073 Hubalek, Michael 583 Hubay, Stacey e16082, e16088, e19077 Hubbard, Antony 5045 Hubbell, F Allan 3594 Huber, Christoph 3053, 4080 Huber, Rudolf M. e19108 Huberman, Mark 8050 Hubert, Ayala 4037, e22111 Hubner, Richard TPS4146, TPS4160 Huddart, Robert 4535 Hudes, Gary R. TPS4592 Hudgens, Stacie 8583 Hudis, Clifford 500, 501, 507, 517, 606, 630, 1007, 1032, TPS3120, 6048, 6575, 9581, 9610 Hudry, Delphine 566 Hudson, John M. 4583 Hudson, Melissa M. 10022, 10032, 10062 Hudson, Michelle 4031, e15126 Huebner, Alexander 7573 Huebner, Dirk TPS8612, 10028 Huesing, Johannes 9612 Huff, Dinah 1080, e11609, e12034, e14646, e19130, e20672, e20697 Hughes, Amanda 4501, 4534 Hughes, Andrew M. e22035 Hughes, Ashley 11026 Hughes, David J. 1542 Hughes, Gareth e15126 Hughes, Melissa E 1006 Hughes, Randall S. 8074 Hughes, Steven George 8523 Hughes, Steven J. e15108, e15145 Hughes, Timothy P. 7001, 7052^, 7053^, 7054^, TPS7129 Hughes-Davies, Luke TPS656, 1015 Huguet, Florence LBA4003, 4046 Huguet, Francoise 7054^ Huh, Warner King TPS3121 Hui, Ai-Min 8514 Hui, David 9611, e20554, e20559, e20581 Hui, Edwin P. e15048, e17017 Hui, Edwin Pun 6015 Hui, Joyce e15048 Hui, Rina 543, 6556, e20584 Hui, Zhu e19085 Huiban, Mickael 635 Huidobro, Gerardo 7549 Huijuan, Wang e19085 Huillard, Olivier 5075 Huisman, Monique 9557 Huitema, Alwin D. R. 4580, e20653 Huitzil-Melendez, Fidel David e15186 Huitzil-Melendez, Fidel David e14703 Hukin, Juliette 10029 Hulikal, Narendra e11588 732s

Hulin, Cyrille 8513 Hull, Pamela e20523 Hullings, Melanie TPS3115 Hulme, Claire TPS656 Hulshof, Maarten C. e15103 Humanes, Blanca e13535 Humbert, Olivier 11007 Humblet, Yves 3511, 3514, 3617, 3620, 3636, 3637 Humerickhouse, Rod A. 2520, 7018, 8520 Humm, John 5073, 5090 Hummel, Michael e15068 Humphrey, Kathryn 7004 Humphrey, Rachel 7116 Humpreys, Vikki 3509 Humprhis, Jeremy e15029 Hung, Gene 8523 Hung, Shih-Kai e13585 Hunger, Stephen 10001, 10002, 10003 Hungria, Vania 8589 Hunsberger, Sally 9517 Hunt, Kelly 502, 526, 1103 Hunter, John G. 4073 Hunter, Robert F. e12544 Hunter, Zachary R. TPS8620 Huntsman, David 3639, e22020 Huo, Dezheng CRA1501, e16006 Huo, Xinying 4106, 10544 Huober, Jens Bodo 1092, TPS1138 Huot-Marchand, Philippe e20654 Hur, Hoon e15020 Hur, Keun e14631 Hur, Soo-Young 5568 Hurbin, Amandine e19058 Hurd, David Duane 2516^ Hurkmans, Coen LBA1001 Hurley, Judith 1586, e11611, e12547 Hurley, Sheilah K e17507 Hurria, Arti 1024, 9515, 9545 Hursting, Stephen D 1515 Hurt, Karla 5019 Hurvitz, Sara A. TPS660, e17527 Hurwitz, Herbert 3520, 3533, 4042, 4520, 11011, 11036, e14505 Hurwitz, Mark 9500, 9565 Hurwitz, Selwyn J. 6083 Husain, Syed e14535 Husaini, Hasan 6091, e17030 Huschens, Susanne 9553 Huse, Jason T. 2057 Hussain, Aneela e12551 Hussain, Arif e16027, e16034 Hussain, Maha 4545, 5026, 5076, TPS5094 Hussain, Syed A. 4518, LBA5000 Hussain, Tasadooq e22123 Hussain, Wasay 1554 Hussaini, Mohammed Omar 11099 Hussein, Atif Mahmoud e14564 Hussein, Lily Parhad e20544 Hutchings, Martin 8555 Hutchison, Robert E. 10000 Hutson, Alan 1561 Hutson, Thomas E. 4563, 4564 Hutt, Emilie 592, e16548 Hutton, Brian 6597, e11574, e16074, e19024


Huynh, Jamie L 9095 Huynh, Minh-Huy 1572 Huynh, Richard e11562 Huynh, Thanh Khoa 10546 Hwang, David M e19032 Hwang, David 9645 Hwang, Deok Won e19128 Hwang, E Shelley TPS1608 Hwang, Eun-Sil Shelley 507 Hwang, In Gyu e15613 Hwang, Jimmy J. 2616, TPS2624 Hwang, Jimmy 1083, 1095, 4055, e14569 Hwang, Jun-Eul e15121, e17005, e20621 Hwang, Jung-Ah e19019 Hwang, Larn e15076 Hwang, Mark e17506 Hwang, Tae-Ho 4122^ Hwang, Tsann-Long 4138 Hwang, Wenke 6558, e17516 Hwang, Young Sil e19156 Hwu, Patrick TPS3109, 9010, 10577, e20036 Hwu, Wen-Jen TPS3114, 9009, 9047, e20036 Hyjek, Elizabeth e19542 Hyland, Andrew 1566, 1603 Hyland, Kelly 1563 Hyman, David Michael 5545, 7120, e13509 Hynes, Deanna e20505 Hynes, Denise Marie e14578 Hyodo, Ichinosuke LBA4024 Hysert, Pat 1566, 1603 Hysert, Robert 1566, 1603 Hyslop, Terry TPS1135 Hyung, Woo Jin e15144 Hörsch, Dieter 4033

I I, Porras 1125 Iachina, Maria e19157 Iacobelli, Stefano e14560 Iacoboni, Daniela 1557 Iacobucci, Ilaria 7025 Iacobuzio-Donahue, Christine A. 4057 Iacono, Carmelo e14557 Iacono, Giuseppina 1036, e17548 Iacopetta, Domenico 579 Iacopino, Bruno e15154 Iacovelli, Roberto 5050, e15524, e16031, e16078 Iadanza, Manlio e11515 Iaffaioli, Rosario Vincenz 631, 11008, e11556 Iafrate, Anthony John 533, 2029, 4125, 7555, 8019, 8032, 8083, 8085, 9019 Iams, Wade Thomas 9019 Iankov, Ianko e13516 Iannessi, Antoine e18508 Ianniello, Giovanni Paolo e14557 Iannone, Maria 567, 1089 Iannone, Marie TPS1134 Iannone, Robert 10026, 10027 Iarovoi, Diana e12543 Iartchouk, Natalia e13531

Iasonos, Alexia

5545, 5550, 5595, e13509

Ibañez de Cáceres, Inmaculada 1575, e13008, e19123 Ibanez Martinez, Jose e22073 Ibata, Hidenori 8006 Iberico, Jorge e12566, e12570 Iborra, Severine 5531 Ibrahim, Ezzeldin M. 3591 Ibrahim, Fady e15084 Ibrahim, Ibrahim Fuad e16555 Ibrahim, Joe 2595 Ibrahim, Nageatte 9010, 9076 Ibrahim, Ramy A. 7045, e18543 Ibrahim, Toni 4091, 9628, 11022, e13007, e19084 Ibuki, Yuta e18563 Ichai, Philippe e19513 Ichihara, Eiki e19167 Ichikawa, Daisuke 4076 Ichikawa, Laura E 559 Ichikawa, Mari e12001 Ichikawa, Tomohiko e15521 Ichikawa, Wataru 3535, 4019 Ichikawa, Yasushi 1047 Ichiki, Masao e19134 Ichimura, Tomoyuki e20676 Ichinose, Yukito 7518, 7529, 8111, e19016 Icli, Fikri e11511, e15191, e20655 Ida, Kohmei 10038 Ida, Satoshi e15039, e15173 Idbaih, Ahmed 2011 Iddawela, Mahesh 1015 Ide, Jennifer 1132 Ideker, Trey 11105, e15562 Idelevich, Efraim e15078, e22111 Idoate, Miguel A. 9074 Idris, Ahmad Fitri e20008 Idziaszczyk, Shelley 3509 Iemma, Antonio Francisco e15155 Iennaco, Pietro Schettini e20640 Ifrah, Norbert TPS3117^ Igaki, Hiroyasu TPS4152 Igami, Tsuyoshi 4119 Igarashi, Kaori e15568 Igarashi, Seiji e18554 Igarashi, Tatsuo e15521 Igawa, Satoshi 7592 Igdem, Sefik e17019 Iglesias, David A. 5596, e16556 Iglesias, Jose Luis 4005^, 4563, TPS5612 Iglesias, Lara 9641, e18558 Ignatiadis, Michail e12008 Ignatov, Valentin e14669 Ignatova, Ekaterina e12027 Iguchi, Yoko 5590 Ihaddadene, Ryma e15591 Ihtiyar, Enver e17529 Iida, Hiroatsu e19521 Ijichi, Hideaki e15146 Ikdahl, Tone 3571, 3597, 4007, e14710 Ikeda, Atsuki e15031 Ikeda, Hideko e18564 Ikeda, Masafumi 2559, 11031, e15031, e15116, e22082 Ikeda, Satoshi e19054 Ikeda, Takeshi 11049

Ikeda, Tetsuo e15158 Ikeda, Yuji e16505, e16506, e21520 Ikejiri, Koji 3518 Ikpatt, Offiong F. e19140 Ikram, Mohammed 2525 Ilacqua, Jackie e22136, e22157 Ilagan, Joseph L. 9047 Ilagan, Venus M 9646 Ilaria, Robert L. 5551 Ileana, Ecaterina 5088 Ilgen, Ufuk e18010 Ilhan, Osman 7038, e18009 Ilhan-Mutlu, Aysegul 2040 Illarramendi, Jose J. e12015 Illei, Peter 7598 Illidge, Tim TPS8611 Illmer, Thomas 1082, 7004 Illueca, Carmen 1543 Ilovich, Ohad 11006 Ilson, David H. 4082, 4101, TPS4153, e15017 Im, Annie P. 7059 Im, Ho Joon 10051 Im, Seock-Ah 551, TPS652, 1039, 1087, 1088, 2565, 3004, 3550, 4013, 4044, e15066 Im, Young-Hyuck 600, 629, 637, 1088 Imada, Hiroshi e15008 Imada, Kazunori 8506 Imada, Toshio 4068 Imai, Atsushi e15565 Imai, Hisao 7572, 7582, 7599, e18556, e19050, e19074 Imai, Kiyotoshi e19507 Imai, Koji 4008 Imai, Yukihiro e19017 Imamura, Fumio e19010^, e19153 Imamura, Hiroshi LBA4002, 4019, 4072 Imamura, Masahiro e19507 Imanaga, Tomotoshi 8111 Imani, Robert e19530 Imbeaud, Sandrine 3562 Imber, Charles 3504 Imbevaro, Silvia e12028, e12534 Imbimbo, Martina 6020 Imbs, Diane Charlotte 4574 Imhof, Marianne 3052 Imhof, Martin 3052 Imperatori, Marco e15528 Imtiaz, Urooj e13021 Ina, Kenji 3516 Inaba, Kazuki 10543 Inada, Tetsuhi 2501 Inagaki, Jiro 10050 Inaji, Hideo 1106, 1116 Inaki, Anri e16072 Inal, Ali e11559, e18521, e18544, e19107 Inamdar, Nitin e18004 Inanc, Mevlude e11559, e14672, e14695, e18516, e18546, e20603 Iñarrairaegui, Mercedes TPS3111 Inbar, Moshe J. 1040 Inbar, Yael 4037, 9500 Indelicato, Daniel J. 10521 Indelli, Monica 9614, e11573 Indio, Valentina 4048, 10540, e21523

Infante, Jeffrey R. 2503, 2507, 2530, 2544, 2567, 2585, 2593, 2617, TPS2620, 3044, TPS3106, 3507, 3564, 4005^, 4042, 4058^, 4059^, TPS4593, 8027, 8028, 9005, 9016, 9066, 11102, e15188^ Ingendahl, Julia e17550 Ingle, Ashish M. 2538 Ingle, James N. 564, 1032, e13516 Inglehart, Marita 568 Inic, Ivana e20002 Inic, Momcilo e20002 Inic, Zorka Momcilo e20002 Inman, Brant Allen e15560 Inno, Alessandro 9554, e15512, e15514 Innocenti, Federico 2570, 4022 Innominato, Pasquale F. 3599, 3606, e20519 Innominato, Pasquale e19513 Inohara, Hidenori 6082 Inoriza, Angel e11583 Inoue, Akira 7530, 8033, e19142 Inoue, Hiroaki e11604, e12026 Inoue, Kohei e13511 Inoue, Koji 8111 Inoue, Yasuhiro e14631, e22205 Inoue, Yuka 3006 Inoue, Yuko 3034 Insa, Amelia LBA8002 Insel, Beverly J. e15074 Insogna, Karl L. e20512 Intagliata, Salvatore e15528, e19084 Inui, Naoki 8038, e20658 Inukai, Michio 3516 Inwards, David James 7041 Inzerillo, John J. 2595 Inzunza, David 3016 Ioannou, Eleni e14699 Ioka, Tatsuya e15116, e15150 Ionescu, Diana 8096 Ionta, Maria Teresa 9614 Ioritani, Naomasa e15570 Iozeffi, Dimitri 9500 Iqbal, Afsheen e13524 Iqbal, Bilal e20611 Iqbal, Nayyar e14619 Iqbal, Sheikh Usman e14576, e14656 Iqbal, Sobuhi 7082 Iqbal, Syma 4110, e14543, e15009, e15022 Iqbal, Yousuf 5571 Irfan, Nabia e12033 Irie, Hanna 11021 Irmscher, Romy e22040 Iruarrizaga, Eluska e13000, e14712, e20718 Irvin, William Johnson 1052 Irving, Bryan A. 3001 Irwin, Blair Billings 6551 Irwin, Gareth TPS11120 Irwin, Melinda e20546 Irwin, Meredith 10015 Isa, Shunichi 8006 Isaacs, Claudine 505, CRA1008 Isaacson, Jeffrey D. 2585, 4007 Isaka, Mitsuhiro 7572, 7599, e18556

Isakoff, Steven J. 533, 1065, 1100 Isambert, Nicolas TPS663, 2548, 2549, 2615, 10506, 10525, 10546, e11529 Isani, Sara e22009 Isaranuwatchai, Wanrudee 6033, e19031 Isayama, Hiroyuki e15116, e15146 Iselin, Christophe E. e15619 Ish-Shalom, Maya e15597, e15598, e16051, e16068 Ishida, Hiroo e19164 Ishida, Masaru e15527 Ishida, Masayuki e19016 Ishida, Mitsuaki 4092 Ishida, Nobuko e15150 Ishida, Tadashi e19017 Ishida, Takashi 8506 Ishida, Yuji 10050 Ishido, Keinosuke e15179 Ishido, Kenji 4070 Ishigami, Hironori e15027 Ishigure, Kiyoshi e14552 Ishiguro, Atsushi 4076 Ishiguro, Megumi 3518 Ishii, Genichiro 7512, 7557, 8037 Ishii, Hiroshi e15031 Ishii, Mari 8054 Ishikawa, Shinya e22108 Ishikawa, Takashi 1029, 1047, e20510 Ishikawa, Tomoyasu e13529 Ishikawa, Youjirou 6086 Ishikawa, Yuichi 8037 Ishiki, Hiroto e13586 Ishiko, Osamu e20676 Ishimaru, Hiromasa 9629 Ishimoto, Osamu e19142 Ishimoto, Takatsugu 11065 Ishioka, Chikashi e14597 Ishitobi, Makoto 1106, 1116 Ishitsuka, Kenji 8506 Ishiyama, Hiromichi 4070 Isichei, Mercy Wakili e15119 Isikdogan, Abdurrahman e11559, e14705, e18544, e18546 Isla, Dolores LBA8002 Islam, K. M. 7571 Isler, Deniz Cagın e11537 Ismail, Balik e18009 Ismail, Jeffri R. M. e14519 Ismail, Soheir Sayed e11599 Ismail-Khan, Roohi 3026, 3069 Isobe, Kazutoshi 11052 Isom, Scott 2516^, e18002 Israel, Gary M. 2587 Israel, Robert Joseph 5018, e16047 Issa, Samar 8537, 8565 Issaragrilsil, Surapol 7054^ Issels, Rolf D. e13540 Italiano, Antoine 6582, 10500, 10506, 10514, 10516, 10517, 10525, 10574, 10575, 10578 Ito, Akihiro e14552, e15570, e15576 Ito, Hiroyuki 7531 Ito, Kazuto e16054, e16090 Ito, Masahiro e11605, e12532 Ito, Sawa 3104 Ito, Seiji 4088 Ito, Yoichi M. 5590

Ito, Yoshinori 557, 561, TPS4152, e11587, e20576, e22027, e22190 Ito, Yuichi 4102 Itoh, Jugoh e14597 Itoh, Kuniaki 1113 Iturbe, Julian 1073, 11118 Ivan, Doina 9047 Ivankina, Oxana e12027 Ivanov, Georgi e14669 Ivanov, Krasimir e14669 Ivanov, Roman A. e20593 Ivanov, Sergey 5002 Ivanova, Anastasia e13507 Ivanova, Victoria Aleksandrovna e16512, e16513 Iversen, Peter 5001 Iversen, Trine Zeeberg 3028, 8084 Ives, Denise I. 4087, 6035, 6061, e15000 Iveson, Timothy e15046 Ivy, S. Percy 1043, 5039, 9517, e13509 Iwae, Shigemichi 6004 Iwagami, Shiro 11065 Iwai, Toshinori 6060 Iwamoto, Mitsuhiko TPS1140 Iwamoto, Shigeyoshi 3516, 3519, e14601 Iwamoto, Yasuo 3072, 7518, 7529 Iwamura, Masatsugu e15576 Iwanaga, Ichiro e14604 Iwasa, Mai 614 Iwasa, Satoru 3559, 4074, 4096 Iwasaki, Yoshiaki 4104 Iwasaku, Masahiro e19017, e19167 Iwase, Hiroaki e15159 Iwase, Satoru 1111 Iwase, Takuji 1106, 1534, 6588, e11587, e20510, e22190 Iwata, Hiroji 561, 571, 613, TPS650^, TPS654, TPS662, 6588, e12001, e12011 Iwata, Takako e20590 Iwata, Takashi e14572 Iwatani, Tsuguo e11519 Iyengar, Neil M. 630, 6048 Iyengar, Puneeth 8074 Iyer, Gopa 5545 Iyer, Gopal 8107 Iyer, Laxmi H. e14647 Iyer, Neel Subramanian 10063 Iyer, Shrividya 8108 Iyer, V. K. TPS4162 Izarzugaza, Yann 11089 Izbicki, Jakob Robert 11014 Izquierdo Manuel, Marta e18513, e19034 Izquierdo, Angel e19159 Izquierdo, Francisco 10529 Izumi, Kouji e16098 Izzo, Francesco 11008, e15061 Izzo, Michela e21500

J Jaafar, Hassan Nadim e19035 Jabado, Nada 10029, 10066 Jabbour, Elias 7010, 7024, 7068, 7074, 7090, 7092, 7095 ABSTRACT AUTHOR INDEX

733s

Jabbour, Melhem 6539 Jablonka, Fernando e16030 Jablons, David e22124 Jaccard, Arnaud e20512 Jacene, Heather A. 1105 Jacene, Heather 5021 Jackisch, Christian 525, 607, 1004, TPS1138, TPS1141, 11061, e17544 Jackman, Anne 6530 Jackman, David Michael TPS1606, 8069, 8077, 8116, e19121, e19125 Jackson, Amanda Lynn 5523, 5607 Jackson, Bradford E. 6559 Jackson, Bradley 7104 Jackson, Cynthia e14637 Jackson, Erica 3026 Jackson, George L. 6555 Jackson, Gilchrist L. 9022 Jackson, Heather 3093^ Jacob, Wolfgang 2522 Jacobasch, Lutz e15607 Jacobi, Kathryn e19519 Jacobs, Barbara e19012 Jacobs, Bart 3526, 3626 Jacobs, Bruce L. 5044 Jacobs, Cindy TPS4588^, TPS5101, TPS5103 Jacobs, Ian 5507^ Jacobs, Linda A. e20553 Jacobs, Lisa K. 507, TPS1144 Jacobsen, Paul B. 6531 Jacobson, Adam 6091, e17030 Jacobson, Alison e20605 Jacobson, Gregory M. e13583 Jacobson, Jon TPS5094 Jacobson, Joseph O. 9537 Jacobson, Robert J. e13539, e19155 Jacobus, Susanna J. 4530, 8592, e19517 Jacoby, Elad 2101 Jacod, Sylvie 5515 Jacques, Christian 8510, 8527, 8528, 8544, 8583, 8585^ Jacquin, Jean-Philippe 1057 Jacquot, Stephane 6603 Jadhav, Ajit 1016 Jado, Juan Carlos e13535 Jaeckle, Kurt A. 1, 1596, LBA2010, 2014, 2046 Jaeger, Bernadette Anna Sophia 11043, e22059 Jaeger, Bernadette 638, 11042, e22075 Jaeger, Dirk 3538, 3625, e15574 Jaeger, Erich e22177 Jaeger, Thomas 583 Jaeger, Wolfgang e15590 Jaen, Ana e11583 Jaenicke, Fritz e16535 Jaffa, Zachary 6058 Jaffee, Elizabeth M. 4040^ Jafri, Syed Hasan Raza e19070 Jagannath, Sundar 8532, 8542, 8543, 8588 Jagannathan, Jyothi Priya LBA10502 Jagannathan, Sajjeev e22030 Jagasia, Madan H. 8605, e19539 Jager, A. 1072, 11045 734s

Jager, Agnes 2579 Jaggi, Rolf 8060 Jagoda, Elaine 11083 Jagsi, Reshma 1025, 6615, 9601 Jaguar, Graziella Chagas 7037 Jagust, William J. 6619, 6620 Jahagirdar, Balkrishna N. 6005 Jahan, Thierry e22124 Jahani, Mohammad 7069 Jahanzeb, Mohammad 1068 Jahn, Thomas Michael 7003, 7017, TPS7133 Jain, Amit e14520 Jain, Angita e22084 Jain, Anjali 4051 Jain, Asheesh e18001 Jain, Hasmukh e19503 Jain, Minish Mahendra 628, 3039, 8095, e13567, e19119 Jain, Minish e19145 Jain, Nitin 7092, 7095, 7102 Jain, Rajul K. e20512 Jain, Rakesh K. 1065, 2056, 4047, 4125 Jain, Rishi 7125 Jain, Rohit e20567 Jain, Tania e15077 Jain, Vikram Kumar TPS2626 Jaiyesimi, Ishmael A. 1541, 6577, e18007 Jajeh, Ahmad e19537 Jakesz, Raimund e14537 Jakob, Jens 10566 Jakob, John Andrew e20034 Jakobsen, Anders Kristian Moeller e19163 Jakobsen, Erik 6570, 7504, e19157 Jakobsen, Jan Nyrop 7504 Jakowatz, James G. 9082 Jakubowiak, Andrzej J. 8542, 8543, 8588 Jalal, Shadia Ibrahim 2529, 2567 Jalan, Pankaj e22181 Jalili, Mahdi 7069 Jallal, Bahija e20047 Jamali, Mina e19542 Jamaludin, Ahmad A e20008 James, Angela 2606, 8522 James, Colin R. TPS11120 James, Danelle Frances 7014, 7056, 7057, 7124, TPS7130, TPS8619 James, Edward Samuel 2587 James, Jacqueline TPS11120 James, Jennifer D e15152 James, Lindsay E. 5514, 7595 James, Nicholas David 4518, 4524, LBA5000, 5012, 5057, e16048 James, Roger David 3532 James, Sarah E. 1069 Jameson, Gayle S. 2580, TPS11123 Jameson, Michael B. TPS1143, e13583 Jamieson, Catriona H. M. 7109, 7110 Jamme, Philippe e11543 Jamous, Houda e19063 Jamshed, Arif e12033 Jamshidian, Farid 520, 565 Janardhan, Radhakrishna e17506


Janega, Pavol 4556 Janelsins, Michelle Christine 9531, 9533, 9572, TPS9647, TPS9651, e20526 Janevski, Angel 1046 Janeway, Katherine A. 1531, 1553, 10536, TPS10591 Jang, Geundoo e17026 Jang, HongSeok e14650 Jang, Jin Sung e19013 Jang, JoungSoon 9633 Jang, Raymond Woo-Jun 9518 Jang, Sekwon 9077, e20700 Jang, You-Jin 4113 Jangard, Mattias e17001 Janisch, Linda A. 2570, 2571 Janjigian, Yelena Yuriy 4011, 4082, 4101, e15017 Jankovic, Radmila e22115 Jankowitz, Rachel Catherine 594 Jankowski, Michelle e16552 Jankowski, Tomasz 604 Janku, Filip 1051, 2506^, 2545, 2604, 2611, 11086, e13534, e13575, e13591, e22086 Janne, Pasi A. TPS1606, 6023, 8029, 8077 Janne, Pasi Antero 8023, 8039, e18512, e19125 Janni, Wolfgang 516, 591, 638, 640, TPS650^, 1082, 1101, 11042, 11043, e11525, e22059, e22075 Jannuzzo, Maria Gabriella e19138 Janosky, Maxwell Dale TPS3122 Jansen, Liesbeth 1502 Jansen, Maurice P. H. M. 11045 Jansen, Mendel 2519, 2583 Jansen, Natalie 2045 Jansen, Rob L. 2001, 3036, 3502 Janssen, Jan 602 Janssen, William 3069 Janssens, Ann TPS7131 Janssens, Jozef 3531 Jantus-Lewintre, Eloisa 7514, 11010, 11073, e22147 Janus, Nicolas 5567, e12504 Janvier, Maud TPS8615 Japuntich, Sandra 7525 Jara-Sanchez, Carlos e12513 Jaradat, Imada A. e16500 Jarboe, Jamie Michelle Bunch 1580 Jares, Pedro e14588 Jarnagin, William R. 3558, 3609, 4116 Jarolim, Ladislav e16002 Jarutat, Tiantom e18514 Jarvis, Claire 2566 Jarzab, Barbara 4, 4031 Jasarevic, Zerina 583 Jasielec, Jagoda 8543 Jaslowski, Anthony John 9513 Jassem, Ewa 11069 Jassem, Jacek 604, 2031, 3511, 3575, 3620, 8043, TPS8117, TPS8121, 11069, e19144 Jatoi, Aminah 2551, 9515 Java, James 5530 Javed, Ahmed Yasir 1068, 7569 Javid, Sara H. 1006 Javle, Milind M. 4064

Jaw-Tsai, Sarah S. 2524, 2585, 2586 Jayani, Reena 9545 Jayaram, Anuradha e13020 Jayasekera, Jinani e16034 Jaye, David L. 8559 Jayson, Gordon C. 5500 Jazieh, Abdul Rahman e17528, e19035 Jazvic, Marijana e15603 Jean, Maureen 8075, e15095 Jean-Pierre, Pascal 9586 JeanLouis, Lisa 4138 Jeddi-Tehrani, Mahmood e22198 Jedryka, Marcin 5569 Jeffers, Michael 3514, 10503, e14507, e22110 Jefford, Michael TPS3649, e14608 Jeffrey, Stefanie S. 11096 Jeffries, Matlock Arizona e15025 Jegatheeswaran, Santhalingam e14547 Jeha, Sima 7097, 10034 Jehn, Christian e20670 Jejurkar, Purvi 7056 Jeldres, Claudio 5071 Jelovac, Danijela 11019 Jemal, Ahmedin 6569 Jemiai, Yannis e12530 Jen, Jin e19013 Jenkins, Marjorie 7060, 8591, e18527, e22003, e22052 Jenkins, Robert B. LBA2010, 2025, 4071, 5027, 11085 Jennings, Jack 10585 Jennings, Lawrence J. 10014 Jensen, Benny Vittrup 3572, 4052, e14593 Jensen, Brita Bjerregaard 3572 Jensen, Kristin C. 1003 Jensen, Lars Henrik 6600 Jensen, LeeAnn 8592 Jensen, Peter Buhl e22065 Jensen, Thomas e22065 Jeon, Eun Kyoung 1540 Jeon, Hae Myung e15164 Jeon, Tae Joo e12005 Jeon, Ung Bae 4122^ Jeon, Yoon-Kyung 8521 Jeong, In Gab e15519 Jeong, Jennie 11018 Jeong, Ji Yun e11505, e11594 Jeong, Jong-Hyeon TPS1139 Jeong, Joon e12005 Jeong, Oh 4105 Jeong, Sang-Ho 4105 Jeong, Seung-Yong 3550 Jeong, Woojin 4113 Jeong, Yi Yeong e19156 Jepson, Debbie e20045 Jeraj, Robert 1, LBA2010, 2537 Jerat, Sandra 9550 Jerevall, Piiha-Lotta 594 Jerome, Mary 7591, 8057, e19143 Jerusalem, Guy Heinrich Maria 505, TPS660, e11549, e11602, e17520 Jeruss, Jacqueline Sara 572, e11572 Jeschke, Udo 3064, e22059 Jessen, Katti 2567, e13531

Jesus, Victor Hugo Fonseca 6017, 11038 Jeter, Joanne M. 9102 Jeter, Stacie TPS1144, 11019 Jeurkar, Neha e17591 Jewell, Sarah 8505 Jewett, Michael A. S. 4503, 4568, 5070, e15510 Jeyakumar, Ghayathri 7115 Jeys, Lee 10518 Jeziorski, Krzysztof LBA4001 Jha, Gautam Gopalji TPS6101 Jhaveri, Komal L. 1042, 11076, 11106 Jheon, Sang-hoon e18553 Ji, Jiafu e14624 Ji, Jiuping Jay 2514, e22080 Ji, Jun Ho 7123 Ji, Linyung e16073 Ji, Qunsheng 8045 Ji, Yongli 1512 Jia, Jun 4097 Jia, Wang Xiao 7590, e12557, e22050 Jia, Xiaoyu 4534, e15517 Jia, Xueke e19161 Jia, Yankai e22192 Jian, Huang e11589, e12557 Jian, Zhou e22133 Jianfei, Jeff e15185 Jiang, Chen 4022, 5509, 11011, 11053 Jiang, Haiyan e19031 Jiang, Haoyuan 6026 Jiang, Kun 8546 Jiang, Liuyan 7047 Jiang, Lw 3049 Jiang, Meiping e16516 Jiang, Nan e15021 Jiang, Ping 4010, e15005 Jiang, Tingting 1013, 1549 Jiang, Wei 1100 Jiang, Yao 7077 Jiang, Yizhou TPS4153 Jiang, Youhua 4094, e15062 Jiang, Zefei 1064 Jiang, Zhi-Qin 3612 Jiang, Zhiqin 3632 Jiang, Zhou e16516 Jiao, Shun Chang e19161 Jiao, Shunchang e19044 Jiao, Wei 11016 Jie, Fei 548 Jilla, Swapna e14694 Jillella, Anand P. 7091, 7105 Jimenez Colomo, Laura 10523 Jimenez, Antonio Martin 7010 Jiménez, Connie R. 11087 Jimenez, Eugenio e22091 Jimenez, Hugo e15049 Jimenez, Jeronimo e11530 Jimenez, John-Paul e19097 Jimenez, Jose 3012, 4135, 8070 Jimenez, Marta 511, 2599 Jimenez, Miguel 4555 Jiménez, Paula 4098, 4587, e14617, e15169, e18513, e19034 Jimenez, Rachel e20606 Jimenez, Valero Pedro e12015 Jimenez, William Andres e15123

Jimenez-Pailhes, Anne-Sophie Jimeno, Antonio

6079 2502, 2557, TPS6098 Jin, Bo e19004 Jin, Dong-Hoon 3628 Jin, Haofan 3031 Jin, Jie e15622 Jin, Jin 644, 646, 2603 Jin, Victor 7573 Jing, Xiang e15040, e15050 Jinno, Hiromitsu e11598 Jirillo, Antonio e12028, e12534 Jirstrom, Karin 3579, e14580 Jitawatanarat, Potjana e11508 Jithesh, Puthen 4518 Jitlal, Mark 4120 Jivani, Manoj A 3057 Jiwatani, Sangeeta Premchand 7080 Jo, Booil 9504, 9532 Jo, Jae-Cheol 10589 Jo, Tatsuro 8506 Jo, Vickie Y 6088 Jobe, Dean A 9038 Jobkar, Terri L. 8543 Jocolle’, Genny e18522 Jodlowski, Tomasz e22196 Joel, Simon 2525, 2576 Joensuu, Heikki 4536, 10503, 10551 Joffe, Johnathan K. 4535 Johann, Donald Joseph e22180 Johannesen, Tom B. 4536 Johannessen, Cory M. 9015 Johannessen, Dag Clement 5068 Johansen, Christoffer 4533, 6570 Johansen, Jakob 8103, e14593 Johansen, Julia S. 3572, 4052 Johansson, Harriet Ann 1517, TPS1610 John, Tom 3011, 7567, 11072, e18559 John, Veena S. e16546 Johne, Andreas 2506^ Johns, Amber e15029 Johnson, Amy J. 7014 Johnson, Bruce E. 8009, 8019, 8085, e19121, e19125 Johnson, Bruce E e18512 Johnson, Clare 9022 Johnson, Cynthia S 3546 Johnson, Daniel E e13587 Johnson, David H. 8046 Johnson, David Michael 7003, 7005, 7017, TPS7131, 8500, 8501, 8519, 8526, 8579, TPS8617, TPS8618 Johnson, Douglas Buckner 9019 Johnson, Douglas 7501 Johnson, Eric e14500 Johnson, Faye M. 8102, 11044 Johnson, Frank E. 6526, e17506 Johnson, Gary L. 512 Johnson, Gary 2558 Johnson, Jonas Talmadge 6043, 6051 Johnson, Karen 1524, 3594 Johnson, Lauren 6013 Johnson, Marcella M. 9047 Johnson, Martin e20587

Johnson, Melissa Lynne

8036, e13568 Johnson, Peter W. M. 11094 Johnson, Phaedra e17509 Johnson, Philip James 4029, e15093, e15162 Johnson, Rebecca H. 9573 Johnson, Ronald 1098, 9643 Johnson, Sarah H. 7568 Johnson, Toby 4519, 4569 Johnson, Tyler e22195 Johnston, Claire e11586 Johnston, Gregory 570, 3582, 3583, e14518, e14566 Johnston, Mary Ann e19100 Johnston, Patrick B. 2058, 7041 Johnston, Patrick TPS11120 Johnston, Richard Bruce 5071 Johnston, Sandra K. e13041 Johnston, Stephen R. D. 531, 535, 610 Jolesz, Ferenc A. 1132 Jolly, Shruti 9607 Jolly, Trevor Augustus 9543, e20582 Joly, Florence 5504, 5542, 5569, 9510 Jonasch, Eric 4517, TPS4595, e15500, e15504, e15538, e15594, e15611, e15612, e17530 Jonassen, Merete 8084 Jonat, Walter TPS650^ Jones, Barry 3058 Jones, Beverley e19145 Jones, Chris e13557, e13559 Jones, Christopher A e20674 Jones, Clare Frances 9045 Jones, Cortney Vanderbilt e19025 Jones, Daniel 8115, 9100, e15034 Jones, David Randolph 7502 Jones, David R. 2529, 7524 Jones, Emrys A. e14620 Jones, Helen LBA5000 Jones, Ian 3598, e14608 Jones, Jason Michael 8538 Jones, Jeffrey Alan 7077, TPS7131 Jones, Jennifer M. 9536, 9551, 9595 Jones, Jeremy 4571 Jones, Kevin 10587 Jones, Lee 1520 Jones, Linda 1015 Jones, Nathan L. e20648 Jones, Richard J. 7006, 7009 Jones, Robert J. 4508, 4511 Jones, Robert R TPS4590 Jones, Robert 4506, LBA4509 Jones, Robin Lewis 535, e21502 Jones, Roy B. 7011 Jones, Siân 2511 Jones, Stephen E. 590, TPS652 Jones, Steven e22020 Jones, Suzanne Fields 2544, TPS2620, 3564, 11102 Jones, Thomas 9089 Jones, Tobin 4100 Jones, Trefor e17552 Jonker, Derek J. 3521, 3528, 3633, TPS3647, 4050, 4053, TPS4161^ Jonsson, Per 7504

Jonveaux, Philippe 1528, 8000 Joo, Jungnam 4045 Joore, Manuela A e11558, e17549 Jootar, Saengsuree 7052^ Jorda, Merce e15596 Jordan, Emmet e14515, e20550 Jordan, Karin e20716 Jordan, Philip 6063 Jordan, Richard 6007, TPS6099 Jorge Fernández, Mónica 3589, e14509 Jorge, Monica 4098 Jorissen, Robert N 3598 Joseph, Andrew 6013 Joseph, David John 1110, 1121 Joseph, Gardith e19508 Joseph, Getrud e12561 Joseph, Jivin e17537 Joseph, Loren 6066 Joseph, Richard Wayne 4567, 9009, 9096, e15539 Joseph, Shibu TPS1143 Joseph, Vijai 4082, 7558 Joshi, Amit 6085, e12520, e17027, e19118, e20678 Joshi, Monika e13530, e13533 Joshi, Nikhil Purushottam e13014 Joshua, Anthony Michael 5007, 5042, 5058, 5070, CRA9003, 9555 Joshua, Anthony 9009 Joski, Peter 6523 Joskin, Julien e11549 Jost, Lorenz M. 8560 Jost, Philipp 10508 Jotte, Robert M. 8028 Jou, Erin e19525, e19529 Jou, Ying-Ming 5518 Jouannaud, Christelle 5567, e12504 Jouary, Thomas 9013, 9036, e20041 Joubert, Philippe 8067 Joubert, Warren Lance TPS3649 Jouhaud, Annie 3542 Jourdan, Eric 7002 Journeau, Florence LBA4500 Jove, Jeremy e14514, e14542 Jove, Richard e15522 Jovic, Gordana LBA10504 Joyce, Doireann 1112 Joyce, Robin 8558 Jreige, Yolla Tanios e20500 Ju, Donghong e22182 Ju, Ji Hyeon 3046 Ju, Lixia e22044 Ju, Yunhe e16516 Ju, Zhenlin 5521 Juan Fita, Maria Jose e12513 Juan, Marta e15609 Juarez Villegas, Luis 10059 Juarez, Asuncion e14671 Juárez, Eva e19068 Juckett, Mark 7126 Jud, Sebastian 1004 Judge, Adam D. TPS2621 Judson, Benjamin 6042, 6076 Judson, Ian Robert 10031, 10500, LBA10507, 10569, e21516 Judson, Timothy J. 6575 ABSTRACT AUTHOR INDEX

735s

Jueckstock, Julia Kathrin 638, 5531, 11042, e22059, e22075 Juergens, Herbert 10031 Juergens, Rosalyn A. 8072 Juhn, Frank e22146 Julian, Thomas B. TPS666, 1000 Juliano, Mary Ann e20701 Julier, Patrick TPS5615 Julka, Pramod Kumar e13014, e13034, e13043, e16511, e20679 Jumaat, Delly Fareda e22107 Jump, Helen e15075 Jumper, Cynthia A. 7060, 8591, e18527 Junck, Larry 2052, 2076 Jundt, Gernot e20542 June, Carl H. TPS7132, TPS10072 Junejo, Muneer e15072 Jung, Andreas LBA3506 Jung, Eun Sun e15164 Jung, Hwoon-Yong e15051 Jung, Hyun Ae 637 Jung, Hyun Jun e11594 Jung, Ji Han e14563 Jung, Joo Young e17026 Jung, JungAh TPS3646 Jung, Kyung Hae 3570 Jung, Minkyu e15098, e15144 Jung, So Youn 551 Jung, So-youn e11584 Jung, Sungmi 8096 Jung, WonKyung 4113 Junghans, Richard Paul 3079 Junior, Rodnei Macambira e15176 Jurcevic, Stipo 8574 Jurczak, Wojciech TPS8617 Jure-Kunkel, Maria 3003^, 3016, 3019 Jurgens, Heribert 10518 Juric, Dejan 533, 2531 Jurik, Andrej e22023 Jurisica, Igor e15599 Juvekar, S 6085, e12520 Jürgen, Piek e13053 Jürgensmeier, Juliane M. 5505 Jäger, Elke 4035, 4079 Jäger, Ulrich 7015, 7101, TPS8619

K K, Adarsh K.V, Jagannathraonaidu

e17034 e16545, e17028 2561^ 6057

Kaag, Audrey Kaanders, J. H. Kaanumalle, Lakshmi Sireesha e18539, e22085 Kaassis, Mehdi 3601 Kabbarah, Omar 5020 Kabbinavar, Fairooz F. 3520 Kaboteh, Reza 5081 Kabraji, Sheheryar 8083 Kabukcu Hacioglu, Sibel e18014 Kaburaki, Kyohei 11052 Kacel, Elizabeth L. e20606 Kachergus, Jennifer M. 1037 Kachesova, Polina Sergeevna 3084, e22002 Kachnic, Lisa A. 9525 Kadakia, Kunal C. e17538, e20605 736s

Kadalayil, Latha Kadamyan, Vera Kadan, Maura Kadan-Lottick, Nina

3532 541 e14647 9584, 10035, 10063 Kadia, Tapan M. 7024, 7029^, 7068, 7074, 7089 Kadlubek, Pamela 9537 Kadoch, Cigall 10515 Kadowaki, Shigenori 4075, e14527 Kadowaki, Tadashi 5520, 5591, 9058 Kadoya, Takayuki 613, 11111, e22113 Kaehler, Katharina C. 9025 Kaempgen, Eckhart 9013 Kaern, Janne 5533 Kafeel, Muhammad I. e16101 Kaga, Kichizo 7550 Kagabu, Masahiro TPS3116 Kagawa, Shunsuke e15161 Kager, Leo LBA10504 Kahalley, Lisa 10009 Kahan, Zsuzsanna 1040 Kahatt, Carmen Maria 547 Kahima, Jackson 5594 Kahl, Brad S. 7003, 7018, 7070, 8518, 8519, 8520, 8526, 8537, 8565, TPS8617 Kahl, Christoph LBA3506 Kahn, Michael 2501, 3568, e14538, e14714 Kahn, Robert S. 2507, 5020 Kahraman, Benan e20503 Kai, Fumitake e15568 Kaijser, Magnus 4536 Kaimakliotis, Hristos K. e15543 Kainuma, Osamu 4008 Kairouani, Mouna e16527 Kaiser, Heather E. e17534 Kaiser, Karen e11572, e15187, e20527 Kaiser, Rolf 4506, LBA8011, 8034, 8056, e19126, e19165 Kaizer, Leonard e17503 Kaji, Reiko 8098, e19017, e19045 Kajitani, Keiko e22113 Kajitani, Tatsuhiro e15170 Kajiura, Shinya 3072, 4075 Kajiura, Yuka e11524 Kakehi, Yoshiyuki 4526, e16054, e22108 Kakeji, Yoshihiro e14633, e15158, e20576 Kakisaka, Tatsuhiko e15038 Kaklamani, Virginia G. 1091, e13568 Kako, Severine 8023 Kakolyris, Stylianos e15063 Kakumanu, Ankineedu Saranya 2053, 5042 Kala, Zdenek 11051 Kalabus, James 2594 Kalachand, Roshni Deepa e15142 Kalaivani, Mani 1099 Kalampokas, Athanasios e20032 Kalari, Krishna R. 1037 Kalayci, Murat e20723 Kalaycio, Matt E. 7008, 7054^ Kalayoglu Besisik, Sevgi 8533, 8534 Kalbacher, Hubert 8084


Kalbakis, Kostas 1045, e22105 Kaldate, Rajesh R. 1544 Kalebic, Thea TPS3646 Kaled, Karim e13025 Kalemkerian, Gregory Peter 7522, 7527, e19009 Kaley, Thomas Joseph 2054, 2057, 2095 Kalhor, Neda 2601, 7552, 8079, TPS8118 Kalina, Philip e14500 Kalinsky, Kevin 560 Kallam, Avyakta 6568 Kallergi, Galatea e22101, e22105 Kalli, Kimberly 5510, 5546 Kallich, Joel D. 9083 Kallischnigg, Gerd 9553 Kalnicki, Shalom 4093 Kalofonos, Haralabos e18507 Kalogeras, Konstantine T. 582 Kalos, Michael TPS7132, TPS10072 Kaloyannidis, Panayiotis 8567 Kalpathi, Krishnamani e18003, e19533, e20684 Kalra, Sarathi e15594, e15611 Kalsa, Remon 3083 Kalykaki, Antonia e22105 Kamachi, Hirofumi e15038 Kamada, Tadashi e15008 Kamai, Takao e15588 Kamal, Arif e17521 Kamal, Maud 2615 Kamalakaran, Aruloly 635 Kamalakaran, Sitharthan 1046 Kamat, Mangesh e19092 Kamath, Geetanjali R. 1564 Kamath, Vidya e18502, e18539, e22085 Kamba, Tomomi e15588 Kambara, Takeshi 3535 Kambartel, Kato 1589 Kambe, Mariko e14597 Kamdar, Manali K. e19154 Kameda, Ryo e15109 Kamei, Takao e15027 Kamel, Ihab R. 4124 Kamel-Reid, Suzanne 2053, 6041, 11002, 11016, e17515, e19032, e19077 Kamen, Charles Stewart 9531, 9533, 9572, TPS9651, e20526 Kamen, Francis 9533 Kameoka, Shingo 3518 Kamihara, Junne 10011 Kamijo, Izumi e22114 Kamikawa, Harumi 9637 Kamikonya, Norihiko 7583 Kamimatsuse, Arata 10038 Kamimura, Mari e11604, e12026 Kamimura, Mitsuhiro 8006 Kaminski, Mark Stefan 8543, e19519 Kaminsky, Britta 8112 Kaminsky, Marie-Christine 6002 Kamiura, Shoji 5538 Kamiyama, Toshiya e14548, e15038 Kamiyma, Yoshiteru 5046 Kamohara, Yukio e11605 Kampmann, Eric e13540

Kamura, Toshiharu 5537, e20576 Kan, Mengyuan e19014 Kanaan, Zeyad e18011 Kanaar, Roland e13540 Kanaev, Sergy 9500 Kanai, Hisako 9629, e20683 Kanai, Michio 4008 Kanakry, Christopher George 7006, 7009 Kanakry, Jennifer Ann 7009 Kanamori, Yasunobu 5526 Kanangat, Sivadasan e18013 Kanani, Samir e14545 Kanao, Shotaro e22116 Kanazawa, Akiyoshi e14649 Kanda, Shintaro 7540, 8064 Kandioler, Daniela e14537 Kane, Anna 572 Kane, Caroline 2075 Kane, Michael P. 1091 Kane, Robert C. 8592 Kaneda, Hiroyasu 8056, e19165 Kaneda, Mari 10539 Kanekiyo, Shinsuke 3006 Kaneko, Masahiro e12541 Kaneko, Tomomi 628, 635, LBA4001 Kanemitsu, Yukihide e14555 Kanemoto, Hideyuki 4008 Kaneoka, Yuji 4008 Kanesvaran, Ravindran 9552, e13582 Kang, Byung Woog 3553, e11505, e11594, e14549, e18017 Kang, Chang Hyun 1590 Kang, Gyeong Hoon 3550 Kang, Han Sung e11584 Kang, Hye Jin 3033 Kang, Hyoung Jin 10051 Kang, Hyunseok 6611 Kang, Jin Hyoung 1540, 6069, 9633, e19041^ Kang, Paul T. 9102 Kang, Seok Yun e15020 Kang, Shin Myung e19129 Kang, Soon-Beom 5568 Kang, Soonmo Peter 9009 Kang, Tongjun 6537 Kang, Won Ki 3608^, LBA4024, e14626 Kang, Won Kyung e14650 Kang, Yibin 11022 Kang, Yoon-Koo 4021, LBA4024, TPS4150, TPS4157, 8521, 10501^, LBA10502, 10503, 10550, 10551, e15026, e15091 Kang, Yubin e19534 Kanie, Hiroshi 10543 Kanitez, Metin e14660 Kanke, Yasuyuki 3063 Kann, Benjamin H. 6019 Kann, Lisa M. 2511 Kannan, Munirajan Arasambattu e17002 Kannan, Narayanan 1099 Kannan, Rajni 9063 Kannan, Sadhna 7043 Kanno, Emiko 11111 Kano, Nobuyuki e14670 Kansal, Kari Joanne 1100

Kansra, Vikram 2513 Kantak, Seema S. 3060 Kantarjian, Hagop M. 7001, 7024, 7029^, 7030, 7048, 7052^, 7054^, 7063, 7066, 7068, 7073, 7074, 7088, 7089, 7090, 7092, 7095, 7099, 7112, 7115, TPS7129, e17570 Kanthan, Selliah 3580 Kantoff, Philip W. 1531, 4561, 5013, 5018, 5034, 5056, 5078, 5086, 9529, e16032, e16036 Kantor, Guy 2007, 10582 Kanz, Lothar 3054, 7019, 10562 Kanzler, Stephan 3586, 4086 Kao, Richard J. 2502 Kao, Simon C. 10012 Kapellos, Gerasimos e18542 Kapelushnik, Joseph e22069 Kapiteijn, Ellen 3036 Kapkac, Murat e17529 Kaplan, Andrew e16019 Kaplan, Edward H. e15023 Kaplan, Ellen B. 5011 Kaplan, Henry G. 554, 1060 Kaplan, Lawrence D. 8524, e19541 Kaplan, Mehmet Ali e14705 Kaplan, Muhammed Ali e18544 Kaplan, Muhammet Ali e11559, e18546 Kaplan, Richard S. 3509, TPS3645 Kapoor, Anil e16011 Kapoor, Deepak A. e16076 Kapoor, Prashant 8516, 8541, 8587, 8600, 8606 Kapoun, Ann 2540 Kappel, Sonja e14537 Kappeler, Christian 10551 Kaptein, Ad A. e20669 Kapur, Payal 4581 Kar, Madhuchanda 8053 Kara, Hasan volkan e14533 Karaba, Marian e22023 Karaboué, Abdoulaye 3599, 3606, e20519 Karabulut, Bulent e12018, e12509, e13578 Karabulut, Senem e11592, e20016 Karaca, Burcak e11501, e12018, e12509, e13578, e13580 Karaca, Halit e14672, e14695, e15623, e18510, e18516, e20603 Karachaliou, Niki 7594, 11010, 11027, 11029, 11067, e22068 Karadogan, Ilker e18540 Karadurmus, Nuri e15623, e18016 Karageorgopoulou, Sofia e12524 Karahan, Vladislav e15546 Karakousis, Giorgos 9017 Karam, Jose A. 4516, 5069 Karam, Nadine e19060 Karamanakos, George e15101 Karamouzis, Michalis e11513 Karanikas, Georgios e22090 Karanlik, Hasan e11534 Karapetis, Christos Stelios 1581, 3528, 3592, TPS3649, 6541, 6598, 11015, e14506, e20577 Karasawa, Katsuyuki e18524 Karaszewska, Boguslawa 516, 9013 Karatas, Aysun TPS4158

Karavasilis, Vasilios

1093, 4558, e19048 Karayama, Masato 8038, e20658 Karayan-Tapon, Lucie 3513, 3536 Karczmar, Greg S. 1506, 11084 Kardos, Magdolna e15523 Kardosh, Adel 3557, 3566, 3567, e14538 Kareclas, Paula 4023 Karginova, Olga 515 Karim, Syed Mustafa 9568, e20613 Karkabounas, Athanasios e16083 Karkada, Mohan 3030 Karlage, Robyn 10022 Karlan, Beth 5515 Karlin, Lionel 8510, 8527, 8528, 8583, e19515 Karlin, Nina J. 1059 Karlov, Petr A. 3073 Karlovich, Chris Alan e22092 Karlsson, Eva e22126 Karmakar, Aditi 7085 Karmali, Rashida A. 2518 Karnes, William 3578 Karovic, Sanja 2571 Karp, Daniel D. 1051, 3103, e13575, e13591 Karp, Judith E. 3104 Karp, Stephen Eric 1018 Karpathy, Roberta TPS3128 Karpenko, Irene TPS5096, e15600, e20549 Karrasch, Matthias e20652 Karri, Sirisha e15200 Karrison, Theodore 2570, 2571, 4012, 6022, TPS7610 Karsan, Aly 8096 Karsh, Lawrence Ivan 5016, 5047^ Karski, Erin E. 10060 Karthaus, Meinolf 3631 Karve, Sudeep e11570, e11571 Karyakin, Oleg 3073, 5002 Karypidis, Kyriakos 8567 Karzai, Fatima H. TPS5095, e16017 Karzai, Fatima TPS5102 Kasahara, Kazuo e18564, e19083 Kasaian, Katayoon e22020 Kasajima, Atsuko e15071 Kasamatsu, Takahiro 5537 Kasamon, Yvette L. 7009 Kasbari, Samer S. TPS9651 Kashani-Sabet, Mohammed e20001 Kashihara, Hideya e14572 Kashii, Tatsuhiko 3072 Kashintsev, Alexey e15165 Kashiwaba, Masahiro TPS654 Kashiwabara, Kosuke e19016 Kasimir-Bauer, Sabine 5556, 5575, e11516 Kasimis, Basil 1602, 9567, e14625, e14661, e14681, e15561 Kasper, Bernd 10553, 10566 Kasper, Stefan TPS3124^, e14502 Kasperbauer, Jan C. 6095 Kass, Samantha Lindsay 8025 Kassab, Tricia e17556 Kassabian, Vahan 5034 Kassalow, Laurent 2560 Kasserra, Claudia 8585^ Kassim, Adetola 8605, e19539

Kassouf, Elie e20534 Kast, Karin TPS1137 Kastenhuber, Edward R. 2057 Kastner, Sabine 508 Kasuga, Akiyoshi e20004 Katabi, Nora 6034 Katada, Chikatoshi 4070, e15122 Katada, Natsuya 4070, e15113, e15122 Katai, Hitoshi 4019, 4104 Katakami, Nobuyuki 7518, 8098, e19017, e19045, e20609 Kataoka, Fumio 5590 Kataoka, Kozo e14649 Kataoka, Masaaki 1124 Kataoka, Masako e22116 Kataoka, Tsuyoshi e22113 Kataru, Sudheer Reddy e15143 Katato, Khalil 6567 Katay, Ildiko 8112 Katayama, Hiroshi 4104 Katayama, Kazuhiro e15150 Katayama, Ryohei 8010, 8083 Katdare, Rahul e22031 Kates, Ronald E. TPS655^, 1092 Katheria, Vani 9545 Kathirvel, M. e15120 Katki, Hormuzd A. 1523 Katler, Ann e14668, e20649 Kato, Atsushi 4056 Kato, Eriko e15159 Kato, Fumiaki e19054 Kato, Ikuko 3594, 9579 Kato, Itsuro 6096 Kato, Junji e15060 Kato, Ken 3082, 3559, 4074, TPS4152, e15016 Kato, Kikuya 2066, e19153 Kato, Makoto 613 Kato, Masahiro e12009 Kato, Ryoichi 7536 Kato, Satoshi e14597 Kato, Shunsuke e14597 Kato, Takahiro 6086 Kato, Takashi e14604 Kato, Takeshi 3516, e14551, e14601 Kato, Terufumi e19054 Katodritis, Nikos e19110 Katsaounis, Panagiotis e12524 Katsaros, Dionyssios LBA5501, 5502 Katsuki, Shinich e15060 Katsumata, Noriyuki 5537 Katsura, Koichi e20004 Kattan, Joseph Gergi e20500 Kattan, Michael W. 5023, e16004 Katz, Amanda 2511 Katz, Artur e14590 Katz, Daniela e21508 Katz, Matthew H. G. 4064, e22012 Katz, Michael S. 6500, 8592, e19517 Katz, Nathaniel 6627 Katz, Ruth 601 Katz, Steven C. 3079 Katz, Steven J. 6615, 9601, e20511 Katzenstein, Howard M. 10037, 10039 Katzorke, Nora 640 Kaubisch, Andreas 4032, 4093 Kaudeer, Naila e19146^ Kauff, Noah D. 1511, 1552, e12536

Kauffman, Eric e15604 Kauffman, Michael 2505 Kaufman, Bella 610, 1040, 11024 Kaufman, Gregory 7064 Kaufman, Howard TPS3114, TPS3128, LBA9008, 9050 Kaufman, Jonathan L. 7035, 8540, 8607, 8609 Kaufman, Michael R e19009 Kaufman, Peter Andrew 520, 523, 1049^, 1050^, 1055^ Kaufman, Samuel R 5044 Kaufman, Susan e13590 Kaufmann, Jörg 2508 Kaufmann, Manfred 1121 Kaufmann, Scott H. 5546 Kauh, John S. 3026, e14579, e14612, e15033, e15140 Kaur, Jaspreet e15138 Kaur, Paramjit 4007 Kavadi, Vivek 7501 Kavalerchik, Edward 8529 Kavan, Petr 2005^, e14556 Kavanagh, Brian D. 8074 Kavantzas, Nicolaos e22160 Kavathiya, Krunal Vasant e19118 Kavianymoghadam, Kaveh e15195 Kavsak, Peter 5039 Kavya, Mahesh 6624 Kawabata, Hidetaka e11519 Kawabata, Kazuyoshi 6004, e17006 Kawabata, Ryohei 4104 Kawachi, Aya 10543 Kawaguchi, Makoto e15579 Kawaguchi, Tomoya 7565, 8006, e18530, e19021 Kawai, Yuki e11555, e12014 Kawakami, Hisato e13501 Kawakami, Satoshi 7548 Kawamoto, Hiroshi 10050 Kawamoto, Yasuyuki e14604 Kawamura, Masafumi 7536 Kawamura, Mikio e22205 Kawamura, Sadafumi e15570 Kawamura, Takahisa 8098, e19045 Kawano, Junko 9629 Kawasaki, Masayuki 8111 Kawase, Ichiro e19021 Kawashima, Mitsuhiko e13586 Kawashima, Yoshiyuki 4104 Kawashima, Yosuke 7530 Kawata, Nozomu e15527 Kawauchi, Akihiro e15576 Kawsar, Hameem 1038 Kay, Amin 6535 Kay, Elaine 3549 Kay, Neil E. 7015, 7086, TPS8619 Kayahan, Sibel e15100 Kaye, Stanley B. 2513, 2580, 5514, 5566, TPS5615, e13502 Kayhan, Arda e12545 Kaynar, Leylagul e18014 Kayser, Sabine 7021 Kazanov, Diana 1526 Kazimirsky, Gila 3100 Kazlauskaite, Rasa e20544 Kazmi, Syed Mohammad Ali 3512 Kazubskaya, Tatiana e12543 Ke, Wei e22094 Ke, Xiao-Yan 8525 ABSTRACT AUTHOR INDEX

737s

Keam, Bhumsuk

6069, e15614, e18555 e13020 7094 e20536

Keane, Maccon M. Keane, Niamh Keast, Russell Keating Franklin, Anna Rachel Keating, Anne Therese Keating, Diana Keating, Karen N. Keating, Katherine E.

10028 548 5054 e20537 7532, TPS11120 Keating, Michael J. 7098, 7102 Keating, Nancy Lynn 616, 6528, 9523 Kebriaei, Partow 7010, 7011 Kebudi, Rejin 10043 Keck, Michaela K. 6008, 6010 Kee, Bryan K. 3512, 3600 Kee, Yuan Chuan 6589, 9506, e20566 Keedy, Vicki Leigh LBA10507 Keefe, Dorothy Mary Kate e20580 Keefe, Stephen Michael 519, e15564, e17009 Keegan, Mitchell TPS2620, e13523, e18541 Keegan, Patricia 2510 Keelara, Abiraj 2522 Keelawat, Somboon e17004 Keen, Corrine 8026 Keene, Kimberly Sue 623 Keeport, Melissa Lina e12503 Keesing, Jeffrey 6508 Kefford, Richard 543, 9005, 9009, 9016, 9026, 9029, 9030, 9062, 9066, e20020 Kehoe, Sean 5500 Keij, Jan 638 Keil, Felix e15041 Keil, Oliver 2508 Keil, Sebastian 11077 Keilholz, Ulrich 6002, 6014, e17015, e17021 Keir, Christopher Hunt 10538, 10545, e21514, e21515 Keisler, Meredith Deal e13507 Keizman, Daniel e15597, e15598, e16023, e16051, e16068 Kelany, Mohamed rada e11599 Kelderman, Sander 3036, 9078 Keldsen, Nina 3572 Kelkitli, Engin e19500 Kelkouli, Nadia e15607 Kell, Malcolm R. 1112 Keller, Evan T. TPS5094 Keller, Frank G. 7097, 10004 Keller, Maren 5569 Keller, Peter M. e20652 Keller, Ralph TPS4158 Kelley, Joseph L. 5585 Kelley, Michael J. 6562, 7538, 7539, 8090, 11053 Kelley, Robin Katie 2517, 2605, 2606, 4014, 4118, e14569 Kellie, Stewart J. 10021 Kellman, Robert 6059 Kellner, Christian 8604 Kellner, Udo 3639 Kelly, Catherine Margaret 598 738s

Kelly, Charles G. Kelly, Ciara Marie

LBA9000 598, e14519, e15196, e20550 Kelly, Daniel F. 9095 Kelly, David R. TPS10073 Kelly, Gloria e17570 Kelly, Kaitlyn Jane 10520 Kelly, Karen 2569, 7511, 8027, 8049, 8110, TPS8126 Kelly, Patrick Francis 7070, 8518 Kelly, Ronan Joseph 7598 Kelly, Tracy R. TPS4147, e15082 Kelly, William Kevin 5061, 11053, e15543 Kelsen, David Paul 4082, 4101, TPS4144, e15017 Kelsey, Christopher Ryan e18506 Kelsh, Michael A. 9083 Kelvin, Joanne Frankel 9524 Kemeny, Nancy E. 3609, 4116 Kemming, Dirk e18511 Kemner, Allison LBA4001 Kemp, Charisse N. 7052^, 7054^ Kempf, Barbara 8566 Kenar, Gokce e20655 Kench, James e18500 Kenchappa, Rajappa e13024, e13026 Kendall, Jude 5030 Kendra, Kari Lynn e20018 Kenmotsu, Hirotsugu 7572, 7582, 7599, 8037, e18556, e19050, e19074 Kenn, Werner e15193 Kennecke, Hagen F. 3569, 3590, 3624, 6502, 9577 Kennedy, Andrew S. e14545 Kennedy, Brooke 5061 Kennedy, Catherine e18500 Kennedy, Dana A. TPS8611 Kennedy, Erin Diane e14664 Kennedy, Jane e20523 Kennedy, M. John e14666 Kennedy, Patrick e11504 Kennedy, Richard D. TPS11120 Kennedy, Timothy J. 4093 Kennedy, Vanessa 9528 Kennes, Lieven 11077 Kenney, Lisa Brazzamano 10035 Kenny, Andrew 3627 Kenny, Kevin e19536 Kenny, Laura M. 635, e22194 Kent Laprise, Jessica 1545 Kent, Erin E. 9594, e20532 Kent, Michael S 7524, 8050 Kentepozidis, Nikolaos K. 1045 Keogh, Louise A. 1559, e20660 Keohan, Mary Louise 10512, 10558, 10580 Keohane, Catherine e13020 Kerboua, Esma 6075 Kerbrat, Pierre LBA4500 Kerenidi, Theodora e22202 Kerkar, Rajendra 5554 Kerkhoff, A. 4009 Kerkhoven, Ron M. 9085 Kerkmann, Markus 6591 Kerle, Irina 10508 Kerlikowske, Karla 559, 587 Kerloeguen, Yannick 2002^ Kern, Teresa 6558


Kerr, Christine 2067 Kerr, Ian G. e20613 Kerr, Jiandong 9619 Kerr, Kathleen 6638 Kerr, Keith M 7514 Kerr, Sarah E 11119 Kersellius, Romona 9060 Kerst, Jan M. 4529, 10553 Kerstein, David 2542 Kerstein, Robin A. 10023 Kertesz, Nathalie e20030, e20038 Kertmen, Neyran e11544, e12521, e15168 Kesari, Santosh 2061 Keshavjee, Shaf 7516, 7602, e18503 Keshtgar, Mohammed R. 1110 Keskin, Onur e18010 Keskin, Serkan e11592, e14594, e15569, e20016 Keskin, Özge e11544, e12521, e12563 Kesler, Kenneth 7605 Kesmir, Can 9085 Kesmodel, Susan TPS648, e22034 Kessels, Lonneke 1028, e22106 Kessler, Elizabeth e16055 Kessler, Jill 11019 Kessler, Larry 7546 Kessler, Luisa e22126 Kessler, Torsten 8548 Ketchens, Charlean 4501, 9632 Ketchum, Norma 3541, e15171 Kets, Marleen 1502 Ketter, Ralf TPS2103 Ketterer, Nicolas 8560 Ketterling, Rhett P. 7047 Kettlety, Timothy R. 5563 Keung, Chi e13512 Keung, Lap-Woon e12502 Keung, Yi-Kong e12502 Key, Jamie M. e17595 Keyes, Ashley 6635 Keymeulen, Kristien 1502 Keys, Henry 5530 Kezouh, Abbas e19520 Khachatryan, Artak 1578 Khachigian, Levon M. e22005 Khadar, Kattie 4543, TPS4589 Khalafallah, Alhossain A. e20610 Khaled, Amr 3085 Khaled, Annette R 3085 Khaled, Hussein Mustafa 4537 Khalid, Fatima e22184 Khalil, Ahmed 3515 Khalil, Daniel e15192 Khalil, Danny 599 Khalil, Maged F. 4026 Khalil, Mohamed Aly 4064 Khamly, Kenneth 10567 Khammari, Amir e20022 Khan, Farrah B. e12000 Khan, Iftekhar 5514, 7595 Khan, Imran 8502 Khan, Khurum Hayat 3062 Khan, Mahmudul H 8531 Khan, Michael 2508 Khan, Mohammad K. 8546 Khan, Mohammad Khurram 3032 Khan, Muhammad Imtiaz 5571

Khan, Muhib Alam e20703 Khan, Mumtaz 6061 Khan, Qamar J. 1026 Khan, Sadya 9574 Khan, Salam 7087 Khan, Seema Ahsan e11572 Khan, Shah Alam 10527, e21522 Khan, Sobia 1508 Khan, Sunniya 1602 Khan, Zeba M. 7086, 8586 Khandan, Fariba 1004 Khandani, Amir H 6018 Khandekar, Alim 7569 Khandelwal, Vilay H. e15011 Khanfir, Kaouthar e17019 Khanin, Raya 4082, 5032 Khanna, Chand 10053 Khanna, Lauren e15074 Khanna, Suneil Kumar 6622 Kharaishvili, Gvantsa 1063 Khare, Sanjay 3024 Kharkevich, Galina e20042 Kharmoum, Jinane e20624 Kharmoum, Saoussane e20516, e20624 Khasanov, Rustem 3073 Khasraw, Mustafa 2086, TPS3649 Khater, Leticia 6073 Khatri, Vijay P. e14570 Khattak, Muhammad Adnan 3018 Khattri, Arun 6008, 6010, 6066 Khattry, Navin 7043 Khazanov, Nikolay 11017 Khder, Gehan e17013 Kheoh, Thian San 5004, 5009, 5010, 5013, 5014, TPS5097 Khera, Nandita 7034 Khiewvan, Benjapa 11079 Khillan, Ratesh e14690 Kho, Dhonghyo e22168 Khoja, Leila e15085 Khor, Andrew Yu Keat e15102, e15137 Khorana, Alok A. e15014 Khorinko, Andrey V. e20593 Khorshid, Ola 7013 Khose, Swapnil 1546 Khosravan, Reza 10547 Khouri, Issa F. 7010, 7011, 8561 Khoury, Hanna Jean 7048, 7066, 7073, 7088, 7099 Khoury, Muin J. 6562 Khozin, Sean 8026 Khuder, Sadik e12016 Khuri, Fadlo Raja 2610, 6083, 6611, 7560, CRA8007, 8019, 8085, e14612, e19094, e20608 Khurshid, Humera 8075 Khushalani, Nikhil I. 4521, e15604 Khushoo, Vishvdeep e20686 Khvalevsky, Elina Zorde 4037 Kiaei, Panteha 2071 Kiani, Alexander LBA3506 Kibel, Adam S. 5016, 5023 Kichenadasse, Ganessan 6541, e20577 Kida, Kumiko 1047 Kida, Yuichi e15159 Kidd, Elizabeth A. 5605 Kidd, Jennifer e22083

Kidd, Mark S. Kiechle, Marion Kiem, Hans-Peter Kieran, Mark W. Kies, Merrill S.

4137 581, e20623 e13041 10030 2604, 6022, 6067, TPS6099 Kieszkowska-Grudny, Anna e20666 Kievits, Tim e14702 Kiezun, Adam 10536 Kigawa, Junzo 5526, 5528, 11049 Kihara, Kiyohiro 6588 Kii, Takayuki 4074, 4076, e14551, e15016 Kijima, Kyoko e13569 Kijima, Takashi e19010^ Kikuchi, Aya 5046 Kikuchi, Eiji e16094 Kikuchi, Ryoko e16505, e16519, e21520 Kikuchi, Shiro e15113 Kikuchi, Yasuhiro 6086 Kikuchi, Yoshihiro e16505, e16506, e16519, e21520 Kilari, Deepak 2601 Kilbreath, Sharon 9616, e20533, e20578, e20584 Kilburn, Lindsay Baker 2036 Kilgore, Joshua 5607 Kilgour, Elaine 7552 Kilic, Leyla e11592, e14594, e15569, e20016 Kilic, Selim e15623 Kilicaslan, Aydan e15540 Kilkarni, Girish 5007 Killelea, Brigid K. 1085, TPS1145, TPS1609, e20546 Killian, Keith 7513 Kilpatrick, Deborah 5061 Kim, AeRang 2554 Kim, Alice Y. 3081 Kim, Annette S 8605 Kim, Baek-Hui 4113 Kim, Benjamin e15130 Kim, Byoung-Gie 5512, 5568 Kim, Byung Sik 10550, e15091 Kim, Byung Soo 8521 Kim, Chae-yong 2098 Kim, Chan Kyu 11030, e22199 Kim, Chan Wook 3628 Kim, Chang Won 4122^ Kim, Chong Sung 1605 Kim, Choung-Soo TPS5099^, e15516, e15519 Kim, Christina e14715 Kim, Chul Woo 8521 Kim, Chul 9048 Kim, Da Rae 1035 Kim, Dae Yong e14504, e14606 Kim, Dae-Eun e15121 Kim, Dae-Yeon 5600, 5601 Kim, David 10018 Kim, Dong-Wan 1590, 2098, 8010, 8029, 8108, 8521, e18555 Kim, Dong-Wook 7001, 7048, 7052^, 7099 Kim, Edward S. 8052, 8079, e21504, e22085 Kim, Ellen J. e22181 Kim, Eric S. 1532, 2601

Kim, Eunhee Kim, George P.

2098 3539, 3640, 4026, e14526 Kim, Grace G 6070 Kim, Hadong 545 Kim, Hak Jae 1590, e18555 Kim, Hanjo 11030, e22199 Kim, Hawk 8521 Kim, Hee Cheol e14626 Kim, Hee Jeong 1070, e11512 Kim, Hee-Seung e20530 Kim, Heung Tae 8014 Kim, Ho Ung 629 Kim, Ho Young e15573, e17026 Kim, Ho-Cheol e19156 Kim, Hoon-Kyo 8087, 8092, e20580 Kim, Hwa Jung 9633, 10550 Kim, Hye Ryun e15098, e15144, e15573 Kim, Hye Sook e22025 Kim, Hyeon Hoe e15614 Kim, Hyeong Ryul e15051 Kim, Hyeong Su e17026 Kim, Hyo Jung 8521, 9633, e17026 Kim, Hyo Song 4089, e15098, e15144 Kim, Hyoung-Il e15144 Kim, Hyun J. 2055, 7562, 7566, e16019 Kim, Hyun Jin LBA10502 Kim, Hyun Jung 11030, e22199 Kim, Hyun Mi e14504 Kim, Hyun Sik e15033, e15140, e15141 Kim, Hyun-Jung e19152 Kim, Hyung Jin e14563 Kim, Hyung-Ho e15129 Kim, Hyunsoo 1012, 11108 Kim, Il Han 2098 Kim, In Ah 2098 Kim, In-Suk e19156 Kim, Inho 1590 Kim, Iris H. e20029 Kim, J. Julie 5574 Kim, Jae Hoon LBA5503, 5557, 5568 Kim, Jae Weon LBA5503, 5601, e20530 Kim, Jae-Wook 5557 Kim, Jane e17553 Kim, Janice N. e12030 Kim, Jee Hyun 2098, 2565, 3570, e15129 Kim, Jenny J. 4523, 4566 Kim, Jeong-Eun 3628 Kim, Jeong-Oh 1540 Kim, Jeri 5069 Kim, Jin Cheon 3628 Kim, Jin Won e15129 Kim, Jisun 551, 1128 KIM, Jiyoun e15051 Kim, John 11034 Kim, Jong Gwang 3553, e11505, e11594, e14549, e18017 Kim, Jong Hoon e15051 Kim, Jong-Hyeok 5600, 5601 Kim, Jongphil 3091, e19516 Kim, Joo-Hang TPS7609, 8014, 8029, 8034

Kim, Joseph W.

TPS3127, TPS5104, e16036 Kim, Joseph 3089 Kim, Ju yeon 1128 Kim, Jun Ki e14650 Kim, Jun Suk 9633 Kim, Jung Han e17026 Kim, Jung Sun e22025 Kim, Jung-AH 6059 Kim, Kab Choong e15091 Kim, Kenneth H. e16529 Kim, Kevin H 9507 Kim, Kevin 9004, 9005, 9016, 9026, 9047, 9058, 11086, e20036, e22081 Kim, Ki Hyang 4089, e15573 Kim, Ki-Hun 10550 Kim, Ku Sang e11512 Kim, Kunhwa e13591 Kim, Kwanil e12025 Kim, Kyoungha 11030, e22199 Kim, Kyu-Pyo 3570, 3628, 10589 Kim, Kyunghee e14606 Kim, KyungMann e18537 Kim, Lucia 6041, 7516 Kim, Mi-Jung 4114, e15056 Kim, Mi-Kyung e20530 Kim, Michelle 8558 Kim, Mimi 8097 Kim, Min Kyoon 551, 1128 Kim, Min Whan 1035 Kim, Miso e15614 Kim, Peter Tae Wan e15087 Kim, Phillip Sangwook 4051, 11113, e14626, e22110 Kim, Richard D. 3644, e15075 Kim, Roger Hoon e20600 Kim, Sang Woo e14650 Kim, Sang Wun 5557 Kim, Sang-Bae 4113 Kim, Sang-We TPS7608, 8029, 9633, e19041^, e19079 Kim, Se Hyung 11030, e22199 Kim, Se-Yeon e15026 Kim, Seok Won e11584 Kim, Seok-Hyun e19156 Kim, Seok-Mo 5568 Kim, Seonwoo 1088 Kim, Seung Cheol 5568 Kim, Seung Jin 1029, e20510 Kim, Seung Tae e22025 Kim, Seung-mi 3628 Kim, Seungwon 6043, 6051 Kim, Si-Young 9633, e15036 Kim, Sinae 1091, 2582 Kim, Stefano Chong Hun e15607 Kim, Su Young TPS3106, TPS3110, TPS3113 Kim, Sun Young 3570, 10589, e14504, e14606 Kim, Sung Whan e14563 Kim, Sung-Bae 600, 1070, 6069, e11512, e15051 Kim, Sung-Won e22063 Kim, Sungeun 5539 Kim, Sunghoon 5557 Kim, Sungjin 6611, 7560, 7589, e14579, e19094 Kim, Tae Min 1590, 2098, 2565, 4504, 8521, 11031, e15614, e18555

Kim, Tae Won

3570, 3573, 3628, 10589 Kim, Tae Yong 3550, 11031 Kim, Tae-Hoon 545, e11566 Kim, Tae-Jin 5601 Kim, Tae-Yong 551, 4044, e15066 Kim, Tae-You 3550, 3570, 4044, 4121, e15066 Kim, Taebong 4105 Kim, Taeryung 1128 Kim, Taewan 7573 Kim, William Y. e15507, e15595 Kim, Won Seog TPS8612, TPS8616 Kim, Woo Ho 4013 Kim, Yang Soo 9633 Kim, Yeonhee 8500, 8501 Kim, Yeul Hong 4013, TPS4151, e22025 Kim, Yong Hee e15051 Kim, Yong-Man 5568, 5600, 5601 Kim, Young Choi 545, e11566 Kim, Young Hak 11041 Kim, Young Saing e15613 Kim, Young Tae 1590 Kim, Young Whan 1590 Kim, Young Woo 4105, 4114, e15056 Kim, Young-Tae 5557, 5568 Kim, Young-Tak 5600, 5601 Kim, Yu Jung 2098, e15129 Kim, YuJung 2565, e18553 Kimata, Tsukasa 10543 Kimby, Eva TPS7131, TPS8617 Kimler, Bruce F. 1026, 1515 Kimmey, Gerrit A. 2089, e13040 Kimmick, Gretchen Genevieve 1007, 1076, 6551, 6558, 6606, e17516 Kimmig, Rainer 584, 5556, 5575, e11516 Kimura, Go 9623, e15527 Kimura, Kiyomi e11604 Kimura, Kosei TPS1140 Kimura, Norihisa e15179 Kimura, Richard 11006 Kimura, Tadashi 5538 Kimura, Tatsuo 7529, 7564, e19053 Kimura, Yasue e15039, e15158, e15173 Kimura, Yasunori e15526, e15531 Kimura, Yusuke TPS4152 Kimura, Yutaka 4102 Kinahan, Paul e13028 Kinar, Abdullah e20502 Kinde, Isaac 11015 Kinders, Robert J. 11103, e22080 Kindler, Hedy Lee 2571, 4011, 4012, 4022, 4032, TPS4144 Kindwall-Keller, Tamila L. 7058 King, Ashley e14569 King, Briana e22142 King, Jonathan Douglas 9566 King, Kelly A. 2554 King, Madeleine 5542 King, Mary-Claire CRA1501 King, Sarah e11602 King, Sinead e15142 King, Stephen Duane Watkins 9573 King, Tari A. 507, 1019 King, Thomas H. TPS3127 ABSTRACT AUTHOR INDEX

739s

King, Thomas e20521 Kingham, T. Peter 3609 Kinoshita, Ichiro 3072, 7550 Kinoshita, Jun e11604, e12026 Kinoshita, Taira 4104 Kinross, James M. e14620 Kinugasa, Yusuke e14555 Kinuya, Seigo e16072 Kinzler, Kenneth W. 11015 Kinzy, Tyler G. 6500, e20633 Kio, Ebenezer A. e15557 Kioi, Mitomu 6060 Kipp, Benjamin 11119 Kipps, Thomas J. 7005, 7018, 7045, 7086, 7124, TPS7130, TPS8619 Kira, Yukimi e19053 Kiran Kumar, K. e15120 Kirby, Brian J. TPS5100 Kirby, Maurice 2573 Kirchbacher, Klaus e19093 Kircher, Sheetal Mehta 6517 Kirches, Elmar e22140 Kirchhoff, Anne C. 6544 Kirchhoff, Tomas 1500, 9021 Kirchner, Lester 5581 Kirilova, Tanya e14669 Kirk, Alan 7544 Kirkin, Alexei e12024 Kirkpatrick, Nathaniel David 2056 Kirkwood, John M. 3041, CRA9007, 9038, 9043, 9075 Kirn, David H. 3608^, 4122^, TPS4161^ Kirova, Youlia M. 1533 Kirschner, Michaela 7586 Kirshner, Jeffrey J. 9527, 9531, e14528 Kirson, Eilon David e22125, e22134, e22138 Kishi, Hiroto e19016 Kishi, Kazuma 8058 Kishida, Takeshi e15527 Kishimoto, Junji 8111 Kishine, Kennji e14651 Kishino, Daizo e19008 Kishino, Satoshi 2559 Kisim, Asli e13578 Kiss, Alex 4583 Kiss, Igor e14622, e15581 Kissmeyer-Nielsen, Peter 3558 Kit, Oleg Ivanovich e14701, e15602, e19047 Kita, Toshiyuki e19083 Kita, Tsunekazu e16505, e16506, e16519, e21520 Kitada, Koji 4019 Kitagawa, Chiyoe e19005 Kitagawa, Mitsuhiro e15568 Kitagawa, Yuko 4096, TPS4152, e11598, e15016, e20576 Kitai, Kanako e19021 Kitai, Toshiyuki e22116 Kitaichi, Masanori e18530 Kitajima, Hiromoto e19054 Kitajima, Masaki e20576 Kitajima, Masayuki e14651 Kitajima, Takahito e22205 Kitamura, Hiroshi 4526, e20004 740s

Kitamura, Yasuo 4526 Kitano, Atsuko e20590 Kitano, Shigehisa 3003^ Kitao, Hiroyuki 1056 Kitayama, Joji e15027 Kitazono, Satoru 7540, e13511 Kitchener, Henry Charles 5500 Kittaneh, Muaiad 2502, 2602, 3044, e15007 Kitto, Alex e20044 Kiura, Katsuyuki 8033, e19023, e19040, e19124, e19167 Kiyama, Yoshio e19507 Kiyohara, Eiji 9095 Kiyohara, Meagan 3080 Kiyokawa, Takako 5526 Kiyono, Yasushi e16502 Kiyota, Naomi 4074 Kiyoto, Sachiko 1124, 11111 Kizilarslanoglu, Cemal e11595 Kizilbash, Sani Haider 2025 Kiziltepe, Melih e18516 Kjær, Ida 3551 Kladi, Athina 11117 Klang, Shmuel e22111 Klare, Peter 1004 Klarquist, Jared S. e22170 Klasa, Richard John 8552, e20045 Klausz, Katja 8604 Klebe, Sonja 7586 Klein, Andreas Kirschmer 1580 Klein, Anja TPS4158 Klein, Baruch e11578 Klein, Eric A. 5029 Klein, Evelyn 581 Klein, Jiri e22109 Klein, Leonard M. 7121, 8598 Klein, Oliver 3093^, 9062 Klein, Paula e20701 Klein, Robert J. 1500, 1552, 1554, e12527 Klein, Vincent 3560 Kleinberg, Lawrence 2065 Kleinerman, Ruth 10019 Kleinfield, Robert 2598 Klement, Ivan 2071 Klement, Tatjana 549 Klemp, Jennifer R. 1026 Klempner, Samuel 5521 Klepczyk, Lisa Caroline 623 Klepin, Heidi D. 9545, e18002 Klepp, Olbjorn Harald 4562 Klepp, Pasquale 3607 Klesczewski, Kenneth 8585^ Kletas, Victoria e15541 Klevesath, Manfred B. 2506^ Klimek, Virginia 7116 Klimstra, David S. 4116 Klingbiel, Dirk 3526, 3577, e20542 Klinger, Mark 3020 Klinger, Matthias 3051, 7020 Klingler, Christoph e15535 Klinkhammer-Schalke, Monika e20517 Kloecker, Goetz H. 3102 Kloepfer, Pia 4507^ Klopp, Ann 5596 Kloth, Jacqueline S. L. 4580, e11548, e13513 Klouvas, George 4558


Kluger, Harriet M. 4514, CRA9006^, 9010, 9012^, 9094 Kluger, Yuval 1549 Klughammer, Barbara 8021 Klümpen, Heinz Josef 4580 Knabbe, Cornelius e20652 Knabl, Julia 3064 Knackmuss, Stefan 3068 Kneba, Michael 4009 Knebel, Philip 3090 Knecht, Rainald 6002, e17003 Kneeshaw, Peter John e22123 Kneisl, Jeffrey e21504 Kneissl, Michelle 2528, 2547 Knestrick, Mark 8557 Knezevic, Dejan 5029 Knight, Catie 1026 Knight, Louise e20638 Knight, Simon 3011, 7567 Knight-Greenfield, Ashley 8555 Knipp, Heike e14502 Knipping, Stephan e17021 Knoblauch, Poul 8507 Knoblauch, Roland Elmar e13512 Knoedler, Maren e17015, e17021 Knol, Anne-Chantal e20022 Knopf, Kevin B. e14576 Knopp, Michael V. 1023 Knoppers, Bartha 10066 Knott, Adam 600 Knox, Jennifer J. 4077, 4130, 4578, 4586, TPS4593, TPS4594, 5058, e15518, e22015 Knox, Jennifer 4504, 4565 Knudsen, Beatrice 5027 Knudsen, Steen e22065 Knutson, Keith L. 521, 522 Ko, Amy 4058^, e19037, e19038 Ko, Andrew H. 2605, TPS2623, 4014 Ko, Beom Seok 1070, e11512 Ko, Dennis 6625 Ko, Emily Meichun 5523, 5607 Ko, Jung Hyun 5031 Ko, Kyungran e11584 Ko, Naomi e12509 Ko, Ryonho e15109 Ko, Stephen 4026 Ko, Yoo-Joung 4015, 4524, 6552, 6639, 10537, e17569 Ko, Yoon Ho e15164 Ko, Yoon-Ho 9633 Koay, Evelyn S. C. 586, e22107 Koay, Mei Y. 4132 Koba, Taro e19010^ Kobayashi, Akihiro e14555 Kobayashi, Daisuke 4088 Kobayashi, Hiroaki 5537 Kobayashi, Hiroshi 11052 Kobayashi, Kleber e22176 Kobayashi, Kokoro e11587, e22190 Kobayashi, Kunihiko 7530, e19142 Kobayashi, Michiya LBA4002 Kobayashi, Mikiro 4109 Kobayashi, Naoki e19507 Kobayashi, Nozomi e14548, e15038 Kobayashi, Satoshi e15109 Kobayashi, Takayuki e11587 Kobayashi, Takehiko e13586 Kobayashi, Yasuhito e22019 Kobayashi, Yukio 8551

Kobori, Yoshitomo e15579 Kobune, Masayoshi e15060 Koc, Basak e18006 Koca, Dogan e14533, e14705, e18546 Kocak, Mehmet 2036, e20673 Kocáková, Ilona 3511, 3620 Kocar, Muharrem e14660 Kocasarac, Selim e11506 Koch, Abby L. 8608 Koch, Arend e15071 Koch, Olaf M. e18511 Kochan, Koray e22061 Kochenderfer, James 10008 Kocherginsky, Masha e17511 Kochhar, Amit 6048 Kocic, Milan e14676 Koczwara, Bogda 6541, 9585, e20577 Koczywas, Marianna 2564 Kodaira, Makoto e20557 Kodali, Manga Devi e14653, e19070 Kodera, Yasuhiro 4088, 4096, e14552, e14614 Kodet, Roman e22208 Koeberle, Dieter 3503, 4035 Koechlin, Alice e12507, e12548, e16056 Koeda, Keisuke 4072 Koehler, Gabriele 8548 Koehler, Maria TPS652 Koehler, Stephen 8026 Koehler-Santos, Patricia e12546, e22154 Koenig, Frank 1571 Koenig, Jochem 4086 Koenig, Karsten e20688 Koenig, Katharina e12517 Koenigsmann, Michael 4079 Koenigsrainer, Alfred 3098 Koensgen, Dominique e16534 Koepfgen, Kathryn M. 5077 Koepl, Lisel e14585 Koeppe, Erika 1530 Koeppen, Hartmut 3001 Koerber, Wolfgang e22201 Koga, Hirofumi e16090 Kogler, Jurgen Wilhelm e20672, e20697 Kogosov, Michael e22076 Kogure, Hirofumi e15146 Kogure, Yoshihito 7529, e19005 Kogure, Yuki 9621 Kogut, Neil Martin 8556 Koh, Danny Ju Yong 2553 Koh, Eileen e22148 Koh, Eng-Siew 9602 Koh, Jane e15048 Koh, Yasuhiro 7572, 7582, 7599, e18556, e19050 Koh, Youngil 6069, 6614 Kohen, Nelson 6596 Kohlgruber, Ayona 10060 Kohlhaeufl, Martin 8013 Kohli, Manish 5082, e16061 Kohls, Andreas TPS1141 Kohls, Nikola e20623 Kohn, Elise C. 2514 Kohn, Martin 6508

Kohn, Nina 8087, 8092 Kohne, Claus-Henning 3538 Kohnen, Ralf LBA2000 Kohno, Mitsuo 7536 Kohno, Naoyuki 6004 Kohno, Norio 1029, e20510 Kohno, Takashi 7540, e19076, e22082 Kohonen-Corish, Maija e18500 Kohrt, Holbrook Edwin 3015, TPS3107, TPS3108, 3622 Koie, Takuya e15565 Koifman, Sergio 9097 Koike, Kazuhiko e15146 Koizumi, Tomonobu 7548 Koizumi, Toshiyuki 6060 Koizumi, Wasaburo 4070, 4110, 4111, e15009, e15022, e15122 Kojima, Atsumi 5526 Kojima, Hiroshi LBA4002, e14510, e14552 Kojima, Masatsugu 4092 Kojima, Satoko e15521 Kojima, Shinsuke e16090 Kojima, Takashi 4074, e13510, e15016 Kojima, Yuki e19521 Kokabi, Nima e15140, e15141 Kolar, Zdenek 1063 Kolatkar, Anand 8109, 11047 Kolb, Brigitte 8513 Kolb, Jen e20570 Kolenic, Giselle 568 Kolesar, Jill 2537, 2607, 8106 Kolev, Nikola e14669 Kolev, Vihren N. e13523 Kolevska, Tatjana 8559 Kolhe, Ravindra B. 7091 Kolibaba, Kathryn S. 7065, 8537, 8559, 8565 Kolitz, Jonathan E. 7100 Koll, Rainer e14513, e14562 Kollar, Attila 3503 Kollender, Yehuda e21521 Koller, Josef e20028 Koller, Michael e20517 Kollia, Georgia 3002^, 3016, 4514, 8030, CRA9006^ Kollmannsberger, Christian K. 2534, 4503, 4578, TPS4590, TPS4593, TPS4594, 5039, 5042, e15541 Kollmeier, Jens 8043 Kolnick, Leanne 6040, 6049 Kolodziejczyk, Milena 10564 Komaki, Ritsuko 1, 2003, 2004, LBA2010, 4078, 4083, 4085, 7501, 7574, e15013, e15053 Komarnitsky, Philip e19002 Komarova, Yekaterina e20005, e22022 Komatsu, Masaaki e13541 Komatsu, Yasuhiko 8551 Komatsu, Yoshito 3519, 3638, 4072, e14604 Komeda, Satomi e16507 Komiotis, Dimitrios e14699 Komiya, Kazutoshi e19016 Komiya, Takefumi 2532 Komoike, Yoshifumi 1106, 1116 Komori, Shouko 4070

Komorowski, Anna 553 Komov, Dmitry 629 Komrokji, Rami S. 7113 Komurcu, Seref e15623 Komurcuoglu, Berna Eren e18535 Komuta, Kiyoshi e19010^ Konala, Venu 7060, 8591, e18527, e22003, e22052 Kondalasula, Sri Vidya e20018 Kondi- Pafiti, Agathi e15114 Kondo, Chihiro 4076 Kondo, Genzo e13536 Kondo, Naoto e12001 Kondo, Nobuyuki e18557 Kondo, Ryoichi 7548 Kondo, Satoru e22205 Kondo, Satoshi 10038 Kondo, Tetsuro 7531, 11055 Kondo, Tsunenori e15527 Konecny, Gottfried E. 5510, 5515, TPS5616 Kong, Anthony TPS1136 Kong, Beihua 5512, 5535 Kong, Christina 6007 Kong, Feng-Ming (Spring) 7579, 7580 Kong, Fengming 7522 Kong, Li e15180, e15197, e18551, e19011 Kong, Sun-Young 4114, e14504 Kong, Weidong e15616 Kong, Xiangbo e15582 Kong, Yan e20027 Kong, Yanan 4107 Kongtim, Piyanuch 7010 Konig-Quartel, Jacqueline M. C. 2592 Konigsberg, Robert 549, e11601 Konishi, Ikuo 5537 Konishi, Koichi 8056, e19165 Konishi, Masaru 4008 Konishi, Muneharu 1029 Konner, Jason A. 5550 Kono, Hidaka e16094 Kono, Scott Arthur 2610 Kono, Scott A 6083 Kono, Yukihiro e14649 Konoplev, Sergej 7011 Konopleva, Marina 7022, 7029^, 7074 Konschak, Robert 6014 Konstantinidis, Ioannis 3558, 4116, 9033 Konstantinopoulos, Panagiotis A. 5524 Konstantinou, Catherine e20642 Konstantinou, Varnavas 8567 Konto, Cyril TPS9103 Konuk, Nahide 7038 Konzelmann, Isabelle e20542 Koo, Dong Hoe e15026 Koo, Khai-Nee 9552 Koo, Si-Lin e15002 Kooby, David A. e14579 Koon, Henry B. TPS9103, e13521 Koop, Dennis R. 5017 Koopman, Cheryl 9532 Koopman, Miriam 3502, 3552, e14584 Koopmeiners, Joseph 10560

Kooshyar, Mohammad Mahdi e22079 Kooshyar, Mohammad Mehdi e22167 Kopetz, Scott 3507, 3512, 3529, 3530, 3612, 3623, 3632, e14567, e22081 Kopic, Asir e14699 Kopp, Hans-Georg 3625, 4079, 4559, 7019, 10562 Kopp, Mikhail V. 3508, e12012 Koppenhoefer, Ursula 3098 Koppert, Linetta 1502 Koppes, Malika 3029 Korach, Jacob 5541 Koral, Lokman e14705, e18517 Korant, Alpesh K. 570, 3582, 3583, e14518, e14566 Korber, Susan 6574 Korch, Mary 1523 Korde, Larissa A. e12030 Korde, Neha 8597, e19506 Koritzinsky, Marianne 5070 Korkmaz, Esra e18540 Korkmaz, Serdal e18014 Korkmaz, Taner e11540, e15100 Korman, Alan J. 3003^, 3019, 3061, 9012^, 9055 Kormos, Mate e11564 Korn, Michael 2605 Korn, Wolfgang Michael 4014 Kornblau, Steven Mitchell 7022, 7029^, 7074, 7090 Korndoerfer, Jelka 1020 Kornek, Gabriela 6029 Korogi, Yohei e19023 Koroleva, Irina e12012, e20593 Korotkova, Olga V. e20042 Koroukian, Siran M. 6525 Korpanty, Grzegorz 4077, e12533 Korse, Catharina M. 7528 Korst, Robert J. 9583 Kortmansky, Jeremy S. 4084 Kortsik, Cornelius 8013 Kortum, Amanda N. e22178 Kortylewski, Marcin 4571 Koru-Sengul, Tulay 1586, e11611, e12547, e15596 Korytowsky, Beata e15508, e15605 Kosaka, Takeo e16094 Kosaka, Yoshimasa 1047 Kosaka, Yoshiyuki 10050 Koscielny, Serge 3010, e22153 Kosela, Hanna Melania 10564, e22046 Koshiji, Minori 4000 Kosir, Mary Ann e22182 Kosloff, Rebecca A. e13045 Kosmehl, Hartwig 3634, e14513, e14562 Kosmider, Olivier 7002 Kosmider, Suzanne 3584, e14583, e14608 Kosmidis, Paris A. 4558, e19048 Kossai, Myriam 7604 Kossoff, Ellen e11508 Kostakoglu, Lale 6019, 6062, 8555 Kostenuik, Paul J. 9628 Koster, Roelof e15584

Kosty, Michael P. Kosugi, Kohji Kota, Rajesh

6533 3101 e18000, e18003, e19533, e20684 Kota, Vamsi 7091, 7105 Kotake, Kenjiro 3518 Kotapati, Srividya e20021 Kotasek, Dusan 1079, 10500 Kote-Jarai, Zsofia 5054, e16000 Kotecki, Nuria e11523, e20630 Kothari, Nishi 3644 Kothwal, Syedakram e16545, e17028 Kotin, Alan TPS3120 Kotiv, Bogdan 3508 Kotoula, Vassiliki e19048 Kotov, Ilya N. 11028 Kotsakis, Athanasios Panayotis 6043, e14639 Kottayasamy Seenivasagam, Rajkumar e17002 Kottorou, Anastasia E. e18507 Kottschade, Lisa A. 9048, 9073, 9513, e20024 Kotzerke, Joerg e21518 Kouakam, Claude e11523 Koubi-Pick, Valerie 2512 Koudelakova, Vladimira 1063 Koudijs, Marco J. 1010 Kouji, Hiroyuki 2501 Koukaki, Triantafyllia e15063 Koukourikou, Ioulia e18507 Koumarianou, Anna e12524 Kountourakis, Pantelis 11117, e20635 Kourelis, Taxiarchis 8516 Kourlas, Peter 1059 Kournioti, Chryssanthi S. 6635 Koussis, Haralabos 5548, 6003, e20541 Koustenis, Andrew LBA8003 Kouta, Hiroko e16519, e21520 Koutoulaki, Anna e14639 Koutras, Angelos 582, 1093, 4558 Koutsopoulos, Anastasios 7594 Koutsoukos, Konstantinos 4558, e15619 Kouvatseas, George 582, 1093, 8567 Kovac, Zeljko e20659 Kovacs, Krisztina e15007 Kovacsovics, Tibor 7100 Kovalchik, Stephanie A 1523 Kovalenko, Nadezhda V. e20593 Kovatich, Albert J. TPS1135 Kovel, Svetlana e15597, e15598, e16023, e16068 Kowalski, Christoph e17550 Kowalski, Dariusz TPS7609, 8051^ Kowalski, Luiz Paulo 6017 Kowanetz, Marcin 3000, 3001, 3622, 4505, 8008, 9010 Koyama, Ryo e19043 Koyama, Takafumi e14670 Koyama, Tatsuki 6532 Koyfman, Shlomo A. 6035, 6061 Koynova, Tatyana e11586 Koyuncu, Ayhan e17529 Koyyalagunta, Lakshmi e20568 Koyyeri, Melike e20503 ABSTRACT AUTHOR INDEX

741s

Kozak, Kevin Robert 10521 Kozloff, Mark 2563, 7086 Kozlova, Larisa e13042, e22022 Kozlovsky, Vlad 6515 Kozlowski, Kasia 635 Kozma, Sara e13518 Kozono, David E. e19121 Kozuch, Peter 4011, e17566 Kozuka, Takuyo 7556 Kozuki, Toshiyuki 7530, 8006, e19040, e19054 Kraan, Jaco 11045, e16504, e22106 Krabbe, Laura-Maria 4581, 5074 Krabisch, Petra TPS1137 Kraemer, Bernhard 5598 Kraetschell, Robert W. 5593 Krag, David N. 1000 Krahn, Murray 6625 Krahn, Thomas e22055, e22110 Krailo, Mark D. 10037, LBA10504, 10528 Krainer, Michael e16042 Krajewski, Katherine Maragaret 4530 Kraljevic, Silvija TPS7130 Kramar, Andrew e11523 Kramer, Gero e15535 Kramer, Joel H. 6619, 6620 Kramer, Rachel V. e15192 Kramer, William G. e16075 Kramer-Marek, Gabriela 11083 Kramkimel, Nora e20032 Kranich, Anne TPS4158 Krappmann, Kristin e22112 Krasnik, Mark e19157 Krasnow, Steven e12531 Krasnozhon, Dmitriy 629 Kratzke, Robert Arthur 8039 Kratzsch, Tobias 2038, 2077 Kraus, Sarah 1526 Krause, Stefan W. 7051 Krause, Steffen TPS4591 Krauss, Daniel J. e16008 Krauss, Jürgen 6002 Krauter, Jürgen 7027 Kravetz, Sara Jane 5595 Krayenbuehl, Niklaus 2081 Krco, Christopher J 3037 Krebs, Paul 6536 Krech, Rainer Horst e14562 Kreienberg, Rolf 640, 1074, 1096 Kreilick, Charles e14658 Kreipe, Hans Heinrich 1092 Kreisler, Esther 3629 Krejcik, Jakub 8512^ Krekow, Lea 590 Kremmidiotis, Gabriel 4563 Krengli, Marco e17019 Krens, Lisanne e14558, e14586, e22156 Kresak, Adam e18526 Kreth, Friedrich Wilhelm 2045 Kretzschmar, Hans A. 2045 Kreutz, Werner e22114 Kreuzeder, Julia 591, e11525 Kreuzer, Karl A 7004 Krichevsky, Brian 11076 Krieter, Oliver 2092 Krill-Jackson, Elisa e11575 742s

Krilova, Anna 4080 Krimm, Michael e22183 Kripas, Chris e14656 Kriplani, Anuja 8594 Kris, Mark G. 6508, 6575, 6583, 7558, 7559, 7570, 7593, 7600, 8018, 8019, 8022, 8025, 8067, 8085, e15079 Krishna, Nina 2550 Krishnamani, K. V. e18000 Krishnamoorthy, Madhumitha e14518 Krishnamurthy, Jairam 8572 Krishnan, Amrita Y. 8556 Krishnan, Kartik TPS9104 Krishnan, Shanmugarajan 2081 Krisna, Sakktee Sai 8107 Krissel, Heiko TPS4163 Kristeleit, Rebecca Sophie 2585, 5514 Kristeleit, Rebecca 2566 Kristensen, Bjarne Winther 2088 Krivak, Thomas C. 5585 Krizman, David e19057 Kroeger, Jodi 9011 Kroeger, Nils 4565, 4578, 4586, e15518 Kroening, Hendrik 3643 Kroep, Judith R. 1028, 1072, 10516, e22106 Kroetz, Deanna L. 11053 Kroez, Matthias e20710 Krohn, Kenneth A. e13028 Krol, Augustinus 8568 Kroll, Stew 8602, e15557 Kroll, Torsten e22201 Kroneman, Trynda 11119 Kronenberg, Stephanie Anne 9012^ Kronenwett, Ralf e22112 Kronthaler, Ulrich 3075 Krontiras, Helen 507, 527, 1052 Krook, James Edward 1080, e11609, e12034, e14646, e19130, e20672, e20697 Krop, Ian E. 500, 513, 1065, 1100, TPS1134, e17574 Kropff, Martin 8544 Kros, Johan M 2001, 2007, 2011 Krouwer, Hendrikus 2076 Krueer, Thomas e18511 Krueger, Janet 1129 Krueger, Joseph e22187 Krueger, Sandia 5551 Kruempel, Amy 11044 Krug, Lee M. 7593, 7600 Krug, Utz 8548 Kruip, Jochen 11006 Kruisbeek, Ada M. 3029 Kruitwagen, Roy F.P.M. e16517 Krulik, Jerome e19056 Krull, Kevin R. 10032 Krumholz, Harlan 6511 Krupa, Ewa 3052 Kruper, Laura e17542 Kruschewski, Michael e15068 Kruse-Jarres, Rebecca e12503 Krzakowski, Maciej Jerzy 7500, LBA8011 Krzakowski, Maciej 8043


Krzystanek, Marcin 3036 Krzyzanowska, Monika K. 3534, 6535, 6628, 9518, 11002 Krzyzanowska, Monika 6625, e14664, e20639 Ktiouet, Meryem e15607 Ku, Geoffrey Y. e15017 Ku, Geoffrey Yuyat 4101 Ku, Ja Hyeon e15614 Kubackova, Katerina e15581 Kuban, Deborah A. 5069 Kubicek, Greg J. 6043 Kubicek, Karen e22060 Kubicka, Stefan 3604 Kubo, Akihito 7565, 8006 Kubo, Jessica 1504 Kubo, Michiaki 11053 Kuboki, Satoshi 4056 Kuboki, Yasutoshi 4075, e13504, e22082 Kubota, Akira 6004 Kubota, Kaoru 8064 Kubota, Yoshihiro e11555, e12014 Kubota, Yoshinobu e16098 Kuchuk, Iryna 6595, e16074, e19024 Kuchuk, Michael e19024 Kucuk, Omer e15617 Kucukoner, Mehmet e11559, e14533, e14662, e18510, e18544, e18546 Kucukoztas, Nadire e11532, e16526, e16528, e16536 Kucuksahin, Orhan e18010 Kuczma, Jane e14569 Kuczyk, Markus A. e22076 Kudchadkar, Ragini Reiney CRA9003, 9011, 9028, 9056^, 9066, 9079 Kuderer, Nicole Maria 6534 Kudinova, Elena Aleksandrovna e13545 Kudo, Daisuke e15179 Kudo, Keita e13504 Kudo, Kenichiro e19167 Kudo, Kenji e22008 Kudo, Masatoshi 4126, TPS4163 Kudo, Mineo e14604 Kudoh, Kazuya e16505, e16506, e16519, e21520 Kudoh, Shinzoh 7518, 7564, e19053 Kuebler, J. Phillip 3640, 8114, e14526 Kueffer, Stefan e14702 Kuei, Andrew e20602 Kuemmel, Sherko TPS655^, TPS1138, 1577 Kueng, Marc 3503 Kuerer, Henry Mark 1017, 11060 Kuerschner, Dorit e15096 Kufahl, J. TPS3119^ Kufer, Peter 3051, 7020 Kuhl, Christiane K. 11077 Kuhlen, Michaela 10017 Kuhlisch, Eberhart 5556 Kuhlmann, Jan Dominik 5556 Kuhlmann, Mareike 8548 Kuhlthau, Karen A. 6544 Kuhn, Peter 4014, 8109, 11047

Kuhn, Susanne Antje 2038, 2077 Kuhn, Walther 1092 Kuhnt, Thomas 6077 Kuijer, Philomeen 595 Kuiper, Justine Leonie 8065 Kuji, Shiho e16507 Kuk, Deborah 9033, 9052, 10520, 10580 Kukar, Moshim e20573 Kukita, Yoji e19153 Kukreti, Vishal e19509 Kulahcioglu, Emre e11537 Kulanthaivel, Palaniappan 2500 Kulinich, Tatyana Michailovna e13545 Kulka, Janina 1549, e15523 Kulkarni, Girish S. 4568 Kulkarni, Hrishikesh e17505 Kulkarni, Shashikant 11099 Kulkarni, Swarupa 2593 Kulke, Matthew 4142, 4143 Kuller, Anne 4051, e14626 Kullmann, Frank TPS3124^, LBA3506, 4086 Kulshreshtha, Pranjal 1099 Kumagai, Naoko 3638 Kumagai, Toru e19153 Kumamoto, Toshihide e20585 Kumano, Tomomi e19134 Kumanogoh, Atsushi e19010^ Kumar, Aalok 3569 Kumar, Akhil 1080, e11609, e12034, e14646, e19130, e20672, e20697 Kumar, Aryavarta M. S. e15015 Kumar, Ashok TPS2627 Kumar, Divjot Singh 9598 Kumar, Gagan 7127, 9558, e18008 Kumar, Kirushna e19145 Kumar, Lalit 7081, 7082, e19524, e19526, e19531, e22098 Kumar, Mahesh 6091, e17030 Kumar, Pallavi 1563, 9534 Kumar, Rachit 4039, e15028 Kumar, Rajiv 1581, 6541 Kumar, Rajive 7081, 7082 Kumar, Rakesh TPS4162 Kumar, Ravi TPS4595 Kumar, Santhosh e18004 Kumar, Satish 3018, 9031 Kumar, Shaji 8514, 8516, 8541, 8581, 8587, 8600, 8606, e19517 Kumar, Shiyam e22099 Kumar, Sonia e11509 Kumar, Sunesh e16511 Kumar, Vijay 577 Kumar, Vikaash 518, 5042 Kume, Haruki e15527 Kumekawa, Yosuke e15105 Kummar, Shivaani 6045 Kummetha Venketa1, Jagadish e19534 Kun, Larry E. 2036 Kundapur, Vijayananda 7596 Kundel, Yulia e15078 Kunhiparambath, Haresh e13014, e13043, e20679 Kunieda, Futoshi 4526 Kunieda, Katsuyuki 3516 Kunikane, Hiroshi e20609 Kunimasa, Kei e19167

Kunin-Batson, Alicia 9606 Kunisaki, Chikara 4068 Kunitoh, Hideo 8058, 8064 Kunju, Priya 4545, TPS5094 Kunkel, Lori A. 7057, TPS8619 Kuno, Takeshi e15159 Kunsman, Janet TPS8620 Kunstfeld, Rainer 9036 Kunstlinger, Francis 3599 Kunyioshi, Renata e20601 Kunz, Pamela L. e15011 Kunz, Sara e19009 Kunzmann, Volker TPS3119^, 4058^, e15193 Kuo, Frank C 1531 Kuo, Han Pin e19041^ Kuo, Raymond Nien-Chen e15043 Kuo, Sung Hsin e13554, e16503, e19523 Kuo, Wen-Liang e13532 Kupelian, Patrick e16004 Kupfer, Sonia 1530 Kurachi, Kiyotaka 3516 Kurahashi, Issei 4019 Kuranda, Mike e13529 Kurata, Takayasu e13501, e19165, e20004 Kurbacher, Christian M. TPS3119^, e16533 Kurbacher, Jutta Anna e16533 Kurbecovic, Ina e18013 Kurdziel, Karen A. TPS4589 Kure, Elin 3571, 3597, e14710 Kurenova, Elena V. e22143 Kurian, Allison W. 1003, 1083 Kurin, Michael e17523 Kurita, Akira LBA4002 Kurita, Nobuhiro e14572 Kurkjian, Carla 2544, 2573, e15025 Kurland, Brenda F. 1089, 1090 Kurland, John F. TPS3107, TPS3108 Kurniali, Peter C. e13047 Kuroda, Ayumi e18557 Kuroi, Katsumasa 571, 613, 1048^, e12011 Kuroishi, Shigeki 8038, e20658 Kurokawa, Koji e18564, e19083 Kurokawa, Tetsuji e16502 Kurokawa, Yukinori 4072, e14551 Kuromitsu, Sadao 5046 Kuronya, Zsofia e15530 Kurosumi, Masafumi e22019 Kurozumi, Sasagu e22019 Kurtagic, Elma e15012 Kurteva, Galina Petrova 3575, 4021 Kurtz, Jean Emmanuel e17543 Kurtz, Jean-Emmanuel 9510, e20513 Kuru, Timur H. e16063 Kuruvilla, Sara e19077 Kurz, Guido e13543 Kurz, Sarah 6024, 6034 Kurzrock, Razelle 1051, 2506^, 2509, 2545, 2611, TPS2619, 3507, 6090, 8523, 9544, 11086, e13534, e13574, e13575, e13591, e22086 Kusagaya, Hideki e20658 Kusche, Manfred TPS655^, e22201 Kushima, Ryoji 4104 Kusic, Zvonko e15603

Kuss, Iris 10503, 10551 Kussick, Steven 8559 Kuster, Niels e15049 Kusumi, Takaya 3638 Kusumoto, Masahiko e12541 Kusumoto, Tetsuya e15039, e15158, e15173 Kusunoki, Masato e14631, e22205 Kutarska, Elzbieta 5572, e16544 Kuten, Abraham 9500 Kutluk, M. Tezer 10067 Kuwakado, Shin e14527, e14551 Kuwata, Takeshi 4075, 4104, e22082 Kuyama, Shoichi 7530 Kuykendal, Adam Rea e15507 Kuzel, Timothy 9087, e15554, e20527 Kuzhan, Okan e15623 Kuzma, Michelle e13503 Kvasnicka, Hans-Michael 7030 Kvistborg, Pia 9078, 9085 Kwak, Cheol e15614 Kwak, Eunice Lee 3507, 4047, 4090, 4125, 8032, e14636 Kwan, Lorna 4540 Kwan, Min-Fun Rudolf e13505 Kwan, Yiu-Lam 8537, 8565 Kwekkeboom, Kristine L. 9635 Kwiatkowski, David J. 8019, 8085, 11085 Kwiatkowski, Fabrice 1057, 1058, e11615, e17022 Kwoh, Theodore Jesse 8523 Kwok, Mary 8597, e19506 Kwon, Eugene D. 3037, 4521, TPS5093 Kwon, Jung Hye e17026, e20554, e20581 Kwon, Myoung 8577 Kwon, Nancy 3540 Kwon, Soonil 6614 Kwon, Tae-Hwan e11594 Kwon, Youngmee e11584 Kwong, Dora Lai Wan e14530 Kwong, Wilson e17525 Kühn, Thorsten 1020 Kühne, Thomas LBA10504 Kyle, Robert A. 8516, 8541, 8606 Kyle, Sarah e19519 Kümmel, Sherko 607 Küpferling, Susanne e20670 Köhler, Karola 2506^ Köhne, Claus-Henning 3537, e14561 Köstler, Wolfgang 622

L López, Diego e19068 La Orden, Beatriz 2087 La Quaglia, Michael P. 3033 La Rosa, Francisco G. e14612 La Russa, Francesca 5050, e16031 La Spina, Chiara Maria e20650 la Torre, Annamaria e14655 La Vecchia, Carlo 1594 La Verde, Giacinto e19527 La Verde, Nicla Maria e12021, e19084 Laabs, Brenda e13572

Laack, Nadia N. 2025 Labatte, Jean Marc e18508 Laberge, Sophie 1104 Labianca, Roberto 3618, e14611 Labiano, Tania e19027 Labib, Alain 10582 Labidi, Soumaya e20721 Labonte, Melissa Janae 3557, 3568, 4110, 4111, e14538, e14543, e14714, e15009, e15022 Labots, Mariette 4566, 11087 Labussiere, Marianne 2024, 2028 Lacaine, Francois 4006 Lacas, Benjamin 10505 Lacau Saint Guily, Jean 6055 Lacave, Roger 6055 Lacher, Markus e22083 Lachi, Pavankumar e16545, e17028 Lachmann, Robert 5556 Lachowicz, Jean E e13013 Lackner, Carolin e15064 Lackner, Mark 11003 Lacombe, Denis A. 2007 Lacombe, Michael Andrew 6059 Lacorte, Teresa Maria e16071 Lacouture, Mario E. 2095, 9018, 9622, e13571, e14713, e20669 Lacroix, Herve e19046 Lacroix, Ludovic 511, 2512 Lacroix-Triki, Magali 511 Lacuna, Kristine Peregrino 5083 Lacy, Cynthia e13001 Lacy, Jill 4084 Lacy, Martha 8510, 8516, 8527, 8528, 8541, 8581, 8583, 8587, 8600, 8606 Lad, Thomas E. e20544 Lada, Martha e22202 Ladanyi, Marc 7600, 8018, 8019, 8022, 8025, 8067, 8083, 11085 Laday, Shell 2604 Ladd, Sharron 2573 Ladefoged, Christian 6600 Ladekarl, Morten 5532 Lademann, Juergen e20688, e20689 Ladenstein, Ruth Lydia 10016, 10031 Ladner, Robert D. e14538, e14543 Ladoire, Sylvain 4525 Ladrón de Guevara, Laura 4126 Lae, Marick 10574, 10575 Lafata, Jennifer Elston 6018 Lafay Cousin, Lucie 10029 Laffranchi, Bernard 4041 Lafleur, Judith 3052 Laforest, Anais 3585 Laforga, Juan e14671 LaFougere, Christian 2045 Lafourcade, Marie-Pierre e19078 Laframboise, Stephane 5561 LaFramboise, William A. 9043 LaFrankie, Debra C. 2030 Lagarde, Pauline 10561 Lage, Agustin 3013, 3086, TPS3123 Lager, Joanne J. 2012 Lagier, Robert 7601 Lagmay, Joanne Pigues TPS10591 Lagoudaki, Eleni 7594

Lagrange, Jean-Leon 10582 Lahav, Maor 4037 Laheru, Dan e15028 Laheru, Daniel A. 4039, 4057, 4063, e14647 Lahn, Michael M. F. 2016, 2039, 2061, 2563, 4118, 5019, 8051^ Lahoti, Amit e20664 Lahr, Angelika 2092 Lahuerta, Juan José 8511 Lai, Albert 2055, 2076, e13017 Lai, Anky 9577 Lai, Chiu-Lin 3554 Lai, Chyong-Huey e16537 Lai, Hung-Chih e13585 Lai, Lee Min e12032 Lai, Lily L. e20651 Lai, Mei-Shu 3554, e15043 Lai, Pamela e14598 Lai, Rensheng e22026 Lai, Ruay-Sheng e19041^ Lai, Xin e16531 Lai, Yun-Ju e13011 Lai-Goldman, Myla 7576 Lainez, Nuria 4587, 10532, e16028 Laios, Ioanna 11003 Laitman, Yael 1552, 9630 Lake, Diana 606 Lakhanpal, Roopa 1079 Lakis, Sotiris e19048 Lakka, Sajani e13038 Lakomy, Radek 3574 Lakoski, Susan G. 1520 Lakoski, Susan 1560 Lakshmanan, Radhika e20588 Lakshmangowda, Preethi Bangalore e17034 Lal, Priti 519 Lalami, Yassine 6002 Lalet, Caroline 3558 Lalier, Lisenn e18532 Lalla, Deepa 625, 642, 6626, 9619, e11603, e17527 Lalla, Rajesh V. 9620 Lallas, Costas D. 5061 Lallemant, Benjamin 6053 Lam, Christine 9536, 9551, 9595 Lam, Elaine Tat 2557, e16055 Lam, Ka On e14530 Lam, Lucia L.C. 4542 Lam, Siu W. 1072 Lamanna, Nicole 7005, 7086 Lamar, Ruth E. e13045 Lamarca, Angela TPS4146 Lamb, Lawrence S TPS10073 Lamb, Tiffany 4100 Lamba, Gurpreet Singh 7076 Lamba, Jatinder Kaur 10005 Lambert, Alexandre TPS9105^ Lambert, Gwendolyn M. 5036 Lambert, Pascal e17596 Lambert, Sylvie D. e20615 Lambertini, Matteo 589, 1036, e17548 Lambiase, Antonio 3038, 7007, 8035, 10568, e13593, e18528, e22145 Lambin, P. e18559 Lamborn, Kathleen 2015 ABSTRACT AUTHOR INDEX

743s

Lambrechts, Diether Lamie, Peter Makram Lamm, Wolfgang Lammersfeld, Carolyn

1078 9099 e16042 5036, e20663

Lamond, Nathan William Dana e17564 Lamont, Elizabeth B. 6604 Lamoril, Jerome e20032 Lamprodimou, Georgia e22202 Lampron, Megan E. 4570 Lamy, Aude e14596 Lamy, Pierre-Jean e14621 Lamy, Thierry 2032 Lan, Lan e15560 Lance, Raymond S. 5047^, 5053^ Lancellotti, Marialuigia 8591 Lancet, Jeffrey E. 7100, 7113 Lanchbury, Jerry S. 5005, 5043 Lanciano, Rachael 5530 Lanctot, Jennifer 10022 Lanczky, Andras e11564 Land, Stephanie R. TPS1139 Land, Susan 7561 Landa, Jonathan 10512, e16001 Landau, Susan M. 6619, 6620 Landeiro, Luciana Garcia e20524 Lander, Mary e19502 Landercasper, Jeffrey e17583 Landers, Donal 531 Landers, Mark 11108 Landesman, Yossi 2505 Landgren, Ola 8597, e19506 Landherr, Laszlo e12022^ Landi, Bruno 10546 Landi, Lorenza 11066 Landier, Wendy 10004, 10020 Landman-Parker, Judith 10028 Landolfi, Stefania 3524, 4135 Landreneau, Rodney Jerome 7502, 7524, 7577 Landrum, Lisa Michelle 3, 5527 Landrum, Mary Beth 6528 Landry, Jerome Carl e14579, e14618 Landsman-Blumberg, Pamela e20525 Lane, Heidi 2566 Lane, Sophia e19120 Lane, Stephen R. 2031 Lanese, Robert 6538 Lang, Alois 583 Lang, Edward 8017 Lang, Hauke TPS3124^, 3538 Lang, Istvan 529, 1040, 3052, 3521 Lang, Jin Yi e16531 Lang, Jinyi e16520 Lang, Joshua Michael e22141 Lang, Lixin 11083 Langberg, Carl Wilhelm 4553, 4562 Langdon, Robert M. 3508 Lange, Carol A. 593, 596, e11543 Lange, Holger e22187 Lange, Julie R. TPS1144 Lange, Marie 9510 Lange, Thoralf 10508 Langeberg, Wendy J. 6608 Langella, Philippe e14525 Langer, Corey J. 6094, 7578, 8031, 8044, 8073, 9613, e20618 744s

Langerak, Anton W 7004 Langermann, Solomon 3044 Langholz, Bryan e17573 Langleben, Adrian 2542 Langley, Emma J. 4051, 11113 Langley, Ruth E. 4020, TPS4156 Langston, Amelia A. 7035, 8540, 8609 Langui, Mario 1073, 11118 Laniado, Michael e21518 Lankes, Heather A. 3077, TPS3121 Lannin, Donald R. 619, 1085, TPS1609 Lannutti, Brian Joseph 8579 Lanocita, Rodolfo e12017 Lanoy, Emilie 9556 Lansiaux, Amelie 10525 Lantuejoul, Sylvie 8099, 8100 Lanuti, Michael 7555 Lanza, Giovanni 2021, 3040 Lao, Christopher D. CRA9003, 9037 Lao, Juan e12015 Laohavinij, Sudsawat 4138 Lapidus, Rena G. 2515 Laplanche, Agnes LBA4500 Lapointe, Real W. 4060 Lapolt, Donna 1565 Lapsiwala, Ritu e19502 Lara, Gisell Anaid e17031 Lara, Matthew Stephen 8049 Lara, Primo 2569, 4517, 7511, 8028, 8049, 8097, 8110, e15073, e19147 Lara-Guerra, Humberto 7516 Lara-Medina, Fernando 634, e11533 Laramas, Mathieu e15593 Larciprete, Ana Luisa de Castro e20640 Lardelli, Pilar 547, 10517 Lardon, Filip 7534 Largillier, Remy e13519 Laribi, Kamel 7002 Larkin, James M. G. 3018, 3036, 9020, 9031, 9046, 9068 Larner, James Mitchell 9500 Larocca, Alessandra 8517 Laroche, Francoise 569 Larouche, Valerie 10029 Larsen, Bryce G. e20508 Larsen, Emily K. TPS8611 Larsen, Eric 10001 Larsen, Jim S. 3572 Larsen, Julie S. TPS5097 Larsen, Ole e14593 Larsen, Stig e12029 Larsen, Stine Kiaer 8084 Larsen, Vibeke Andree 2092 Larsimont, Denis 11003, e12008 Larson, Andrew C. e22204 Larson, Martha M. e17025, e18537 Larson, Melissa L. 7106, 7108 Larson, Richard A. 7052^, 7054^ Larson, Steven M. 5073, 5090, 11076 Larussa, Francesca e15512 Laskar, Siddharth e19503 Laskin, Janessa J. 7551, e19039, e19131, e22020 Lassau, Nathalie 2535, e22153 Lassen, Soeren e16540, e16541


Lassen, Ulrik Niels

2092, 2505, 2522, 8512^ Lasser, Philippe 3596 Lasserre, Susan 3619^ Lasset, Christine 1528 Lassi, Kiran Krishan e19015 Lassman, Andrew B. 2095 Last, David e13002 Lastoria, Secondo 11008 Lathan, Christopher S. 6562 Lathan, Christopher 1563 Lathia, Chetan e14507 Latiano, Tiziana Pia e14655 Latiano, Tiziana 11058 Latif, Asma 6540, 6613, e15580 Latif, Maimoona e20610 Latif, Naeem e15018 Latimer, Nicholas 636, 9040, 9044 Latini, David M. 4551 Latini, Luciano TPS651, e11616 Latorre, Agnese e11502 Latorzeff, Igor TPS5099^, e16009 Latos, Kunibert TPS1141 Latreille, Jean 3515 Lau, Anthea e19031 Lau, Christopher Y. 7513 Lau, Dawn PX 8107 Lau, Derick H. M. 2564 Lau, Derick e19147 Lau, Harold Y. e12505 Lau, Helen TPS650^ Lau, Mike 635 Lau, Ryan A. e12502 Lau, Sze Man June 4117 Lau, Yi-Yang Yvonne 8010 Lau, Yiu-Keung e20525 Laubach, Jacob 8512^, 8584, 8602 Laubender, Ruediger Paul 3630 Lauber, Juergen e22035 Laud, Purushottam 6642 Lauer, Richard C. 4563 Lauer, Ulrich 3098 Laufer, Ilya 9501 Launay-Vacher, Vincent 5567, e12504 Laura, Oliva e18522 Laura, Perelli e16100 Laurell, Anna 4553 Laurent, Dirk 3514, 3636, 3637 Laurent, Stephane e13589 Laurent-Puig, Pierre 3525^, 3562, 3585, 3596, 3614, e14600, e22001 Laurenti, Luca 7101 Lauria, Rossella LBA5501, e11528 Lauricella, Calogero 11005 Laurie, Scott Andrew 6041, 8048, 8072, e19033, e19077 Lauritsen, Jakob 4502, 4532, 4533, e20561 Lauseker, Michael 7051 Lausoontornsiri, Wirote 531 Lautenschlaeger, Tim 7573 Lavasani, Sayeh Moazami 3594 Lavergne, Emilie 6056, 10582 Lavernia, Javier 10523 Lavertu, Pierre 6035 Lavertu, Sophie e15094 Lavie, Ofer 5576 Laviraj, M. A. e13043, e20679

Lavole, Armelle 7515, 8081 Lavranos, Tina C. 4563 Lavu, Kalyana C e14653 Law, Calvin 10537, e14573 Law, Ethel 9524 Lawal, AbdulRazzaq Oluwagbemiga e11612 Lawal, Ishak 1576 Lawler, Jack e17014 Lawless, Claire 9590 Lawlor, Elizabeth R. 10045 Lawrence, Cheryl 5514 Lawrence, Donald P. 3002^, CRA9006^, 9010, 9015, 9064, 9066, 9076 Lawrence, H. Jeffrey 5029 Lawrence, Julia 1034, e18002 Lawrence, Theodore Steven 2052, 7522 Lawrence, Yaacov Richard 1503, 2100, e17535 Lawrenson, Lesley e11610 Lawsin, Catalina e20615 Lawson, Amber 7084, e18001 Lawson, David H. 3032, CRA9003, 9022, 9050, TPS9103 Layman, Rachel M. 1023, 1043 Lazar, Alexander J. F. e20034, e20036 Lazar, Vladimir 511, 2512 Lazare, Michael e18539, e19536 Lazarev, Alexander Fedorovit e12560 Lazaridis, Georgios e19048 Lázaro Quintela, Martin 7549 Lazaro, Alberto e13535 Lazaro, Conxi e12516 Lazarus, Cathy L 6091, e17030 Lazarus, Hillard M. 7036, 7058 Lazzarelli, Silvia 4112, e15086 Lazzaretti, Maria Grazia e11515 Lazzari, Chiara LBA8005 Lazzari, Elisa 7060, 8591, e22003 Lazzeroni, Matteo 1517 Le Berre, Marie-Aude TPS4163 Le Cesne, Axel 10500, 10503, LBA10507, 10514, 10516, 10525, 10542, 10546, 10548, 10551, 10563, 10568, 10574, 10575 Le Corre, Delphine e14600 Le Coutre, Philipp D. 7048, 7052^ Le Deley, Marie-Cécile 2577, 10031, 10518 Le Fel, Johan 9510 Le Floch, Anne 2068 Le Gal, Gregoire e15591 Le Guellec, Sophie 10574, 10575 Le Maignan, Christine 10563 Le Malicot, Karine 3525^, 3614 Le Marechal, Cedric 8000 Le Monies, Alise e14514, e14542 Le Moulec, Sylvestre 5063, 8059 Le Pechoux, Cécile 10582 Le Pimpec-Barthes, Francoise e22001 Le Poole, I. Caroline e22170 Le Rhun, Emilie 2020, 3065^ Le Teuff, Gwenael 10031 Le Tourneau, Christophe 2615, 6036, e13553

Le Treut, Jacques e19078 Le, Anh T. 3545, 8023, 8024 Le, Dung T. 4039, 4040^, 4057, e14647, e15028 Le, Lisa 5025, e19077 Le, Ngocdiep T. 4042 Le, Quynh-Thu 6007, TPS6099 Le-Guennec, Solenn 10506 Le-Petross, Huong T. TPS1608 Leabman, Maya 3000 Leach, Corinne 9594 Leach, Joseph W. 1129, 4038, e15128 Leader, Joseph B. 5581 Leahy, Michael Gordon 4529, 10503, 10517, 10551 Leahy, Patrick e22032 Leal, Alexis D. e17538, e20605 Leal, Ticiana A. B. e14550, e18537 Leal, Viola 1564 Leary, Sarah 2538 Leavey, Patrick 10064 Lebbé, Céleste 9053, 9059, 9069, 9084, TPS9105^, TPS9106 Lebeau, Annette 1020 Lebedinsky, Claudia 7109, 7110 Leber, Brian 7053^ Leblanc, Eric 5602, e16548 LeBlanc, Thomas William e17521, e20674 LeBlang, Suzanne 9500, 9565 Leboulleux, Sophie 6092, e20512 Lebouvier-Sadot, Sophie 2032 Lebovic, Daniel 8543, e19519 Lebrecht, Antje 615 Lebrun, Fabienne 553, 557, e12008 Lebwohl, David Edward 505 Lebwohl, Mark 3014 Lecaille, Cedric 3536 Lecce, Ferdinando e15154 Lecerf, Celine e19078 Lecomte, Thierry 3536, 3585, 3601, 3614 Lecuyer, Emmanuelle e19078 Ledermann, Jonathan A. 3532, 5505, 5514 Ledezma, Rodrigo e16084 Lee, Abraham 625 Lee, Adam 3510 Lee, Adrian e22017 Lee, Andrew 5054, 5069, e12554 Lee, Annette e16546 Lee, Benny 8552 Lee, Byung-In 11108 Lee, Chae-Won e15026 Lee, Chalen e14515 Lee, Chee 4053, 4544, 5542, e19132 Lee, Ching-Chih e13585 Lee, Christopher W. 9032 Lee, Clara Inkyung 1079 Lee, Clara N 9534 Lee, Claudia TPS4149 Lee, Dae Ho e19079 Lee, Dae-Won 3550 Lee, Daniel Warnell 10008 Lee, David J. 1586, e11611, e12547 Lee, Dawn 9084, e20021 Lee, Eimon e11590 Lee, Eudocia Quant 2013, 2030, TPS2104

Lee, Eun Sook 551, e11584 Lee, Eunsik e15614 Lee, Eunyoung 1590 Lee, Fa-Chyi e15136 Lee, Fook Thean 2583 Lee, Francis 4117 Lee, Geon Kook e19019 Lee, Gin-Hyug e15051 Lee, Guek Eng 2091 Lee, Gyeong-won e19156 Lee, Hae Kyung 2073 Lee, Hak Min e12005 Lee, Haur Yueh 8107 Lee, Hsiao-Wei e13554 Lee, Hy-De e12005 Lee, Hyo Jin e15573 Lee, Hyun Jung 3550 Lee, Hyun Woo 9633, e15020 Lee, I-Ling C. 4538 Lee, J. Jack 4036, 6030, 6067, 6087, 7552, 8079, 8102, 8104, TPS8118 Lee, Jae Hoon 3595, e19129 Lee, Jae Kwan 5539 Lee, Jae-Lyun 3570, 3628, 4565, 4578, 4586, 10589, e15516, e15519 Lee, James 6034 Lee, Jang-Ming 4099 Lee, Jean Kyung 1555 Lee, Jeanette Y. 8524 Lee, Jeeyun 3608^, 10589, e14626, e15613 Lee, Jeffrey Edwin 9047, e22169 Lee, Jeffrey H. 4078, 4083, 4085, e15013, e15053 Lee, Jeong-Ok e15129 Lee, Jerry 11108 Lee, Ji Yoon e19051 Lee, Ji-Hyun 6531, 10556 Lee, Jieun e14650 Lee, Jih-hsiang 8055 Lee, Jihye 3608^ Lee, Jill Lunsford 9606 Lee, Jin Soo 8021, 8045, e19019 Lee, John Y 9088 Lee, Jong Deog e19156 Lee, Jong Jin LBA10502 Lee, jong Won 1070, e11512 Lee, Jong-Seok 8521, 10589, e15129, e18553, e19041^ Lee, Ju-Seog 4113 Lee, Ju-Whei 6016, 6028, 6081 Lee, Jun Ho 4105, 4114 Lee, Jun Woo 551, 1128, 4122^ Lee, Jung Shin e19079 Lee, Jung-min 2514 Lee, Junglim 7123 Lee, Justin 6585, e17526 Lee, Keun Seok 628 Lee, Keun Wook 2565, e15129 Lee, Keun-Seok e11584 Lee, Keun-Wook 1590, 4013, 4113, 6069 Lee, Kuan-Der 4018 Lee, Kye Young 8016, 8061 Lee, Kyu Taek 11030, e22199 Lee, Kyung Hee 4013, LBA4024 Lee, Kyung-Hee 8521 Lee, Kyung-Hun 551, 3550, 4044, 11031, e15066

Lee, Kyung-Min Lee, Kyunghee Lee, Mark

e22063 e12025 3524, 5029, e14526, e14569 Lee, Martin 5 Lee, Mi-Joung e20533, e20578 Lee, Michael W 3085 Lee, Min Young TPS8123 Lee, Min Young 11030, e22199 Lee, Min-Jung 2527, e19097 Lee, Ming K. CRA1501 Lee, Moon Soo 11030, e22199 Lee, Myung Ah e14650 Lee, Namsu 11030, e22199 Lee, Nancy Y. 6034, 6594 Lee, Peter TPS2621 Lee, Po-Huang e15032 Lee, R. Jeffrey 2003, 2004 Lee, Richard T. 9642 Lee, Robert 6554 Lee, Sandra J. CRA9007, 9038 Lee, Sang Cheol 11030, e22199 Lee, Sang Eog 4105 Lee, Sang Ho 4113 Lee, Sang-Cheol e15613 Lee, Sang-Joon 629, 7076 Lee, Se Ryeon 9633 Lee, Se-Hoon 1590, 2098, 6069, e15614, e18555 Lee, Seeyoun e11584 Lee, Seung Ah e12005 Lee, Shih-Yuan 5076 Lee, Shin-Wha 5568, 5600 Lee, Shing Mirn 3635 Lee, Si-Nae e19152 Lee, Soo Jung 3553, e11505, e11594, e14549, e18017 Lee, Soo-Chin 586, 1535, e17017 Lee, Soo-Youn 1088 Lee, Soohyeon 1035 Lee, Soon-Nam 9633 Lee, Soonil e15613 Lee, Stephanie 7034 Lee, Steve 3060 Lee, Suee e15573, e19156 Lee, Sung Sook LBA4024, 4113 Lee, Sylvia Mina e20048 Lee, Sze Ting 2583 Lee, Tani Ann T. e14626 Lee, Todd e14578 Lee, Valerie e15037 Lee, Victor H. F. e14530 Lee, Vinson C. e16091 Lee, Won-Suk 3595 Lee, Woo Jin 4045 Lee, Yeon-Su e19019 Lee, Yoo Jin 3553, e11505, e11594, e14549, e18017 Lee, Young H. 4543 Lee, Young-Joon 4105 Lee, Yuan-Chin Amy 1582, 1594 Lee, Yun-Gyoo 1590, 6614 Lee-Ng, Michelle e22175 Lee-Ying, Richard M. 9550 Leenhardt, Laurence 6093 Leenstra, James L. 4026 Legare, Robert Duffy 619, 1545 Legendre, Benjamin Jr. 11044 Legenne, Philippe 2031, 2536 Legg, Jason C. e17509

Leggett, David 2542 Legouffe, Eric 510 Legrand, Catherine e16010 Legros, Laurence 7066 Lehman, Robert James 630 Lehmann, Brian D. 1005 Lehmkuhl, Michelle 9625 Lei, Lei 7590, e22050 Lei, Xiudong 1017, 1022, 1131, e12002 Leibovich, Bradley C. 4521, 4567, e15539 Leibowitz-Amit, Raya 5058, e16068, e22015 Leichman, Lawrence P. 3587 Leighl, Natasha B. 1579, 6543, 7516, 7526, 8027, 8028, 11002, 11057, e19031, e19077, e20639 Leip, Eric 7099 Leis, Anne 3580 Leisenring, Wendy M. 6544, 10032, 10062 Leitao, Mario M. 3 Leitch, A. Marilyn 502, 526 Leitch, Ian M. TPS2619 Leite, Ana Maria Matias e20640 Leitzel, Kim 622, 643, 9634 Leja, Monika 10584 Lekatis, Kiki TPS3106 Lekka, Marilena e16083 Lele, Shashikant B. e16553 Leleu, Xavier 8513, 8530 Leli, Renzo e20562 Lella, Yugandhar e14694 Lemaire, Bertrand e19078 Lemaire, Céline LBA4510 Lemay, Frederic 4069 Lemech, Charlotte Rose e17532 Lemens, Maureen 5577 Lemieux, Julie 1033, e17517 Leming, Philip D. CRA9007 Lemke, Sheila M. e20547 Lemmens, Ed 4040^ Lemonnier, J TPS653 Lemort, Marc e12008 Lencioni, Riccardo 4126, TPS4161^ Lendinez, Alberto 11089, e19000 Leng, Roger 11110 Lennes, Inga Tolin 7525 Lennon, P. Alan e22139 Lennox, Genevieve 5543 Lentzsch, Suzanne 8588 Lenz, Heinz-Josef 2501, 2526, 2564, 3007, 3514, 3527, 3537, 3557, 3565, 3566, 3567, 3568, 3587, 3611, 3636, 3637, 4012, 4032, 4110, 4111, 4128, 6022, 6545, 11062, e14538, e14543, e14714, e15009, e15022, e15073, e17559 Leo, Silvana Assunta e20681 Leon Mateos, Luis 4587, e15586, e16095 Leon Rodriguez, Eucario e15131 Leon, Ana 11089, e15107, e19000, e19109 Leon, Larry 8073, 8080, e19022 Leon, Luis e16028 Leon-Rodriguez, Eucario e15186 Leonard, David 10064 Leonard, Gregory D. e15196 ABSTRACT AUTHOR INDEX

745s

Leonard, John 7017, 8500, 8501, 8519, 8526, 8559, TPS8617 Leonard, Robert C. F. 2576 Leonard, Robyn 6585, e17526 Leonard, Seamus e20505 Leonardi, Vita e11526 Leone, Bernardo Amadeo 1073, 11118 Leone, Francesco TPS3648, 4129, e14654 Leone, Jose Pablo 1073, 11118, e22017 Leone, Julieta 1073, 11118 Leong, Cheng Nang 4066 Leong, Sai Mun e22107 Leongamornlert, Daniel e16000 Leoni, Pietro 7025 Leoni, Simona e15149 Leopold, Lance 3025 Lepage, Come 3525^, 3614 Lepère, Céline 3542, 3599 Lepique, Jutta e16533 Leporati, Meri e11515 Lepoutre-Lussey, Charlotte 6093 Lerch, Erika 8560 Lerchenmueller, Juergen LBA3506 Lerchenmuller, Christian A. 8051^ Lerda, Daniel e13036 Lerma, Pauline Marie O. 1091 Lerner, Seth P. 4547^, e15522 Lerner, Susan 7086 Lerner, Tatiana Goberstein e20601, e20631, e20680 Lerner-Ellis, Jordan 5508 Leroith, Derek e12507 Leroux, Agnès e11560 Leroy, Karen 3562 Lesaca, Reynaldo e20696 Lesinski, Gregory B. e20018 Leslie, Kimberly K. 5597 Lesnikoski, Beth-Ann 6511 Lesokhin, Alexander M. 3003^, TPS3113, 9012^ Lessa, Rafael Costa e11503 Lesser, Glenn Jay 2008, TPS2104 Lesser, Glenn 6564, 9505 Lesser, Martin 8087, 8092 Lestini, Brian Joseph TPS8122 Letendre, Caroline e15094 Lethen, Jan E. 9083 Letoublon, Christian 3596 Letourneau, Richard e15094 Letrent, Stephen P. TPS8123 Letrero, Richard 9017 Letsa, Ioanna e19007 Leuci, Valeria e14654 Leung, A. K. 4117 Leung, Kenneth e15087 Leung, Linda 6015 Leung, Nelson 8516, 8606 Leung, Sing Fai 6015 Leung, To Wai e14530 Leutgeb, Barbara LBA2000 Leutzow, Bianca e16534 Levaggi, Alessia 1036, e17548 Levallet, Guenaelle 7515 Levart, Alice 2548, 2549 Leveiller, Guillaume e19078 Leventakos, Konstantinos e14675 Leverson, Glen E. e17025 746s

Levesque, Eric e16082, e16088 Levi, Francis 3599, 3606, e20519 LeVieux, Jane 10064 Levillain, Pierre 3513, 3536 Levin, Jeremey 2031 Levin, Jeremy TPS664 Levin, Michael e20663 Levine, Alexandra M. e17556 Levine, Benjamin e16019 Levine, Bruce TPS7132, TPS10072 Levine, Ellis Glenn 3057, e11508 Levine, James D. 8558 Levine, Mark Norman 574 Levine, Mike 2054 Levine, Paul H. 11106 Leviov, Michele 1108, 5576 Levis, Mark J. 7012, 7021, 7023, 7026 Levitan, Denise A. 2516^ Levitt, Daniel 2550, e13572, e13581, e15128 Levonian, Peter J. e17583 Levy, Antonin 3010 Levy, Benjamin Philip 6571 Levy, Benjamin e17589 Levy, Christelle 510 Levy, Daniel Eduardo e20715 Levy, Lawrence B. 7521 Levy, Ronald 3015, 3017, TPS3107, TPS3108, TPS8614^ Levy, Ryan M. 4103 Levy, Samuel 11018 Levy-Santoro, Marcelle e17537 Lew, Danika TPS657, CRA1008 Lewczuk, Anna e15045 Lewin, Jeremy 10567 Lewin-Koh, Sock-Cheng 645 Lewis, Catherine Renee e12573 Lewis, Colleen Margaret 6083 Lewis, Grant Carlton 3501 Lewis, Ian 10031 Lewis, Jason Stuart TPS3115, 11076 Lewis, Karl D. 9005, 9066 Lewis, Katherine 3019 Lewis, Keeli B 3555 Lewis, Marcia E. 11044 Lewis, Meredith W 5581 Lewis, Yvonne 635 Ley, Jessica C. 10585, e21501 Leyland-Jones, Brian 525, 2613, 5565, 5583, e13570, e20616 Leyvraz, Serge 10582, e20011 Lezama del Valle, Pablo 10059 Lhomel, Christine 1562, 6563, 6603, 9069 Lhuillier, Nathalie e17514 Li Torres, Walter Antonio e14617, e19034 Li, Aiwu e19166 Li, Baoping e19098 Li, Benjamin C. e13588 Li, Benjamin e20600 Li, Changfu e15582 Li, Changyou e13587 Li, Chengge e15582 Li, Chiang 2542 Li, Christopher 554 Li, Chun-Yang e14634 Li, Chunze 646 Li, Cong 4107, e15047


Li, Daniel Li, Danni Li, Dapeng Li, Dong-Hai Li, Dongdong Li, En Xiao Li, Estelle Li, Fang Li, Gavin Li, Haifu Li, Hailun Li, Hao Ran Li, Henry Li, Hequan Li, Hong-Xia Li, Hongying Li, Hua Li, Jia Li, Jiali Li, Jian Feng Li, Jian

7003, 7014, 7017 5573 e15023 e19055 1551 e22096 e15590 e19044 e15616 e13528 6058 8503 3544 e22054 e14634 7124 3004 4084 3017 11105 1547, 4097, e13544, e15174 Li, Jian-ye e15181 Li, Jie 4097, 5521, e15174 Li, Jin 1064, LBA4001, 4109, e14644 Li, Jing 5041, e19077 Li, Jinhui 5013, 5014, TPS5097 Li, Joseph Ethan 3557, 3565, 3566, 3567, 3568, 4110, 4111, e14538, e14543, e14714, e15009, e15022 Li, Juan 6523 Li, Junxin e22034 Li, Lang e16516 Li, Leung e15048 Li, Li Jun e19028 Li, Li e14634, e20629 Li, Ling 7579 Li, Long-Yuan 1600 Li, Longjiang 6080 Li, Lu e12010, e14689, e19122 Li, Madeline 7067, 7071 Li, Mai e19504 Li, Meng e14645 Li, Ming e22169 Li, Minghuan e13052, e15180 Li, Mingyu 9030, e20025 Li, Mo-Huang e22107 Li, Na e15590 Li, Nanxin e13590 Li, Ning 7519 Li, Qian Yun e22193 Li, Qian 2500 Li, Qianyi e22172 Li, Qiaozhi 10032 Li, Qing 2097, 2614, e14663, e16033, e18502, e22085 Li, Qiu TPS4154, e14645 Li, Qiyu 8060 Li, Rebecca Yuan e20610 Li, Rubi Khaw 629 Li, Ruifeng 612 Li, Shaoyi 2035 Li, Shuai e19166 Li, Shuhong 11046 Li, Shuli 6005, 6006 Li, Si Ming e20027 Li, Szu-Chin e13585 Li, Terri 11035 Li, Tianhong 2569, 8097

Li, Tianyu e15559 Li, Wan e14634 Li, Wei 2542, 3031, 4025, 7507, 8016, 8061, 8525, e15198, e18550, e19166 Li, Weimin 5004 Li, Wenhua e14644 Li, Wenhui e15125, e16516 Li, Xiangrong e12501, e17522 Li, Xiao-Feng e22084 Li, Xiao-Nan 2036 Li, Xiaochun 1042 Li, Xiaofan e22024 Li, Xiaosong e19044 Li, Xiaoyan e13525, e17509 Li, Xiaoyun (Nicole) 9009 Li, Xing 538, 4131, e15021, e16077, e19504 Li, Xiuqin 5512 Li, Xue Ying 8503, 8508, 8573 Li, Xuefei e22186 Li, Yan 4097, e15174, e18550 Li, Yang e15021 Li, Yanhong 6554, 6631 Li, Yi e22096 Li, Ying 3612 Li, Yisheng 6566, 9576 Li, Youzhi 2542 Li, Yu-hong 4107, e15047 Li, Yuelin 10019 Li, Yufeng 527, 1052 Li, Yunfeng 10555 Li, Yvonne e22020 Li, Zhen e14615 Li, Zhenhua e15582 Li, Zhiru e16520 Li, Zhiyong 2022 Li, Zhong-Qian 5563 Li, Ziming e19014 Li, Zujun 6091, e17030 Liakos, Panagiotis e16083 Lian, Bin e20027 Lianes, Pilar e19089 Liang, Chao Yong 8503, 8508, 8573 Liang, Jane Q. TPS8123 Liang, Meina 7045 Liang, Shile 11102, e22139 Liang, Tony e22183 Liang, Wei e15522 Liang, Wenhua 8089 Liang, Xuefeng e15582 Liang, Xueqing 3023 Liang, Yali 2568 Liang, Ying 4107 Liao, Jason 6558 Liao, Jianqun e22143 Liao, Meilin LBA8011 Liao, Tsai-Tsen e13584 Liao, Wei-Li e19057 Liao, Yu-Min 6052, e20604 Liao, Zhongxing X. 4085, 7521, 7574, e15030 Liauw, Winston S. 6556 Liaw, Bobby Chi-Hung 9080 Libener, Roberta e14657 Libera, Ermelindo Della e22074 Liberati, Sonia e15513, e15515 Liberman, Eliezer 1526 Libertini, Michela 10565, 10576

Liboy, Idalia e11610 Licata, Lauren 3079 Licchetta, Antonella e11517, e20681 Lichinitser, Mikhail 503 Lichtenegger, Werner 5593 Lichtensztajn, Daphne 1083 Lichtman, Stuart M. 9515, 9545 Licitra, Lisa F. 6020, 6027, 6046, 6065, 6066 Licon, Katherine 11105 Licour, Muriel e19060 Liddle, Christopher 543 Lidereau, Rosette 1528 Lie, Yolanda 604 Liebaert, Francois 3562, e14600 Lieberman, Frank S. 2044, 2080 Liebermann, Nicky e22111 Liebes, Leonard 2591 Liebman, Hannah M. 4125 Liede, Alexander e12508, e16040, e16052, e16066, e20690 Liedke, Pedro Emanuel Rubini TPS661 Liedtke, Cornelia 1020, 1092 Liefers, Gerrit-Jan 1028, e20545, e22106 Liegeois, Philippe e11607 Lien, Kelly 4015, 6552 Lien, Winston Wei e15001 Liepman, Marcia K. 2033 Liersch, Torsten 3538 Lieser, Elizabeth Ann Teresa e20003 Lieskovsky, Gary e16020 Liew, Mun Sem e18559 Lifeng, Wang e19013 Light, Rebecca e13502 Ligibel, Jennifer A. 1032, 1033, TPS1608 Ligon, Azra 2030 Ligon, Keith L. 2015, 2030, TPS2104 Liguigli, Wanda 4112, e15086, e15502 Lii, Joyce 616 Lilenbaum, Rogerio 6635 Lilian, Rebecca 2587 Lilja, Hans 1554, 5032 Lillemoe, Tamera 1129 Lillis, Sue 11094 Lim, Alvin S. T. 8107 Lim, Bora e18506 Lim, Carol Sunghye 6614 Lim, Cindy 6618, 9509 Lim, Dean 2526, 2564, 3089, 6022 Lim, Elaine Hsuen 6063 Lim, Emerson A. 560 Lim, Eric Kian Saik 7544, 7602 Lim, Ho Yeong 3608^, e15573, e15613 Lim, Howard John 3569, 6502, 9542, e15084, e15153, e22020 Lim, Hyeong-Seok 4114 Lim, Jae Yun 4113, e15132 Lim, Joanne Siok-Liu 2588 Lim, Joo Han e19152 Lim, June e14619 Lim, Kiat Hon 8107, e14520, e15002, e15097 Lim, Pei Li e17017

Lim, Robert S. C. Lim, Sang-Chul Lim, Seok-Byung Lim, Seungtaek Lim, Sung Hee Lim, Wan-Teck

e14501, e14507 e17005 3628 e15144 e19051 6618, 8107, 9509, e17017 Lima, Agnaldo Soares e15199 Lima, Carmen Silvia Passos 6073, e11551 Lima, Eduardo Nobrega Pereira 6017, e14638 Lima, Jacqueline Miranda e22074 Lima, Joao Paulo Da S. N. e11500, e13557, e13559, e18534 Lima, Joao Paulo e20506 Lima, Joema Felipe 7568 Lima, Vladmir C. 11038, e11503, e17032, e18548 Lima, Vladmir Claudio Cordeiro 7037 Limacher, Jean-Marc TPS4161^, e20022 Limaye, Sewanti Atul 6023, 9530 Limon, M. Luisa 4098 Limonero, Joaquin T. e20704 Lin, Amy M. 5077 Lin, Bruce S. 4043 Lin, Chen-Yen 5011 Lin, Chen-Yuan 6052 Lin, Cheng-Tao e16537 Lin, Chi 1127 Lin, Chia-Chi J. 4099, e15127 Lin, Chia-Chi 4576 Lin, Chih-Yun e15157 Lin, Ching Chan 6052 Lin, Chun Chieh e16029, e16039 Lin, Chung-Wu e19523 Lin, Daniel W 5092 Lin, Gingin e16537 Lin, H. Mark 5076 Lin, Haibo 7578 Lin, Heather 6067, 6087, e12550 Lin, Hillary e15011 Lin, Hongxia 2553, 2582 Lin, Horng-Chyuan e19030 Lin, Hui-Min 3041 Lin, Hui-Ming e22175 Lin, Jeff Feng-Hsu 5585 Lin, Jen-Kou e14501 Lin, Jennifer TPS8619 Lin, Jia Tian 8503, 8573 Lin, Jianqing 5061, e15563 Lin, Karen Yin e19516 Lin, Kedan 2507, 5020 Lin, Lilie 5609 Lin, Lin e19075 Lin, Lizhu 6026 Lin, Luping 11004 Lin, Meng-Chih e19041^ Lin, Mingyan e22009 Lin, Nancy U. 513, 515, 527, TPS664, 1006, 1052, TPS1134, 1531, e17574 Lin, Nancy 616, 630 Lin, Peggy L. e15500, e15504, e15538 Lin, Po-Han 1600, 6052 Lin, Qi zhan e15567 Lin, Qi 3610

Lin, Qu 538, 4131, e16077, e19504 Lin, Sey-En e19029 Lin, Stephanie Chen Xing e19077 Lin, Sue-Hwa e15575, e22047 Lin, Suling Joyce 4020 Lin, Ting e15135 Lin, Tongyu 8503, 8508, 8573 Lin, Wenjie e22043 Lin, Xihong e19080, e19081 Lin, Xun 4572, e15624 Lin, Yan 3041, 9043 Lin, Yi 8516, 8587, 8606 Lin, Yiheng e14704 Lin, Yu-lin 8055 Lin, Yvonne Gail 9632 Lin, Ze-Xiao 538, 4131, e15021, e16077 Lin, Zhong-Zhe 3554, e15043 Linardou, Helena 1093, e19048 Linari, Alessandra 10572 Linassier, Claude LBA4500, 10563, 10582 Linch, Mark David e21516 Lind, Guro E 3607 Lind, Michael e22123 Lind, Pehr 624 Lindau, Stacy Tessler 9528 Lindberg, Patricia e20517 Lindblom, John M. e17512 Lindebjerg, Jan 6600 Lindeman, Geoffrey John e22144 Lindeman, Neal Ian 1531, 2030, 11085 Linden, Gabriele e14502 Linden, Hannah M. 1090 Lindenberg, Maria Liza TPS4589 Linder, Suzanne K. 1564 Lindh, Maja Bradic 3571 Lindhorst, Scott Michael 2090 Lindkair-Jensen, Steen e12024, e12029 Lindner, Lars e13540 Lindquist, Deborah 590 Lindquist, Diana C. 2553 Linehan, David 4051 Linehan, W. Marston 4584 Linetskaya, Regina 4014 Linette, Gerald P. 3022, CRA9003 Ling, Jiayu e14704 Ling, Yonghua 1043, 7077 Ling, Zhiqiang 7590 Linga, Vijay Gandhi 7061, e18000, e18003, e19533, e20684 Lingen, Mark W. 6008, 6010 Lingle, Wilma L. 5546 Lingua, Alejo e13036 Link, Brian K. TPS3108, 8504, 8563 Link, Charles J. 3007, 3026, 3069, 8094 Link, Hartmut 6591 Linkins, Lori-Ann e14630 Links, Matthew e19132 Linn, Jennifer 2045 Linn, Sabine C. 1072, 11023 Linnebacher, Michael e13053 Linnemann, Dorte 3572 Lino, Aline Rocha e15176 Linthacum, Tonya A. e12569 Lion, Maeva e11560 Liontos, Michael 4558, e15619

Liotta, Lance A.

5560, TPS11123, e22155 Liou, Song 9027 Lip, Gregory Y. 3042 Lipari, Helga Maria Alessandra e16532 Lipkin, Steven M. e12527 Lipovac, Markus 3052 Lippek, Frank e14562 Lippert, Hans e22040 Lippman, Scott Michael 1532 Lips, Esther H. 1010 Lipscomb, Joseph 1130, 5067, 6523, 6558, e16029, e16039 Lipscombe, Lorraine 5007 Lipson, Brynna Lane 6024 Lipson, Doron 1009, 8020, 8023, 9002, 10513, 11000, 11020, 11068, 11100, e15035, e22146 Lipson, Jafi A. 1003 Liptay, Michael J. 11114 Lipton, Allan 622, 643, 9628, 9634, 9640, e22072 Lipton, Jeffrey H. 7066, 7099, TPS7129 Lipton, Jeffrey Howard 7053^, 7073, 7088 Lipton, Lara Rachel 3598, TPS4157, e14583 Lira, Ruth R 3015 Lis, Christopher G. e17502 Lisby, Steen 6065, 8512^ Lisle, Richard 9068 Lissia, Amelia e20013 List, Alan F. 7028, 7113 Lister, John 7075 Liston, Dane 11103 Lisyanskaya, Alla 5544 Liszkay, Gabriella 9004 Litière, Saskia 10500, 10553 Litique, Valere e17543 Litta, Pietro 5548 Little, Louisa 3500, 3504 Little, Melvyn 3068 Little, Richard F. 8524, 8592, 10588 Little, Shonda M. 9005, 9016, 9066 Littman, Jason 7558 Litton, Jennifer Keating 557, 598, 3096, e12550 Litwiniuk, Maria Malgorzata 604 Litzow, Mark Robert 7064, 7094 Liu, Angen 11091 Liu, Betty 10039 Liu, Biao e13505 Liu, Binya e22169 Liu, Cheng 3047 Liu, Dage e22108 Liu, Dan 2521, 2556 Liu, David M. e15084 Liu, Delong 7076 Liu, Diane 2063 Liu, Fang CRA1501, 8547 Liu, Fei Fei 6550 Liu, Feng 7109, 7110 Liu, Feng-yuan e16537 LIU, Fumin 5525 Liu, Geoffrey 1579, 4077, 6033, 6543, 7516, 9536, 9551, 9595, 11057, 11109 Liu, Glenn 2537, 2607, 5085, e22141 ABSTRACT AUTHOR INDEX

747s

Liu, Han 4573 Liu, Heshan 1059 Liu, Hongjun 1084, e12006 Liu, Hua 2598 Liu, Huan 6572 Liu, Jibin e15040 Liu, Jihong 5512 Liu, Jing e15160, e18533, e19011 Liu, Jingmin 1524 Liu, Jingyi LBA8003, 8004, 8012, 8086, e19150 Liu, Jinli e19522 Liu, Jinshi e15062 Liu, Joanna e13538 Liu, Joyce 5524 Liu, Leihua e13517 Liu, Li 11026 Liu, Liang 4094 Liu, Lihong e14653 Liu, Liming 2502 Liu, Lucy 2578 Liu, Lun-Xu 1547 Liu, Luying 8553 Liu, Mei-Lan 11018 Liu, Meilan 1025 Liu, Mengzhong e15135 Liu, Miao 1084, e12006 Liu, Min-Ling L. e12531 Liu, Minetta C. 507, 515, 527, 1032, 1052 Liu, Patrick e13548 Liu, Peng 1084, e12006 Liu, Qian e13527 Liu, Quentin 538, 4131 Liu, Rico KY e14530 Liu, Shujun 7064, 7094 Liu, Stephen V. 5062, 11040 Liu, Tao 2515 Liu, Tasnuva Munir e20633 Liu, Tianshu 3610, e14644 Liu, Tingzhi 8503, 8508, 8573 Liu, Tsai-Ling 6018 Liu, Wei Yao 10039 Liu, Wei 10004, e22050 Liu, Xiaochun e13534, e13575, e17554 Liu, Xiaofeng 3060 Liu, Xiaohui 1132 Liu, Xiaoqing 7507, 8015 Liu, Xin e13530, e13533 Liu, Xinjun e14626, e22110 Liu, Yanyou e16516 Liu, Yi 2071 Liu, Yongyu 1547 Liu, Yuan 562, 3021, 3032, 4042, 11026, e11582, e15617 Liu, Yun e19014 Liu, Yunpeng 7507, e15160, e19004 Liu, Zhaozhe e15582 Liu, Zhe e19149 Liu, Zheng e20047 Liu, Zhengou e22071 Liu, Zhenzhen e22071 Liu, Zhi-Dong 1547 Liu, Zhimei e15500, e15504, e15511, e15538 Liverani, Chiara 11022 Livingston, John Andy 7107 Livingston, Michael B. 10522, e21504 748s

Livingston, Robert B.

CRA1008, 1089, 1090 Livingstone, Ann 2017 Livneh, Jessica e17536 Lizcano, Jose M e13526 Llarena, Natalia 572 Lledo, Gérard 3515 Llombart, Antonio 517, TPS665, e14671 Llombart-Cussac, Antonio 555 Llorca, Cristina e12020 Llorente, Rosa e12020 Llort, Gemma e12513 Llovet, Josep M. TPS4163 Lloyd, Bryony 4518 Lluch, Ana 503, 537, 1014, 1031, e12019, e12513 Llugdar, Jose Roberto e13036 Lo Dico, Rea e14534 Lo Re, Giovanni 5050, e15514, e15524, e15615, e16031 Lo, Dennis Y. M. 6015 Lo, Gregory TPS7609 Lo, Pechin 7562, 7566 Lo, Peter C. 8077, e19121 Lo, Richard H. G. e15102, e15137 Lo, Soo Kien 6589, 9506, e20566 Lo, Woei-Chung 6052 Loadman, Paul 2525 Loaiza-Bonilla, Arturo e15007 Lobb, Richard J e13583 Lobbezoo, Dorien JA e17549 Lobeck, Hartmut 3634, e14513 Loberg, Robert D. 5515 Loberiza, Fausto R. 1570, 8572 Loblaw, D. Andrew e16070 Lobo Acosta, M. e22073 Lobo, Francisco 11089, e19000, e19109 Lobo, Nazleen Carol 4568 LoBuglio, Albert F. 527, 623 Locatelli, Franco 10007, 10028 Locatelli, Giuseppe 2530, 4041 Locatelli, Marzia Adelia 589, 617, 1595 Locati, Laura D. 6020, 6027, 6046, 6066 Loch, Michelle Marie e12501, e17522 Locher, Christophe 3585 Locher, Chrystele e19060, e19078 Locke, Susan C. e17521 Locker, Gershon Y. 3587 Locker, Gottfried J e15535 Locker, Michael 4527^ Lockhart, Albert C. 605, 2560 Lockman, Paul R 514 Lockton, Steve 11113 Lockwood, Christina 11099 LoCoco, Jordan 4128 LoConte, Noelle K. 2607, e14550 Lodde, Michele 5050, e16031 Lode, Holger N. 10017 Loeb, David Mark TPS10591 Loeffler, Markus 2027, 3521 Loehrer, Patrick J. 7605 Loembe, Arsene Bienvenu TPS4160, 4506 Loeppenberg, Bjoern 9580 Loesch, David M. 590 Loesch, David TPS11123


Loffredo, Marian Logan, Susan Logan, Theodore F. Logan, Theodore

5051, e16026 e16057 TPS3112 TPS3107, TPS3109, 4563 Loges, Sonja 7027 Loggers, Elizabeth Trice 9540, 9573 Loghin, Monica Elena 601, 2006, 2019^, 2051, TPS2106 Logothetis, Christopher LBA4500, 5009, 5010, 5026, 5069, TPS5093, e15575, e16038, e22047 Loh, Elwyn TPS4153, e15046 Loh, Mignon L. 10001 Loh, Thomas Kwok Seng 6063, e17017 Lohmann, Ana e11522 Lohr, Frank 4065 Lohrisch, Caroline A. 518, 1102, 9542 Lohse, Christine M. 4567 Lohsiriwat, Visnu e20634 Loi, Sherene 3012, 11003, 11061 Loi, Shrushma TPS667 Loi, Sie Wuong e20610 Loibl, Sibylle 1004, 1082, TPS1137, TPS1138, TPS1141, 11061 Loizzi, Vera e16538 Lok, Edwin 2080 Lokay, Kathleen 6643 Lokhorst, Henk M 8512^ Lokiec, Francois 2599 Lokker, Nathalie Andrienne e14561 Lolkema, Martijn P. J. K. 2522, 2536, 4580, e15012 Lolkema, Martijn 2579 Lolli, Cristian 10540, e21511, e21523 Lolli, Ivan e14557 Lollo, José Guilherme e20579 Lombana Quinonez, Milton Alberto 9541 Lombard, Janine Margaret TPS5614 Lombardi, Davide e22149 Lombardi, Giuseppe 2024, 2028, 2043 Lombardi, Lucia e14687 Lombari, Maria Cristina 631 Lonardi, Sara 3505, 3563, TPS3648, 6593, e14574 Londhe, Anil 5010, 5037, 5059 London, Wendy B. 10015, 10054 Long, Georgina 9005, 9016, 9026, 9029, 9062, e20020 Long, Harry J. 3 Long, Jessica B. 6549 Long, Jessica 1510 Long, Kara C 1511 Long, Lauren 10522 Longacre, Teri A. e15011, e16518 Longenbach, Sherri 5082, e16061 Longo, Flavia e19084 Longo, Valter 9632 Longpre, Lara 4122^, TPS4161^ Longtine, Janina A. 1531 Lonial, Sagar 7035, 8517, 8531, 8532, 8540, 8542, 8584, 8588, 8609 Lonning, Per Eystein TPS650^ Loo, Tenneille T. 6543

Looker, Sherry e20605 Looney, Stephen W. e17524 Loong, Herbert H. F. TPS10593 Loong, Herbert H. e15048 Loosveld, Olaf JL 3502 Lopa, Ramon Antonio B. 6063 Lopatin, Margarita e14526, e14569 Lopera Sierra, Maribel TPS649 Lopes, Ademar 10586, e14688, e14691, e21507 Lopes, Antonio de Barros e15067, e15083 Lopes, Gilberto 6548, 8040, e11591, e17505 Lopes, Luana Joyce Silva 10534 Lopes, Tito 5500 Lopes, Vrishali 1545 Lopez Brea, Marta 4550, 4560, e15609 Lopez Chuken, Yamil Alonso e14708 Lopez de Argumedo, Gonzalo e20718 Lopez Escola, Cristina e13000, e20718 López López, Rafael 5603, e16095 Lopez Martin, Ana 4550 Lopez Rios, Fernando e11531 Lopez Vacas, Rocio 608 Lopez, Carlos 4098, e15107 Lopez, Carolina Muriel TPS5616, e18513 Lopez, Carolina e22058 Lopez, Gabriel 9642 Lopez, Ines e19112 Lopez, Jose L. 7054^ Lopez, Lina e22058 Lopez, Lourdes 7072 Lopez, Pablo e20504, e20657 Lopez, Rafael e12015, e20708 Lopez, Sandra e17580 Lopez-Campos, Jose Luis e22045 López-Casas, Pedro P. 2511 Lopez-Chavez, Ariel 6524, 7513, e19141 Lopez-Crapez, Evelyne e14621 Lopez-Doriga, Adriana 3629, e14554, e14613 Lopez-Gomez, Luis 4098, e14648 Lopez-Gomez, Miriam e14648, e15107 Lopez-Guerrero, Jose Antonio 1543, 10532 Lopez-Knowles, Elena 506 López-López, Carlos e15169 Lopez-Martin, Jose A. 9641 López-Picazo, José María e19106, e19114 Lopez-Pousa, Antonio 10506, 10523 López-Ríos, Fernando 2511, 2600, 3543, e19123 Lopez-Tarruella, Sara e12513 López-Terrada, Dolores H. 10023 Lopez-Torrcilla, Jose e15107 Lopez-Vivanco, Guillermo LBA8002, 11028, e12558, e13000, e14628, e14648, e14712, e20718

Loprinzi, Charles L. 3501, 3618, 9513, e17538, e20605 Loquai, Carmen 9026, 9030, 11009, e20025, e20028 Lora, David 1041 Lorch, Anja 4559 Lorch, Jochen H. 6023, 6054, 6058, 6088, 9530 Lord, Raymond S. 9533 Lord, Sally e19132 Lord-Dufour, Simon e13013 Lordick, Florian 3078, TPS3124^, 3538, 4021, 4080, TPS4155, e15042, e16547 Loree, Jonathan e14575, e14595 Loren, Alison W. TPS7132 Lorens, James B. 7027 Lorent, Julie e22126 Lorente Estelles, David 5049^, 5052 Lorente, David 9530 Lorenz, Andreas 11042 Lorenz, Robert 6035, 6061 Lorenz, Wilfried e20517 Lorenz-Salehi, Fatemeh 1577 Lorenzana, Edward e13590 Lorenzen, Sylvie TPS4158 Lorenzi, Maria 1551 Lorenzo Lorenzo, Isabel e14706 Loretelli, Cristian 3591, 4123, e15058 Lorigan, Paul 3036, LBA9000, 9004, 9027, 9031, 9046, 9068 Lorimier, Gerard e14534 Loriot, Marie-Anne 3614, e15592 Loriot, Yohann 5014, 5049^, 5065, 5075, 5088, TPS5093 Lortholary, Alain 6603 Lorusso, Domenica 5569, 5593, 11037, e16538 LoRusso, Patricia 2502, 2504, 2509, 2519, 2528, 2573, 2585, 2602, 3044, 3621, 6045 Lorusso, Vito 618, 3521, 5559, 8071, e11502, e20681 Los, Maartje 595, 1072, e16059 Losa, Ferran 3589, 10529, 10532 Losito, Simona 11037 Lossos, Izidore S. TPS3108, 8576 Lotan, Yair 4581 Lotem, Michal e20039 Lotesoriere, Claudio e18545 Lothe, Ragnhild 3607 Lotz, Jean-Pierre 569 Lou, CaiJin 7590 Lou, Emil e22007 Lou, Feiran 7570 Lou, Feng 10544 Loubani, Mahmoud 7544 Loudat, Laurin 8088^ Lougnarath, Rasmy e15094 Louie, Alexander V. e19120 Louie, Arthur Chin 7100 Louis, David N. 2029 Loundou, Anderson 2024, 8014 Loupakis, Fotios 3505, 3527, 3557, 3563, 3565, 3566, 3568, 3602, 3603, 3613, 3615, 11058, 11062, e14531, e14543, e14574, e14577, e22056

Loureiro, Luiz Victor Maia e13003 Lourenco, Gustavo Jacob 6073, e11551 Loury, David 7056, 7057, e15014 Loustalot, Catherine 1114 Louveau, Anne-Laure 4576 Louvet, Christophe 3515, 3639, LBA4003, 4046, 4069 Louwagie, Joost 3552 Lovat, Katherine Mary e20706 Love, Erica 4011 Love, Neil e14564, e17570 Love, Sharon 9068 Lovecchio, John L. e16546 Lovejoy, Chandra e16544 Lovly, Christine Marie 9019, 10513 Lovosgaldeano, Jimena 2535 Low, John Soon Wah e17017 Lowdell, Charles 3532 Lowe, Mitzi 7039 Lowery, Maeve Aine 4017, TPS4144 Lowes, Christina e18539 Lowy, Andrew M. TPS4145 Lowy, Israel 2502, 2517, TPS2618 Lozano Sepulveda, Sonia e22016 Lozano, Alicia e17010 Lozano, Maria D. 9074, 11010, e19027, e19106 Lozano, Marisa 4516 Lozano, Rebeca e22058 Lu, Bing e19082 Lu, Brian 4058^, e15188^ Lu, Charles 6067, e19066 Lu, Dan 644 Lu, Haolan TPS8117 Lu, Hong 2561^ Lu, Hongyang 7590 Lu, Hui-shan 4025 Lu, Jiade Jay 4066 Lu, Jianfeng e19103 Lu, Jiangyang e19080, e19081 Lu, John 2541 Lu, Karen H. 1569, 2611, 5521, 5580, 5584, 5596, e13534, e16556 Lu, Kurt Quoc 7036 Lu, Li-Chun e15182 Lu, Li-Sheng 3061 Lu, Maggie e20664 Lu, Maio lu e19073 Lu, Mason e22169 Lu, Ming 4097, e15174 Lu, Sheng-Nan e15157 Lu, Shir Kiong e19007, e19146^ Lu, Shun 8015, 8016, 8061, e19014 Lu, Stanlee Santos e14675 Lu, Ting Wei e15171 Lu, Wei 7605 Lu, Weidong 6058 Lu, Xian e16055 Lu, Xiaochun e20030, e20038 Lu, Xiaomin 10003, e15108, e15145 Lu, Yi e13038 Lu, Yicheng 2022 Lu, You e15030, e15125 Lu, Zhihao 4097, e15174 Luaces, Patricia Lorenzo 3013 Luan, Jennifer 3507 Lub-de Hooge, Marjolijn N. 2050 Lubeck, Deborah P. e19530 Lubenau, Heinz 3090

Lucas, David M 7077 Lucas, David Robert 10524 Lucas, Margaret 7077 Lucchesi, Maurizio 4062, e20711 Lucchesi, Sara 1086, e14574 Lucchini, Eleonora e15057 Lucio-Eterovic, Agda Karina e22081, e22177 Ludlow, Anna 1026 Ludovini, Vienna e22155 Ludwig, Joseph A. 10522 Luebbe, Kristina 1082 Lueck, Hans-Joachim 1082, e17544 Luecke, Klaus e22055 Luedke, Eric A. e20018 Luedke, Gerd e20652 Lueftner, Diana 591, e11525, e20670 Luengo-Gil, Gines 585, 3042 Luesley, David 5500 Luevano Gonzalez, Arturo e14708 Luger, Selina M. 7116 Lugowska, Iwona e22046 Lui, Jeff 2008 Lui, Weng-onn e22099 Luini, Alberto e20634 Luis, Ines Maria Vaz Duarte 616, 1006, e17574 Lukas, Rimas Vincas 2076 Luke, Jason J. 10558 Luketich, James D. 4103, 7577 Lukyanchikova, Valentina e13005 Luley, Kim 4079, 4095 Lulla, Premal 8577 Lum, Christopher A. e20029 Lumingu, Julienne e12522 Luna Fra, Pablo 10532 Luna, Herdee Gloriane Cristal e20696 Lund, Peder 3015 Lungershausen, Juliane 8061 Luo, Hong-He 7537 Luo, Huiyan 4107, e15047 Luo, Jialing 8553 Luo, Jingqin e21501 Luo, Juhua 1504 Luo, Kongjia e15135 Luo, Min e18520, e18531 Luo, Rongcheng 4109 Luo, Ruili 6634 Luo, Suhong e17546 Luo, Xianghua 10561 Luo, Xiaobing e20047 Luo, Yan 2584^ Luo, Yang 2614 Lupi, Cristiana 3563, 3613 Lupo, Janine 2044 Lupo, Laura Isabella e11517 Lupo-Stanghellini, Maria Teresa 7007 Luporsi, Elisabeth e20654 Luporsi-Gely, Elisabeth 9564, e20513 Lupparelli, Giulia 8517 Luppe, Denise 8075, e15095 Luppi, Gabriele 4504 Luppi, Mario 7025 Luptakova, Katarina 8558 Luque Cabal, Maria e19034 Lush, Richard 3026

Lusk, Christine TPS4590 Luskin, Marlise Rachael 8578 Lusky, Monika TPS4161^ Lusso, Maria Rita e13009 Lust, John Anthony 8516, 8541, 8600, 8606 Lustberg, Maryam B. 1023, 1043, 2608 Lustgarten, Stephanie 7001, 7048, 7065, TPS7129 Luthra, Rajyalakshmi 3632, e20036, e22081 Luttgen, Madelyn 8109, 11047 Lutz, Manfred P. 3531, TPS4158 Lutzky, Jose TPS3128, CRA9003, 9050 Luu, Thehang H. 1024, 2526 Lux, Michael P. 591, 607, e11525 Luzi Fedeli, Stefano e15615 Luznik, Leo 7006, 7009 Ly, Marleesa 6541, e20577 Lüchtenborg, Margreet e19157 Lüdecke, Gerson 1571 Lyden, Elizabeth 10012, 10554 Lyerly, Susan 2516^, e18002 Lykka, Maria 4558, e15619 Lyle, Stephen 9022 Lyman, Gary H. 6503, 6534, e20564 Lyman, Jaclyn P. 507 Lynch, Charles 4536 Lynch, Henry T. 1573 Lynch, Jodi 543 Lynch, Julie Ann 6562 Lynch, Patrick M. 1525, 1546, 1573 Lynch, Thomas James TPS8121, TPS8122, e17570 Lyon, Liisa L 2062 Lyons, Joanne 1508 Lyons, Roger M. 7122 Lyons, Tomas G. e12565 Lyons-Mitchell, Kimberly Anne 6641 Lypas, Georgios e12537 Lyratzopoulos, Georgios 6621 Lyss, Alan P. 9513 Lyttle, Christopher 1513

M M, Cano 1125 M, Deepajoseph e16545, e17028 M, Gopichand 577 M, Juan Cruz e17031 M, Montero 1125 M, Rajendran e13043, e20679 Ma, Bo 8009 Ma, Brigette 6015, e14501, e15048 Ma, Cynthia TPS650^, 1024 Ma, Daniel 6095 Ma, Ding 5535 Ma, Fei 2614 Ma, Haitao 1547 Ma, Hong TPS5613, TPS8125 Ma, Jie 1588 Ma, Kewei e19161 Ma, Patrick C. 11091, e19012, e22032 Ma, Shan e18519 Ma, Wei-li 3554 ABSTRACT AUTHOR INDEX

749s

Ma, Wen Wee 2557, 4005^ Ma, Xiao-Kun 538, 4131, e16077 Ma, Xiaomei 6549, 10063 Ma, Yan 11018 Ma, Yuk Ting TPS4160, e15085 Ma, Zeqiang 11102, e22139 Maañon, Jose Claudio e12013 Maartense, Eduard 595, 1028, 3524 Maass, Nicolai 1082 Maat, Lex 7534 Maawy, Ali e22011, e22012, e22013 Mabro, May 3515 Mabuchi, Seiji 5538 Mac Mathuna, Padraic M. 1542 Macapinlac, Homer A. 11079 Macarulla, Teresa 2563, 2567, 3573, 3574, 4041, e14656 Maccaroni, Elena 4123, e14610 Macchini, Marina 4048, e15069 Macciò, Antonio e20556 MacConaill, Laura E. 1531 MacDiarmid, Jennifer 7586 Macdonald, David R. 2008, 2053 MacDonald, David 8537, 8565, e19518 MacDonald, Fiona 11094 MacDonald, Lisa 3030 MacDonald, Neil e20598 Macdonald, Ryan e15123 MacDonald, Shannon M. 10018, e17553 MacDonald, Tobey 10030 Macedo, Mariana Petaccia 11038 Macedo, Omar e15131 MacEneaney, Peter e14519, e15566 Macfarlane, Alexander 3058 Macfarlane, Robyn Jane TPS4594, 5042 Mach, Nicolas 8060 Mach, Robert e16508 Mach, Stacy L. 8077, 8116 Machado, Manuel e20632 Machado, Marcos Tobias e16030, e16058 Machado, Maria Cecília Mathias e12562 Machado-Lopes, Taisa Manuela Bonfim 1539 Machiavelli, Mario Raul 1073, 11118 Machicado, Jorge e13031 Machida, Nozomu 4075, e14623 Machida, Shizuo 5552 Machiels, Jean-Pascal H. 2521, 6002, e16010 Machover, David e19513 Maciá, Sonia 4587 Macias, Amparo 3086, TPS3123 Macias, Ismael e16049 Maciejewski, John Joseph e18013 Maciejewski, Michal 5569 Maciejewski, Paul K 6529, 9521, 9522 Mack, Philip C. 7511, 8110, e15073, e19147 Mackall, Crystal 10008, 10013 Mackay, Helen 5508, 5517, TPS10593 Mackay, James 5507^ Mackean, Melanie J. 5571 Mackenzie, Catherine 9585 750s

MacKenzie, Mary J. 4565, 4578, 4586, TPS4594, e15518 MacKenzie, Shawn 4038 Mackey, John Robert 1031, 4006 Mackillop, William J. e15616 Mackinnon, Alexander C. TPS4147 Mackley, Heath B. 6558 Macklin, Eric 6058 MacLachlan, Ian TPS2621 MacLean, David 5076 MacLeod, A. Robert 8523 Macleod, Kay e13532 MacLeod, Nicholas James 4506 MacNeil, Mary Valeria 2053 Macon, William R 8504 Macpherson, Euan 5505 MacPherson, Iain R. 2589 MacRae, Robert Malcolm 7501 Macrini, Sveva e15512 Macro, Margaret 8536 Macuch, Jan e22023 MacVicar, Gary R. e15554 Macy, Lori e20698 Macy, Margaret 10030 Madan, Ravi Amrit TPS3127, TPS4589, TPS5095, TPS5102, TPS5104, e16017, e16036 Maddala, Tara 5029 Madden, Erik K e20044 Madden, Kathleen M. 9063 Madden, Stephen F. e11536 Maddern, Guy 6598 Maddi, Rahul Narayan 7061, e18003, e19533 Maddula, Krishna e22185 Madeddu, Clelia e20556 Madelaine, Jeannick 8028 Mader, Robert M 573 Madhukumar, Preetha 6589, 9506, e20566 Madhusudan, Srinivasan 1016, LBA4004, 4023 Madi, Ayman 3509 Madonna, Gabriele Di e20031 Madoz, Juan 11089, e19000, e19109 Madroszyk, Anne 7505, e19056 Maeda, Masaharu e18524 Maeda, Masahiro e15060 Maeda, Naoaki e15161 Maeda, Shigeto e11605 Maeda, Tadashi e19008 Maegga, Bertha e12561 Maehara, Yoshihiko 1056, e14633, e15039, e15158, e15173, e20576 Maehr, Bruno e20693 Mael, Heiblig e19515 Maemondo, Makoto 7530, 8033, e19142 Maeng, Chi Hoon e15613 Maeng, Jeheon e15026 Maennlein, Gudrun 3561 Maerevoet, Marie 8536 Maerklin, Melanie 7019 Maertens, Geert 11086 Maes, Jean-Michel e12552 Maes, Tamara e13543 Maetens, Marion 3012, e12008 Maetzold, Derek 7605, 9022 Maganti, Manjula 4130 Magargal, Wells W. e16007


Magazu’, Marcello e13514 Magazzu, Domenico 503, 537, 1014 Magbanua, Mark Jesus Mendoza 1095 Magbanua, Mark Jesus M 2605 Magdi, Hadeel 10044 Magers, Martin J 4554 Magestro, Matt 10545, e21514, e21515 Maggi, Carlo Alberto 5522^, e16510^ Maggiore, Ronald John 9545 Magherini, Emmanuelle 5002 Magi-Galluzzi, Cristina 5029 Magidson, Jay 9080 Magley, Andrea 10538 Magli, Amanda R e20549 Magnani, Katia e20541 Magnani, Mauro e22206 Magni, Elena e22078 Magometschnigg, Heinrich e22090 Magri, Elena e13046 Magri, Ignacio e13036 Magrinat, Gustav 9515 Mahadevan, Daruka 7062, e13574 Mahaffey, Nichole 2569, e15073 Mahajan, Anita 10009 Mahajan, Sandeep e19526 Mahale, Sakshi 8023, 8024 Mahalingam, Devalingam 2578, 3541, e15012, e15171 Mahamat, Abakar 4031 Mahammedi, Hakim e16021 Mahapatra, Kaushiki 645 Mahapatra, Tapan e22123 Mahar, Alyson L. 1592, 10537 Mahaseth, Hemchandra e15077 Mahasittiwat, Pawinee 7579 Mahbubunnabi, Tamal TPS4146 Mahdavi, Morteza e22079 Mahdi, Haider 1527 Mahe, Mercedeh e11607 Mahenthiran, Ashorne Krithiesh e18523 Mahesh, Sameer A. e15014 Maheshwari, Amita 5554 Mahfouz, Rami e12525 Mahi, Lamine e20654 Mahipal, Amit 2505, 2606, 3069, 8522, e15004, e15115 Mahlberg, Rolf 4079 Mahler, Mary 9536, 9551, 9595 Mahmoud, Anna e15082 Mahmoudian, Jafar e22198 Mahmud, Nadim e13038 Mahmud, Nadiya e16000 Mahmud, Salah e12549 Mahner, Sven 5531, 5553, 5575, 5593, e16535 Mahon, Brett 11114, e19113, e19117 Mahon, Garry e14591 Mahon, Kate Lynette e22175 Mahoney, Janine M. 621 Mahoney, John Francis 11053 Mahoney, Martin 1566, 1603 Mahoney, Michelle R. 3523, 3539, TPS10592, TPS10594, 11011 Mahpara, Eisha e14680 Mahraj, Rickhesvar 7553 Mahtani, Reshma L. TPS11124

Mai, Julie 9527 Mai, Marion 1020 Mai, Sabine Kathrin 4065 Maia, Joyce Maria L. e11503, e15184 Maia, Mauricio 2603 Maiello, Evaristo 576, 4091, 6003, 8071, 11058, e14565, e14655 Maier, Jacqueline 10508 Mailhot, Raymond e17553 Maillet, Denis 5063 Mailliez, Audrey e11523, e11529, e20630, e22127 Maimon, Natalie e15597, e15598, e16051, e16068 Maines, Francesca 5050, e11569, e16031, e16053, e16078 Maingon, Philippe 3560 Mainwaring, Paul N. 4058^, 5009, 5059, TPS5099^ Maio, Michele 9027, 9035, 9053, 9059, TPS9106, 9548, e20040 Maiolino, Piera 631 Maione, Federica e14654 Maiorana, Antonino 530 Mair, Debbie 11094 Maire, Jean Philippe 2032 Mais, Anna 3625, e15088 Maisonnette, Yolande 1122 Maithel, Shishir K. e14579 Maitland, Michael L. 2570, 2571 Maitra, Anirban 4063, e22103 Maitra, Radhashree e14540 Maity, Debdatta 10069 Majem, Margarita 2581, LBA8002, 11027, 11029, 11067, 11078, e22068 Majewski, Ian 3530 Majewski, Tadeusz 4538 Majid, Adnan 8050 Major, Gene e22181 Major, Pierre e14630 Majunke, Leonie 638, e22059 Majzoub, Nadim e12525 Mak, Milena Perez 9561, e20691 Mak, Raymond H. 8069, e19121 Makarov, Danil V. 6549 Makarova, Olga V. 11046 Makatsoris, Thomas 4558 Makelarski, Jennifer 9528 Makhson, Anatoly 629 Maki, Ellen e11542 Maki, Robert G. 10503, LBA10507, 10514, 10521, 10538, 10551, e13524 Makishima, Hideki e15097 Makita, Chiyoko 6086 Makiyama, Akitaka e15170 Makker, Vicky 5524, 5550, 5595 Makris, Andreas TPS656 Makrutzki, Martina 3604 Mala, Carola 508 Malafa, Mokenge Peter e15115 Malangone, Elisabetta e14576, e15511 Malanowska-Stega, Jeanetta e22095 Malard, Olivier 6053 Malats, Nuria 1529 Malchau, Gebhart 7015 Maldarelli, Frank TPS10595 Maldonado, Fabien e19013 Maldonado, Xavier e16045

Maldonado-Seral, Cayetana e20015 Malek, Nisar P. 3098 Malenke, Elke 10562 Maleski, Janet 3025 Malfait, Thomas 7541 Malhaire, Jean-Pierre LBA4500 Malheiros, Suzana Maria Fleury e13003 Malhotra, Akshiv e16087, e20547 Malhotra, Bharti 7079 Malhotra, Hemant 7079, 8053, e16062 Malhotra, Usha 4067 Maliakal, Pius e14508 Malik, Ghada 10033 Malik, Hassan Zakria 4132 Malik, Jahangeer e16069 Malik, Kamran Ahmed e22099 Malik, Monica e14694, e16545, e17028 Malik, Zafar I. 5055 Malin, Jennifer 6508, 6528, 9537 Malka, David 3585, 4127 Malkawi, Ahmed e18011 Malkin, David 10066 Malkin, Mark Gordon 2076 Mallavarapu, Krishna Mohan V. T. e13010 Mallick, Rajiv e15187, e19139, e20618 Mallick, Ranjeeta e11597 Mallick, Supriya e13014 Mallon, Elizabeth A. 529, 588 Mallouri, Despina 8567 Malmgren, Judith April 554, 1060 Malogolowkin, Marcio H. 10037 Malone, Hani e13017 Malone, Michael D. 4511 Maloney, David J. 1016 Maloney, Kelly W. 10001, 10002 Maltese, Mariangela 4112, e15086, e15502 Maltoni, Roberta e11521 Maltzman, Julia D. 1037 Maluccio, Mary A. 3546 Maluf, Fernando C. e13562 Malvar, Jemily 2049, 10039 Maly, Rose C. 9597, e20620 Mamedov, Alexandre e16070 Mamet, Rizvan 1006 Mammen, Joshua 1026 Mammoser, Aaron G. TPS2106 Mamo, Aline e14556 Mamon, Harvey J. 4047 Mamot, Christoph 7503 Mamounas, Eleftherios P. TPS666, 1000, TPS1139 Mamounas, Eleftherios P. TPS657 Mamounas, Michael J. 2503 Mamtani, Ronac e17591 Man, Sally e15541 Manabe, Mitsuaki e14511 Manali, Efrosyni D. e12524 Manasanch, Elisabet E. 8597, e19506 Manasova, Denisa e22023 Manca, Antonella e20013 Manca, Antonio 10552, 10583 Mancao, Christoph 3035

Manceau, Gilles 3562 Mancera, Y. e22207 Manchanda, Naveen e15621 Manchanda, Ranjit 5507^ Mancini, Julien 10546 Mancini, Pierre e19049 Mancuso, Gianfranco 8066 Mandal, Subrata 7083 Mandala, Mario 9035, 9046, 9065, 9070, 9548, e20028 Mandel, Jacob 2042 Mandel, Nil Molinas e20006 Mandoky, Laszlo e19090^ Mandolesi, Alessandra 3591, 4123, e15058, e15081 Mandrekar, Sumithra J. 2577, 6520, 7502, 7509, 7510, 7524, 11119 Mandrioli, Anna 10540, e21511, e21523 Mane, Joan Manel e13000, e14628, e14712, e20718 Manegold, Christian CRA8007 Manente, Stefania 641 Maneval, Daniel C. 4010, e15005 Manfredi, Mark e13531 Mangaali, Margaret 5609 Mangana, Joanna 9025 Mangas-Izquierdo, M. e15169 Mange, Sarah 1557 Mangel, Laszlo e12022^ Manges, Robert e15014 Mangeshkar, Milan 6000, 6090 Mani, Sridhar e13550 Maniar, Hina 563 Maniar, Tapan TPS662, 5079 Manickavasagam, Meenakshisundaram e15143 Manikhas, Alexey 503, 517, e11586 Manivel, Carlos 10560 Manjarrez, Kristi 3077 Manjunath, N.M.L. e21506 Mankoff, David A. 5003 Mankoo, Parminder e14539 Mann, Bhupinder Singh 1596 Mann, Bruce 1559, e20660, e22144 Mann, Elaina e22092 Mann, Helen 531 Mann, Michael J. e22124 Manne, Sharon 6500, e20633 Manneh Kopp, Ray e18558 Mannel, Robert S. 5527, 5588 Manning, Aidan 1112 Mano, Max S. TPS1136, e20691 Mano, Roy 4525 Manoharan, Amanda S. e17557 Manoharan, Murugesan e15596 Manoharan, Prakash TPS4146 Manokumar, Tharsika 9555 Manola, Judith 1003, e20520 Manos, Manuel e17010 Manschreck, Christopher 1552, e12555 Mansel, Robert E. LBA1001 Mansfield, Aaron Scott 2551 Mansfield, David 3062 Mansfield, Paul F. 4134 Mansmann, Ulrich Robert 3630, e13544 Manso, Luis 608, 1041, 9641, e11561, e12015, e12020

Manson, JoAnn E Mansoor, Wasat

1504 4023, 4031, TPS4156 Mansour, Hicham e14525 Mansour, Marc 3030 Mansuet-Lupo, Audrey 8100 Mansueto, Giovanni e19084, e20619 Mansutti, Mauro 503, 537, 1014, e11565 Mant, David 3500 Mant, Tim 8574 Mantha, Laura 7561 Mantke, Rene 3634, e14513, e14562 Mantovani Loeffler, Luisa e15096 Mantovani, Giovanni 603, 6003, e20556 Mantzourani, Marina e18542 Manu, Michell 2532 Manuel, Megan 2516^, e18002 Manunta, Silvia 1595 Manyam, Ganiraju C. 3529, e22064 Manzano, Aranzazu e16543 Manzano, Joanna-Grace 6634 Manzano, Jose Luis 4098, e14648 Manzullo, Ellen F. 9642 Mao, Chenyu e22192 Mao, Jun J. 6560, 6610, 9613, 9639 Mao, Li Li e20027 Mao, Weimin 4094, 7590, e15062, e18520, e18531, e19073 Mao, Ying 2022 Marachelian, Araz 2049, 10039 Maragkouli, Eleni e16083 Marak, Creticus Petrov 9558, e18008, e22179 Maran, Avudaiappan 10531 Marangoni, Francesca e17545 Marantidou, Athina 3065^ Marantz, Adolfo B. e20715 Marantz, Jing L. 7065 Maraskovsky, Eugene 3093^ Maraval-Gaget, Raymonde e13594 Maraveyas, Anthony 3018 Marballi, Abhishek 7076 Marbella, Leo e20696 Marcacci, Gianpaolo 8564 Marcello, Norina 2048 Marcellusi, Andrea e11616 Marchal, Dominique 3560 Marchal, Frederic 10546 Marchand, Christina e17557 Marchbank, Adrian 7544 Marchello, Benjamin T. 2562, TPS10594 Marchesi, Emanuela 10568 Marchet, Alberto e15148 Marcheteau, Elie e22121 Marchetti, Antonio 7514, e19020 Marchetti, Paolo 9035, e14596, e19138 Marchetti, Serena 2579 Marchiano’, Alfonso 6020 Marchionni, Luigi 4566 Marco, Siano 6027 Marcom, P. Kelly 1076, 6551 Marcom, Paul K. 515 Marconcini, Riccardo 9035, 9070, e22056

Marcott, Valerie Marcou, Kristen Marcoux, J Paul Marcq, Marie Marcucci, Lorenzo

4517 e17583 8116 e19046 1086, 3505, 3615, e14574 Marcuello, Eugenio 3521 Marcus, David Mitchell 3032, 7589 Marcus, Elizabeth A. 6609 Marcus, Karen Chayt 10018 Marcus, Leigh 2554 Marcus, Robert TPS8614^ Mardiak, Jozef LBA4500, LBA4509, 4556, e15599, e22023 Mardones, Mabel A 4525 Mardor, Yael e13002 Marec-Berard, Perrine 10031, 10518 Marek, Billie J. 7122 Margel, David 5007 Margeli, Mireia 608, 1027 Margenthaler, Julie A. 6526, e17506 Margevicius, Seunghee 6500, e20633 Marghoob, Ashfaq A. 9018 Marginean, Horia 3633 Margiolakis, Patricia e20504, e20657 Margolies, Liz e17597 Margolin, Kim Allyson 4521, 9041, 9050, e20048 Margulis, Vitaly 4581 Mari, Véronique TPS1607 Maria Grazia, Distefano e16538 Mariadason, John 3545 Mariani, Cinzia e11616 Mariani, Gabriella 537, 1014, e12017 Mariani, Luigi 3641, 6020, e14716 Mariani, Mariangela e15061, e19138 Mariani, Narciso e14657 Mariani, Odette 2615 Mariani, Paola 2535, e12017 Mariani, Pascale 9057 Mariani, Sara 2084 Mariano, Caroline Joy 9542 Maric, Irina e19506 Marie, Jean-Pierre 7023 Marik, Jan 11083 Marin i Borras, Susanna e16539 Marina, Neyssa LBA10504, 10528, TPS10591, e17504 Marina, Ovidiu 1123, e16008 Marinaccio, Marco 5559, e16538 Marincola, Francesco TPS3122 Marinelli, Sara e15149 Marinho, Eduardo e20032 Marini, Luca 516, 530, 635 Marino, Antonella e14605, e18545 Marinsek, Nina e17520 Marinucci, Michelle 5518 Mariotto, Angela 6521, 6522 Marisi, Giorgia e14512, e22056 Mark, Eugene J. 7555 Mark, Patrick 2589 Markel, Gal e20039 Markides, Constantine 2578 Markman, Maurie e20663 Markomanolaki, Haris e22101, e22105 ABSTRACT AUTHOR INDEX

751s

Markovic, Svetomir 3037, 7041, 9073, e20003, e20024, e20037, e20046, e20051 Markovich, Alla e15546 Markowitz, Arnold 1555, 8571, e12536 Markowitz, Joseph e20018 Marks, Jeffrey 5509 Marks, Lawrence B. 1069 Markus, Peter e14502 Markwordt, Janett e20575 Marler, Ronald J. e20003 Marme, Frederik 5582, 11012, 11023 Marmol-Navarro, Salvador e15533, e15550 Marmor, Schelomo e12506 Marmorino, Federica 3563, 3565, 3566, 3568, 3602, 3603, 3613, e14531, e14574, e14577 Marom, Edith M. 7098 Maron, Steven Brad 6042 Marone, Ugo Di e20031 Maronge, Genevieve Folse e17522 Marosi, Christine 2040, 2078, TPS2103 Maroto, José Pablo 4550, 4560 Maroto, Pablo 4529 Maroto-Rey, Pablo e16049 Maroun, Jean Alfred 3633 Marousi, Stella e18507 Marples, Maria 3018, LBA9000 Marques, Daniel Fernandes e13003, e14652 Marques, Mateus e15172 Marques, Raul A. 11038 Marques, Teresa e15118 Marquette, Carrie Lee 8057 Marquez, Mirari 1529 Marquez-Rodas, Ivan e12513, e20015 Marr, Alissa S. 7571 Marr, Brian 10019 Marr, Lisa 6529 Marra, Alessandro e18511 Marra, Domenico TPS1610 Marra, Marco e22020 Marrades, Ramon M. 7547 Marrapese, Giovanna 3581 Marrari, Andrea 10565, 10568, 10576 Marreaud, Sandrine 4529, 10500, 10553, 10573 Marrelli, Daniele e15148, e22037 Marrero, Jorge A. 4126 Marrero, Luis e13581 Marrocolo, Francesca e16093 Marrodan, Ines e13000, e14628, e14712, e20718 Marron, Marilyn 567, 8562 Marrone, Kristen 6076 Marroni, Paola e12518 Marrupe, David e15609 Marschke, Robert Frederick 1558, 11050 Marsh, Andrew 3022 Marsh, J. Wallis 9507 Marsh, Robert de Wilton 2570, 4012 Marshall, Andrea 5, TPS656, 4023, LBA9000 752s

Marshall, Deborah e17509 Marshall, Ernest LBA9000 Marshall, Ernie 9027, 9031 Marshall, James Roger 1561, 1566, TPS1608 Marshall, John 2616, e13574 Marshall, Marita 4535 Marshall, Richard Aaron 8555 Marshall, Shannon 3044 Marsoni, Silvia TPS3648 Mart, Dylan A. e12030 Marta, Gabriel e20693 Marte, Jennifer L. e16036 Martel-Planche, Ghyslaine e22154 Martell, Lori A. 3022 Martell, Robert E. 2513, 7116, 8535 Martella, Stefano 589 Martellucci, Ignazio e15512 Martens, Daniel e15502 Martens, John W. M. 2597, 11045, e22106 Martenson, James A. e14711 Marth, Christian 583, TPS3119^, 5593, e16524 Marti, Thomas 11028 Marti-Ciriquian, Juan Luis 2581 Martignoni, Marcella e15061 Martin Broto, Javier 10500, 10523, 10529, 10532 Martin Lorente, Cristina e16049 Martin Reinas, Gaston Flavio e20715 Martin Reinas, Gaston 6596, e17539, e20636, e20656 Martin, André-Guy LBA4510 Martin, Andrew TPS4157, e20584 Martin, Anne-Laure TPS653 Martin, Anne-Marie 9020, 11026, e20030, e20038 Martin, Christine Agnes 7578 Martin, Darryl T e15543 Martin, Dena 6059 Martin, Francis e19078 Martin, Janice 5577 Martin, John D. 1065 Martin, Lainie P. 2504, 2584^, 3621 Martin, Ludmila Katherine e14535 Martin, Marta e15107 Martin, Michael John e20008 Martin, Michel e19078 Martin, Miguel 547, TPS652, TPS662, 1027, 1031, e12513, e22112 Martin, Neil E 5024, 5086 Martin, Paul J. 9573 Martin, Peter TPS8614^ Martin, Petra 6543, e19077 Martin, Thomas 8529, e19530, e19541 Martin-Algarra, Salvador TPS3114, 9013, 9074, e19027, e19114, e20015 Martin-Carnicero, Alfonso e20015 Martin-Castillo, Begoña e19003 Martin-Elbahesh, Karen 10034 Martin-Gonzalez, Manuel e20015 Martin-Juan, Jose e22045 Martin-Richard, Marta e14541 Martin-Romano, Patricia e19114 Martin-Valades, Jose Ignacio 11089, e19109


Martinelli, Erika Martinelli, Giovanni

e14565 7012, 7021, 7023, 7025 Martinello, Rossella e11581 Martines, Giuseppe Fabio e18518 Martinetti, Antonia e22056 Martinez Breijo, Sara 5087 Martinez del Prado, Purificacion e12513 Martinez Guisado, Antonia e11583 Martinez Iniesta, Maria 3629 Martinez Lago, Nieves 5603, e16095, e20708 Martinez Marti, Alex 2581, 8070 Martinez Trufero, Javier 10523 Martinez, Alberto J. 9011, 9056^ Martinez, Brandon Keith e14698 Martinez, Eduardo 1027 Martinez, Juan Carlos 2064 Martinez, Lukas e22114 Martinez, Maria Jose e22200 Martinez, Michele 4100 Martinez, N. 7549 Martinez, Nieves 11073, e22147 Martinez, Noelia e12558 Martinez, Pablo 8070 Martinez, Pedro 1543 Martinez, Rafael 8511 Martinez-Ammoros, Brezo 11089 Martinez-Balibrea, Eva e14609 Martinez-Bueno, Alejandro e22119 Martinez-Cardus, Anna e14609 Martinez-Cedillo, Jorge 4555 Martinez-Garcia, Maria 2522 Martinez-Lopez, Joaquin 8511 Martínez-Marín, Virginia e14509 Martínez-Mesa, Jeovany e12510 Martinez-Serrano, Sergio e22200 Martinez-Trufero, Javier 10529, e21509 Martino, Cosimo TPS3648 Martino, Silvana 1007, 1032 Martinotti, Mario e15086 Martinovic, Aleksandar e14676 Martins Castro, Luiz Henrique 2060 Marton, Ashley e19520 Marton, Matthew John 11059 Martone, Brenda K. 9087, e15554 Marty, Michel E. 610 Marty, Michel 1578 Martyn, Julie TPS5612, TPS5614 Maru, Dipen M. 3612, 3632, e22081 Marucci, Gianluca 2021 Maruno, Motohiko 2066 Marur, Shanthi 6005, 6030, 6068 Marusch, Frank 3634, e14513 Maruyama, Dai 8551 Maruzzo, Marco e15512, e15606 Marvaki, Anastasia 8567 Marvin, Kimberly 1123, e16008 Marx, Dagmar 3094 Marx, Gavin M. e20514, e22175 Marymont, MaryAnne H. 2083 Marzese, Diego M 9095 Marziali, Andre e22041 Masalu, Nestory Andrew 5594, e16530 Masaquel, Anthony 625, 6626, 9619

Mascarenhas, Leo

10020, TPS10591 Mascarenhas, Monica 5500 Mascaró, Cristina e13543 Mascaux, Celine 6543 Maschmeyer, Georg e17021 Masi, Gianluca 3505, 3602, 3603, 3613, 3615, e14531, e14577 Masini, Cristina e15615 Maslyar, Daniel J. 2507, 5020 Mason, Clinton C 2026 Mason, David P. 4087, 8113, e15000 Mason, Jay e20539 Mason, Malcolm David 5012 Mason, Robert TPS4156 Mason, Warren P. 2007, 2053 Mason, Warren 2002^, 2005^, 2023^ Masood, Nehal e14501 Massacesi, Cristian 2015 Massard, Christophe 2512, 3010, 5049^, 5063, 5075, 5088, 7604, 9556 Massarelli, Erminia 6067 Massari, Francesco e11573, e15512, e16031, e16053, e16078, e17555 Massarweh, Suleiman Alfred 541 Massett, Holly 1596 Massey, Dan 8016, 8061, 8063 Massi, Daniela e20013 Massicotte, Marie-Helene 6092 Massopust, Kristy 9632 Massuti, Bartomeu 2581, LBA8002, 11027, 11028, 11029, 11067, 11078, e22068 Masszi, Tamás 8507 Mast, Catherine Patricia TPS2621 Master, Viraj A. e15617, e16029, e16039 Masters, Gregg 3019 Masters, Gregory A. 7501, 7506 Masters, Joanna 2568 Mastrangelo, Michael J. e15563 Masuda, Hiroko 1005 Masuda, Mari e15080 Masuda, Masafumi e20658 Masuda, Msafumi 8038 Masuda, Munetaka 4068 Masuda, Norikazu 505, LBA509, 561, 571, 613, TPS654, 1048^, 1106, 1116, 6588, e12011 Masuda, Noriyuki 7592 Masuishi, Toshiki 4096 Masumori, Naoya 4526 Masumoto, Norio 11111, e22113 Masuzawa, Toru 10539 Matano, Elide 7603, e21500 Matei, Daniela 2580, 3059, 5505, TPS5612 Mateo, Joaquin 2535, 2586, 2608, 3062 Mateos, Concepcion 2064 Matera, Jeri 517 Mates, Mihaela 518 Mateus, Christine e20041 Matheny, Shannon 5010, TPS5097 Mathew, Libin 7043 Mathias, Clarissa e12562 Mathiesen, Hanne From e16540, e16541

Mathieu Daude, Helene 2067 Mathieu, Jean-Pierre e19078 Mathieu, Marie-Christine 511 Mathijssen, Ron H. J. 2597, 4580, 5064, 10573, e11548, e13513 Mathiot, Claire 4046 Mathis, Sarah E 2089, e13040 Mathoulin-Pelissier, Simone 3558, 6582, 10570 Mathur, Nitin e22098 Matias, Margarida 9634 Matin, Surena F. 5069 Matloff, Ellen T. e12542 Matoba, Ryo 2066 Matos, Ignacio e22058 Matos, Rachel da Silveira Lucas e12562 Matous, Jeffrey 8585^, 8592 Matrana, Marc Ryan e15594 Matrosova, Marina P. e20593 Mats, Hansen 5081 Matsangou, Maria e22062 Matsubara, Akio e15588 Matsubara, Nobuaki 1113 Matsubara, Nobumichi e19142 Matsubara, Yoshihiro 3518 Matsuda, Naoko e11524 Matsuda, Tadashi e15576 Matsuguma, Haruhisa e18554 Matsui, Reiko 9621 Matsui, Takanori 4102 Matsui, Tomoharu e18564 Matsumoto, Akiko e11598 Matsumoto, Alvin M. e16015 Matsumoto, Hiroshi 3519, e22019 Matsumoto, Ippei 4008 Matsumoto, Kazuhiro e15527 Matsumoto, Koji 5537 Matsumoto, Noriko e14572 Matsumoto, Seiji e18557 Matsumoto, Shingo 7512, 7557, 8078, e19076, e22082 Matsumoto, Takeshi 8098, e19017, e19045 Matsumoto, Tsuneo e19008 Matsumoto, Yoshinari e20676 Matsumura, Akihide e18530 Matsumura, Manabu 2583 Matsumura, Noriomi 5537 Matsunaga, Takeshi 7575 Matsunami, Nobuki 1048^ Matsuno, Yoshihiro 7550 Matsuo, Keitaro 4076, e12001 Matsuo, Yo e13569 Matsuoka, Masaki e14601 Matsusaka, Satoshi 4108, e15105 Matsusaki, Keisuke e20591 Matsushita, Hideki e20004 Matsushita, Hiroshi 3071 Matsushita, Hisayuki TPS4152, e15016 Matsushita, Mina 7548 Matsuura, Hiroshi e15158 Matsuura, Kuniomi e19053 Matsuyama, Hideyasu e16092 Matsuyama, Jin 4072 Matt, Laurie Beth 2089 Matta, Mona 2024 Mattair, Danielle 532 Mattano, Leonard A. 10001, 10002

Mattar, Bassam Ibrahim

2562, 4026 Matter-Walstra, Klazien 3503, e20542 Matteucci, Federica TPS649 Matthay, Katherine K. 10015, 10039, 10060 Matthes, Burkhard e20710 Matthes, Harald e20710 Matthews, Amber 9528 Matthews, Stephen 6558 Mattioli, Rodolfo e14557 Mattison, Ryan J. e17025 Mattonet, Christian 8112 Matulonis, Ursula A. 5524, 5588 Matulonis, Ursula 1531, 5505 Matus, Geoffrey 5055 Matuschek, Christiane 1101, e13035, e13051 Matuszak, Martha 7522 Matveev, Vsevolod 4576, 5002, TPS5099^ Matysiak-Budnik, Tamara 3536 Matzas, Mark 591 Maubec, Eve e20032 Mauch, Cornelia 9013 Mauer, Murielle E. 3531 Mauersberger, Elias e15096 Maugard, Christine TPS1607 Maugeri, Antonio e13579 Maughan, Tim 3504, 3509, TPS3645 Mauldin, Jeremy Preston TPS3105^ Maunsell, Elizabeth 6557 Maurea, Carlo 631 Maurea, Nicola 631, e11556 Maurel, Joan 10523, e14588 Maurel, Juan 3589, e14509, e15107 Maurer, Matthew A. 560 Maurer, Matthew J. 5546, 8504 Mauri, Chiara 4136^ Mauro, David J. 3635, TPS8118 Mauro, Michael J. 7063 Maus, Martin K. H. 3527, 4110, 4111, 11062, e14543, e15009, e15022 Maute, Luise 4035, e15070 Mauz-Körholz, Christine 10028 Mavroudis, Dimitrios 1045, 7594, e14639, e22101, e22105 Mawrin, Christian e22140 Maxwell, Kara Noelle 1510 May, Betty J. 1572, 1601 May, Calloway B. 6641 May, Jasmine e22204 May, Rena 3044 Mayadagi, Alparslan e11540 Maybody, Majid TPS3120 Maybon, Laura e20560 Mayer, Alexandra e15118 Mayer, Erica L. 1117, 1133, TPS1134, e17574 Mayer, Frank 3625, 3643, 4079, 4095 Mayer, Ingrid A. 1033, TPS1608 Mayer, Julie Ann e22047 Mayer, Musa 523 Mayer, Robert J. TPS4144, 11011, e14711 Mayerhoefer, Marius e22090

Mayerle, Julia 4006 Mayers, Andrew e20713 Mayfield, William 7560 Maynard, Julie 3509 Mayne, Susan T. 1574, e20017 Mayo-de las Casas, Clara 2581, 11029 Mayorga-Butron, Jose Luis 3050 Mayr, Doris 3064 Mazaki-Tovi, Shali 1503 Mazal, Daniel e14682 Mazanec, Jan 11051 Mazanet, Rosemary e11509 Mazard, Thibault 4028 Mazhar, Danish 4535 Maziarz, Richard T. e20627^ Mazieres, Julien 7505, 7515, 8000, 8009, 8027, 8029, 8059, 8081, e19036, e19056 Mazorra, Zaima 3013 Mazoyer, Clement 2512 Mazumder, Koustav e20707 Mazurczak, Miroslaw 3640, 9513, e14526 Mazurek, Magdalena e12028, e12534 Mazzarello, Sasha 6595 Mazzarotto, Renzo e15154 Mazzeo, Salvatore 4062 Mazzerello, Sasha e11574 Mazzocco, Ketti 9582 Mazzola, Antonella e11527 Mazzola, Giulia 3038 Mazzone, Massimiliano 3588 Mazzone, Peter J. 8113 Mazzoni, Enrica e14605, e18545 Mc Intyre, Chelsey 8102 McAlearney, Ann Scheck e17592 McAleese, Fionnuala 3068 McArthur, Grant A. 3093^, 9028 McArthur, Heather L. TPS3120 McAuliffe, Priscilla F. 1098, 9643 McBain, Catherine 2092 McBride, Mary L. 1551 McBride, Russell 6613 McCabe, Christopher TPS656 McCabe, Kelly e15608 McCabe, Mary S. 10019 McCaffrey, John 598, e14519, e16550 McCahill, Laurence E. 4038 McCall, Bradley e21504 McCall, Bruce 3622 McCall, Linda Mackie 526 McCall, Shannon 11036 McCarl, Christie-Ann 522 McCarthy, Alexandra 9516 McCarthy, Fiona Margaret 11071 McCarthy, Lauragh e14519 McCarthy, Philip L. 8517 McCarthy, William J. 4540 McCartney, Elaine 9590 McCaughan, Brian e18500 McCauley, Dilara 2505 McCaw, Larissa e13503 McClanahan, Pamela e14516 McClean, Megan 7554 McCleary, Nadine Jackson 4090 McClellan, Steven e13566 McCluggage, W. Glenn 5500

McClure, Ty TPS4595, TPS6098 McCluskey, Christine Sceppa 2013, TPS2104 McCollum, Michael TPS5616 McConkey, David James 4538, 4548, e15522 McConville, Holly TPS7132 McCool, Rachael e11602 McCorkle, Ruth 6529 McCormick, Jennifer B. e20608 McCourt, Carolyn K. 3077 McCoy, Candice 5016, 5034, 5047^ McCoy, J. Phillip 3104 McCoy, Moly e12509 McCready, David R. 1002, 1018, e11542 McCulloch, Colin 2097, e16033, e19536, e22085 McCullough, Ann E. 1037 McCullough, Laurence B. 10023 McCurdy, Arleigh Robertson 8541, 8587, 8600, 8606 McCusker, Margaret Elizabeth e12500 McDaid, Hayley M. 2612 McDermott, David F. 3002^, 4505, 4512, 4514, 4521, 4570, TPS4593, CRA9006^, CRA9007, 9050, 9076 McDermott, Gregory C. 9060 McDermott, Martina 632 McDermott, Raymond S. e15019, e15163, e15566 McDermott, Ultan 7581 McDonagh, Kevin T. 7084, e18001 Mcdonald, Alec 4006 McDonald, Dan TPS3110 McDonald, Robert LBA509 McDonnell, Kathryn 8543 McDonnell, Shannon 5082 McDonough, Liz e22085 McDonough, Shannon TPS4145, 7028 McDowell, Bradley D. e15052 McDowell, Diane Opatt TPS8117, 9053, 9059 McDuffie, Jeremy Scott 8605, e19539 McDunn, Susan H. e17593, e20544 McDyer, Fionnuala A. TPS11120 McFadden, David G 6025 McFarland, Braden C e13011 McGarry, Carolyn e16075 McGarry, Ronald 7523 McGee, Sharon F. 598 McGettigan, Suzanne 9088 McGinley, Kathleen F. e16041 McGinness, Marilee 1026 McGirr, Analia TPS3108, TPS3114 McGowan, Patricia M. 1054 McGowan, Tracy 5059 McGree, Michaela 5577 McGregor, Bradley Alexander CRA1008 McGregor, Lisa M. 10026 McGuigan, Christopher 2576 McGuire, Amy L. 10023 McGuire, Franklin 6584 McGuire, Joseph P. 1083 McGuire, Kandace P. 507, 1098, 9643 ABSTRACT AUTHOR INDEX

753s

McGurk, Katherine L. 9061, e20026 McGurk, Mark 3035 McHale, Michael T. 6636 McHenry, Brent TPS5093, 9053, 9059 McHugh, Deaglan Joseph e15163 McHugh, Jonathan B. 10584 McKay, Rana R. 4572 McKee, Dave C. 2583 McKee, Krista e19002 McKee, Mark D. 2584^ McKee, Megan Jean e11582 McKeegan, Evelyn Mary 2036 McKeever, Elizabeth 4130 McKendrick, Joseph James 11015, e14640 McKendrick, Joseph 3574, 3584, e14583 McKenzie, Stuart 7532 McKhann, Guy e13017 McKibbin, Trevor e20596 McKiernan, James M. 4552 McKinley, Arin 10509 McKinley, Marti 3587 McKinney, Carolyn 6566 McKinnon, Karen P. 6070 McKoy, June M. 9545 McLaren, Duncan LBA5000 McLaughlin, Patrick e15566 McLean, Scott A. 9607 McLean, Sean 2518 McLeer Florin, Anne 8099, 8100 McLeod, Howard L. 2595, 6501, 11053 McLosky, Jennifer 1557 McMahon, Ray TPS4146 McMahon, Sheri TPS3127, TPS5104, e16036 McManus, Penelope Louis e22123 McMaster, Christopher 10066 McMeekin, D. Scott 5551 McMillan, Kirsty e20615 McMurdie, Janine 11040 McNamara, Deborah A. 3549 McNamara, Mairead Geraldine 4130, e22015 McNamara, Michael J. 4087, e15000 McNaughton, Kristin K. 6539 McNeel, Timothy S. 6521 McNeish, Iain A. 5514 McNeish, Iain 2525 McNicoll, Yannic 4060 McNitt-Gray, Michael F. 7562, 7566 McNutt, Todd R. 9636 McPhail, Sean 6621 McPherson, Christopher e13023 McPherson, Eugene e19540 McPherson, John D. 11016, e17515 McPherson, Monica 1602, 9567, e14681, e15561 McQuestion, Maurene e17007 McQuinn, Lacey e13575 McShane, Lisa M. 1592 McSherry, Frances 2090, e13015^ McVie, J. Gordon 9582 McWhirter, Elaine 9032 McWilliams, Robert R. 9005, 9016 Mead, Graham 4529, 4549 Mead, Kelly 6541 754s

Meade, Angela M. 3509 Meade, Cathy e12556 Meadows, Helen 3532 Meadows, Kellen 11036 Mealing, Stuart 636 Meani, Francesco 5560 Mears, J. Gregory 7031 Medalia, Gal e15078 Medeiros, Michelle e20574 Medeot, Marta 7006 Medford-Davis, Laura Nyshel 7554 Mediano, M. Dolores e22045 Mediano, Maria Dolores e15533, e15550, e19160 Medici, Michele e20028 Medina Villaamil, Vanessa 5087, e15532, e15542, e15558, e22171 Medina, Ana e12558 Medina, Diane M. 2584^ Medina, Francisco e12013 Medina, Pedro 7115 Medina-Lopez, Rafael A e15533, e15550 Medkour, T. 569 Medri, Matelda e15529 Medvedev, Sergey e15546 Meek, Elaine 9027 Meershoek – Klein Kranenbarg, Elma 597, 1028 Meerten, Esther Van e16504 Meeus, Pierre 10579, 10582 Mega, Anthony E. 5018, 6574 Megalakaki, Aikaterini e20642 Megerian, Mark 6508 Mego, Michal 4556, e15599, e22023 Mehedint, Diana e15604 Mehigan, Brian e14666 Mehmood, Tahir e12033 Mehnert, Janice M. 2553, 2582 Meholick, Patricia D. 2594, e13505 Mehra, Maneesha e17510 Mehra, Ranee 6006, 6090, 8010 Mehra, Rohit TPS5094 Mehrotra, Divya e17020 Mehrotra, Nitin 2510 Mehta, Amit R. 2533 Mehta, Arjun 609 Mehta, Jayesh 8586, 8596 Mehta, Keyur 1004, 1082, TPS1138 Mehta, Minesh P. 1, 2003, 2004, 2008, LBA2010, 2033, 2047, 2083 Mehta, Paras 10009 Mehta, Rita S. e11562 Mehta, Rutika e20567 Mei, Gangwu 11096 Mei, Qi e20695 Meier, Friedegund Elke e20050 Meier, Urs R. 7503 Meier, Werner 5505, 5531 Meignan, Michel TPS8615 Meijer, Gerrit A. 3552, 4566, 11087 Meijerink, Martijn R. 11087 Meijers-Heijboer, Hanne E.J. 1502 Meijnen, Philip LBA1001 Meiler, Johannes 4079, e14502 Meireles, Ozanan e12559 Meirelles, Priscila 10057 Meirovitz, Mihai 5541 Meisel, Christian 3643 Meisel, Jane L. 1117, 1133


Meister, Bernhard 10017 Meixensberger, Juergen TPS2103 Mejia, Ervido e19540 Mekata, Eiji 4092 Mekenkamp, Leonie e14584 Mekhail, Tarek 8062, 8114, e19025 Melani, Lorenzo e16510^ Melanie, Janning 7027 Melanthiou, Andriane 8594 Melaragno, Renato 10057, 10065 Melbert, Danielle 6522 Melcher, Carola Anna 640 Melcher, Chatrina e17545 Melcher, Lucinda e20709 Meldgaard, Peter 7504, 7514 Mele, Emilia 5559 Melegari, Elisabetta e11521, e13007 Melemed, Symantha LBA8003 Melendez, Jorge 10536 Melendez, Ricardo e22045 Melero, Ignacio 3053, TPS3107, TPS3111 Melezinkova, Helena 4021 Melguizo, Isaac TPS2106 Melhem-Bertrandt, Amal 515, 601 Melichar, Bohuslav 557, 605, 4000, 4576, 11051, e14622, e15581 Melink, Teresa J. 7074 Melisi, Davide e15057 Melisko, Michelle E. 515, 1083, 1095, 2605, 6619, 6620 Mellado, Begoña 5019, e16014, e16049 Mellas, Nawfel e21513 Mellemgaard, Anders LBA8011, 8084, 8103, e19157 Mellinghoff, Ingo K. 2012, 2015, 2095 Mello, Celso Abdon 10586, e11503, e14638, e15184 Mello, Celso Lopes e14688, e14691, e20640, e21507 Mellor, Jane 3500 Mellstedt, Hakan 3053, 7087, e22198 Melnik, Marianne TPS9647 Melnikova, Vladislava O. 11044 Melnychuk, David e14556 Melnyk, Nataliya 2553 Melo, Leila Maria Magalhães Pessoa 7037 Melosky, Barbara L. e19131 Melotte, Veerle e14503 Melotti, Barbara 8043, e18509 Melotti, Flavia e14716 Meltzer, Paul S. 7513 Melucci, Elisa e19052, e22206 Memmott, Regan 2532 Memon, Azra e19152 Mena, Esther 11083 Menander, Kerstin B. 4054, 8095 Mencarini, Ana Cristina Malacarne 2060 Mencoboni, Manlio LBA8005, e12518 Mendel, Jennifer Robin 2610, 6083 Mendelsohn, John e22081 Mendelson, David S. 3059 Mendenhall, Nancy Price e17571 Mendenhall, William M. TPS6097

Mendes, Gelcio L. Q. Mendez Vidal, Maria Jose

9097 4587, e15586 Mendez, Catalina 9541 Méndez, Miguel e12020 Mendez, Miriam e19532 Mendez, Pedro 11025 Mendiboure, Jean 10574, 10575 Mendiola, C. 5569 Mendiola, Cesar 608, 1027, 5541, 9641, e11561 Mendoza, Andres Moran e17031 Mendoza, Arnulfo 10025 Mendoza, Julia 4555 Mendoza, Tito R. 9646, e17508, e17560, e17588 Mendrinos, Savvas E. e16076 Ménégaux, Fabrice 6093 Menendez Prieto, Maria Dolores e14617 Menendez, Javier A. e19003, e19159 Meneses, Nicole 5520, 5591, 9026 Meneses-Lorente, Georgina 2522 Meneveau, Nathalie 1122, e11579 Meng, Wei 7573 Meng, Xia 8547 Meng, Xu 612 Meng, Xue e15030, e15167, e19011 Meng, Xuli e12557, e22050 Meng, Zhi-Yun e19075 Menge, Franka 10566 Menges, Craig e18541 Meniai, Fatima-Zhora 2548, 2549 Menjak, Ines Barbara e11542 Menon, Daniela 9554, e15512, e20541 Menon, Hari e18004, e19503 Menon, Krishna E. TPS2627 Menon, Santosh 5554 Menon, Saurabh e13529 Menon, Usha 5507^ Menozzi, Silvia e13579 Menssen, Hans D. 7052^, 7054^ Menteer, John David 10020 Mentuccia, Lucia e12021, e12031, e20619 Menzel, Alain e14591 Menzies, Alexander M. 9062, e20020 Menzies, Alexander M. 543 Menzin, Andrew e16546 Mer, Jesse 8591, e18527, e22003, e22052 Mera, Kiyomi 8056, e19165 Merad, Miriam 3014 Merajver, Sofia 1557 Mercado, Gabriela 10536 Mercanti, Anna e17551, e20617 Mercatali, Laura 11022 Mercedes, Taheri 7097 Mercer, Carol A. e13518 Merchan, Jaime R. e15007, e15596 Merchant, Mark 11083 Merchant, Melinda S. 10013 Merchant, Thomas E. 10021, 10034 Mercier, Cedric 7117 Mercier, Florence 5063 Mercier, Francois e16047 Mercuro, Giuseppe 603

Merdan, Thomas 2520 Meredith, Rhonda 11108 Merek, Stephanie 9079 Merenbakh, Keren e11578 Merghoub, Taha 9060 Mergler, Patrick 6538 Mergui-Roelvink, M. 2536 Mergui-Roelvink, Marja 2579 Meric-Bernstam, Funda 502, 526, 532, 1005, 3632, 5524, 6566, 9576, 10577, 11013, 11060, e22081 Merims, Sharon e20039 Merimsky, Ofer LBA10507, e21521 Merino, Maria TPS4589 Merkelbach-Bruse, Sabine 1589, e12517 Merla, Amartej e14540 Merle, Patrick 7505, 8081, e19058 Merle, Philippe 4028, 4118 Merlin, Jean-Louis 2599, e11560, e13519 Merling, Shahar e22111 Merlini, Giampaolo 8545 Merlio, Jean-Philippe 8000, 8100 Merlo, Domenico Franco TPS7606, 10519, 11063 Merlo, Franco e17548 Mermershtain, Wilmosh e15597, e15598, e16051 Merom, Hadar e17536 Meropol, Neal J. 6500, 6538, e14711, e20633 Merrell, Ryan 2019^, 2076 Merrihew, Lindsey Elizabeth 10046 Merriman, Michelle 9043 Merritt, Hanne e13590 Merritt, Ryan M. 9064 Merritt, William McIver 5513 Merseburger, Axel S. e16064, e22076 Mertens, Ann 6544 Merz, Maximilian 8590 Mescam-Mancini, Lenaig 8099 Mesia, Carlos e13016 Mesia, Ricard e17010 Mesmoudi, Mohamed e20624 Messer, Jeannette S. e13532 Messer, Karen 7124, 11098 Messersmith, Wells A. 2502, 3507, 3587, TPS3646 Messina, Antonella 10565 Messina, Carlo G. M. LBA1001, 3531 Messina, Caterina 5050, e16031, e16078 Messina, Catherine R. 1524 Messing, Edward M. 9549 Messinger, Yoav H. 10024 Mester, Jessica 1527 Mesters, Rolf M. 8548 Mesterton, Johan e16066 Meszoely, Ingrid M. 507 Metcalfe, Kelly A. 1507 Metcalfe-Klaw, Robin 6091, e17030 Mete, Mihriye 6561, 11054 Meterissian, Sarkis H. 1018 Metges, Jean-Philippe 3601 Metheny, Trina 1515 Metrakos, Peter e14556 Metran Nascente, Cristiane 4049 Metser, Ur 4049

Mettetal, Jerome 2598, e13529 Metwalli, Adam R. 4584 Metz, James M. e20671 Metzger Filho, Otto 525, 529 Metzger, Brigitte e14591 Metzger, Severine 4574 Meulenbeld, Hielke Jodie e16059 Meulendijks, Didier 2522 Meurer, Luise e12546, e15067 Meyer, Andrew D. 7121 Meyer, Anne-Marie 6572 Meyer, Frank e22040 Meyer, Ines 3075 Meyer, Jack E. 1065 Meyer, Joshua E. 9500, 9565 Meyer, Krista 5575, 8044 Meyer, Meghan E. 6507, e20508 Meyer, Michael e22031 Meyer, Ralph M. TPS3647, 9502, e17525 Meyer, Roberto 1539 Meyer, Tim TPS4160, 8522, e15004, e15085 Meyer, William H. 10554 Meyers, Brandon Matthew 3548, e20522 Meyers, Bryan F. 7502, 7524 Meyers, Gabrielle e20627^ Meyers, Jeffery P. 2562 Meyers, Jeffrey P. 3520 Meyers, Marlene 1042 Meyers, Michael O. 3639 Meyers, Paul A. 3101 Meyers, Rebecka 10037 Meynier, Faustine e20030, e20038 Mezes, Maria TPS3113 Mezger, Jorg 8051^ Mezheyeuski, Artur 3571, 3597, 11097 Mezhir, James J. e15052 Mezzanzanica, Delia 11037 Mhadgut, Hemendra 5580, 5584 Mhango, Grace 7533, 7543 Mi, Shijun e22009 Miah, Aisha e21516 Miano, Eleonora e11526 Miao, Feng 1586, e11611, e12547 Micallef, Ivana N. M. 7041 Micco, Ellyn e20618 Miceli, Rosalba 3641, e14716, e15589 Michael, A. I. e20000 Michael, Helen E. 3 Michaelidou, Kleita 11117 Michaelis, Laura Christian e14578 Michaelson, M Dror 4512, 5076 Michaelson, Richard Alan 565, 1032 Michail, Iskas 8567 Michailidis, Prodromos e15063 Michalaki, Vasiliki e15114 Michallet, Mauricette 7066, 9564, e20513 Michalopoulos, Nikolaus 1110 Michalski, Jeff M. 7501, 10554, e17553 Michaut, Magali 1010 Michel, Daniela 9028 Michel, Pierre 3536 Michelazzi, Luigi e12518

Micheli, Elvia Michelli, Rodrigo Augusto Depieri Michels, Jean-Jacques

641

e22154 10574, 10575 Michener, Tracy 9041 Michiara, Maria 2048 Michie, Caroline Ogilvie 2513, 2586 Michielin, Olivier Alain 9024, 9078 Michielin, Olivier 9014, 9025, e20011 Michiels, Stefan 610, 11003, e12008, e19060 Michina, Zoya e15546 Michl, Patrick 4034 Michon, Jean Marie 10031 Michy, Thierry e11579 Mickey, Mary 6539 Micol, Vicente e19003 Middleton, Gary William TPS3645, LBA4004, 4023, TPS4156, 7595 Middleton, Mark R. 2531, 2586, 3018, LBA9000, 9004, 9068, e15061 Middleton, Steven 10514 Midgley, Rachel A TPS5615 Miele, Gino 11064 Mielgo Rubio, Xabier e12020 Mieno, Hiroaki e15113 Mier, James Walter 9076 Mierski, Joseph 7039 Miesfeldt, Susan e12561 Mietlowski, William Leonard 11082 Mietzel, Melissa A 8543 Migden, Michael R. 9037 Migliardi, Giorgia 11005, e14654 Miglietta, Loredana 1036, e17548 Migliorati, Cesar A. 6040 Migliori, Giuseppe 3040 Mignot, Laurent 1578 Miguel, Isalia Margarida Campos e15118 Mihalcioiu, Catalin Liviu Dragos 518, 9032 Mihaly, Zsuzsanna e11564 Mii, Sumiyuki e13577 Mijangos, Erika e19088 Mikami, Chie e14572 Mikami, Kazuya e15531 Mikami, Yoshiki 5526 Mikan, Sabrina Q. e20668 Mike, Makio e14670 Mikesch, Jan-Henrik 8548 Mikhaylova, Irina N. e20042 Mikheeva, Olga N. 5520 Mikhina, Zoja e15583 Miki, Akira 4096 Miki, Izumi e22082 Miki, Tsuneharu e15526, e15531 Mikkelsen, Tom 2054, 2065, 2073 Mikolajczyk, Steve e22047 Mikovits, Judy e22038, e22039 Mikus, Gerd 3090, 9612 Milan, Stacey e15183 Milani, Andrea e11581 Milano, Gerard 3596, 3606, 7117, e13519 Milano, Michael T. e20667 Milburn, Christy 9043

Milella, Michele 4041, e15057, e17555, e19020, e19052 Miles, David 600, TPS667, TPS1142^ Miles, Joshua TPS11121 Miles, Kiersten Marie 4582 Mileshkin, Linda R. TPS5614, e17535 Miley, Debi 7591, 8057, e19143 Milhem, Mohammed M. CRA9003, 9020, 10522, TPS10591, e15557 Milione, Massimo e14716 Militello, Loredana e22149 Miljkovic, Milos e20685 Millán, Isabel e19532 Millard, Frederick E. 5047^ Miller, Andrew TPS7607 Miller, Anthonette M. TPS5613 Miller, Anthony 6550 Miller, Antonius Arthur 7506 Miller, Brigitte E. 5588 Miller, Chris 9037 Miller, Christopher P. e22178 Miller, Christopher 9017 Miller, Daniel L. 2610 Miller, David Christopher 5044 Miller, David S. 5520, 5527, 5591, 5593 Miller, Dawn M. 6500, 6538, e20633 Miller, Fiona e17515 Miller, Frank e15554 Miller, Jeffrey S. TPS6101 Miller, Jessie TPS4594 Miller, Jill e15106 Miller, Kathy 6527, 9508 Miller, Kenneth David e20567, e20685 Miller, Kurt 5079 Miller, Laura Elizabeth 7569 Miller, Lonnie D. e17575 Miller, Melissa F. 9599 Miller, Michelle 9585 Miller, Paul J. E. 8044, e13574 Miller, Paul e15012 Miller, Robert Clell 4026, e17019 Miller, Susan 6590, e20543 Miller, Suzanne M. 6500 Miller, Therica M. e17507 Miller, Thomas P. 7018, 8562 Miller, Vincent A. 534, 1009, 8020, 8023, 8036, 8039, 9002, 10513, 11000, 11020, 11068, 11100, e15035, e22146 Miller, Wilson H. 518, 9013 Miller, Wilson H. 9029, 9046 Milligan, Scott 6553 Millikan, Randall E. 4548, e15612, e16038 Milliron, Kara J. 1557 Millis, Sherri 11001 Mills, Glenn Morris 8592, e14653, e17585, e19070, e20600 Mills, Gordon B. 5521, 5524, 6011, 11013, 11060, e22081 Mills, Jennifer 8017 Millward, Carl 5029 Millward, Michael 9013 Milne, Roger 1529 Milner, Alvin 4041 Milojkovic Kerklaan, Bojana 2536 ABSTRACT AUTHOR INDEX

755s

Milone, Francesco e15071 Milosevic, Michael 4049 Milot, Laurent M. 4583 Milowsky, Matthew I. e15595 Milpied, Brigitte e20041 Milstein, Arnold 6581 Milton, Ashley 2598 Mimae, Takahiro e18563 Mimaki, Sachiyo 7512, e19076 Mims, Martha P. 8577 Min Hoe, Chew e14520 Min, Kyung Jin 5539 Min, Trisha 4130 Mina, Lida A. 2580 Mina, Zhang e19085 Minagawa, Nozomi e14548, e15038 Minami, Hironobu 5528, 9623 Minami, Seigo e19010^ Minami, Yosuke e13520 Minamimura, Keisuke 3535 Minarik, Gabriel e22023 Minarik, Ivo e16002 Minarik, Tomas e22023 Minasian, Lori M. 2514, e20520 Minauchi, Koichiro e19507 Minca, Eugen C. 11091 Minczewska, Joanna e16097 Minden, Mark D. 7067, 7071, 7078 Mindruta-Stratan, Rodica 1567, e12543 Minegishi, Yuji 11049 Minella, Gloria Terase 4103 Mineur, Laurent 3514, 3560, 3636, 3637, LBA4003, 4046 Minguez, Beatriz 4118 Minguzzi, Martina e13579 Mini, Enrico 3525^ Minichsdorfer, Christoph 573, e20693 Minicuci, Nadia e13514 Minisini, Alessandro e11565 Ministrini, Silvia e15148 Minna, John D. 8019, 8085 Minnema, Monique 8512^ Minni, Francesco 4048 Mino-Kenudson, Mari 7555, 8083 Minomo, Shojiro e19021 Minor, David R. 9041, TPS9105^, e20001 Minton, Susan E. 3026, 3069 Minuti, Gabriele 11066, e14574 Miodini, Patrizia 1014 Mion, Marta e13514 Mir, Alain 11096 Mir, Olivier 5567, 10542, e12504 Mirabile, Aurora 6020, 6027, 6046 Miraglio, Emanuela 3615 Mirakhur, Beloo 9013 Miralbell, Raymond e15619 Miramon, Jose 608 Miranda, Christine e12544 Miranda, Debora Marques e15199 Miranda, Vanessa Costa 2060, 5540, e15090 Mirander, Markenya 4082 Mirandola, Leonardo 7060, 8591, e18527, e22003, e22052 Mirchandani, Deepu 5042 756s

Mireia, Gil raga e14671 Mirghani, Haitham 6055 Mirick, Dana e14585 Mirimanoff, Rene-Olivier 7503 Mirnezami, Reza e14620 Mirza, Mansoor Raza 2505, LBA5503, 5542, e16540, e16541 Mirzoeva, Olga K. 4014 Misauno, Micheal Ayedima e15119 Misawa, Kazunari 4088 Mischel, Paul S. 2012, 2606 Misemer, Benjamin 10560 Mishima, Hideyuki 3516, 3519 Mishima, Michiaki 11041 Mishra, Durga Prasad e17020 Mishra, Gauravi 2 Misiorowski, Waldemar e20512 Misitzis, Ioannis 11117 Misiukiewicz, Krzsztof 6019, 6023, 6062, 6078 Miskimen, Kristy 1046 Miskin, Hari 8575, e19528 Miskovska, Vera 4556, e15599 Misra, Srimanta e19513 Missiaglia, Edoardo 3526, 3577, e14544 Missy, Pascale 8000 Mistry, Reena 8523 Mistry, Shams 570, 6567 Misumi, Yuuki 8054 Mita, Alain C. 2560, e13572, e15128 Mita, Monica M. 2606, 8522, e13572, e15004, e15128, e17507 Mitani, Hiroki e17006 Mitchell, Aaron Philip e15572 Mitchell, Alan 8539 Mitchell, Catherine 10567 Mitchell, Edith P. TPS1135, e14528, e15089 Mitchell, Gillian 11024 Mitchell, Hannah-Rose 10063 Mitchell, Jacqueline e17547 Mitchell, Lada 9036, 9046 Mitchell, Paul Leslie 3011 Mitchell, Paul 5571, 7500, 7567, e18559 Mitchell, Sandra A. e17560 Mitchell, Scott e21516 Mitchell, William M. 5072, 11013, 11060 Mitra, Anirban Pradip 4542, 5033, e16044 Mitra, Priti 7083 Mitrica, Ionel 5512 Mitropoulos, Dionysios e15619 Mitry, Emmanuel 2615, 3585, 3614, e14514, e14542 Mitsiades, Constantine S. 11039 Mitsudo, Kenji 6060 Mitsudomi, Tetsuya 7518 Mitsunaga, Shuichi 2559 Mitsuoka, Shigeki 7564, e19053 Mittal, Kriti 4515, e13521 Mittal, Sushant S. 7043 Mittapalli, Rajendar K. 9048 Mittendorf, Elizabeth Ann 1103, 1131, 3005, 3095, 3096, 3097, TPS3126 Mittlboeck, Martina e14537 Mittmann, Nicole 6552, e17569


Mittra, Indraneel 2 Miura, Daishu 1029, e11519 Miura, Fumiharu TPS3116 Miwa, Haruo e15109 Miwa, Hiroto 4096 Miwa, Shinji e13576, e13577 Miwa, Toshiro 3072 Miyagaki, Takuya 3535 Miyagishima, Takuto e14604 Miyajima, Akira e16094 Miyake, Hideaki e15588 Miyake, Yasuhiro 3071, e14551, e14601 Miyamoto, Atsushi 7555, e15031 Miyamoto, Hiroshi e15060 Miyamoto, Shingo e19054 Miyamoto, Takashi e13569 Miyamoto, Takeshi 1048^ Miyamoto, Toshihiro 8506 Miyamoto, Yuji e14665 Miyanishi, Koji e15060 Miyashita, Kencho e14604 Miyashita, Masaru 1029 Miyashita, Yumi LBA4002, 4102 Miyata, Yasuhiko e19521 Miyata, Yoshihiro e18563, e22053 Miyata, Yoshinori e14511, e14527 Miyatani, Tomohiko e14572 Miyauchi, Hideaki 3535 Miyazaki, Masaki 8056, e19165 Miyazaki, Masaru 1097, 4056 Miyazaki, Miki e15568 Miyoshi, Chika 2559 Miyoshi, Eiji 7550 Miyoshi, Yasuhide e16098 Mizoguchi, Akira e22205 Mizokami, Atsushi e16072 Mizrak, Dilsa e11511 Mizugaki, Hidenori 7540 Mizuno, Aya 4092 Mizuno, Nobumasa 4120 Mizuno, Ryuichi e15527, e16094 Mizuno, Yoshio 3034, e12009 Mizunuma, Nobuyuki 4108, e15105 Mizusawa, Junki 4104, TPS4152, e14555, e15016 Mizutani, Makiko 1048^ Mo, Frankie 6015, e15048 Mo, May F. 3575 Mo, Shuyuan 10501^ Moasser, Mark M. 1095, 2605, 6619, 6620 Moats, Rex A. 2018 Mocci, Evelina 1529 Moch, Holger 9025 Mochalova, Anastasia e12012 Mochizuki, Hidetaka 3518 Mochizuki, Izumi 3518 Mochizuki, Nobuo 2559 Mochizuki, Satoshi 4074 Mochizuki, Teruhito 1124 Mochizuki, Yoshinari 4088 Mocquery, Magali e20519 Modak, Shakeel 3033 Modena, Alessandra e16053 Modena, Yasmina 9554 Modenesi, Caterina e15512 Modest, Dominik Paul LBA3506 Modi, Shanu 606, 11076 Modiano, Manuel LBA8003

Modlin, Irvin M. 4137 Modonesi, Caterina e13514 Modugno, Caroline 11012 Modur, Vijay e22185 Moebus, Volker TPS1137, e20616 Moeckelmann, Nicolaus e17003 Moehle, Robert 3098 Moehler, Markus Hermann TPS3124^, 4086, TPS4151, TPS4158 Moehler, Markus 3524, 4021 Moeller, Karen e21000 Moen, Catherine 9606 Moertel, Christopher L. 10522 Moes, Gregory S. 2062 Moeslein, Fred M. e14545 Mogaki, Masatoshi 1047 Moghaddamjou, Ali 9593, 9598, e14603 Mogri, Huzefa J. 7009 Mogul, Mark Jeffrey 2089, e13040 Mohamed, Iman e12016 Mohamed, Tarek Yakout 7013 Mohammad, Khalid S. e22072 Mohammad, Tariq 2576 Mohan, Diwakar e19525, e19529 Mohan, Pedapenki Ravi 8053 Mohan, Vivek 1016 Mohanti, B. K. TPS4162, 10527, e12539, e15138, e21522 Mohanty, Kirti Ranjan 6089 Mohd Sharial, Mohd Syahizul Nuhairy e13020 Mohedano, Nicolas e15620 Mohelnikova-Duchonova, Beatrice 11051 Mohile, Supriya Gupta 9545, 9549 Mohiuddin, Jahan 1077 Mohn-Staudner, Andrea e19093 Mohr, Michael 8548 Mohr, Peter 9020, e20028 Mohri, Yasuhiko e22205 Mohyuddin, Adil I. 2544 Mohyuddin, Adil 3564 Moiraghi, Beatriz 7053^ Moiseenko, Fedor Vladimirovich e13005 Moiseyenko, Tatiana e22022 Moiseyenko, Vladimir 3088, 3574, 4021 Mojtahedi, Golnessa 5508, 5543 Mok, Tony 8021, TPS8119, TPS8123, e19002, e19041^ Mok, Young-Jae 4113 Mokatrin, Ahmad 3000, 3001, 4505, 8008, 9010 Mokhles, Abir 10044 Mokhtari, Karima 2020 Mol, Linda 3502 Moldovan, Cristian e11529 Molife, L Rhoda 2513, 2535, 2566, 2586 Molin, Yann 6056 Molina, Ana M. e15517 Molina, Arturo 5004, 5009, 5010, 5013, 5014, 5037, 5059, TPS5097, 9617, 9618 Molina, Julian R. 2551, 6095, 6587, 7509, 7545, 11119, e18538, e19013, e19096

Molina, Matias e16100 Molina, Violeta Moreno e17031 Molina-Garrido, M. J. 1529 Molina-Pinelo, Sonia e22045 Molina-Vila, Miguel Angel 2581, 11027, 11029, e22068, e22119 Molinas, Emiliano e11600 Molinier, Oliver 8081 Molins, Laureano 7547 Moliterni, Angela 537 Moliterno, Alison 7032 Mollberg, Nathan M. 7535 Molloy, Mark P. e22175 Molloy, Sean e20507 Molnar, Istvan 4 Moloci, Nicholas M. 6044 Molthrop, David C. e11590 Momen, Lamia 4501 Momin, Fayez 7016 Mommersteeg, Monique e14629, e22156 Momota, Hiroyuki e13012 Mondejar, Tamara 11033 Mondello, Patrizia 8047 Monden, Kazuya 8098, e19017, e19045 Mondschein, Joshua Keith 6044 Monedero, Alicia P. 1586, e11611 Monfardini, Silvio 6593 Monforte, Joseph 11108 Mongan, Anne-Marie e15142 Monia, Brett P. 8523 Monitto, Drew C. 9505 Monk, Bradley J. 3, 3077, TPS3121, LBA5503, 5566, 5602, e16548 Monma, Tomoyuki 3063 Monnereau, Alain e14542 Monnet, Isabelle e19036, e19058 Monohan, Gregory 7084, e18001 Monroe, Alan TPS6097 Monroe, Philip J. 10042 Montagna, Daniela 4575 Montagna, Elisa e16081 Montagut, Clara e14554 Montal, Robert e14554 Montalban, Maria Angeles 8511 Montanana, Myriam e19027 Montanino, Agnese 8066 Montbarbon, Xavier 6056 Montcuquet, Philippe 1122, e11579 Monteforte, Marta e14611 Montefusco, Vittorio 8509 Montejano, Laura 8511 Montella, Tatiane Caldas e18515 Montemurro, Filippo e11581 Montemurro, Severino e22104 Montero, Alberto J. 6548, TPS11124, e11591, e22135 Montero, Maria Angeles 4135 Montes, Ana TPS5615 Montes, Marta e14589 Montesarchio, Vincenzo 8066, e14565, e15088 Montgomery, Luke e21501 Montgomery, Robert B. 5014 Montgomery, Susan 1538 Montheil, Vincent e17514 Monti, Manuela e18561 Monti, Maria Gaia 631

Montiel Rayo, Ana Belen e20705 Montiel, Monica 6596, e17539, e20636, e20656 Montillo, Marco 7101 Montin, Lisa e20541 Montironi, Rodolfo e15536 Montoro-Garcia, Silvia 3042 Montoya, Jose Enrique e20696 Montrone, Michele 8071, e18545 Montroni, Isacco 9557 Montserrat, Emili 7101 Mony, Ullas 3101 Monzo, Mariano 7547 Monzon, Federico A. 10023 Monzon, Jose Gerard 9032 Monzoni, Adriana 546 Moody, Justin 9098 Moon, Elena e20045 Moon, Hyeong-Gon 551, 1039, 1128, e22063 Moon, James 7511, 7527 Moon, Joon Ho 3553, e18017 Moon, Kyung Chul e15614 Moon, Thomas E. e20539 Moon, Woo Kyung 1039 Moon, Yongwha 11034 Mooney, David James e19143 Moonka, Ravi 4043 Mooppan, Unni e16101 Moore, Anne e20641 Moore, Bartlett 10009 Moore, David 6581 Moore, Dennis F. e13006 Moore, Dennis Frederic 2006, 2051, e20526 Moore, Dennis F. e13006 Moore, Dominic T. 5523, e13546, e16529 Moore, Eric J. 6095 Moore, Halle C. F. CRA1008 Moore, Joseph A e13006 Moore, Kathleen N. 2519, 2573, TPS2620, TPS3121, 5518 Moore, Katrina H. e20533 Moore, Malcolm A.S. 3101 Moore, Malcolm J. 3528, 4005^, 4006, 4032, 4053, 4059^, 4061, TPS4144, 4503, TPS10593, e15510, e20639 Moore, Matthew B e13006 Moore, Richard G. 5563 Moore, Timothy David CRA1008 Moore-Smith, Lakisha 1548 Moorhead, Martin 8601 Moorji, Sameer M. e16007 Moorthy, Ganesh e13518 Moosmann, Peter 3503 Mora, Jaume 10536 Mora-Pineda, Mauricio De Jesus e14703 Morabito, Alessandro 8066, 8071 Moraco, Nicole H. 10580 Morales, Diana e16055 Morales, Domingo e20023 Morales, Rafael e16045 Morales, Rita Elena 10558 Morales, Serafin e12015, e12558 Morales-Espinosa, Daniela e22068, e22151 Morales-Oyarvide, Vicente 7555

Moran, Cesar 7552 Moran, John 6558 Moran, Susan 5076 Moran, Teresa LBA8002, 8063, 11025, 11027, 11029, e19088, e19089 Morandi, Luca 546, 2021 Morando, Claire 8014 Morante, Zaida e12538 Moratello, Giacomo e17551, e20617 Mordan, Anna Iurievna e16558 Mordichai, S. e22069 Moreau, Lionel e19056 Moreau, Marie 3614 Moreau, Philippe 8510, 8513, 8527, 8528, 8530, 8542, 8583 Morehouse, Chris e20047 Moreira, Andre L. 3101, 7559, 8022 Morel, Alain 3601 Morelli, Daniele 6046 Morelli, Franco e15524, e16031 Morelli, M. Pia 3512 Morelli, Maria Beatrice e15513, e15515 Morelli, Maria 3632 Morelos, Amherstia e20696 Moreno Aguado, Victor e14554 Moreno, Carol 7101 Moreno, Fernando 4587, e11561 Moreno, Irene 11089, e19000, e19109 Moreno, Maryangely e11568 Moreno, Victor 3530, 3629, e14613, e15107 Moreno-Aspitia, Alvaro 1037, 1059 Moreno-Jiménez, Marta e19114 Morere, Jean F. 1583, 5567, 6563, e12504, e20654 Morere, Jean Francois 1562 Morere, Jean Francois 3606 Morere, Jean-Francois e19513 Moresino, Cecilia e20538 Moreton, Jane 1559, e20660 Moretti, Anna e11573, e12021 Moretto, Patricia e15591, e16074 Morey, Adrienne 7567 Morgado, Margarita 9611 Morgagni, Paolo e15148 Morgan, Adrienne TPS656 Morgan, Dal e11608 Morgan, David A. L. e20588 Morgan, Jeffrey A. 10511 Morgan, Jenny e14566 Morgan, Michael A. e16024, e16064 Morgan, Robert 5517 Morgan, Sherif S. 10581 Morgan, Shethah TPS2626 Morgans, Alicia Katherine 6532 Morganstern, Daniel 513, 9515 Morgenfeld, Eduardo L. 6596, e17539, e20636, e20656 Morgenfeld, Mirta e20504, e20657 Morgenstern, Daniel Alexander 10015 Morgensztern, Daniel 6042, 6076, 6635, 7033, 8041, 8076, e19158 Morgenthaler, Nils G. e22055 Mori, Kazuyuki e15565 Mori, Keita 7572, 7599, e14623, e16507, e18556, e19050

Mori, Kristina Mori, Masahide Mori, Masanori Mori, Motomi Mori, Stefano Di Mori, Tetsuya Mori, Tsuyoshi

5574 e19010^ e20717 5017 e20031 e16502 4092, e11555, e12014 Mori, Yukiko e15054 Moriarty, Thomas e21000 Morikawa, Aki 514 Morimoto, Takashi 613, 1048^ Morimoto, Yuhki e22205 Morin, Franck 7505, 7515, 8000, 8081, e19058 Morinaga, Ryotaro e20585 Morinaga, Soichiro 4008 Morini, Silvano 1086 Morinieres, Sylvain 6053 Morishita, Naoko e19021 Morita, Jun e15527 Morita, Masaru 1056, e15039, e15158, e15173 Morita, Satoshi 613, 1047, 1048^, 3519, 3535, LBA4002, 4088, 4096, 4102, 5528, 11049, e15109, e15112, e19010^, e19054 Morita, Shane Young 9073, e20029 Morita, Takayuki 3638 Morita, Tatsuya e20717 Morita, Yoshitaka 3516 Moritani, Suzuko e19521 Moritz, Berta 4035 Moriuchi, Yukiyoshi 8506 Moriya, Hiomitsu e15113, e15122 Moriya, Yoshihiro e14555 Morizane, Chigusa e15031 Mork, Maureen M. 1525, 1546 Morlan, John 11018 Morlock, Robert e14585 Mormont, Christine 6041 Moro-Sibilot, Denis 7505, 7515, 8059, 8081, 8099, e19056, e19058 Morohoshi, Toshio e12035 Morosi, Carlo 10565 Morote, Juan e16045 Morra, Enrica 7025 Morrill, Paul e22164 Morrione, Alienne 6635 Morris, Anne e20618 Morris, Arden M. 9579 Morris, Carol 10528 Morris, Elizabeth Ann TPS3120 Morris, Jeffrey 3600 Morris, Jennifer 2532 Morris, John Charles 2560, 2609, 8094, e13518 Morris, Luc G. 6048 Morris, Michael J. 5021, 5066, 5073, 5081, 5090, e16001 Morris, Patrick Glyn 630, 6048 Morris, Stephan 1067 Morris, Van Karlyle 3632 Morris, W. James 5035 Morrison, Carl D 5574 Morrison, Christopher 4540 Morrison, Paula 2589 Morrison, Sherie L. 3024 ABSTRACT AUTHOR INDEX

757s

Morrissey, Lisa H. 11102 Morrissey, Michael 7111 Morrone, Robert J. 7601 Morrow, Betsy 2532, 7513 Morrow, Gary R. 9533, 9572, TPS9647, TPS9651, e20520, e20526 Morrow, Monica 507, 1019, 1021, TPS3120 Morrow, Phuong Khanh H. e20564 Morschhauser, Franck 8502, TPS8615 Morse, Emma Perry e12561 Morse, Janet e15162 Morse, Michael 3030, 3070, 4031, 4040^ Mortara, Virginia e12518 Morten, John 8045 Mortensen, Frank 3558 Mortensen, Mette Saksoe 4502, 4533, e20561 Mortensen, Neil 3500 Mortier, Laurent 9036, 9037, 9069, e20630 Mortimer, Jim A. e17530 Mortimer, Joanne E. 1024, 2564, TPS9648, TPS11121 Mortimer, Peter 5076 Morton, Donald L. 9095 Morton, Gerard e16070 Morton, Kyana e17524 Morton, Lindsay M. 4536 Morvillo, Manfredi 3613, e14574 Morysinski, Tadeusz 10564 Mosca, Franco 4062 Moscetti, Alessandro e19527 Moscetti, Luca I. e12031, e15615, e19084 Moscow, Jeffrey 2534 Moseley, Angelena e17586 Moser, A Jim 4038 Moserova, Irena 3076 Moshfegh, Ali 7087 Moshier, Erin L. 4525, 6540 Moskalenko, Marina 3014 Moskaluk, Chris 6021 Mosnier-Pudar, Helen e17514 Mosquera, Juan Miguel TPS5096 Moss, Alexandra e17592 Moss, Jonathan e14564, e17570 Moss, Ralph W. e13029 Moss, Rebecca Anne 2553, 2582 Mosse, Claudio A 8605 Mosser, Jean 8000 Mostert, Bianca 11045, e22106 Mostyn, Patrick J. TPS8620 Motamed, Kouros e15076 Motiwala, Shweta e15564 Motola, Daniel e22151 Motomura, Kazuya e13012 Motomura, Kazuyoshi 1107 Mottolese, Marcella e19052, e22206 Motwani, Monica 3507 Motzer, Robert John 4501, 4504, 4513, 4519, 4534, 4564, 4569, 4573, 4585, TPS4592, e15517, e15624, e17530 Mouarrawy, Doraid 11043 Mougalian, Sarah Schellhorn 1017 758s

Mouillet, Guillaume 1122, e11579 Moulder, Stacy L. 532, 601, 1051, e13591 Moulton, Carol-Anne e14573, e15087 Mounier, Nicolas 8524, TPS8615 Mount, David 7062 Moura, Fernando e22176 Mouret-Reynier, Marie-Ange 1057, 1058, e11615 Mourey, Loic TPS5099^, e16009 Mourlanette, Pierre e19058 Mouro, Larissa R. e12007 Mousavi, Seyed Asadollah 7069 Moussa, Ali H. 9094 Moussa, Davina 7056 Mousseau, Mireille e13519, e15593 Moustafa, Karim G e15571 Moutinho, Catia 3581, e14609 Mouw, Kent 10018 Mowat, Rex B. 2562, 3640, 9525 Mowat, Rex Bradford e14526 Mowles, Delores 2546 Moy, Beverly 533, 630, 647, 1006, 6557, 9534 Moy, Christopher H. 3507 Moy, Ofie C. e22081 Moyer, Anne e12542 Moyers-Ruiz, Liliana e20713 Moylan, Eugene J. 598, e13020 Moynahan, Mary Ellen 606, TPS4144 Moynihan, Timothy Jerome 1024, 5082, e16061 Mozayen, Mohammad 2089 Mozessohn, Lee 6592 Mozley, P. David 3635 Mozzicafreddo, Matteo e15513, e15515 Mozzillo, Nicola e20013, e20031 Mpaziotis, Nikos e20635 Mrabti, Hind e16527, e20516, e20624 Mrhalova, Marcela e22208 Mrozek, Ewa 1023, 1043 Mrugala, Maciej M. e13017, e13018, e13041 Mu, Dianbin e15167, e18533 MU, Hua e19042 Mucci, Lorelei A. 5078, 5086 Mucciarini, Claudia 2048 Muche, Rainer 4034 Mudad, Raja e17540 Mudalagiriyappa, Chidananda 633 Muddu, Vamshi e20678 Muehlethaler, Katia 9014 Mueller, Berit 11061, 11112 Mueller, Boris 6034 Mueller, Carsten 8570 Mueller, Christian 4080 Mueller, Hans Helge 4030 Mueller, Jeffrey 11021, 11035 Mueller, Justus e15193 Mueller, Lothar 3508, TPS4158 Mueller, Martin Rudolf 7019, 10562 Mueller, Rebecca 1510 Mueller, Sebastian LBA3506 Mueller, Udo W. e13548, e13551, e13552, e13555, e17572


Mueller, Volkmar 638 Mueller-Holzner, Elisabeth 583 Mueller-Huebenthal, Jonas e22114 Mueller-Mattheis, Volker e16003 Mueller-Tidow, Carsten 8548 Muenscher, Adrian e17003 Muerdter, Thomas E. 2588 Muftuoglu, Meltem e22004 Muggia, Franco 1042, 2591, 5581 Mugishima, Hideo 10050 Muglia, Valdair Francisco e12007 Mugridge, Nancy 7586 Muhammad, Furrukh e22099 Mujib, Marjan 7042 Mujib, Nusrat 7042 Mujika, Karmele e20007 Mukai, Hirofumi 1113, 3082 Mukai, Shizuo 10018 Mukaiyama, Akihira e20004 Mukherjee, Abhik 1016 Mukherjee, Anindya e20707 Mukherjee, Bhramar 1542 Mukherjee, Siddhartha 7031 Mukherjee, Som Dave 1033, 5039 Mukherjee, Sumana e22180 Mukherji, Deborah 5052, e12525 Mukhopadhyay, Ashis 7083, 7085, 7114, 10069, e16542 Mukhopadhyay, Pabak 505 Mukhopadhyay, Soma 7114, 10069 Mukhopadhyay, Sutapa 8531 Mukkamalla, Shiva Kumar Reddy e12564 Mukundan, Srinivasan 2075 Mulcahy, Mary Frances 3007, 3540, 4022, 4118, e15187 Mulder, Jan 3571 Mulder, Karen E. e14575, e14595, e14715 Mulder, Lennart 1010 Mulders, Peter 5009, 5010 Muldoon, Robert T. 4058^ Mulford, Deborah A. 7028 Mull, Ruslan e22095 Mullady, Daniel 4051 Mullamitha, Saifee e22035 Mullan, Mohmaduvesh e15085 Mullan, Paul B. TPS11120 Mullane, Michael Russell e12523 Muller, Leandro Bizarro e15067, e15083 Muller, Susan 2552 Mullie, Patrick 1519 Mulligan, George 8559 Mulligan, Jude M. TPS11120 Mulligan, Jude 7532 Mulligan, Stephen P. TPS8618 Mullinax, Jennifer Rose 2085 Mullins, C. Daniel 9599, e14524, e14602, e16027, e16034, e20618 Mullins, Christina S. e13053 Mullins, David W. TPS3118^ Mullooly, Maeve 1054 Mulquin, Marcia 8597, e19506 Mulrooney, Daniel A. 9606 Mulshine, James L. 1561, 11114 Multz, Alan S. e17537 Mulvihill, Erica e14519 Mummy, David G e14585 Munar, Myrna 5017

Munari, Enrico 4523 Munarriz, Blanca e22112 Munasinghe, Wijith 2520 Munawar, Atif e12033 Munden, Reginald F. 1564 Mundy-Bosse, Bethany L. e20018 Munemoto, Yoshinori 3516 Mungall, Andrew e22020 Mungall, Karen e22020 Munhoz Piotto, Gustavo Henrique e20691 Muni, Alfredo e20694 Muniz, Luciana V. e22122 Muñoz, Alberto e14628, e20718 Munoz, Francisco 6529, e20606 Muñoz, Silvia e19159 Munoz, Vicente 3074 Muñoz-Couselo, Eva TPS649 Munoz-Garcia, Camen 6072 Munoz-Mateu, Montserrat 1027 Munsell, Mark F. 4528, 5596, TPS6100 Munshi, Anusheel e18525 Munshi, Nikhil C. 3067, 8592 Munshi, Pashna Neville 1091 Munsoor, Husna e20613 Munster, Mijal e22125, e22134, e22138 Munster, Pamela N. 1095, 2605, 2606, TPS2623, 6619, 6620, 8522, e13574, e19541, e20010 Munteanu, Mihaela C. 8537, 8565, e19518 Munzone, Elisabetta 1061, 9582 Muo, Chih-Hsin 1600 Muppidi, Samatha 8540 Murad, André M. TPS4153 Murad, Faris 4051 Muragaki, Yoshihiro 2066 Murakami, Haruyasu 7556, 7572, 7582, 7599, e13500, e18556, e19050, e19074 Murakami, Koichiro 4092, e12014 Murakami, Shuji 7531, 11055 Murakawa, Yasuko e14597 Muraki, Keiko e19043 Murali, Rajmohan 1552, e12527 Murali, Sujatha 562 Muranyi, Andrea 3576 Muraro, Silvia e17551 Murata, Asuka 11065 Murata, Ryoichi 8601 Murata, Satoshi 4092, e12014 Murata, Takeshi e11598 Murata, Yasunori e19164 Murawski, Niels 8566, 8569, 8570 Murazov, Yaroslav e13005 Murer, Carla 9028, 9071 Murga, Jose D. e16007 Murgia, Viviana LBA5501 Murgo, Roberto 576 Muro, Kei 3519, 4076, e14527 Murone, Carmel 3011, 7567 Murphy, Aimee 4040^, TPS7607 Murphy, Alexandra 9609 Murphy, Anne Marie 6609 Murphy, Barbara A. 6030, 6040, 6047, 6049, e20531, e20555 Murphy, Conleth G. 1115, 3627 Murphy, Janet E. e14636

Murphy, Joan Murphy, Karen Murphy, Kate Murphy, Maureen E. Murphy, Patrick Murphy, Philip S. Murphy, Robert F. Murphy, Stephen J. Murray, Helena Murray, James L. Murray, Joseph Murray, Nevin Murray, Nicholas Murray, Nicola Murray, Paul Gerard Murrell, Dedee F. Murthy, Sudish C.

5543, 5561 e16550 3627 e22163 2544, 3564 635 2554 7568 e22074 532, 3095 TPS2624 e19131 1015 4118 e17017 9037 4087, 8113, e15000 Murtola, Teemu Johannes 1514 Murtra-Garrell, Nuria 8070 Muscarella, Lucia Anna e14655 Muscato, Joseph J. TPS664 Musella, Valeria 1014 Mushtaq, Rao 6567 Musi, Eleonora e13579 Musini, Silvina Laura e20504 Muslimani, Alaa 6577 Musolino, Antonino TPS651 Muss, Hyman Bernard 564, 1007, 9543, e20582 Muss, Hyman 9515 Mustacchi, Giorgio 546 Mustafa, Rasha e19035 Mustea, Alexander 5531, e16534 Mustian, Karen Michelle 9531, 9533, 9572, TPS9647, TPS9651, e20526 Musto, Alberto E. e13581 Musto, Grace 1597 Musto, Pellegrino 8509, 8517 Mutch, David Gardner e16508 Mutchler, Jan 6529 Muth, Mathias 591, e11525 Muthukumar, Dakshinamoorthy 7595 Muto, Giovanni e16099 Muto, Satoshi e19162 Mutyaba, Innocent 10070 Muwakkit, Samar 10052 Muzaffar, Jameel 8595 Muzaffar, Mahvish e12016 Muzi, Mark 5003, e13028 Muzikansky, Alona 2013, TPS2104 MV, Chandrakant e18004 Myers, Andrea P. 5521, 5524 Myers, Jay T. e22158 Myers, Jeffrey A. e17503 Myers, Jeffrey 6011 Mykulowycz, Kristine 2536 Müller, Martin C. 7001, 7048, 7051 Müller, Volkmar 607 Myneni, Praveen Chowdary 7080 Myrand, Scott 8086 Mystakidou, Kuriaki e20635 Møller, Henrik e19157

N Na, Young-Soon Nabholtz, Jean Marc

e15026 1057

Nabholtz, Jean-Marc 1058 Nabid, Abdenour LBA4510, 9502 Nabissi, Massimo e15513, e15515 Nabors, Louis B. LBA2009, 2044, 2054 Nacci, Angelo 618, 8066, e14605, e18545 Nacciarriti, Dania e11616 Nachat-Kappes, Rachida e11552 Nachman, James B. 10001 Nadal, Ernest 11056 Nadal, Marga e14554 Nadal, Tamara 2563 Nadeem, Zaineb 9067 Nademanee, Auayporn 8556 Nader, Ralph 10052 Nadiminti, Kalyan 9090 Nadler, Eric S. e19139 Naeim, Arash e17509 Nag, Shona Milon 8053 Nagahara, Kunihiko 6004 Nagai, Hirokazu e19521 Nagai, Kanji 7512, 7557, 8037 Nagai, Masazumi e19097 Nagamine, Kimberly e16501 Nagano, Masafumi e14670 Nagao, Kazuhiro e16092 Nagao, Shoji 5526, 5528 Nagaoka, Isao e14651 Nagaraj, Gayathri 7563 Nagarkar, Rajnish Vasant e15178 Nagase, Seisuke 3072, 9621 Nagashima, Fumio e15031, e20004 Nagashima, Kengo e20585 Nagashima, Takeshi 1097 Nagata, Kazuma 8098, e19017, e19045 Nagata, Misato 7564, e19053 Nagata, Naoki 3516 Nagata, Nobuhiko e19016 Nagata, Yasuhiro e11605 Nagayama, Aiko e11598 Nagel, Sylke 8013 Nagilla, Madhavi 6066, e13532 Nagino, Masato 4119 Nagle, Raymond B. 10581 Nagler, Arnon 8509, 8556 Nagliati, Michele e13046 Naglieri, Emanuele e16538 Nagorsen, Dirk 3051 Nagourney, Robert Alan e13558, e13562, e22188 Nagpal, Seema e13021 Nagpal, Sunil e14518 Nagrial, Adnan e15029 Nagtegaal, Iris D. 3552 Nagy, Andras e12022^ Nagyivanyi, Krisztian e15530 Nahi, Hareth 8512^ Naidoo, Jarushka e20687 Naidu, K. V. Jagannath Rao e14694 Nail, Carmel TPS3118^ Naina, Harris V. K. e16555 Naing, Aung 2506^, 2545, 2604, 2611, 11086, e13534, e13575, e13591, e22086 Naini, Pranitha 1067 Naini, Vahid 5059 Nair, Bijay P. 8515 Nair, Reena e20686

Nair, Suresh G. Naito, Seiji

e20046 4526, 9623, e15576, e15588 Naito, Tateaki 7572, 7582, 7599, e18556, e19050, e19074 Naito, Yoichi 1113, 8058, e22082 Naitoh, Hiroyuki 4092 Naizabekova, Svetlana Shamshykeevna e16557 Najjar, Yana George e15534 Naka, Shigeyuki 4092, e12014 Naka, Tetsuji 10539 Nakabayashi, Mari 5056, e16032 Nakagaki, Noriaki 8111, e19016 Nakagawa, Atsushi 8098, e19045 Nakagawa, Hideyuki 8006 Nakagawa, Kazuhiko 7518, 7529, 8033, 8056, TPS8123, TPS8126, e13501, e19165, e20004 Nakagawa, Ken 3072, e15576, e16094 Nakagawa, Satoru TPS4152 Nakagawa, Taku 7530 Nakagawara, Akira 10015 Nakahara, Rie e18554 Nakahara, Susumu 6082 Nakahara, Yoshiro e18524, e19133 Nakai, Toshiyuki 7564, e19053 Nakai, Yousuke e15146 Nakajima, Akio e14649 Nakajima, Keiko 4126 Nakajima, Kenichi e16072 Nakajima, Masayuki 4056 Nakajima, Naomi 1124 Nakajima, Ryu 8037 Nakajima, Takashi 7572, 7582, 7599, e18556, e19050 Nakakura, Eric K. 4143 Nakamichi, Shinji 7540, e13504, e13511 Nakamori, Shoji 4008, e15031 Nakamoto, Yoshihiko 3518 Nakamura, Akito e13529 Nakamura, Fumitaka 3638 Nakamura, Hiroyuki e19521 Nakamura, Izumi 3063 Nakamura, Kazuhide e13529 Nakamura, Kenichi 4104, TPS4152 Nakamura, Kumi 9637 Nakamura, Masato 3516, 3519, 9637, e14601 Nakamura, Masayuki e19134 Nakamura, Michio 4076, e14604 Nakamura, Seigo 1126, 1534, e11524, e12011, e12035, e20683, e22064 Nakamura, Shigeo 4119 Nakamura, Takatoshi 3556 Nakamura, Takayuki 4008 Nakamura, Tatsuya 6086 Nakamura, Terukazu e15526, e15531 Nakamura, Tsutomu e15016 Nakamura, Tsuyoshi e15588 Nakamura, Yoshiaki e14670 Nakamura, Yukiko 7556, e19050 Nakamura, Yusuke 534, 3006, 3092, 11053, 11104, e13569 Nakamura, Yutaro e20658 Nakanishi, Katsuyuki 1107 Nakanishi, Yoichi 7518, 7529, e20576

Nakano, Kenji e17006 Nakano, Masahiro e11557, e13536 Nakano, Takashi 7583 Nakao, Keiko e19021 Nakao, Masahiko 9621 Nakao, Shinji 8601 Nakaseko, Chiaki 7054^ Nakashima, Hideyuki 6060 Nakashima, Jonathan 10555 Nakashima, Kazuaki e11605 Nakashima, Masanao e19164 Nakata, Cintia Mara de Amorim Gomes e22150 Nakata, Masanobu e19507 Nakatani, Akinori e14651 Nakatani, Hiroaki 6004 Nakatsukasa, Katsuhiko 1106, 1116 Nakayama, Goro e14552, e14614 Nakayama, Haruhiko 7531 Nakayama, John e16529 Nakayama, Mitsuo 7536 Nakayama, Takahiro 1107 Nakayama, Yoshie e22027 Nakazawa, Hayakazu e15527 Nakazawa, Mitsuhiro 6096 Nakazawa, Yukie e19010^ Nakhlis, Faina 1105 Nallur, Sunitha 6016 Nam, Brian T. e17595 Nam, Byung-Ho 3570, LBA4024, 4045, 4105, LBA10502 Nam, Do-Hyun LBA2009 Nam, Eun Ji 5557 Nam, Hae-Seong e19152 Nam, Hyun-Jin 2565 Nam, Joo-Hyun 5600, 5601 Nam, Robert 5072, e16070 Namal, Esat e19127 Naman, Herve L. 6603 Namba, Yoshinobu e19010^ Namer, Moise e11607 Namiki, Mikio e16072 Namour, Alfred Elias 7013 Nanda, Rita 515, 527, 1024, 1052, 2571, 11035 Nandini, Pkl 6624 Nandy, Argha 10069 Nanfro, John 9645 Nangia, Chaitali Singh 3578, e14529 Nangia, Julie R. 1052 Nangia-Makker, Pratima e22168 Nanjo, Shigeki e19017 Nankivell, Matthew 4020, 5500 Nanni, Oriana 552, TPS649, 3040, 3517, 5594, e11521, e14512 Nannini, Margherita 10540, e21511, e21523 Nanson, Gemma LBA4004 Nanus, David M. TPS5096, TPS5100, 11081, e15600 Naoe, Tomoki e13520 Naoshy, Sarah e14576 Napoli, Alessandro 9500 Nappi, Lucia 7603, e18536, e21500 Nara, Eriko e20557 Narang, Mohit 8586, 8596 Narasimhan, Narayana I. 8031 Narasimhan, Vivek 2550 Narayan, Nitya e21000 Narayan, Samir 7501 ABSTRACT AUTHOR INDEX

759s

Narayana, Arvind 6627 Narayana, Ashwatha e13033 Nardelli, Giovanni B. 5548 Narducci, Filomena e20619 Narendran, Aru 10030 Narimanov, Mekhty e15194 Narita, Yoshitaka 2066 Narjoz, Celine e15592 Narod, Steven 1507, 5072, 5561 Naruge, Daisuke e20004 Nasabzadeh, Teresa J. 9077 Nasaka, Srividya e18003, e19533 Nascimento, Ivana Lucia Oliveira 1539 Nash, Garrett Michael 3605 Naskhletashvili, David e15546 Naso, Virginia e19527 Nason, Katie Sue 4103 Nass, Dvora e13002 Nassani, Najib Antoine e20534 Nassar, Aziza 1059 Nasseri, Morad e13001 Nassir, Mani 5549, e22102 Nassir, Youram 8598, 8599 Nassiri, Mohammad Reza e22079 Nassiri, Mohammadreza e22167 Nasti, Guglielmo 11008, e14560 Natale, Ronald B. 8051^, e13572 Natarajan, Arutselvan 11006 Natarajan, Kannan e14698 Nateras, Rafael Nunez e16065 Nathan, Paul C. 10032, 10062 Nathan, Paul D. LBA9000, 9020, 9031, 9068, e15608 Nathan, Sunita e18013 Nathanson, Katherine L. 1510, 9017, e15584 Nathavitharana, Ravindhi Lakmalee e15093, e15162 Natowicz, Rene 1013 Natsugoe, Shoji e14633 Natsume, Atsushi e13012 Nattam, Sreenivasa R. 4012 Nattinger, Matthew 6542 Nau, Peter N. e12559 Nauf, Yousseff Ibrahim 9568 Naughton, Michelle Joy 2006, 2051, 3611, 6564, 9505 Naumann, Gert 615 Naumann, R. Wendel 5572, TPS5613, e13502, e16544 Navalpotro, Begona e15107 Navari, Rudolph M. 9631 Navarria, Piera 10519 Navarro, Alejandra e16045 Navarro, Alfons 7547 Navarro, Paloma 11033 Navarro-Mendivil, Alejandro 8070 Navarro-Perez, Valentín e14609, e16539, e17010 Navid, Fariba TPS9104 Nawata, Shuichi 1047 Nawrocki, Sergiusz 7500, e16097, e20666, e22087 Naya, Yoshio e15526, e15531 Naya, Yukio e15521 Nayak, Lakshmi 2030, TPS2104 Nayl, Beatrice 1057 Nazabadioko, Serge 5504 Nazarova, Valery V. e20042 760s

Nazir, Tariq 7042 Nazmy, Nashwa e12023 Neal, Chris 11044 Neal, David 5054 Neal, Joel W. 2524 Neal, Maxwell e13017 Neal, Richard 6621 Nearchou, Andreas Demetrios 624 Neben, Kai 8590, 9612 Neben-Wittich, Michelle A. 6095 Necchi, Andrea 4525, 4539 Necela, Brian M. 1037 Nechaeva, Marina P. e20593 Neciosup, Silvia P. e12566 Neckers, Len e19097 Necozione, Stefano e14521 Nedergaard, Bettina S 5532 Nedzi, Lucien Alexander 7501, 7523 Needham, Charles Scott e17533 Needles, Burton M. 2006, 2051 Neefjes, Jacques 7581 Neely, Douglas 8607 Neerincx, Maarten 11087 Neese, Patrice TPS3118^ Neglia, Joseph Philip 9584, 10004, 10032 Negoro, Shunichi 5528 Negri, Federica 4112, e15086, e15502 Negrier, Sylvie 4574 Negron, Edris J. e16084 Negron, Vivian 5546 Negron, Viviana e11610 Nehaeva, Tatyana Leonidovna 3088 Neidhardt, Eve-Marie 10579 Neiman, Victoria e16023 Nejjari, Chakib e20516 Nekljudova, Valentina 610, 1082, TPS1137, TPS1141 Nelson, Alan e22031 Nelson, Edward L. 6632, 6633 Nelson, Garth D. 3523 Nelson, Megan e20626 Nelson, Peter 5071, e22212 Nelson, Rebecca A. 4579 Nelson, Sarah 2044 Nelson, Tyrrell 11004 Nemashkalova, Ludmila Anatolievna e16515 Nemec, Kathleen N. 3085 Nemer, Georges e12525 Nemeth, Hajnalka e15530 Nemsadze, Gia 629 Nemunaitis, John J. 2555, 2606, 3022, 3030, 3099, TPS3128, 8523, e15004, e16043 Neninger, Elia 3013, 3086 Neoptolemos, John P. LBA4004, 4006 Nepal, Barsha e14627, e17598, e20529 Nepal, Sujana e20610 Neradilek, Moni B. e12030 Neri, Eric 9504, 9532 Nerodo, Ekaterina Alekseevna e16512, e16513, e16514, e16515 Nerodo, Galina e16512, e16513, e16514, e16515, e16558, e22002


Nerurkar, Ashutosh 535 Nery, Lisa e20533 Nesland, Jahn M. 5533 Ness, Kirsten K. 10022, 10062 Nesselhut, Jan 3094 Nesselhut, Thomas 3094 Nestorovic, Milica 9557 Netchaeva, Maria e18511 Neto, Oseas Castro Neves e16058 Netto, Cristina e12546 Netto, George J. 4523, 4566 Neubauer, Andreas 7051 Neubauer, Hans 1030 Neubauer, Marcus A. 6580 Neuberg, Donna S. 5511 Neugebauer, Julia Katharina 638, 640, 11042, 11043, e22059, e22075 Neuger, Anthony 3026 Neugut, Alfred I. 6505, 6509, e15074 Neuhaus, Peter 4016 Neuhoeffer, Tanja 1082 Neumaier, Carlo Emanuele e22132 Neuman, Heather B. e14550 Neumann, Avivit e15597, e15598, e16068 Neumann, Frank e12554 Neumann, Stefan 1537 Neumann, Thomas e22031 Neumann, Ulf P. e14532 Neuner, Joan 6642 Neupane, Prakash e22048 Neurath, Markus F. 3561 Neuser, Petra 5531 Neuville, Agnes 10578 Neuwelt, Edward A. e13001 Neuwirth, Rachel 2528, 2547 Nevadunsky, Nicole 5592 Nevala, Wendy Kay e20003, e20046 Neven, Patrick 529, 553, 595, TPS651, 1078, e17520 Neveux, Nathalie e20535 Neville, Deirdre A. TPS3120 Neville, Kathleen 10028 Nevin, James E. 5587 Nevola Teixeira, Luiz Felipe e20634 New, Pamela Z. e13032 Newcomb, Lisa F. 5092 Newell, Mary 562 Newell-Price, John 4031 Newman, Edward M. 2526, 2564 Newmark, Joshua e17532 Newsome, Scott D. e22181 Newstead, Gillian 1506, 11084 Newton, Robert Charles 3025 Newton, Yulia 5006 Neyns, Bart 9046, 9053, 9059 Ng Tang, Derek 3043 Ng, Chaan S. e15612 Ng, David Chee Eng e15102, e15137 Ng, JoAnna e15097 Ng, Karen 11016 Ng, Kenneth K. 6034 Ng, Kimmie 4090 Ng, Matilda e19077 Ng, Matthew 2566, 2608, e15002 Ng, Quan Sing 8107, e20566 Ng, Raymond C. H. 2588, 6589,

9506, e20566 Ng, Sherry C. Y. e14530 Ng, Siobhan TPS5099^ Ng, Terence e20566 Ng, Terry L. e16074 Ng, Yuen Li 8107 Ng, Yvette e17510 Ngamphaiboon, Nuttapong e11508 Ngan, Hextan Yuen Sheung 5512 Ngan, Sam 10567 Ngarmchamnanrith, Gataree 3024 Ngeow, Joanne Y. Y. 1527 Nghiemphu, Phioanh L. 2055 Ngo, Vy 11048 Ngo-camus, Maud 2512 Nguyen Dang, Delphine M. 7541 Nguyen, Bich e15094 Nguyen, Binh 5572 Nguyen, Cang T. 3079 Nguyen, Danny e11582 Nguyen, Dao M. e22062 Nguyen, Diane Duyen Thuy e22052 Nguyen, Hoang Q. 7074 NGuyen, Jean-Michel e20022 Nguyen, Nathalie T. 2062 Nguyen, Paul Linh 5024 Nguyen, Quan 9611 Nguyen, Sa Thi Nguyen 1546 Nguyen, Suzanne 4046 Nguyen, Teresa T. 3545 Nguyen, Thi Xuan Quyen 5049^ Nguyen, Thierry 1122, e15607 Nguyen, Trung T. e13563 Nguyen, Tuan 8086 Ni, Grace 2568 Ni, Shujuan 8547, e14685 Nicacio, Leonardo V. TPS5100 Niccolai, Linda 1574 Nicholas, Martin Kelly 2076 Nichols, Craig R. 4503 Nichols, Francis C. 7502, 7524, e19013 Nichols, Gwen L. 10514, e13508 Nichols, Laura L. 3509 Nicholson, Andrew G. 7544 Nicholson, Jeremy K. e14620 Nicholson, Steve LBA9000, 9031 Nickel, Sebastian e20575 Nickles Fader, Amanda 5589 Nickman, Nancy A. e16091 Nickols, Nicholas George e13588 Nicodemo, Maurizio e15514, e19138 Nicolaije, Kim A. H. e16517 Nicolardi, Linda e15512, e20541 Nicolas, Patrick 1583 Nicolas-Virelizier, Emmanuelle TPS8615 Nicolau, Ulisses Ribaldo 6017, e14638 Nicoletto, Maria Ornella 5548 Nicolini, Franck E. 7001, 7048, 7066, 7073, 7088 Nicolini, Mario 8043 Nicoll, Jonathan 5 Nicolla, Jonathan 6506, 6516 Nicolson, Marianne 7514 Nicum, Shibani TPS5615 Nieboer, Peter 3502 Niederhagen, Manuel e15070 Niederle, Norbert 3586

Niedermeier, Michael Niederwieser, Dietger Niedobitek, Gerald Niedzwiecki, Donna

TPS1137 10508 3634 3611, 4022, 11011 Niegisch, Guenter 4524, 4525, 4539 Niehaus, Kate e12536 Nielsen, Dorte e14593 Nielsen, Hans J. e14710 Nielsen, Kaspar 4052 Nielsen, Kirsten Marie e15099 Nielsen, Matthew Edward 4522, 6530, e15507 Nielsen, Ole Steen 10570 Nielsen, Patricia Switten 5532 Nielsen, Soren e11507 Nielsen, Svend Erik 3572, 4052, e14677 Nielsen, Torsten O. 506 Niemierko, Andrzej 9064 Niepomniszcze, Jose Leonardo e20715 Niermann, Kenneth J. 6049 Nieroda, Carol Ann e15123 Nies, Christoph e14562 Niessner, Heike e20050 Niesvizky, Ruben 8514, 8529 Niethammer, Andreas G. 3090 Nieto Garcia, A. e22073 Nieto, Antonio 5566, 10517 Nieto, Yago 7011 Nietsch, Josef 6591 Nieuweboer, Annemieke J. M. 2597 Nieuwenhuijzen, Grard A. P. LBA1001 Nieva, Jorge J. 6047, 7509, 8109, e17533 Nigam, Rita 3030 Nihei, Naoki e15521 Niho, Seiji 7512, 7557, 8037, 8078, e19076 Nii, Kazuhito e22108 Niikura, Naoki e22064 Nikcevich, Daniel A. 4026 Niki, Toshie e19153 Nikipelova, Elena A. e14701 Nikkhah, Guido TPS2103 Nikolai, Michele e13047 Nikolic, Srdjan e14676 Nikolinakos, Petros G. TPS659 Nikolova, Tanya e20677 Nilsson, Sten 5038 Nimako, Kofi e19007 Nimeiri, Halla Sayed 3540, e14711 Nimi, Tatsuya 5046 Nimunkar, Amit J. 9635 Ninane, Vincent 7541 Ning, Yan 2501, 3557, 3565, 3566, 3567, 3568, 4110, 4111, e14538, e14543, e14714, e15009, e15022 Ning, Yangmin M. e16017 Ning, Yaoyu 10509 Ning, Yi 7049 Niolat, Julie 4504 Nipp, Ryan David 9560, e17521 Nippgen, Johannes 3008 Niraula, Saroj 5025 Nirmalanandhan, Sanjit e18523,

e22048 e19016 e15054 10503, 10539, 10551 Nishida, Yasunori 4096 Nishihori, Taiga 8608, e19516 Nishikawa, Atsushi 1124 Nishikawa, Kazuhiro LBA4002, 4096, 4102 Nishikawa, Kazuo e20585 Nishikawa, Ryo 2002^, 2005^, 2023^ Nishikawa, Shingo e18564, e19083 Nishimura, Kazuhiko e14651 Nishimura, Kazuo e15588 Nishimura, Masato 5528 Nishimura, Mashiho e20717 Nishimura, Naoki 9629 Nishimura, Reiki 1106, 1116, e11557, e13536 Nishimura, Ryuichiro 5526, 5537 Nishimura, Sadako 5537, 5590 Nishimura, Seiichiro 1534 Nishimura, Takafumi e15054 Nishimura, Taku 3006 Nishina, Tomohiro 4075 Nishino, Kazumi e19010^, e19153 Nishino, Koji e12540 Nishino, Mizuki e19125 Nishio, Kazuto 7518 Nishio, Koujiro e15579 Nishio, Makoto 7556, 8033, TPS8119, e13504 Nishiyama, Akihiro e19017, e19023, e19040 Nishiyama, Kenichi 7529 Nishiyama, Yasuyuki e11557, e13536 Nishiyama, Yukihiro 3099 Nissan, Aviram e14500 Nissen, MaryJo e20560 Nissim, Ouzi e13002 Nitsche, Dieter 3643 Nitz, Ulrike TPS655^, 1092, e20616 Niu, Chao 3031 Niu, Chongya 9536, 9551, 9595 Niu, Jiangong 6630 Niu, Qun CRA1501 Niu, Xiaomin e19014 Niu, Zhimin e20692 Niwakawa, Masashi 4526 Nix, Jeffrey 4584 Nixon, Andrew B. 4042, 4520, 11011, 11036 Niyonzima, Nixon 6578 Njanang, Freddy-Joel 1101 Njei, Basile M. 4546 Noal, Sabine 9510 Nobel, Leila e14637 Noberasco, Cristina 4121 Nobes, Jenny 3018, LBA9000 Nobuoka, Takayuki e15060 Nocent-Ejnaini, Cecilia e19078 Noda, Kiichiro 5506 Nodin, Bjorn 3579, e14580 Noe, Allard e15525 Noe, Dennis A 2555 Noe, Jeanne 512 Nishida, Chinatsu Nishida, Naoshi Nishida, Toshirou

Noel, Mary Noergaard, Henrik Nogal, Ana Nogales, Esteban

e13047 e14593 e22045 e22073, e22091, e22131 Nogami, Naoyuki 8033, 9621, e19040, e19054 Nogaret, Jean-Marie e12008 Nogawa, Takayoshi 5537 Nogova, Lucia 1589, 8112, e12517 Noguchi, Emi e20557 Noguchi, Masayuki 8037 Noguchi, Shinzaburo LBA509, 553, 557, 558, 561, e20510 Nogueras-Gonzalez, Graciela M. e16038 Nogues, Catherine 1528, TPS1607 Noh, Dong Young 551, 1039, 1128 Noh, Dong-Young e22063 Noh, Sung Hoon 4113, e15144 Noh, Yook-Hwan 2565 Noize, Pernelle e14514, e14542 Nokihara, Hiroshi 7540, 8064, 8105, 8108, e13504, e13511 Nol-Boekel, A. 2536 Nolan, Cathy E. 7018, 8520 Nolan, Craig 2095 Noldus, Joachim 9580 Nole, Franco e22078 Noma, Kazuhiro e15161 Nomizu, Tadashi 1534 Nomura, Hiroyuki 5590 Nomura, Shogo 2559 Non, Lemuel e22049 Nonomura, Norio 9623 Nooijen, Peet e14629 Nooka, Ajay K. 7035, 8540, 8584, 8609 Noonan, Anne M. 2514 Noonan, Krista e19039 Nor, Aiman Mohd 3627 Nora, Richard E. e20698 Norberg, Adam S. e20044 Norden, Andrew David 2013, 2030, 2075, TPS2104 Nordle, Orjan 3073, 5081 Nordlinger, Bernard 3531 Nordstrom, Jeffrey L. 3004 Normanno, Nicola e14565 Normolle, Daniel Paul 7577 Noronha, Vanita 6085, e12520, e17027, e19095, e19118, e20678 Norris, Dan 8523 Norris, LeAnn B. 5091, e22181 North, Marie- Odile e20032 North, Scott A. 4565, 4578, 4586, 5009, 5042, e15503, e15518 North, Susan E. e15023 Northfelt, Donald W. 521, 522, TPS2621, 6527, 9508, e16065 Northover, John 3500 Nortier, J. W. R. 595, 597, 1028, e22106, e22152 Norton, Isaiah 1132 Norton, Larry 507, 630, 1007, TPS3120, 6508, e22148 Norton, Nadine 521, 522 Norvell, Max 6539 Noryk, Dzmitry 629

Nosaka, Kisato 8506 Noshiro, Hirokazu 4096 Nosov, Dmitry 4564, 10501^ Nota, Nienke M. 1072 Noto, Laura e19086 Nott, Louise M. TPS3649, TPS4157, e14583, e14640 Nourbakhsh, Ali 8586, 8596 Nouriani, Bita 9504, 9532 Noursalehi, Mojtaba 5026 Nouso, Kazuhiro e15161 Novak, Anne 8538 Novello, Silvia LBA8005, LBA8011, e19138 Novick, Steven C. 10501^ Novik, Alexey Viktorovich 3088 Novik, Yelena 1042, TPS3122 Novikova, Inna Arnoldovna e16558 Novoa, Robert 7036 Novotny, Jan 3575 Novotny, Jr., Jim 3016 Novotny, Paul J. 9513 Novy, Diane M. e20568 Nowak, Anna K. 2017 Nowak, Frederique 1528, 8000 Nowroozi, Sasan e20036 Noy, Ariela 8524, 8571 Noyes, David 3091 Noyes, Katia 9549 Nozaki, Isao TPS4152 Nozawa, Masahiro e16092 Ntalageorgos, Themis e12526 Nucera, Carmelo e17014 Nucifora, Martina e14536 Nuciforo, Paolo 3012, 8070 Nuding, Benno TPS655^ Nuernberg, Dieter e14513, e14562 Nugue, Pedro B. e18548 Nukiwa, Toshihiro 7530, e19142 Numico, Gianmauro 4091, e18522 Nunes, Raquel 11054 Nuñez, Isaac e16045 Núñez, Juan A. e18558 Núñez, Marlene 4555 Nunez, Omar 572 Nunez, Patricia e22060 Nussey, Fiona 5571 Nutt, Stephanie 9608 Nutting, Charles W. e14545 Nutting, Christopher 4 Nuzzo, Carmen e15057, e21517 Nuzzo, Gennaro 4129 Nwizu, Tobenna Igewonu 6061 Nwogu, Chukwumere E. 1566, 1603, 4067 Nyakas, Marta 9004, 9028 Nyalendo, Carine 10048 Nydegger, Jennifer L. 1515 Nygaard, Anneli Dowler e19163 Nyman, Jan 7500 Nzokirantevye, Axelle 10573 Nägele, Virginie 7020

O O Connor, Miriam O Mullane, Denise O Suilleabhain, Criostoir O Sullivan, Roisin O’ Keeffe, Jo ABSTRACT AUTHOR INDEX

e16550 3627 e14519 3627 3627 761s

O’ Riordan, Lynda e13049 O’Boyle, Erin 9626, e20518, e20539, e20569, e20587 O’Briant, Kathy e22178 O’Brien, Cathal e19064 O’Brien, James P. 5520, 5591, 9026, 9058 O’Brien, Mary 7584, 7585, 9503, e19007, e19146^ O’Brien, Maureen Megan 10003, 10007 O’Brien, Michelle e13019, e19015 O’Brien, Neil A. 1054 O’Brien, Patti TPS3647 O’Brien, Paul E. 6029 O’Brien, Shalana e13556 O’Brien, Susan Mary 7005, 7024, 7090, 7092, 7095, 7102, TPS7133, TPS8619 O’Brien, Tim S. 4508 O’Bryan-Tear, C. Gillies 5021, 5060, 5068, 5080 O’Byrne, Kenneth John 7514, e15142, e19064 O’Callaghan, Christopher J. 3528, 4053, TPS4157 O’Cearbhaill, Roisin Eilish 5550 O’Connel, Rachel TPS5614 O’Connell, Casey Lee 7116 O’Connell, Colleen 10066 O’Connell, Joseph P. TPS8123 O’Connell, Joseph 2568 O’Connor, Derbrenn 1115 O’Connor, Erin S e14550 O’Connor, Miriam 598, e14515, e20550, e20687 O’Connor, Owen A. 8507, 8575, TPS8611 O’Connor, Robert e11536 O’Connor, Stephen 9550 O’Connor, Tracey L. 2594, e11508 O’Connor, Tracy 3057 O’Day, Steven 9026, 9053, 9058, 9059, TPS9103 O’Donnell, Elizabeth 4561 O’donnell, Lynellen e20030, e20038 O’Donnell, Patrick e22092 O’Donnell, Paul V. 7006 O’Donnell, Peter H. 4524, 4527^ O’Donovan, Norma 632, 1054, 1066 O’Driscoll, Lorraine 620, e11520 O’Dwyer, Peter J. 519, 3025, 4063, e14561, e14711, e15564 O’Farrell, Niamh e15142 O’grady, Anthony 3549 O’Hanlon, Deirdre 1115 O’Hare, Thomas 7063 O’Kane, Grainne 10530, e12533 O’Keane, Conor 10530 O’Keefe, Graeme J. 2583 O’Keefe, Jo 1115 O’Keeffe, Bridget e16018 O’Keeffe, Carmel e20550 O’Keeffe-Rosetti, Maureen Cecelia 6018 O’Leary, Erin 5586 O’Leary, James J. 2573 O’Mahony, Deirdre 10588 O’Malia, Joanne 1558, 11050 O’Malley, Martin e15510 762s

O’Neil, Bert H. 2595, 3587, e14522 O’Neill, Allison Frances 10071 O’Neill, Anne M. 6088, 9508, 9530 O’Neill, Anne 6527 O’Neill, Brian 3549 O’Neill, Eric 11115 O’Neill, Fiona e11536 O’Regan, Kevin N. e14519 O’Regan, Ruth 505, 562, TPS650^, 1007, e11582 O’Reilly, Aine e14519 O’Reilly, Derek TPS4146 O’Reilly, Eileen Mary 4017, 4022, TPS4144, e15012, e20586 O’Reilly, Seamus 598, 3575, 5515, e13020, e14519 O’Riordan, Lynda M. e13019, e13022 O’Rourke, Colin 1508 O’Shannessy, Daniel J. 1037 O’Shaughnessy, Joyce 563, 590, 593, 596, 1087, TPS1142^, e11543, e17570, e20616 O’Sullivan, Adrian e14519 O’Sullivan, Brendan 11094 O’Sullivan, Gerard J. e20008 O’Sullivan, Joe M. 5068 O’Toole, Gary 10530 O’Toole, Sandra 1053 Oades, Grenville 4508 Oades, Kahuku 11108 Oakley, Gerald 2089 Oaknin, Ana 3 Oates, Jacqueline Rose e14616 Oba, Koji 3516, LBA4002 Oba, Mari Saito 10050 Oba, Shigeyuki e19153 Obara, Wataru e15587 Obasaju, Coleman K. LBA8003, 8012, e19150, e20629 Obeid, Elias 1506, 11021, 11035, 11084 Obel, Jennifer Carrie 3007 Ober, Angelika 1082, TPS1137, e22075 Oberg, Ann L. 5546 Oberg, Kjell E. 4031 Oberlin, Odile 10031 Oberstein, Paul Eliezer e15074 Obertova, Jana 4556, e15599 Oblitas Alca, George e22060 Oblitas, George e16521 Obrador, Antonia 10532 Ocana, Alberto 539, e22000, e22015 Ocean, Allyson J. e14517, e15089, e15600, e20549 Ochiai, Atsushi 4019, 4075, e22082 Ochiai, Kazunori 5506 Ochiai, Takumi e14651 Ochoa-Bayona, Jose L. 8608, e19516 Ochs-Balcom, Heather 1603 Ochsenbein, Adrian 7503, 8060 Ochuwa, Nwabugwu e15551 Ocio, Enrique M. 8522 Ockert, Detlev 3538 Ocon-Revuelta, Elisa M. e15533 Ocvirk, Janja 3521 Oda, Hisanobu e15170


Oda, Katsutoshi Oda, Kyota Odabas, Hatice Odabasi, Hatice Odarchenko, Petro oden-Gangloff, Alice Odonye, George Odunsi, Kunle Oechsle, Karin Oeffinger, Kevin C.

e16519 9637 e11540 e15100 629 3614 1576 3030, 5574 4559 630, 10019, 10032, 10062 Oelschlager, Kristen M. 7605, 9022 Oesterlind, Kell 3572 Oettel, Kurt R. e18537 Oettle, Helmut TPS3119^, 4016 Offiong, Richard 1576 Offit, Kenneth 1500, 1511, 1552, 1554, 1555, 4082, 7558, e12527, e12536, e12555 Offit, Lily 1552 Ogara, Sue e13518 Ogata, Haruki 1047 Ogata, Yoshitaka e19010^ Ogata, Yutaka e14633, e14684 Ogawa, Atsushi 10050 Ogawa, Haruki 5538 Ogawa, Miho e20717 Ogawa, Osamu e15588 Ogbata, Obiageli Uchenna 9619 Ogbonna, Celestine C. 1576 Ogburn, Emma TPS667 Ogden, Angela e20521 Ogden, Janet 2530 Ogden, Lorna 599 Ogg, Robert J. 10034 Ogiya, Akiko e22190 Ogliosi, Chiara e15512 Oguchi, Masahiko e17006 Ogura, Kaoru e11604, e12026 Ogura, Mariko 4108, e15105 Ogura, Michinori 2574, 8551 Ogura, Takashi e19054 Oguri, Senri 6060 Oh, Do-Youn 3550, 4044, e15066 Oh, Jae Hwan e14504, e14606 Oh, Ji-Eun 1540 Oh, Jisu 2565 Oh, Kevin S. 9064 Oh, Sang Cheul 4021, 4113 Oh, Seong Taek e14650 Oh, Shiaki 7575, e18549 Oh, Sung Tae 10550, e15091 Oh, Sung Yong e19156 Oh, William K. 3014, 5015, 6540, 6613, 9080, e16032 Ohara, Toshiaki e15161 Ohashi, Haruhiko e19521 Ohashi, Rina e19043 Ohashi, Toshio e16090 Ohashi, Yasuo 3535, 4008, 5506, 8058, 11049, e20609 Ohde, Sachiko e20590 Ohde, Yasuhisa 7572, 7599, e18556 Ohe, Yuichiro 7512, 7557, 8033, 8064, 8078, e19076 Ohi, Masaki e22205 Ohishi, Masahiko e13506 Ohishi, Susumu e15179 Ohkawa, Shinichi e15109, e15116 Ohki, Shinji 3063

Ohkubo, Toshiki Ohlmeyer, Michael Ohmae, Masatoshi Ohmatsu, Hironobu

2559 9091 6096 7512, 7557, 8078, e19076 Ohmori, Tohru e19164 Ohnishi, Tsukasa e19164 Ohno, Izumi 2559, e15031 Ohno, Kouichi 3638 Ohno, Shinji 571, 613, 1048^, e12011 Ohnuma, Hiroyuki e15060 Ohori, Hisatsugu e14597 Ohr, James 3099, 6043 Ohremenko, Natalya V. e16514 Ohri, Nitin 4093 Ohsugi, Jun e19162 Ohsumi, Shozo 1124, 1534, 3082, 6588 Ohta, Keiichiro e20591 Ohta, Mitsunori 7518 Ohta, Shigeyuki e15579 Ohtake, Shinji e16098 Ohtani, Shoichiro 613, TPS654, 1048^, 6588 Ohto, Hitoshi 3063 Ohtsu, Atsushi 4074, 4075, 4109, TPS4150, 11031, e13500, e13510, e14527, e22082 Ohtsuka, Masayuki 4056 Ohuchi, Noriaki e12532 Ohue, Masayuki e14555 Ohyama, Chikara e15565 Ohyanagi, Fumiyoshi 7556, 9621, e13504 Oidtman, Jessica 1572 Oikonomopoulos, Georgios 11117 Oishi, Keiji e19008 Oishi, Masakatsu e15531 Oizumi, Satoshi 3072 Oja, Conrad D. 1033 Ojeda, Belen 503, 537 Ojha, Rohit P. 6559 Ok, Engin e17529 Ok, Oh-Nam 637, 1088 Oka, Masaaki 3006 Oka, Takako e19053 Okabayashi, Koji e11598 Okabe, Hidetoshi 4092 Okabe, Hiroshi TPS4152 Okabe, Naoyuki e19162 Okada, Hideaki 8056 Okada, Hideho e22017 Okada, Hiroshi e15579 Okada, Morihito 7518, 7583, 11111, e18563, e20510, e22053, e22113 Okafor, Amaka e20523 Okamoto, Akiko e15565 Okamoto, Hiroaki 8054 Okamoto, Isamu 7518, 8056, e19165, e20004 Okamoto, Norio e19021 Okamoto, Wataru 4072, e13501, e20004 Okamoto, Yasuhiro 10050 Okamura, Daiki 4056 Okamura, Tatsuru e18524, e19133 Okaniwa, Masanori e13529 Okano, Gary J. e16091 Okano, Tetsuya e19142 Okano, Yoshio 8006

Okazawa, Hidehiko e16502 Okcu, M. Fatih 10009 Okeya, Masayuki e15159 Oki, Eiji 1056, e14633, e15039, e15158, e15173 Oki, Masahide e19005 Oki, Yasuhiro 7070, 8502, 8518, 8561 Oki, Yasunari e19164 Okigami, Masato e22205 Okines, Alicia Frances Clare 4020 Okishio, Kyoichi e18530 Okita, Natsuko 3559 Okoh, Alexis K. e11537 Okoroji, Grace-Julia 8561 Okoronkwo, Nneoma Olivia e14625, e14661, e14681 Oksuzoglu, Berna e11559, e15110 Oksuzoglu, Omur Berna e15175, e18510 Oktay Tanyildiz, Gulsah 10068 Oktem, Ozgur e22004 Okubo, Fumie e11604, e12026 Okubo, Satoshi e14651 Okuda, Hiroyuki 4072 Okuda, Kentaro e19164 Okugawa, Yoshinaga e22205 Okuma, Yusuke e18524, e19133 Okumura, Yasuhiro 1106, 1116 Okuno, Kiyotaka 3006 Okuno, Scott H. 6095, 10521, 10531, TPS10591 Okuno, Tatsuya e15016, e15031 Okusaka, Takuji 4120, e15031, e15116 Okutani, Yukihiro 3535, 11049 Okuyama, Hiroyuki 2559 Okuyama, Takako e19153 Okwan-Duodu, Derick 8546 Olagunju, Andrew Toyin e20675 Olagunju, Tinuke Oluwasefunmi e20675 Olajide, Oludamilola A. 2595 Olaniyan, Olayinka 1576 Olarte, Alicia e19112 Olawaiye, Alexander 5585 Olawoye, Olayinka Adebanji e20000 Oldenburg, Jan 4562 Olencki, Thomas e20018 Olgiati, Angelo e20647 Olgunus, Ozlem e19071 Oliner, Kelly S. 3511, 3617, 3620, 3631, 6029 Olinski, Ryszard e22197 Oliva, Cristiano 10572 Oliva, Stefano 631, e11556 Olivares, Robert e12554 Oliveira, Aline Crisitna Conceicao e22176 Oliveira, Camila Borges Martins e11551 Oliveira, Celia Tosello 508 Oliveira, Giacomo 7007 Oliveira, Juliana e22074 Oliveira, Leandro Nascimento e18515 Oliveira, Mafalda 547, TPS665 Oliveira, Maria de Lourdes e14568 Oliveira, Mario e15172 Oliveira, Nivia Fernanda e22176

Oliveira, Pedro Oliveira, Renato Guedes

e19069 10057, 10065 Oliveira, Tatiane M. G. e12007 Oliveira, Thiago Bueno 6017 Olivera, Mivael e16539, e17010 Oliveras-Ferraros, Cristina e19003, e19159 Oliverius, Martin 11051 Olivier, Kara M. 4512 Olivieri, Eloisa e14688 Oliviero, Gerard e19058 Olivo, Martin S. 1049^, 1050^, 1055^ Ollier, Jean Claude 3560 Ollila, David W. 501 Ollila, David 500 Olmos, David 2600, e16000 Olocco, Ricardo e13036 Olopade, Olufunmilayo I. CRA1501, 1506, 1530, 11021, 11035, 11084 Olow, Aleksandra E 10060 Olowokere, Idowu Emmanuel 5606 Olschwang, Sylviane 511, 1528, 3596 Olsen, Kerry D. 6095 Olsen, Mark R. 8004, 8012, e19150 Olsen, Steven 645 Olson, David C. e14642 Olson, Erin Macrae 1023 Olson, Jeffrey J. 2054 Olson, Kari e19015 Olson, Kevin Donald e20668 Olson, Lawrence Karl e13047, e13048 Olson, Richard D. 2575 Olson, Robert Anton e20589 Olson, Tim 6629, e17579, e17581, e17582 Olson, Walter C. TPS3118^ Olson, William C. e16007 Olsson, Carl A. e16076 Olszanski, Anthony J. 2519, 2547, 11092 Olszewski, Adam J. 8075, 8549, 8550, 9051, e15095 Oluwasola, Abideen Olayiwola e20000 Oluwole, Olalekan O. 8605, e19539 Olver, Ian N. e17587 Omar, Walaa 3083 Omarini, Claudia 556 Omary, Reed A. e22204 Omel, James 8592 Omeroglu, Atilla 1018 Omi, Hideo TPS3116 Omlin, Aurelius Gabriel 2513, 4511, 5049^, 5052 Omori, Takeshi 10539 Omoto, Itaru e20556 Omuro, Antonio Marcilio Padula 2012, 2015, 2032, 2057, 2095, 2518 Onar-Thomas, Arzu 2036 Onaru, Koichi 11041 Onate-Ocana, Luis F. 4555 Ondet, Valérie e16089 Ondovik, Michael S. 8531 Ondrus, Dalibor 4556, e15599 Onega, Tracy 559

Onetti-Muda, Andrea 576 Ong, Anna 4014 Ong, Caroline e17597 Ong, Michael 2535, 2580, 4511 Ong, Teng Jin 2097, e22085 Ong, Whee Sze 6618, 9509, 9552 Onikubo, Toshihide 9637 Onitake, Yoshiyuku 10038 Onners, Beth 4040^ Ono, Akira 7529, 7572, 7582, 7599, e18556, e19050, e19074 Ono, Mayumi 11027 Onodera, Manabu e14604 Onoe, Shunsuke 4119 Onofri, Azzurra e14560 Onozawa, Yusuke e11563, e14623 Onstenk, Wendy 11045, e22106 Ontko, Mary TPS9647 Onukwugha, Ebere 9599, e14524, e16027, e16034 Onur, Handan e20655 Oochi, Takafumi e14684 Ooi, Wei Seong 6589, 9506, e20566 Ooki, Akira 4075 Oostendorp, Linda J. M. e20583 Oosterkamp, Hendrika M. 2001, 5544 Oosterom, Ilse e15012, e20653 Opat, Stephen 7004 Opdam, Frans 595 Operana, Theresa N. e19072 Opitz, Isabelle 7526, 7587 Opocher, Enrico 4129 Opper, Chris 6538 Opplinger Leibundgut, Elisabeth 8060 Oprea, Corina 5516 Opyrchal, Mateusz e13516 Oran, Betul 7010, 7011 Oratz, Ruth TPS3122 Oravcova, Eva e22023 Ordonez, Esther 2600 Ordonez, Jose Manuel 2087 Orecchia, Sara e14657 Orell, Emily 1021 Orem, Jackson 6578, 10070 Orford, Keith W. 3507 Orgiano, Laura 603, e20556 Orito, Etsuro 10543 Orkin, Stuart 10536 Orlandi, Francisco Jorquera 5002 Orlandi, Paola 1086, 3602, 3603, e14577 Orlando, Laura 618, e14605, e18545 Orlemans, Everardus O. 2617 Orlov, Sergey LBA8011 Orlowski, Robert Z. 8515, 8592 Orodel, Oana 5595 Orr, Andrew C. 10066 Orr, Christine 1593 Orr, Maria 5505 Orringer, Mark 7522 Ortega Granados, Ana Laura e12513 Ortega, Alberto e13543 Ortega, Carolina e19000 Ortega, Cinzia e15528, e16031, e16099 Ortega, Jose Luis e19505, e19510

Ortega, Luis 4140, 10529, 10532 Ortega, Vanessa e12558 Ortega-Parra, Camilo A. e13539, e19155 Ortendahl, Jesse e15104 Ortiz Lopez, Rocio e14708, e22016 Ortiz, Eduardo 1073, 11118 Ortiz, Karen e19505 Ortiz, Maria Jose e11530 Ortiz-Urda, Susana e20010 Ortmann, Olaf TPS11124 Ortner, Petra Angelika 6591 Ortuzar, Waldo Feliu LBA8003 Oruezabal, Mauro e19000 Orui, Hayato e18557 Orvoen, Galdric e17514 Ory, Catherine 6055 Orzalesi, Lorenzo LBA1001 Osaka, Wakako e20590 Osako, Tomofumi e11557, e13536 Osann, Kathryn 6632, 6633, e16518 Osarogiagbon, Raymond U. 1067, 7569, 8080 Osborne, Joseph 11081 Osborne, Stuart 3521, 3604 Osei-Boateng, Kwabena 2070, 2096, 9086, e15537 Oshima, Takashi 4068 Oshiro, Takashi 3516 Oshita, Fumihiro 7531, 8037, 11055 Osinaga, Eduardo e14682 Oskay-Özcelik, Gülten 5569, e20670 Osman, Iman 9021, 9023, 9054, 9067, 9089, 9091 Osman, Nemer e19064 Osman-Garcia, Ignacio e15533, e15550 Osorio, Cynthia A. B. T. e22154 Osowiecki, Michal e19535 Ospovat, Inna e20039 Ossenkoppele, Gert J. 3029 Ostashko, Anton 3015 Ostellino, Oliviero 6038 Österborg, Anders 7087 Osterlund, Pia J. 3604 Ostermann, Thomas e20623 Ostermeier, Nicola 3561 Ostman, Arne 3571, 3597, 11097 Ostoros, Gyula e19090^ Osumi, Hiroki e15105 Osunkoya, Adeboya O. e15617 Ota, Shuichi e19507 Otegbeye, Ebunoluwa 1511, 1552 Otero, Antonio V. e17558 Otero, Jorge Miguel e22028 Othman, Edress 1512 Othus, Megan 7028 Oton, Ana Belen e18032 Otoshi, Takehiro 8098, e19045 Otranto, Isabella 5522^, e16510^ Otremba, Michael 6042, 6076 Otsu, Satoshi e14527, e20585 Otsuji, Toshio 3535, e14601 Otsuka, Kojiro 8098, e19045 Otsuka, Kyoko 8098, e19017, e19045 Otsuka, Tomoyuki e19021 Ott, Miles 6590, e20543 ABSTRACT AUTHOR INDEX

763s

Ott, Patrick Alexander TPS3107 Ottaiano, Alessandro 11008 Ottaviani, Davide 10572, e19084 Ottaviano, Margaret 7603, e18536, e21500 Otte, Melanie 4086 Ottensmeier, Christian H. H. 9068 Ottensmeier, Christian 3018, 7595, 9031, 9078 Otterson, Gregory Alan 7506, 7542, 8114, 9600 Ottesen, Rebecca A. 1006 Ottevanger, P. B. e20583 Ottillinger, Bertram e20563 Ottman, Susan 1023 Otto, Geoff 1009, 9002, 10513, 11020, 11100, e22146 Ottstadt, Martine 4065 Oturai, Peter Sander e20561 Ou, Sai-Hong Ignatius 7565, 8032, 8083, e13558 Ou, Wei 7519 Ouafik, L’houcine 2024, 7117, 8000 Ouali, Monia 10570 Oudard, Stephane LBA4509, 5011, 5063, 5079, 5567, e12504, e16009, e16010, e16089 Oude Munnink, Thijs H. 2050 Oue, Takaharu 10038 Ouellet, Danielle 9066 Oumzil, Khalid e16067 Ousager, Lillian Bomme 6600 Ouyang, Fangqian e15548, e15551, e15552 Ouyang, Pamela 1572 Ovchinnikova, Elena G. e20593 Oven Ustaalioglu, Bala Basak e15117 Oven Ustaalioglu, Basak e12037 Oven, Basak Bala e22061 Overkamp, Friedrich TPS3124^, 4009, e14532 Overman, Michael J. 3512, 3529, 3600, 3612, 3632, 4133, 4134, e14567, e20664 Overmoyer, Beth 1105, TPS1134, e17574 Ow, Samuel Guan Wei 1535 Owada, Yuki e19162 Owaki, Toshihiro 10543 Owen, Carolyn 7004, TPS7131 Owen, Kate TPS2626 Owen, Laurie e13566 Owen, Scott Peter e19037 Owonikoko, Taofeek Kunle 2610, 6083, 6611, 7560, e14612, e19094, e20608 Owusu, Cynthia 6525, 9545 Owzar, Kouros 4022, 5509, 6501, 11011, 11053 Oxnard, Geoffrey R. TPS1606, 8077, 8085, e19121 Oya, Mototsugu e15527, e16094 Oyakawa, Takuya e19074 Oyama, Ryo e13500 Oyama, Takashi 8551 Oyama, Yu e14670 Oyan, Basak e20723 Oza, Amit M. 2505, TPS2622, 3030, 5508, 5517, 5518, 5541, 5547, TPS10593, 11002, e20639 764s

Ozaka, Masato

4108, e15031, e15105 Ozawa, Yuichi e20658 Ozaydin, Nilufer e12545 Ozaydin, Sukru e15623, e18016 Ozcan, Muhit 7038, e18009 Ozdemir, Evren e15623 Ozdemir, Nurıye Yıldırım e15110 Ozdemir, Nuriye e14662, e14705, e15175, e18510, e19107, e20614 Ozdener, Fatih e17529 Ozdogan, Mustafa e14683, e14696, e20006 Oze, Isao 4076, e19023, e19167 Ozeki, Mizuharu e14510 Ozen, Mehmet 7038, e18009, e18010 Ozen, Ozlem e16526, e16528, e16536 Ozer, Howard e14578 Özer-Stillman, Ipek e15601 Ozeri, Delrose e20645 Ozet, Ahmet e14533, e15623 Ozet, Gulsum e15623 Ozguroglu, Mustafa 505, 5063 Ozisik, Yavuz Yasin e11553 Ozisik, Yavuz e11595 Ozkan Gurdal, Sibel e12545 Ozkan, Efe 7542 Ozkan, Metin e11559, e14672, e14695, e14705, e18516, e19107, e20603 Ozkara, Selvinaz e22061 Ozkok, Hale Basak e17019 Ozkok, Serdar e18540 Ozmen, Vahit e12545, e17529 Ozono, Seiichiro e15568 Oztop, Ilhan e14533, e18546, e19107 Oztuna, Derya Gokmen 10068 Ozturk, Akin e19127 Ozturk, Banu e14662 Ozturk, Bekir e15623 Ozturk, Bengi 7038, e18009 Ozturk, Erman e18014 Ozturk, Mehmet Akif e14660, e20723 Ozturk, Mustafa e15623, e18016 Ozturk, Selcuk Cemil e14533 Ozyar, Enis e11539 Ozyoruk, Derya 10068

P Pérez, Dana P, Cantizani Pabst, Thomas Paccagnella, Adriano Paccagnella, M. Luisa Pace, Daniele Pace-Emerson, Tamara P. Pacheco, Christian Pachmann, Katharina Pachter, Jonathan A. Pachter, Jonathan A. Pacilio, Carmen Pacini, Furio Paciolla, Immacolata Paciorek, Alan T Pack, Svetlana


e19068 e14559 8560 6003 2574 e22132 10036 e12538 e22201 e18541 e13523 e11556 4 e11528 5024 7513

Packer, Roger 2035 Padbury, Rob 1581, 3592 Padbury, Robert 6598 Padeano, Marie-Martine 1114 Padhiar, Amie 636 Padhye, Nikhil S e20528 Padrini, Robeto e13514 Padron, Eric 7113 Padval, Mahesh TPS2620, e13523 Paepke, Stefan 581, TPS1138 Paesmans, Marianne 528, 575, e12008 Páez, David e14541 Paganelli, Giovanni TPS649 Page, Elizabeth 5054 Page, Ray D. 4504, e19038 Pageaux, Georges-Philippe 4028 Pagel, John M. 7018, 8520 Pagliaro, Lance C. LBA4500, 4517, 4528, e15575 Pagliarulo, Arcangelo e16081 Paglino, Chiara 4575 Pahernik, Sascha TPS4591 Pahwa, Punam 3580 Pai, Lori H. 1584 Pai, P. S. 6085 Pai, Sara I. 6013, CRA6031 Paice, Judith A. 3540 Paietta, Elisabeth 7126 Paik, Chang 11083 Paik, Paul K. 7559, 7600, 8022 Paik, Soonmyung TPS657, TPS1139 Paillusson, Alexandra 9014 Pain, Scott 2561^ Paintaud, Gilles 2599, 3606 Paithankar, Mahesh 577 Paiva, Bruno 8511 Paiva, Henrique Soares e20680 Paiva, Tadeu Ferreira 6017, 11038 Pajares, Bella 1031 Pajares, Isabel e21509 Pajic, Marina e15029 Pak, Yvonne 8574 Paker, Nurcan e22061 Pal, Navdeep 2611, 5521, 5584, 5596 Pal, Raveen 6625 Pal, Sujoy TPS4162 Pal, Sumanta Kumar 4525, 4565, 4571, 4578, 4579, 4586, TPS4593, e15500, e15504, e15511, e15518, e15522, e15538 Pal, Tuya e12556 Pala, Cigdem e18014 Palacios Ozores, Patricia 5603 Palacios, Daisy Maria 6091, e17030 Palacios, Gemma 555 Palacka, Patrik 4556, e15599 Palaia, Raffaele 11008 Palasamudram Shakar, Saketh e20664 Palassini, Elena 10565, 10568, 10576 Palazzini, Simonetta e13579 Palazzo, Felipe e20514 Paleologos, Nina 2019^, 2076 Palesandro, Erica 10552, 10583 Palesh, Oxana 9061, 9504, 9532, 9533, 9572, TPS9647, TPS9651, e20026

Paley, Carole S. 7122, 8531 Palisaar, Jueri 9580 Palka, Magda e19532 Palla, Shana L. 9642, e20664 Palladini, Giovanni 8545 Palladino, Maria Angela 9614 Pallares, Cinta 2581, 11078 Pallaud, Celine 2023^ Pallier, Karine e22001 Pallis, Athanasios G. 7584, 7585 Pallisgaard, Niels e19163 Pallotti, Maria Caterina 10540, e21511, e21523 Palma, David 7520, e19120 Palma, Gabriel Lopes e13003 Palma, Norma Alonzo 8020, 11020, 11068 Palmas, Marco 9512, LBA9514, e20716 Palmer, Daniel H. 4006, TPS4160, 4518, e15085 Palmer, Edwin 6025 Palmer, Gary A. 1009, 2545, 8020, 10577, 11000, 11020, 11068, 11100, e15035, e22086 Palmer, Hector G. 4135, 8070 Palmer, J. Lynn e20626 Palmer, Jeanne M. 6586 Palmer, Joycelynne 8556 Palmer, Michael 7111 Palmer, Steven C. e20553 Palmerini, Emanuela 10568, 10571 Palmero, Edenir Inez e22154 Palmero, Ramon 2581, 11056 Palmieri, Giovannella 7603, e18536, e21500 Palmieri, Giuseppe e20013 Palomba, Grazia e20013 Palomba, Maria Lia 8571, TPS8620, e12527 Palomo-Jimenez, Paloma Isabel e14648 Palos, Guadalupe R. e20645 Palou, Joan e16049 Palshof, Torben 7504 Palti, Yoram e22125, e22134, e22138 Paluch-Shimon, Shani 610, 1503 Palucka, Karolina 3014 Palumbo, Antonio 8509, 8517, 8544 Palumbo, Michael Ostaric e14556 Palwe, Vijay Sukhdeo e15178 Pameijer, Colette R 9039 Pamidighantam, Suresh e14694, e16545, e17028 Pamukcu, Ozgul e19127 Pan, Chong-xian 2569 Pan, Chuan-Ju G. e12528 Pan, Hongming 4109 Pan, I. Wen e19139 Pan, Jian-Ji 6026 Pan, Jing e13538 Pan, Jinhong e15547 Pan, Qing Ging e19135 Pan, Sharon e15622 Pan, Summer 8107 Pan, Xueliang Jeff 1556 Pan, Zhi-Wen e12557 Panageas, Katherine S. CRA9003, 9033, 9049, 9052

Panagiotarakou, Meropi e19087 Panasci, Lawrence e14556 Panayiotidis, Panayiotis 7101 Pancisi, Elena 3040 Panda, Dipanjan e19531 Pandey, Anjali 8574 Pandey, Avinash 7043 Pandey, Prasamsa e15545 Pandey, Shivlal 8541 Pandit-Taskar, Neeta 3033, 5021 Pandya, Chintan 9549 Pandya, Shuchi Sumant 4054, TPS4595, TPS6098 Pang, Brendan e14507 Pang, Danmei 1064 Pang, Herbert 7506, 11036 Paniago, Mario Del Giudice 10533 Panjabi, Sumeet e19530 Panneerselvam, Ashok 553, 557, 558, 561, 4138 Panni, Stefano 4112, e15086, e15502 Pannier, Diane 536, 544 Panozzo, Susan 8595 Pant, Alok 5570 Pant, Shubham 3564, 6029 Pantaleo, Maria A. 10540, e15003, e21511, e21523 Pantano, Francesco 4091, e15528, e19084 Pantazis, Nikos e12524 Pantel, Klaus 7027, 11012, 11014, 11042, 11043, e22075 Pantin, Jeremy Mark 7091, 7105 Pantoja, Norma 2605 Pantuck, Allan J. 4507^, 4521 Panzer, SarahLena e20553 Pao, William 8019, 8085 Paoletti, Xavier 2615, e13553 Paolini, Biagio 1014 Paolini, Stefania 7025 Paoluzzi, Luca 9091 Papadaki, Chara 7594 Papadaki, Helen e18507 Papadaki, Maria A. e22101 Papadimitrakopoulou, Vassiliki 6067, 7552, TPS8118, 11044 Papadimitriou, Christos A. 516, 582, 1093 Papadopoulos, John N. 5069 Papadopoulos, Kyriakos P. 2500, 2503, 2504, 2517, 2540, 2602, TPS2618, 3621, e22088 Papadopoulos, Nicholas E. 9047, e20036 Papaemmanouil, Virginia e20642 Papageorgiou, Konstantina e12537 Papageorgiou, Sotirios e20642 Papai, Zsuzsanna 10506 Papai-Szekely, Zsolt 2031 Papaioannou, Alexandra e20522 Papakostas, Pavlos e12537 Papalini, Francisco e13036 Papamichael, Demetris 3524 Papamichail, Michael 3005, 3095, 3097, e16037 Papandreou, Christos 4126, e15607, e16083 Papanicolaou, Genovefa A. 8571

Papanikolaou, Nicolas e20642 Papanikolaou, Xenofon Dimitrios 8515, 8610 Papappicco, Pasqua 4118 Papasotiriou, Ioannis e14699 Papatsoris, Athanasios 4558, e15619 Papavassiliou, Athanasios e11513 Papayannidis, Cristina 7025 Papiris, Spyros e12524 Paplomata, Elsa e11582 Pappa, Vassiliki e20642 Pappagallo, Giovanni L. 5050, 8071, e16031, e16078 Pappo, Alberto S. TPS9104 Pappou, Efi 3095, e16037 Paquet, Agnes 604 Paquet, Lise 542, e12522 Paquette, Ronald 7048 Paquola, Maria Grazia TPS1610 Paracha, Norman 636 Parada, Keila 5585 Parakh, Sagun e14583, e14640 Parangi, Sareh e17014 Paranjape, Trupti 6016 Parasramka, Mansi 4567, e15539 Parchman, Andrew J. 6538 Parchment, Ralph E. 11103, e22080 Pardanani, Animesh Dev 7109, 7110 Pardee, Timothy S. 2516^, e18002 Pardo, Beatriz e16539 Pardo, Nuria e19088 Pardo, Patricia 2568 Pardo, Wandaly Ibis e19510 Pardo-Coto, Pablo e18513 Pardoll, Drew M. 3002^, 3044, TPS3110 Pare-Brunet, Laia e14613 Parekh, Samir S. 8579 Parekh, Trilok V. 5566, e13512 Parent, Florence e12515 Parent, Teresa e19154 Parente, Phillip 3093^, 5055, TPS5099^, e14583 Pargament, Kenneth I. 9573 Parham, David 10012, 10554 Paridaens, Robert 1078 Parides, Michael 3014, 6078 Parikh, Purvish M. 1071, 7066, e19116 Parikh, Ravi e19121 Parikh, Tapan e14517 Parimi, Vamsi e22204 Parinyanitikul, Napa e12002 Paris, Pamela 11048 Parise, Carol e12511, e12512 Parise, Edison Roberto e15155 Parizadeh, Amir Reza e22079 Park, Ben Ho 11019 Park, Cho Hyun e15164 Park, Chul-Kee 2098 Park, Do Joong e15129 Park, Elyse R. 1563, 6544, 7525 Park, Eun Sung 4113 Park, Haeseong e22203 Park, Han Na e15144 Park, Hee Sook 11030, e22199 Park, Heungkyu e12025 Park, Ho Yong e11505, e11594, e14549

Park, Hyoung Soon e15144 Park, In Ae 551 Park, In Hae e11584 Park, In Ja 3628 Park, In-Ae 1039 Park, Inkeun e15026, e15519 Park, Jae-Gahb 3550 Park, Jeong A 10051 Park, Jeong-Yeol 5600, 5601 Park, Ji Soo 4089, e15098, e15144 Park, Ji Won e14504, e14606 Park, Ji-young e11505, e11594 Park, Jinha Mark 3081, TPS11121 Park, Jinny 3595, e19129 Park, John W. 1095, 6619, 6620 Park, Jong-Soon 3016 Park, Joon Oh 3570, 3608^, LBA4001, 4013, 4021, e14626 Park, Julie R. 2538 Park, Jun Seok e14549 Park, Kang-seo 11034 Park, Kay J. e16518 Park, Keon Uk 9633 Park, Keunchil 8027, 8028, 11113, e19002, e19041^, e19051, e19128, e22092 Park, Kwonoh e15516 Park, Kyong Hwa 6069, e22025 Park, Kyu Hyun 4089 Park, Kyu Joo 3550 Park, Kyung-Mi 2565, e13505 Park, Noh Hyun e20530 Park, Noh Jin 7601 Park, Sang Jae 4045 Park, Se Hoon e14626, e15613 Park, Seong Joon 3628, 10550 Park, Seong Kyu 11030, e22199 Park, Silvia 11113 Park, Sook Ryun LBA4024, 4114, e15056 Park, Suk-Young 3045, 11030, e22199 Park, Sung Jun 1039 Park, Sung-Chan e14504 Park, Yeon Hee 551, 637, 1088 Park, Yeon Ho 3595 Park, Youn Choi 5009 Park, Young Iee LBA4024, 4114, e15056 Park, Young Suk 3570, 3608^, 4138, 10589, e14624, e14626 Park, Young-Kyu 4105 Park, Yun-Yong 4113 Park-Simon, Tjoung-Won 1082, 1121 Parker Struckhoff, Amanda 2085 Parker, Alex e22146 Parker, Alexander S. 4567, e15539 Parker, Chris LBA5000, 5012, 5038, 5060, 5068, 5080, e16000 Parker, Christopher 636 Parker, Erik e13033 Parker, Fabrice 2068 Parker, Jayson L. 8040 Parker, Joel S. 4522 Parkes, Sheamus 6553 Parks, Ruth M. e20588 Parmakhtiar, Basmina 9082 Parmar, Mahesh 5012, 5500 Parmiani, Giorgio 3053, 9035, 9065, 9070, 9548

Parnes, Howard L. 4543, TPS4589, TPS5095, TPS5102, e16017 Parney, Ian F. 2025, 2072 Parolin, Veronica e20541 Parpia, Sameer 574 Parra, Jesus Felipe e21512 Parrella, Paola 576, e14655 Parren, Paul 3066 Parrens, Marie TPS8615 Parrilla, Lucia e18558 Parrott, Karen 2575 Parry, Carla 9594 Parsons, Benjamin Marshall e19511 Parsons, Christopher e13581 Parsons, Donald W. 10023 Parsons, Simon L. 3078 Parthasarathy, Sampath e22071 Partis, William J. e14635 Partlova, Simona 3076, e22129 Partridge, Ann H. 1117, 6507, 6527, 9534, e20552 Partridge, Ann TPS658, 1133, 9530, e20508 Partridge, Arun e17503 Partridge, Edward 6559 Parulekar, Wendy 1033, 4053, 4061, e17518 Pascale, Valeria e22037 Pasche, Boris 1548, e15049, e15155 Paschke, Ralf 4 Pascoe, Jennifer S. 5587 Pascual, Tomas e18558 Pasculli, Barbara 576, e14655 Pasetka, Mark e17523 Pashos, Chris L. 7086, 8586, 8596 Pashtan, Itai Max 5511 Pasic, Maria D. e19077 Pasieka, Janice L. 4031 Pasini, Felice 9554, e13514, e15512, e15514, e20541 Pasini, Giuseppe 2048 Paskett, Electra D. 9581 Paskulin, Diego D. 3545 Pasqualetti, Francesco 4062 Pasquinelli, Patricia 8097 Pasquini, Ricardo 7052^ Pass, Harvey I. 7523, 11109 Passalacqua, Rodolfo 4000, 4112, e15086, e15502 Passardi, Alessandro 3517, e14512, e15055 Passioukov, Alexandre 3035 Passot, Guillaume 3642, e14534 Pasteka, Mark e17569 Pastor, M. Dolores e22045 Paszat, Lawrence Frank 1002 Paszkiewicz-Kozik, Ewa e19535 Patel, Amila e20048 Patel, Anush V. e14632, e14709 Patel, Chintan 5032, e16005 Patel, Chirag G. 2567 Patel, Gargi Surendra 3592 Patel, Hermant e15023 Patel, Jai Narendra 2595, 11053 Patel, Jyoti D. 8004, 8012, 8036, 8073, 8086, e13568, e19022, e19150, e22093 Patel, Keyur e20036 Patel, Kiran 3507, 9005, 9016, 9066 ABSTRACT AUTHOR INDEX

765s

Patel, Kirtesh R 2552 Patel, Manali I. 1504, 6581 Patel, Manish R. 2544, 2585, TPS2620, 7070, 8518 Patel, Mayank 2567 Patel, Neal e14625, e14661, e14681 Patel, Nihar Kiritkumar e12531 Patel, Nirali e14522 Patel, Oneel e16016 Patel, Poulam M. 4504 Patel, Prapti Arvind 6601 Patel, Rajesh D. 6008 Patel, Ravi e11611, e19140 Patel, Sandip Pravin 3070 Patel, Sapna Pradyuman e20036 Patel, Shivani C. 6601 Patel, Shreyaskumar 10049, 10517, 10577 Patel, Snehal G. 6048 Patel, Sukeshi R. 3541 Patel, Sunita K. 9575 Patel, Vipul M. 8044 Patel-Donnelly, Dipti 8599 Patenaude, Andrea Farkas 9644 Paterson, Daniel 11064, e13523, e18541 Pathak, Purnima e20012 Pathy, Sushmita e15138 Patiño-García, Ana e19112 Patikis, Angela 2525 Patil, Ritesh 3096, TPS3126 Patil, Shekhar 6624 Patil, Sujata 606, 630, 1019, 1021, 1052, TPS3120, 4501, 4534, 9597, 9610, e15517, e20620 Patil, Vijay Maruti e12520 Patil, Vijay 6085, e17027, e20678 Patki, Abhay 7109 Patnaik, Amita 2500, 2503, 2517, 2547, 2602, TPS2618, 9009, e19002, e22088 Patnaik, Mrinal M. 7064 Patocka, Kurt e19093 Patocskai, Erika 1018 Patriarca, Francesca 8509 Patrick, Donald e20514 Patrick-Miller, Linda J. 1538, 11084 Patrick-Miller, Linda 1506 Patridge, Eric e17597 Patrie, James e18005 Patruno, Rosa e22104 Patrzyk, Maciej e16534 Patsouris, Efstratios e22160 Patt, Debra A. 9604, 9605 Patt, Joshua e21504 Patt, Richard H. 4122^, TPS4161^ Patt, Yehuda Z. e15136 Pattenden, Holly 7544 Patterson, Christopher J. TPS8620 Patterson, James W. TPS3118^ Patterson, Janice 10509 Patterson, Molly 8575 Patterson, Scott D. 2071, 3511, 3617 Patton, Jeffrey 3564 Patuzzo, Roberto 9092 Paty, Philip 3605 Patzelt, Alexa e20688, e20689 Pau, Gregoire e14505 Paucar, Daniel CRA9003 Paul, Alyssa 4545 766s

Paul, Andreas e14502 Paul, Bonnie K. e20018 Paul, Devchand 590 Paul, Diane B. e17560 Paul, James 9590 Paul, Les 2041, 11001, e19006 Paul, M. A. 8065 Paul, Zachary 9591 Paúles, Maria Jose e15111 Pauli, Emily K. e19528 Pauli, Roland 3634, e14513, e14562 Pauligk, Claudia 4079, 4095 Paulino, Arnold 10009, e13032 Paulk, M. Elizabeth 6529, e20606 Paulus, Elena Mantas 9042 Paulus, Patrick 11032 Paulus, Rebecca 7501, 7523 Paulussen, Michael 10031, 10518 Pauly, Marc e14591 Pauly, Mary Pat 9645 Paun, Oana Valeria 7036 Paunesku, Tatjana 3083, e22204 Pauporte, Iris e17567 Pautier, Patricia 5541, 10505 Pavan, Thayse e14590 Pavel, Marianne E. 4138, e15071 Pavese, Ida e12021 Pavey, Emily S 3510, 3639 Pavia, Orestes Antonio e11610, e19510 Pavlakis, Nick TPS3649, 4081, TPS4157, e22175 Pavlick, Anna C. 2528, 9021, 9023, 9041, 9054, 9063 Pawar, Rahul 7076 Pawar, Yeshwanth S. e15120 Pawaskar, Manjiri e11570, e11571, e18543 Pawlak, Amanda 7555, 8083 Pawlik, Timothy M. 4039, 4057, 4124, e15028 Pawlowski, Ryszard 11069 Paydas, Semra 9587, e19512, e20006 Paye, Francois 4069 Payne, Kathryn 5536 Payne, Sheila e20695 Paz, Isaac Benjamin e20651 Paz, Keren 2511 Paz-Ares, Luis G. 2606, 8522 Paz-Ares, Luis 2016, 4550, 8068, e22045, e22085 Paz-Querubin, Emma R. 1602, 9567, e14625, e15561 Pazdur, Mary e16036 Pazienza, Paola 10572 Pazooki, Mohammad e19514 Pazzagli, Ilaria 1086 Pazzaglia, Laura 10571 Pazzola, Antonio 8014 Peale, Franklin V. 2503 Pearlberg, Joseph 2050, 2609 Pearlstein, Kevin A. 9592 Pearsall, Scott TPS6098 Pearson, Andrew D. J. 10015, 10016, 10026, 10027 Pearson, Sarah R TPS5615 Peccatori, Fedro 589 Pechan, Juraj e22023 Pechanska, Paulina 3634


Peck-Radosavljevic, Markus TPS4159, TPS4160 Peckitt, Clare e14616, e19543 Pecora, Andrew 9050 Pecorari, Giancarlo 6038, 6039 Pecorelli, Sergio L. 5560 Pectasides, Dimitrios G. 582, 1093, e19048 Pectasides, Eirini 6081 Pécuchet, Nicolas e22001 Pedani, Fulvia 6038, 6039 Peddareddigari, Vijay Gopal Reddy 8027, 8028 Peddi, Prakash e19070 Pedersen, Kasper 632 Pedersen, Michelle 2520 Pedersen, Mikkel W. 3551 Pederson, Holly Jane 1508 Pedrazzoli, Paolo 4091, 4575 Pedruzzi, Hector e11538 Peer, Avivit e15597, e15598, e16023, e16068 Peer, Cody 2527, 10588 Peereboom, David M. 514, 2044 Peeters, Dieter 11045 Peeters, Marc 2521, TPS3124^, 3617, e14587^ Peggins, James O. 11103 Pegoraro, Cristina e15514, e16031 Pegoraro, Stefano e15088 Pegram, Mark D. 521, 522 Pehamberger, Hubert 9024 Pei, Lixia 8545, e19509 Peifer, Martin e12517 Peiffer, Ann 2006 Peikert, Tobias 7568, e19013 Peipp, Matthias 8604 Peiro, Rafael e20705 Peixoto, Renata D’Alpino e11522, e15084, e15153 Pejovic, Tanja 3030 Pel, Marcella 7586 Pelayo, Michael 1095 Pelham, Robert J. 5029 Pelkey, Gregory e22130 Pellegrin, Andrea e13046 Pellegrini, Fabio 576 Pellegrini, Marco e11569 Pellegrino, Arianna e12021 Pellegrino, Christine M. 1118 Pellegrino, Renata 6073 Peller, Patrick J. 4026 Pellizzon, Antonio Cassio Assis 6017 Pelosi, Giuseppe 3641, 6066 Pelosof, Lorraine Cheryl 3552 Pelov, Diana 4576 Pelusio, Adina 3608^ Pelz, Enrico 1092 Pelzer, Uwe 4016 Pelzl, Le Hang 9612 Pemmaraju, Naveen 7024, 7068, 7074, 7090 Pena, C. 7549 Pena, Rhoneil 3060 Peña-del-Castillo, Humberto 10056, 10058 Penalver, Manuel e16525 Penas-Prado, Marta TPS2106, e13039

Penault-Llorca, Frederique Madeleine 8000 Penault-Llorca, Frederique 610, 1057, 1058, 1578, 3562, 8100, e11615 Pencheva, Pepi 2557 Pendergast, Jane F. 6602, e19065 Pendurti, Gopichand e13550 Penel, Guillaume e12552 Penel, Nicolas 2548, 2549, 10505, 10506, 10516, 10517, 10525, 10563, 10570, 10574, 10575, 10582 Peng, Feng e13592 Peng, Jiewen e19161 Peng, Li e19085 Peng, Yingwei e15616 Peng, Zhihua e15106 Penley, William Charles 3564, e19062 Pennathur, Arjun 4103 Pennell, Nathan A. 8113, 8114, 11091, e13030, e19012, e19025 Pennella, Eduardo J. 8012, e19150, e20629 Penner, Louis e20646 Pennington, Kenneth Lee e15557 Pennison, Michael J. e15049 Pennock, Gregory K. TPS9103, TPS9105^ Penson, David F. 4540, 6522, 6532 Penson, Richard T. 5520, 5591 Pentheroudakis, George E. 582, 1093 Pentsova, Elena 2095, 7120 Pentz, Rebecca D. e20608 Peoples, Anita Roselyn 9531, 9533, TPS9651, e20526 Peoples, George Earl 3005, 3095, 3096, 3097, TPS3126, e14500 Pepels, Manon J. 1028 Pepin, Francois 8511 Peppercorn, Jeffrey M. 1076, 1520, 6503, 6506, 6516, 6551 Peppone, Luke Joseph 9531, 9533, 9572, TPS9651, e20526 Perabo, Frank 5001 Peralta, Guilhermina e15118 Perea, Rachelle 2533 Perea, Sofia e11531 Pereda, Saray 540 Pereda, Teresa e22131 Pereira, Augusto Akikubo Rodrigues e18548 Pereira, Emiliano da Costa e18548, e20640 Pereira, Guilherme Abreu 10061 Pereira, Jose Rodrigues e18548 Pereira, Jose e20507, e20598 Pereira, Verónica 6072 Perello, Antonia e12020, e12558 Perelman, Michael Sidney 9563 Perepletchikov, Aleksandr e22010 Perera, Rafael 3500 Peresi, Patricia 11038 Peretolchina, Nina e22097, e22162 Peretz, Tamar 1598, e20039, e21508 Perez Alvarez, Sandra Ileana e15131 Pérez Arnillas, Quionia e14617, e15169, e18513, e19034

Perez Carrion, Ramon Maria 608 Perez de Oteyza, Jaime 7045 Perez Gracia, Jose Luis e19112 Perez Ronco, Julian 5544 Perez Ruiz, Elisabeth e11583 Pérez Segura, Pedro 2087 Perez, Alejandra T. LBA509, 558 Perez, Carlos 9641 Perez, Cesar Ochoa e22184 Perez, David e19532 Perez, Diego e12013, e22091, e22131 Perez, Edith A. 520, 521, 522, 1007, 1037, 1049^, 1050^, 1055^, 1059, 1087, TPS1136, e22093 Perez, Francisco Javier 4587, e15586 Perez, G. Micheal 3085 Perez, J. Manuel 3085 Perez, Javier e13016 Perez, Jimena 6016, 6047 Perez, Juan Eduardo 1073, 11118 Perez, Kimberly 8075, e14637, e15095 Perez, M. Assumpcio 1509 Perez, Maria Angelina e22060 Perez, Maria Angelina e21512 Perez, Maria 11025 Perez, Rolando 3086, TPS3123 Perez, Sonia A. 3005, 3095, 3097, e11513, e16037 Perez, Wendy TPS8125 Perez-Campos, Ana 1041 Perez-Carrion, Ramon 3589, e12020, e12558, e14509, e19148 Perez-Cruz, Pedro Emilio e20606 Perez-Gonzalez, Nuria 11089, e19000, e19109 Perez-Gracia, Jose Luis TPS3107, 4550, 9074, 11010, e19027, e19106, e19114 Perez-Lougee, Giselle K. 6544 Pérez-Montiel, Delia 4555 Pérez-Ruiz, Elisabeth e12013, e22091, e22131 Perez-Soler, Roman 8097 Perez-Valderrama, Begoña e15533, e15550, e16014 Perfetti, Vittorio 10568 Peria, Fernanda Maris e15190 Perier-Muzet, Marie 9093 Perin, Alessandra 5050, 5548 Perkins, Julia Jane 4572, e15624 Perkins, Sherrie L 3055 Perkins, Susan M. 2529 Perl, Alexander E. 7012, 7021, 7023 Perlman, Elizabeth 10014 Perlman, Scott 2537 Perlorentzou, Stavroula e20642 Pernia, Olga 1575, e19123 Perniceni, Thierry 4069 Pernicone, Joseph e13047 Pernot, Simon e22121 Pérol, David 4574, 7505, 10516, 10542 Perol, Maurice 8059, e19056 Peron, Jean-Marie 4028 Perona, Rosario 1575, e13008, e19123

Perotti, Antonella Perotti, Cesare Perou, Charles M.

2535 4575 500, 512, 515, 7576, 11021 Perpich, John e15611 Perren, Timothy 5500 Perrin, Christophe 10578 Perrin, Paul 5022, e16050, e16056 Perro, Gerard e20041 Perrone, Federica 3641, 6020, 6027, e14716 Perrone, Francesco LBA5501, 11008, e19031 Perrone, Giuseppe 576 Perrone, Vittorio 4062 Perrot, Serge 569 Perrucci, Bruno 4112, e15086, e15502 Perry, Arie 10522 Perry, David John e14675, e15577 Perry, James R. LBA2009 Perry, James 7573 Perry, Michael C. 8046 Perry, Philip 5 Persic, Mojca 5514 Persky, Mark 6091, e17030 Personeni, Nicola e14611 Persson, Bo-Eric e16066 Pertino, Antonella e20694 Pertschy, Jörg 3634, e14513, e14562 Perumal, Karthikeyan 2083 Pervez, Nadeem 9525 Peschel, Christian 10508, e15042 Pestalozzi, Bernhard C. e20542 Pestka, Aurelia 638, 11043, e22059, e22075 Petak, Istvan e19090^ Petekkaya, Hilbrahim e11537, e11544, e11545, e12563 Peterman, Sissy 7003, TPS7133, 8519, 8526 Peters, Frank P. J. e17549 Peters, Godefridus J. 11087 Peters, Inga e22076 Peters, John 4508 Peters, Katherine B. 2090, 2094, TPS2102, e13015^ Peters, Malte e13525 Peters, Natascha A. J. B. e17549 Peters, Solange 7503, 7514, 8060, 9014 Petersen, Benjamin e14500 Petersen, Lone 3525^ Peterson, Amy C. 5066 Peterson, Amy e20646 Peterson, Bercedis 6503 Peterson, Do 9573 Peterson, Douglas E. 9620 Peterson, Lisa A 9607 Peterson, Susan K. 6566, 9576 Peterson, Timothy 2072 Peth, Karissa 11107 Petit, Robert G. 5529 Petit-Monéger, Aurelie 6582 Petrakova, Katarina 553, 557, 628 Petrau, Camille 1104 Petrella, Maria Cristina e11573 Petrella, Teresa M. 9032 Petric, Marija e13009

Petricoin, Emanuel 2612, 5560, TPS11123, e22155 Petrilli, Antonio Sergio 10533, 10534, 10535 Petrini, Massimiliano 3040 Petrini, Michaela 5018 Petroccione, Anna e15061, e19138 Petrocelli, Teresa 11016 Petroff, Brian K. 1515 Petroni, Gina R. TPS3118^, TPS3125, 6021 Petroni, Stella e11502 Petros, John 5067 Petrova, Valentina Dmitrievna e12560 Petrovsky, Alexander e12027 Petru, Edgar 5541 Petrucci, Maria Teresa 8544 Petrucelli, Luciana e11517 Petrucelli, Nancie 1557 Petruckevitch, Ann e15608 Petry, Christoph 581, e22112 Petrylak, Daniel Peter LBA4509, 5002, 5011, 5018, e19145 Pettaway, Curtis A. 5069 Pettengell, Ruth 1078 Petterson, Stine Asferg 2088 Pettersson, Kim 1554 Pettijohn, Erin 9087 Pettine, Stefan 11050 Pettinger, Mary 1505 Pettitt, Jessica e15029 Petty, Nathan 8515 Peureux, Marc e19078 Peuvrel, Lucie e20022 Peyrade, Frederic 8536 Peyrard, Severine e16009 Peyrat, Jean-Philippe 536, 544 Peyro Saint Paul, Helene P. 1092 Peyton, James D. 2093 Pezaro, Carmel Jo 5052 Pezaro, Carmel 5049^ Pezet, Denis 3596 Pezzilli, Raffaele e15069 Pezzolo, Elisa e20541 Pezzutto, Antonio TPS8616 Pfaff, Holger e17550 Pfannenberg, Christina 3098 Pfanner, Elisabetta e14531 Pfanzelter, Nicklas e17591 Pfeffer, Raphael M. 9500 Pfeffer, Ulrich 11063 Pfeifer, John 11099 Pfeifer, Per e14710 Pfeiffer, Per 3571, 3572, 3597, e15099 Pfeil, Alena 1078 Pfeiler, Georg 549, e11601 Pfirrmann, Markus 7051 Pfister, David G. 6024, 6034, 6048, 6090, 6594 Pfisterer, Jacobus 5522^, 5553, e16510^ Pflug, Natali 7015 Pfreundschuh, Michael 7051, 8566, 8569, 8570 Pham, Alice e12552 Pham, Can G. 4573 Pham, Huyen 5527, 9632 Pham, Nhu-An e18514

Pham, Trang Phan, Alexandria T. Phelps, Charles Phelps, Mitch A. Phelps, Robert Philip, Deepa susan Philip, Philip Agop

9537 e15126 8530, e13512 1043, 7077 3014 e18004 TPS4145, e15077

Philipp-Abbrederis, Kathrin e15042 Philippe, Peggy 2548, 2549 Philips, Daisy 9078, 9085 Phillips, Brooke Elizabeth e15000 Phillips, Charles A 9609 Phillips, Jane e20584 Phillips, John G. e16026 Phillips, John 5051 Phillips, Jonathan 4134 Phillips, Kelly-Anne 1559, e20660 Phillips, Larry e14656 Phillips, Melissa 11071 Phillips, Teresa A. 1515 Phillips, Therese 3016 Phillips, Tycel Jovelle 7036 Philpott, Susan 5507^ Phipps, Alex e13508 Phipps, Sean e20646 Phipps, Warren 10070 Phung, De 5001 Phuphanich, Surasak 2019^ Phyu, Pyar Soe 1535 Piacentini, Federico 530, 556 Piacentini, Paolo e17551, e20617 Piana, Raimondo 10572 Pianowski, Luiz Francisco e13557, e13559 Pianowski, Luiz e20680 Piantadosi, Steven e17507 Piao, Ying e15582 Picard, Martin LBA2009 Piccardo, Arnoldo TPS649 Piccart-Gebhart, Martine J. LBA509, 525, 528, 575, 610, 11003, e12008, e12515 Picci, Piero 10571 Picciotto, Maria e19086 Piccirillo, Maria Carmela 11008 Pichelbauer, Ernestina e22060 Pichler, Bernd e20050 Pichler, Josef TPS2103 Pichler, Martin e15064 Pichna, Peter e14700 Piciocchi, Alfonso 7025 Pickens, Allan 2610 Pickford, Emily 5562 Pickles, Tom 5035, e16086 Picot, Marie Christine 1528 Picozzi, Vincent J. 4040^, 4043, e15089 Picquenot, jean-Michel 1104 Piedbois, Pascal 3542 Piekarz, Richard 2526, 2527 Pienkowski, Tadeusz 537, 1031 Pienta, Kenneth James TPS5094 Piephoff, James 2006, 2051 Piepszak, Alexandra M. 8028 Pierce, Lori J. 1025 Pierce, Michael e17556 Pierce, Sherry 7068, 7090, 7095, 7112, 7115 ABSTRACT AUTHOR INDEX

767s

Pierce, Stuart e16529 Pierceall, William E. 7022 Pierga, Jean-Yves 555, 569, 1533, 4046 Pieri, Gabriella 6003 Pierobon, Mariaelena 5560, TPS11123, e22155 Piessen, Guillaume e15134 Pieta, Katharin 3052 Pietanza, Maria Catherine 6583, 7593, 7600, TPS7608, e15133 Pietenpol, Jennifer A. 1005 Pietkiewicz, John e16553 Pietrantonio, Filippo 3641, 8035, e14716, e22056 Pietras, Kristian 3571, 3597 Pietri, Elisabetta e11521 Pietrogiovanna, Lisa 3581 Pietsch, Torsten 2027 Pietzner, Klaus 5582 Pignata, Sandro LBA5501, LBA5503, 5544, 5569, 11037 Pigneux, Arnaud TPS3117^ Pignochino, Ymera 10552, 10583 Pignon, Jean-Pierre 4127 Pigorsch, Steffi 1121 Pigozzo, Jacopo 9070, 9548, e22036 Piha-Paul, Sarina Anne 2506^, 2604, 2611, 11086, e13534, e13575, e13591, e22086 Pijnenborg, Johanna M. A. e16517 Pike, Malcolm C. 1511 Pikiel, Joanna 516, 5019 Piko, Bela e12022^ Pilat, Mary Jo 6045 Pilati, Pierluigi 3563 Pilbeam, Carol C. 9620 Pilegaard, Han Kristian 7504 Pileri, Stefano A. e21511 Pilewskie, Melissa Louise 1021 Pili, Roberto 4582, 5081, e15597, e15598, e15604, e16051, e16068 Pillai, Madhavan V. e15183 Pillai, Raji 2562, e22033, e22172 Pillai, Rathi Narayana 7560, e19094 Pillai, Sreeraj 633 Pillar, Nir 1503 Pillarsetty, Naga Vara Kishore 11076 Pillay, Sada 2016, 2563 Pillemer, Stanley 3044 Pilop, Christiane 8060 Pilotti, Silvana 6020, 6027, 10565 Pilotto, Alberto 6593 Pilotto, Sara e16053, e17555 Pilz, Korinna 2521, 2556, 5504 Pimenta, Celia Aparecida Marques e22074 Pimentel, Lindsey E. e20559 Pina, Filomena e15172 Pinato, David James e15101 Pinder, Mary Colleen 3091, 8001, 8051^ Pinder, Sarah TPS656 Pineda, Beatriz e12571 Pineda, Begoña e12019 Pineda, Maria Dolores e14648 768s

Pinese, Mark e15029 Ping, Huang e11589 Pingali, Sai Ravi 8505 Pingpank, James F. 9043 Pinguet, Frederic e13519 Pini, Alejandra e11600 Pini, Sara e14717, e15154 Pinilla-Ibarz, Javier 7048, 7113 Pinker-Domenig, Katja 11088, 11093, e22090 Pinna, Antonio Daniele 4129 Pino, Alejandro 6048 Pino, Luis 9541 Pinotti, Graziella e11573 Pinski, Jacek K. 5062, TPS5096, 11040, 11047, e16020, e16073 Pinter, Ferenc e19090^ Pinter, Tamas 3575, 5520 Pinter-Brown, Lauren C. 8507 Pinthus, Jehonathan H. e16011 Pintilie, Melania 7517, 8096, e18514 Pinto, Alvaro e15609, e15620 Pinto, Antonio 8564 Pinto, Carmine TPS3648, e14557, e14717, e15154, e18509 Pinto, Clovis e17032 Pinto, Flavio Augusto Ismael 11038 Pinto, Joseph A. e12566, e12570, e22165 Pinto, Paula Nicole 6017 Pintoffl, Jan P 607 Pinzon-Ortiz, Maria e13525 Piovano, Pierluigi e14657 Pipas, J. Marc 3639 Piperdi, Bilal 3616, 8097 Piperno-Neumann, Sophie 9057, 10516, 10517, 10525, 10563, 10574, 10575 Pippen, John E. 590, 6533 Piras, Alessandra 603 Pirc, Louise e14506 Pircher, Tony J. e22047 Pires, Ricardo e22072 Pirl, William F. e20551 Pirnasch, Anett 6077 Pirolli, Melissa A. e12508, e20690 Pirotta, Marie 1559, e20660 Pirotta, Nicoletta TPS5616 Pirrie, Sarah LBA5000, 5057 Pisa, Aleydis e15107 Pisanello, Anna 2048 Pisanidis, Nikolaos 582 Pisano, Carmela LBA5501 Pisansky, Thomas Michael 9525 Piscaglia, Fabio e15149 Piscitelli, Angela Pamela e18518 Pisconti, Salvatore 618, 8071, e14565, e18545 Piscopo, Giovanna 631, e11556 Pishvaian, Michael J. 2616 Pishvaian, Michael TPS2624 Pistelli, Mirco e15081 Pisters, Louis L. 5069 Pistilli, Barbara 557, 561, e11616 Pistillucci, Giorgio e19099 Pistola, Lorenza e22155 Pitini, Vincenzo 8047 Pitman, Michael 6091, e17030 Pitot, Henry Clement 3539, 5082, e16061


Pittaluga, Stefania Pittelkow, Mark Pittman, Kenneth B. Pitz, Marshall W.

10588 e20037 4504 1597, 2053, e17596 Piva, Sheila e12021 Pivot, Xavier B. 555, 1122, 1562, 6563, e11579, e11607 Pivot, Xavier e13519 Piya, Madan Kumar e12572 Pizzolo, Giovanni 7025 Pizzuti, Laura e12031, e15065 Plambeck-Suess, Stacey e16508 Planas, Jacques e16045 Planchard, David 8009, 8029, e19056 Planchat, Eloise e16021 Plancher, Corine 9057 Planci, Kezban Nur e19127 Plastaras, John Peter 7578 Plato, Leah 2502 Platonova, Natalia 7060, e18527, e22003, e22052 Platt, Adam 8045 Platzek, Ivan e21518 Plaxe, Steven C. 6636 Plaza, Carlos 3543 Pleasance, Erin e22020 Plesec, Thomas e15000 Plesner, Torben 8512^ Pless, Miklos 7503, 8060 Plessis, Virginie e20519 Pliarchopoulou, Kyriaki 582 Plimack, Elizabeth R. 4527^, TPS4593, TPS4595 Pliner, Lillian F. 1091 Plitas, George 1019 Plon, Sharon E. 10023 Ploquin, Anne e15134 Plotka, Anna 2568 Plourde, Paul V. 7097 Plummer, Elizabeth R. e19138 Plummer, Ruth 2586, 3018, 9068, e11586 Pluta, Andrzej TPS7131 Plyler, Ryan 8597 Poast, Erica 9087 Pocard, Marc 3642, e14534 Pochettino, Paolo 10572 Pockaj, Barbara A. 1037, 9034 Poddubskaya, Elena Vladimir CRA8007 Podratz, Karl C. 5510, 5577 Podrazil, Michal e16002 Poeschel, Viola 8570 Poeta, Maria Luana 576 Poggiali, Giulia e16510^ Poggio, Francesca 1036, e17548 Pogoda, Janice M. e14517 Pohl, Gerhardt e20525, e20629 Pohlen, Michele 8548 Poiesz, Bernard J. e16087 Pointreau, Yoann e11607 Poirier, Brigitte 1018 Poisson, Laila 2073 Pokataev, Ilya e14674, e15585, e16509 Poklepovic, Andrew Stewart e22203 Poku, Kofi TPS11121

Poladia, Bhavesh

6085, e12520, e17027 Polanec, Stephan 11088 Polenkov, Serhii 3073 Polenz, Chanele K. e17557 Poletto, Elena e11565 Poli, Anne TPS2620 Poli, Rossana 4112, e15086, e15502 Policastro, Tania e21500 Polissar, Nayak L. e12030 Polite, Blase N. 1513, 9581 Politi, Mary C. 6590 Politi, Mary e20543 Polizzotto, Mark Niccolo 10588, TPS10595 Poljak, Alexandra 7019 Polkinghorn, William Reilly 11010, 11067 Pollack, Ian 2036 Pollack, Seth e21502 Pollak, Michael N. 1518, 1578, TPS3647, 5070, e14615 Pollán, Marina 1031, e12513 Pollard, Jack e14539 Pollett, Aaron 5508 Polli, Anna 8105 Polliack, Aaron TPS7130 Pollina, Luca 4062 Pollock, Brad H. 3541, e15171 Polo, Susana Hernando 4587, e15586, e16014 Polockii, Boris e15585 Polonifi, Katerina e18542 Polsky, David 9023, 9054 Polterauer, Stephan e16524 Polyak, Kornelia TPS1134 Polyzos, Aristidis 1045, e18542 Polyzos, Nikolaos P. 624 Pomerantz, Mark M. 4570, 5056 Pomerantz, Mark e16032 Pommier, Pascal 6056, e17011, e17012 Pompeo, Antônio C. L. e16058 Ponce Aix, Santiago e18558 Ponce, Jose Luis Aguilar e17031 Ponce, Mario e19140 Ponce-Aix, Santiago 11028 Pond, Gregory Russell 574, 4524, 4539, 5586, 10029, e14582, e20522 Pond, Gregory 2505 Ponhold, Lothar e15535 Poniewierski, Marek S. 6534 Ponni, T.R. Arul e17034 Ponniah, Sathibalan 3005, 3095, 3096, 3097, TPS3126 Ponomarova, Olga V. 8095 Ponti, Antonio TPS1610 Pool, Mark e19113, e19117 Poole, Christopher John 5 Poole, David 6500 Poon, Cheryce e16019 Poon, Daniel J. e13590 Poon, Donald 4031, 9552 Poon, L. M. 8561 Poon, Ronnie Tung Ping 4125 Poon, Ronnie Tung Ping 4117 Poondru, Srinivasu e13502 Poortmans, Philip M. 1094 Pop, Simona e13553

Popa, Andra M. Popa, Elizabeta C.

2069 TPS6098, e15600, e20549 Popa, Xitlally 3013 Popat, Sanjay TPS2626, 7585 Popat, Sanjaykumar e19007, e19146^ Popat, Uday R. 7010, 7011 Pope, Ann LBA5000 Pope, Janice 9542 Pope, Whitney B. 2055 Popescu, Onsina e11502 Popescu, Razvan A. 3503, e12515 Popescu-Martinez, Andrea M. e12526 Poplin, Elizabeth 4007 Popov, Alexander 10055 Popovici, Vlad Calin 3522, e14544 Popplewell, Leslie 8507 Poprach, Alexandr e14622, e15581 Porat, Yaara e22125, e22134, e22138 Porcu, Luca e11573 Porfiri, Emilio LBA5000, e16048 Porock, Davina e20540, e20588 Porrata, Luis F. 7041, 8581 Porschen, Rainer 3533 Porta, Camillo TPS4159, 4575, e15524, e15589, e16053 Porta, Rut e19089, e19159 Portela Pereira, Paula 5087 Porten, Sima P. 4538 Portenoy, Russell 6627 Porter, Aaron T. 6602 Porter, Christopher R. 5071 Porter, David James 1081 Porter, David L. TPS7132, TPS10072 Portera, Chia C. 2503 Portielje, Johanna Elisabeth A. 1072, e14558 Portier, Kenneth M. e16029, e16039 Portlock, Carol S. 8571, e12527 Portnow, Jana 2018 Porto, Gislaine Machado 6017 Portschy, Pamela R. e12506 Portyanko, Anna 3597 Porzner, Marc 4034 Posch, Christian e20010 Poskitt, Ken 10029 Posner, Marshall R. 6019, 6023, CRA6031, 6054, 6058, 6062, 6078, TPS6098, 9530 Pospisilova, Sarka 7101 Postmus, Pieter E. TPS8117 Poston, Graeme John 3504, 3558, 4132 Postow, Michael Andrew 9012^, 9024, 9052 Potanina, Larissa e17515 Potemski, Piotr 516 Potenzoni, Michele e15502 Pothier, Kristin Ciriello e11504 Pothuri, Bhavana 2591 Potler, Hannah 1100 Potosky, Arnold L. 9077 Potter, Mike e19543 Potter, Vanessa Alice e14561 Potthoff, Karin e15574 Pottow, John A.E. 9601

Potts, Steven James e22187 Pouget, Mélanie e16021 Poulalhon, Nicolas 9093 Pounds, Stanley 10005 Poupart, Marc 6056, e17011, e17012 Pouptsis, Athanasios e11576 Pourroy, Bertrand 7117 Poveda Velasco, Andres 10500 Poveda, Andres 1543, 5502, 5566, 10532 Powderly, John D. 3000, 3001, 3002^, 3044, 3622, 4514, CRA9006^ Powell, Alisa 567 Powell, Bayard L. 2516^, e18002 Powell, Erin Diana e11580 Powell, Gerard 10567 Powell, Matthew A. 5520, 5591, 5602, e16508, e16548 Power, Derek Gerard e12533, e13020, e14519, e15196, e15566, e20550 Powers, Celeste N. e22203 Powers, Jacqueline 1510 Powers, Penny TPS1144 Powis, Garth TPS8118 Powles, Thomas 4505, 4508, 4525 Poyet-Gelas, Fanny e20030, e20038 Pozdnyakova, Victoria e20005 Pozzati, Eugenio 2021 Prabhakar, Dhivya 1046 Prabhash, Kumar 6085, 8053, 8068, e12520, e17027, e18525, e19095, e19118, e19119, e20678 Prabhu, Sujit S. e13035, e13051 Pradere, Bernard 3596 Pradervand, Sylvain 9014 Prado, Carla M. M. e19100 Prados, Michael 2012, 2015, 2035 Prajapati, Hasmukh J. e15033 Prakash, Om e13581 Prasad, Krishna 577 Prasad, Nagendra K 2529 Prasad, Sandip M. 5091, e16006 Prasad, Shreya 1069 Prasnikar, Nicole 4079 Prat, Aleix TPS665, 1011, 11021 Prat, Ricardo e13008 Prati, Andrea e15502 Prati, Veronica e15528, e16099 Prausová, Jana 3574 Pravettoni, Gabriella 9582 Prebet, Thomas 7126 Preet, Mohan e19522 Premasekharan, Gayatri 11048 Prendes-Garcia, Maria e22083 Prenen, Hans 3588 Prentice, Ross L 3594 Presant, Cary A. e16525 Presant, Cary e18538 Prescott, James 11102 Presley, Chris e22031 Press, Michael F. 3081, LBA4001, 4527^ Pressey, Joseph Gerald TPS10073, TPS10591 Prestifilippo, Angela 11058, e11526 Prestipino, Anthony e15183 Pretorius, Maria 3607

Pretzsch, Shanna M. Preusser, Matthias

4538 573, 611, 2040, 2059 6095 TPS5095 8102 529

Price, Daniel L. Price, Douglas K. Price, Justina Price, Karen N. Price, Katharine Andress Rowe 6095 Price, Timothy Jay 1581, 3531, 3592, TPS3649, 4081, TPS4157, 6598, e14501, e14506 Pricolo, Victor e14637 Prieto, DaRue e22180 Prieto, Jesús TPS3111 Prieto, Victor G. 9047, e20034 Prigerson, Holly Gwen 6529, 6573, 9519, 9521, 9522, 9540, e20606 Prim, Nathalie e17543 Primrose, John Neil 3500, 3504 Prince, Mark E 9607 Pringle, Dan 9536, 9551, 9595 Prins, Judith 10549 Prinzler, Judith 4016 Priolo, Carmen e17014 Priolo, Domenico e11526 Priou, Franck e16009 Pritchard, Kathleen I. 553, 555, 557, 558, 561, 564, 574, 1033, 1550 Pritesh, Chaudhari 4128 Privat, Maud 1058 Pro, Barbara TPS8611 Probst, Stephan 4079 Procopio, Giuseppe 5050, e15524, e15528, e15589, e16031, e16078 Procter, Marion Jennifer 525 Prod, Michele e18013 Prodi, Elena 2074 Proetel, Ulrike 7051 Proia, David A e19097 Prokopenko, Tatiana I. e20593 Prola Netto, Joao e13001 Prolla, Joao Carlos e12546 Proniuk, Stefan 2608 Pronzato, Paolo 1036, e17548, e20616 Propper, David LBA4004 Proschek, Dirk e21505 Pross, Matthias 3634, e14513, e14562 Protásio, Bruno Mendonça 2060, 9561 Protheroe, Andrew 4508 Protic, Mladjan e14500 Proto, Claudia e19086 Protsenko, Svetlana 3088, LBA4001 Provan, Pamela 543 Provansal, Magali TPS663 Provencher, Diane M. 5502, 5515 Provencher, Louise LBA509, 627, 1018 Provencio Pulla, Mariano e19532 Provencio, Mariano LBA8002 Provenzale, Dawn T. 6555 Provenzano, Elena 1015 Prow, Debra M. 2562 Prozorenko, Evgeny e15546

Prudkin, Ludmila 3012, 8070 Pruemer, Jane e15185 Pruijt, Hans e14629 Pruitt-Thompson, Solida TPS2627 Pruneri, Giancarlo 589, 1517 Pruthi, Rajiv 7094 Pryer, Nancy e13590 Przybyl, Joanna e22046 Pshevlotsky, Eduard M. 4010, e15005 Psimaras, Dimitri 3065^ Psyrri, Amanda 6012, 6081 Ptaszynski, Konrad e22046 Pu, Daniel e22071 Pu, Jeffrey J. 7032 Pu, Minya 11098 Puccetti, Maurizio 5594, e15055, e16530 Pucci, Francesca 4136^ Pud, Dorit 9630 Puduvalli, Vinay K. 2019^, 2042, TPS2106 Puente, Javier e15609 Puente, Xose S. e12516 Puerta, Sonia 2600 Puertas, Javier L. e15609 Puertolas, Teresa e20015 Pugh, Cheryl TPS3645 Pugh, Sian Alexandra 3500 Pugh, Stephanie L. 2003, 2004, 9525, 9527 Pugh, Thomas J. 5069 Pugia, Michael 591 Pugliano, Lina 575, 610, 11003 Puglisi, Fabio e11565, e11573 Puglisi, Martina e19007, e19146^ Puhalla, Shannon 515, 527 Pui, Ching-Hon 10022 Pujade-Lauraine, Eric 510, LBA5501, 5504, 5516, 5542, 5547 Pujana, Miguel Angel e12516 Pujantell-Pastor, Laia 11029 Pujol, Jean-Louis 7515 Pujol, Pascal 1528 Pukac, Laurie e13551 Pukkala, Eero 1514, 4536 Pulcrano, Giuseppe e13046 Pulczynski, Elisa Jacobsen TPS7131 Pulido, Gema e11530 Puligedda, Rama Devudu e22163 Pun, Rashmey e12572 Punatar, Sachin e17027 Punatar, Snehal e12520 Punt, Cornelis J. A. 3502, 3533, 3552, e14584 Puntoni, Matteo TPS649, 1516, 1517, TPS1610 Pupic, Gordana e20002 Pupo, Alexandra e15172 Purim, Ofer e15078, e22111 Purkayastha, Das 7053^ Pursglove, Stephanie 10541, e21503 Purtell, Michael J. e14647 Pusceddu, Sara 4136^ Pushpalatha, Kameshwarachari e16511 Pusztai, Lajos 532, 598, 1013, 1549, 1565, 2587 ABSTRACT AUTHOR INDEX

769s

Putnam, Joe B. 7502, 7524 Putnam, Samuel G. e14545 Puttabasavaiah, Suneetha 2596 Puttawibul, Puttisak 558, 561 Putter, Hein 595, 597, 1028, 8568 Puzanov, Igor CRA9006^, CRA9007, LBA9008 Puzone, Roberto 11063

Q Qaddoumi, Ibrahim A. 2035 Qamar, Rubina 3501 Qaqish, Bahjat F. TPS6097 Qazilbash, Muzaffar H. 7010, 7011 Qi, Jing 3635 Qi, Lihong 8049 Qi, Songtao 2022 Qi, Yingwei 2551 Qi, Yuan 1013 Qian, Dajun 3089 Qian, Junqi e22203 Qian, Liting e22018 Qian, Wendi 3018 Qian, Yi e20514 Qiang, Zhou e15125 Qiao, Gui-bin 7537 Qiao, Wei 7089 Qiming, Wang e19085 Qin, Dujie e13538 Qin, Jing 7590 Qin, Li-Xuan 10512, 10520, 10558, 10580 Qin, Lu 3104 Qin, Rui TPS1608, 3501, 4032, 5517, 6587, e16061, e17538 Qin, Shukui LBA4001, 4109, TPS4163, 7507, 10501^, e15622 Qin, Xinyu 3610 Qiu, Jianhong e15547 Qiu, Lu-Gui 8525 Qiu, Xin 4077, 6543, 9536, 9551, 11057 Qu, Angela Q. 4524, 4530, 4539 Qu, Jinglei e15160 Qu, Kunbin 11018 Qu, Shuxian e15582 Qu, Xiujuan e15160, e19004 Quach, David e12508, e20690 Quadrini, Silvia e12031, e20619 Quadt, Cornelia 2531 Quagliuolo, Vittorio 10519 Quah, Cheng Seok 523 Quale, Renae M e20565 Quan, May Lynn 1002 Quaranta, Annamaria 618, e14605 Quaresma, Luisa e15172 Quattrone, Pasquale 6020 Quebbeman, Edward TPS4147 Queirolo, Paola 9035, 9046, 9065, 9070, 9548 Queiroz, Cleberson Jean dos Santos e22150 Quek, Ruben G. W. e16029, e16039 Quenet, Francois e14534, e14621 Quer, Nuri e19159 Queralt, Cristina e19088 Quereux, Gaelle e20022 Quesada, Jean-Louis e15593 Quesenberry, Peter J. e14637 770s

Quevedo, Fernando 5082, CRA9003, 9037, e16061 Quiel, Luis e12526 Quigley, Jane M e12508, e20690 Quigley, Michael 3061, 11074 Quijano, Yolanda 3543 Quiles, Francisco e12516 Quill, Timothy A e17530 Quinatana-Angel, Begona e15107 Quinaux, Emmanuel 3542 Quindós Varela, Maria e15542, e22171 Quinlan, Michelle 2593 Quinn, David I. 4501, 4527^, 4531, 5062, 9632, 11040, 11047, e15624, e16020, e16073 Quinn, David 4517 Quinn, Gwendolyn P. e12556 Quinn, Jennifer E. TPS11120 Quinn, Michael TPS5614 Quinn, Susan 6041 Quinones, Adolfo 2594 Quintana, Shirley 7072 Quintanal, Alvaro e22045 Quintanilla Guzman, Arturo e14708, e22016 Quintanilla-Fend, Leticia e20050 Quintas-Cardama, Alfonso 7090 Quintela-Fandino, Miguel 11033 Quinton, Cindy L. e17503 Quintyne, Keith Ian 1591 Quiroz, J. e22207 Quispel Janssen, Josine 7581 Quitadamo, Daniela e22149 Quoix, Elisabeth A. 7505, 7515, 8009, 8081, e19058 Quon, Doris 2550 Qureshi, Sophia e22184 Qureshi, Waqas e22184 Qvortrup, Camilla e14710

R R, Rodriguez e14559 R, Serrano e14559 Raab, Hans-Rudolf 3538 Raab, Marc S. 8542 Raab, Rachel Elizabeth 1069 Raab, Stefanie 3054 Raamanathan, Archana 1569 Rabe, Kari G. 7015 Raben, Adam 9525 Raben, David 6007 Rabin, Michael S. 8116, e19125 Rabinovitch, Rachel TPS666 Rabinowits, Guilherme 6023, 6088 Rabius, Vance A. 1564 Racadio, John M. 10047 Racadot, Severine 6056, e17011, e17012 Racca, Manuela 10583 Race, Amanda 2525 Rack, Brigitte Kathrin 638, 640, 3064, 11042, 11043, e22059, e22075 Radbruch, Lukas 9563 Radecka, Barbara 604 Rademaker, Alfred 8036, 9087, e13568 Radford, John TPS8612


Radford, Nina 1520 Radhakrishna, Khajjayam e15143 Radhakrishnan, Vivek Sulekha e20686 Radheshyam, Nayak 6624, e19092 Radhi, Saba 7060, 8591, e18527, e22003, e22052 Radi, Sanaa H 3083 Radic, Jasna e15603 Radice, Davide e15124 Radimerski, Thomas 7111 Radina, Elise e20558 Radke, Cornelia 3634, e14513, e14562 Radosevic-Jelic, Ljiljana 3560 Radosevic-Robin, Nina 1057, 1058, e11615 Radossi, Andrea 9530 Radova, Lenka 1063, e22109 Radovich, Milan e22192 Radulovic, Sinisa e22115 Radwan, Rachel R. 5563 Raef, Hussein 4138 Raefsky, Eric 2544, e22139 Raetz, Elizabeth A. 10001, 10002, 10003 Raez, Luis E. e17540 Rafeeq, Safia 4134 Raffaele, Palmirotta e14581 Raffeld, Mark 7513, 8026 Rafii, Saeed 5587 Rafiq, Sobia e14680 Raftopoulos, Harry e19145 Ragazzini, Angela 3517, e14512 Raghav, Kanwal Pratap Singh 3529 Raghavan, Derek 4531 Raghavan, Vidya e20677 Raghavendra, Rao M. 6624, e19092 Raghupathy, Radha e19525, e19529 Raghuvamsi, Nadiminty e15143 Ragin, Camille 7560 Ragupathy, Rajan TPS1143 Rahatli, Samed e11532, e16526, e16528, e16536 Rahberg, Robert e15018 Rahma, Osama E. e15177 Rahman, Abu Ahmed Zahidur 7042 Rahman, Farah 9546 Rahman, Nam Atiqur 2510 Rahman, Rifaquat 2075 Rahnenfuehrer, Joerg 615 Rai, Kanti Roop 7017, TPS7133, 8500 Raimbourg, Judith e18532 Raimondi, Susana 10005 Raimondo, Luca 6038, 6039 Raina, Vinod 628, TPS4162, 7081, 7082, 8053, e12539, e19524, e19526, e19531, e22098 Rainey, Kim 1538 Rainville, Irene R. TPS1606 Raisch, Dennis W. e22181 Raiti, Concetta e20541 Raizer, Jeffrey J. 2013, 2019^ Raj, Ganesh 4581 Raja, Fharat 5514 Rajagopal, Sudhashree e17503

Rajala, Jennifer e16086 Rajamanickam K., Deepan 7043, e18004 Rajan, Arun 2527, 6524, 7513, 8026 Rajapaksa, Amanda 3015 Rajappa, Senthil Jagannathan e13010 Rajappa, Senthill J. 577 Rajaraman, Preetha 4536 Rajdev, Lakshmi 4011, 4012 Raje, Noopur S. 8584, 8588, 8589 Rajec, Jan 4556, e15599 Rajendra, Rajeev e21502 Rajeshkumar, N. V. 4063 Rajguru, Saurabh 6512 Raji, Olaide TPS11120 Rajkumar, S. Vincent 8541, 8600 Rajkumar, Vincent 8516, 8517, 8592, 8606, e19517 Rajky, Orsolya 2059 Rajmohan, Yanchini 6585, e17526 Rajpal, Megha 2553 Rajpal, Tanuja 5564 Raju, Savitha S. 5563 Rakovitch, Eileen 1002 Ralya, Andrew T. 2538 Ram, Siya TPS2627 Ram, Zvi 2080 Ramacci, Carole e11560 Ramadan, Islam Elsayed e12567 Ramadan, Wegdan 3083 Ramade, Antoine e17011, e17012 Ramaekers, Ryan C. 6539 Ramage, John 4031 Ramaiya, Nikhil H. e19125 Ramaiya, Nikhil LBA10502 Ramakrishna, Bharath e16019 Ramakrishna, Satvik 7554 Ramakrishnan Geethakumari, Praveen e17578 Ramakrishnan, Vanitha 645 Ramalingam, Suresh S. 2610, 6611, 7510, 7560, CRA8007, 8073, 8106, TPS8126, e14612, e19094 Ramalingam, Suresh S 6083, 7508, 7589, e20596 Ramamurthy, Rajaraman e17002 Ramamurthy, Uma 10023 Raman, Siva P. 4057 Ramanathan, Ramesh K. 2580, 2593, 2608, 2617, TPS2621, 4005^, 4038, 4058^, 4059^, 4063, e15014, e15089, e15128, e15188^, e19002 Ramani, Rupal 9545 Ramaswamy, Bhuvaneswari 1023 Rambally, Brooke S. 5519 Ramchandren, Rod 8533, 8534 Ramdani, Mohamed 4028 Ramée, Jean François 3515 Ramello, Monica e13514 Ramesh, K. H. 7125, e22196 Ramesh, Naveen 10577 Ramirez, Carey e20677 Ramirez, Gabriela 9615 Ramirez, Jacqueline 2570 Ramirez, Jose Luis 11025 Ramirez, Jose 7547 Ramirez, Pedro T. e16556 Ramirez, Robert A. 7569 Ramjeesingh, Ravi 1593

Ramkissoon, Shakti Ramlau, Rodryg

2015, 2030 2031, 7500, 8043, 8051^ Ramnath, Nithya 7522 Ramon y Cajal, Teresa e12513 Ramondetta, Lois M. 3, 5527, 5608 Ramos Vazquez, Manuel 1027, 1031, e12558 Ramos, Corinne 2616 Ramos, Rafael 10529, 10532 Ramos, Ricardo Emanuel De Oliveira e20691 Ramos, Teresa e19027 Rampias, Theodoros 6012 Rampini, Mariana Pereira 6071 Ramsden, Katherine 7551, e19039, e19131 Ramsey, Scott David 1505, e14585, e17527 Ramsey, William Jay 3026, 3069, 8094 Rana, Cheena e20012 Ranade, Anantbhushan 1071 Ranade, Koustubh e20047 Ranallo, Lori 1026 Ranasinghe, Weranja Kalana Bodhisiri e16016 Ranchere-Vince, Dominique 10574, 10575, 10578, 10579 Ranchon, Florence e13594 Randall, James Michael e15562 Randall, R. Lor LBA10504, 10528, 10587 Randerath, Winfried 1589 Randhawa, Jaskirat Singh 1038 Randi, Lorenza e20694 Randolph, Shannon 6581 Randolph, Sophia 519, TPS652 Rane, R. C. 577 Ranft, Andreas 10031 Ranganath, Praveen e19009 Rangarajan, Sunil 7104 Rangarajan, Venkatesh e19503 Rangaraju, Ranga Rao 8053 Ranger-Moore, Jim e11507 Rangwala, Reshma A. 5572, e16544 Rani, Aradhana 8574 Rani, Lata e22098 Rani, Sweta 620, e11520 Ranieri, Girolamo e22104 Ranjan, Smita 3102 Ranjan, Tulika 2094, e13015^ Ranpura, Vishal Navnitray e13573, e15577, e15578, e20700 Ranson, Malcolm 4511, e22035 Rao, Aparna e17535 Rao, Arati 7107 Rao, Aroor R. e15001 Rao, Deva Magendhra e17002 Rao, Donald e16043 Rao, Gowtham A. 5091 Rao, Kamakshi V. e13507 Rao, Madhu TPS4146 Rao, Naveen 9608 Rao, Raghunadha 8053 Rao, Shyam S. 6034 Rao, Srikar 6062 Rao, Uma N. M. CRA9007, 9043 Rao, Vijay Phooshkooru LBA8003

Raoul, Jean-Luc TPS4159 Rapado, Immaculada 8511 Rapatoni, Liane e15190 Rapold, Roland e20542 Raponi, Mitch 4007, e22092 Rapp, Stephen R. 2006, 2051, 9505 Rapp, Steve 6564 Rappold, Erica 628, 8029 Raptis, George 1118 Rasch, Coen R.N. 6057 Raschella’, Guido 9554 Raschioni, Carlotta e14611 Rasco, Drew Warren 2500, 2547, TPS2618, e22088 Rashed, Waffa 10044 Rasheed, Zeshaan 4063, e14647 Rashid, Asma e12033 Raskin, Stephen 4037 Rasool Javaheri, Khodadad e14603 Raspagliesi, Francesco LBA5501, TPS5616, 11037 Rassool, Feyruz 7049 Rastogi, Priya TPS657, 1033, TPS1139 Rastogi, Shishir 10527, e21522 Rasul, Kakil e19035 Ratain, Mark J. 534, 2570, 2571, 6501, 6612, 9520, 11053 Rath, Goura Kishor e13014, e13034, e13043, e20679 Rath, Sushmita 6085, e12520 Rathbone, Dustin D. 10512 Rathenborg, Per 5001 Rathkopf, Dana E. 5004, 5009, 5010, 5013, 5037, 5066, 5073, 5090, e16001 Rathmell, Kimryn 4522 Rathod, Shrinivas Narayan e18525 Rathode, Om Singh 7079 Rathore, Bharti e15095 Ratti, Margherita 4112, e15086, e15502 Ratto, Giovanni Battista TPS7606, 11063 Rau, Jörn LBA5503 Rau, Kun-Ming 4018 Rau-Murthy, Rohini 1552, 1555, e12527, e12536 Raubitschek, Andrew Antony 8556, TPS11121 Raucci, Maureen 6635 Rauch, Daniel 7503, 8060 Rauckhorst, Myrna TPS3127, TPS5104, e16036 Raufi, Ali 7084, e18001 Rauh, Jacqueline 3586 Rauh-Hain, Jose Alejandro 5604, e13564 Raut, Chandrajit P. 10510, 10538 Rauthan, Amit e11510 Ravaggi, Antonella 5560 Raval, Priyanka 7105 Ravandi, Farhad 7024, 7029^, 7068, 7074, 7089, 7095 Ravaud, Alain 4576, TPS4592 Ravegnini, Gloria 10510 Ravelo, Arliene 2005^ Ravenda, Simona Paola e22078

Ravi, Diwakar B 6624 Ravi, Vinod 10049, 10577 Ravichandran, Sriram e20686 Ravipati, Hari Prasad 8609 Ravizza, Davide e15147 Ravn, Jesper 7504 Rawat, Krishna e11546 Rawcliffe, Charlotte Louise 4006 Ray Coquard, Isabelle 10548 Ray, Arghya 8582 Ray, Monali e11597 Ray, Satadru e11588 Ray, Sudeshna e20707 Ray, Ujjal Kanti 7114, e16542 Ray-Coquard, Isabelle Laure 5567 Ray-Coquard, Isabelle LBA5503, 5504, 5515, 5516, 10525, 10542, 10546, 10563, 10568, 10579, e12504 Rayfield, Corbin e13038 Raymond, Eric 4041, 4118, 6036 Raymond, Marilyn J. 6533 Raymond, S P e12032 Raymond, Steve e16079 Raynaud, Florence I. 2608 Rayson, Daniel TPS664, e17564 Rayter, Zenor 5 Raz, Avraham e22168 Raza, Azra 7031 Raza, Fatima Zehra 3102 Razak, Albiruni R A 2505, 2561^ Razak, Albiruni R.A. 2517, 2534, TPS2618, 6022, TPS10593 Razis, Evangelia 1093 Razmaria, Aria e16084 Razzini, Giorgia e11515 Re, Juan Pablo e11600 Rea, Daniel 5, TPS656 Rea, Delphine 7048, 7053^, 7066 Rea, Domenica 631 Rea, Silvio e14521 Reade, Clare J. 5543 Ready, Neal 7506, TPS8121 Real, Francisco X. 1529 Reale, Michael A. e19514 Reardon, David A. LBA2009, 2013, 2015, 2030, 2075, TPS2104 Reaume, M. Neil Neil TPS4594, e15591 Reaume, Martin Neil TPS4593 Reber, John e17512 Rebollo, Joseba 3074, e22120 Reboucas, Danilo Souza 9589 Recchia, Cornelia Ortensia Carla e14521 Recchia, Francesco e14521 Rechis, Ruth 9608 Rechoum, Yassine 579 Rechsteiner, Markus 9025 Recht, Abram 7553, 7554, e18506, e18552 Recht, Cathy Kahn e13021 Recht, Lawrence David e13021 Recine, Federica 4525 Reck, Martin TPS7608, LBA8011, 8013, 8014, TPS8117, e19022, e19126 Reckamp, Karen L. 2564, 8026, 8027, 8028 Recklitis, Christopher J. 6544, 9529, 9644

Redana, Stefania e11581 Reddy, Akhila Sunkepally 9642 Reddy, Chandana A. e16004 Reddy, Nishitha M. TPS8619 Reddy, Pavan S. 9531, TPS9651 Reddy, Poluru L. 6066 Reddy, Rishinda 6637 Reddy, Sandeep K. 2041, e19006 Reddy, Sangeetha Meda 3540 Reddy, Vishnu 7591, 8057 Redfern, Charles H. 5047^ Redhu, Suman 8029 Redlich, Ines e17015 Redman, Mary Weber 7510, 7511, 7527 Redmond, Kevin P. 6007 Redner, Robert 7059 Redon, Christophe E. 2527 Redondo, Andrés 5544, e12558 Redondo, Maximino e22091, e22131 Ree, Anne Hansen 3547 Reece, Donna Ellen 8542, 8545 Reece, Donna E. e19509 Reed, Damon R. LBA10507 Reed, Daniel R. 9525 Reed, Eddie e13566, e22008 Reed, Greg 2558 Reed, Kathleen 9012^ Reed, Michael 7553, e18506, e18552 Reed, Nicholas 5571 Reed, Robert 1566, 1603 Reed, Shelby D. 6554, 6631 Reed, Thomas D. 3022 Reeder, Alex TPS11123 Reeder, Bruce 3580 Reeder, Craig B. 8514 Reeder-Hayes, Katherine Elizabeth 1077, 6572 Reeh, Matthias 11014 Rees, Jeremy 2007 Rees, Myrrdyn 3504 Reeve, Bryce B. 6530, 6555, e17560 Reeves, James Andrew 8559 Refaat, Tamer 3083, e17013, e22204 Refshauge, Kathryn M. 9616, e20533 Regales, Lucia e15059 Regan Downey, Cara e14519 Regan, Meredith M. 529, TPS4588^ Regan, Scott 3500 Rege, Jessicca 563 Regina, Anthony e13013 Regitz, Evi 8569 Regnier, Catherine 7111 Regnier, Veronique e13594 Regnier-Rosencher, Elodie e20032 Regolo, Lea TPS1610 Reguart, Noemi e19089 Rehal, Pauline 11094 Rehemtulla, Alnawaz TPS5094 Rehman, Zia e14515, e20550 Reich, Gernot e14532 Reich, Lilian 4534 Reich, Richard R. 9603 Reich, Steven D 612 Reichardt, Peter 10501^, 10503, 10551 ABSTRACT AUTHOR INDEX

771s

Reichert, Dietmar Arno Reichert, Sonia Evelyn Reichman, Leah Reichrath, Joerg Reid, Glen Reid, Gregory K. Reid, Joel M. Reid, Julia E. Reid, Mary E. Reid, Thomas J. Reid, Tony R. Reid, Victoria Ann Reidy, Diane Lauren Reifenberger, Guido

602 e13524, e20570 10020 8569 7586 7116, 8535 2538, e17017 5005, 5043 1566, 1603 3 4054 e11509 3605, 4032, e15133 2027, 2081, TPS2103

Reifer Hildebrand, Jessica Ann e17500 Reiffers, Josy 7052^ Reifur, Lucas e20631 Reig, Óscar e14588, e16049, e17580 Reijm, Esther Anneke 11045 Reilly, Paul e20663 Reilly, Robert TPS8122 Reimer, Daniel Uwe 5569 Reimer, Peter e14502 Reinel, Hans 3531 Reiner, Maureen e20564 Reinert, Anne 1095, 2605, TPS2623 Reinke, Denise K. 10522, TPS10591 Reinke, Denise 10524 Reinthaller, Alexander e16524 Reis, Rui Manuel e13557, e13559 Reis, Rui M. e19069 Reisman, Arlene 8108 Reisman, David 4077, 11057 Reiss, Krzysztof e13581 Reitsma, Dirk J. 3009, e17586 Reitze, Nicholas J. 7532 Rekhi, Bharat 5554 Rekhtman, Natasha 7559, 7593, 7600, 8022 Relling, Mary V. 10004 Reman, Oumedaly TPS8615 Rembert, Debra 7065 Remick, Scot C. 8524 Remon, Jordi e19089 Remotti, Helen Elaine e14659 Ren, Li 3610 Ren, Min 5520, 5591, 9026 Ren, Shengxiang e19166, e22186 Ren, Tong e13530 Ren, Xiu-Bao e15622 Renault, Patrick 7505 Rendleman, Justin 1500, 9021 Rendon, Ricardo A. 5048 Renfro, Lindsay A. 3618, 3640, 7510, e14526 Rengan, Ramesh 7578 Rengucci, Claudia e16530 Reni, Michele 4005^, e15057 Renn, Alex 3036 Renne, Giuseppe 589 Renne, Mariuccia TPS1610 Rennert, Gad 5576 Rennert, Hedy S. 5576 Renouf, Daniel John 2534, 3569, 3624, 4061, 4077, 6502, e14607, e22020 772s

Renschler, Markus F. 9030, e19037, e19038, e20025 Renschler, Markus Frederic 4005^ Renton, Corrinne e14582 Rentschler, Jochen 8560 Repp, Roland 8604 Reschovsky, James D. 6544 Resci, Federica e19527 Rescigno, Paola e12028, e12534 Rescigno, Pasquale 7603, e18536, e21500 Resemann, Karin 3625 Resende, Alexandre Prado e15199 Reshef, Ran 8578 Reske, Thomas e12501 Resnick, Matthew 6532 Resnick, Murray B. 3639 Ress, Anna Lena e15064 Resteghini, Carlo 6020, 6027, 6046 Restrepo, Alejandro 8539, 8595 Restuccia, Silvia e13579 Rethwisch, Volker e17021 Retout, Sylvie e13508 Retseck, Janet 9566, 9635 Retz, Margitta TPS4591 Reuben, James M. 9646, TPS9650, e14567, e22023 Reungwetwattana, Thanyanan 11119 Reusch, Uwe 3068 Reuschenbach, Miriam 4065 Reuss, Alexander 5553 Reuter, Christoph W. e16024, e16064 Reuter, Christoph 5019 Reuter, Dirk 4009 Reveles, Xavier e22088 Revels, Sha’Shonda L. 6637 Revillion, Francoise 536, 544 Revnic, Julia 9563 Rey, Augustin A. 5516 Rey, Jean-Baptiste 5567, e12504 Rey, Severino e22120 Reyderman, Larisa e11586 Reyes, Carolina M. 7016 Reyes, Carolina 6546, e17561 Reyes, Diane K. 4124 Reyes, Evelyn e11583 Reyes-Botero, German 2020, 2067 Reymond, Marc A e16523 Reynes, Gaspar 2087 Reynolds, Christopher M. 2562 Reynolds, Craig H. 8004, 8012, 8052, 8086, e19150 Reynolds, John Vincent e15142 Reynolds, Kerry Lynn 647 Reynolds, Robert B. e11590 Reynoso, Nancy 4555 Rezaee, Rod 6035 Rezaei Kalantari, Hassan e14587^ Rezaei, Mansour e15195 Rezai, Keyvan 2599 Rezai, Mahdi TPS655^, 1004, 11042 Rezash, Victoria e16022 Rezk, Julie 6040 Rha, Sun Young 4089, 4504, 4565, 4578, 4586, e15098, e15144, e15518, e15573 Rhee, Ina Park 4505, e14505 Rhee, Ye-Young 3550


Rhei, Esther Rheingold, Susan R.

1117, 1133 7097, 10007, TPS10072 Rhines, Laurence D. e17588 Rhodes, Dan 11017 Rhodes, Lori e20567, e20685 Ribas, Antoni 2528, 3020, 9009 Ribeiro, Adriana Regina G. e11503, e15184, e17032 Ribeiro, Heber Salvador de Castro e15184 Ribeiro, Karina Braga 10010, 10011, 10036, 10054, 10061 Ribeiro, Larisse Soares e20524 Ribeiro, Rachel e22176 Ribeiro, Raul Correa 10005 Ribeiro, Rosy Iara Maciel Azambuja e22122 Ribeiro, Sofia e22072 Ribelles, Nuria 1027 Ribera, Josep-Maria 8524 Ribero, Dario 4129 Ribrag, Vincent 8522, 9556 Ricard, Sevrine 9069 Ricart, Alejandro D. 612 Ricasoli, Miriam 11058 Ricca, Luana 3606 Ricchini, Francesca e12017 Ricci, Claudio 4048, e15069 Ricci, Deborah Sokol 5004 Ricci, Marianna 11022 Ricci, Sergio 4136^, 4138, e15589, e20711 Ricciardi, Giuseppina R. R. 1062 Ricciardi, Giuseppina e11526 Riccobon, Angela 3040 Rice, David C. 4083, 4085, 7552, e15013 Rice, Kevin R. 4554 Rice, Michele A. e17590 Rice, Shawn J e13530, e13533 Rice, Thomas W. 4087, e15000 Ricevuto, Enrico e14596 Rich, Elizabeth Shima e18013 Rich, Shayna Eliana e17571 Richard, Carole S. e15094 Richard, David J. 7022 Richardet, Eduardo Arnoldo e15610, e16100 Richardet, Martin Eduardo e15610 Richardet, Martin e16100 Richards, Alison 6541 Richards, Catherine A. 6509 Richards, Donald A. 2533, 8027 Richards, Kelly 10008 Richards, Kyle A. e16084 Richards, Lori 3015 Richards, William G. 7588 Richards-Yutz, Jennifer e15563 Richardson, Andrea L. e17574 Richardson, Andrea 1132 Richardson, Harriet 6557 Richardson, Jennifer e22183 Richardson, Katherine 11044 Richardson, Lisa Carolyn 1130 Richardson, Lyndsay 1593 Richardson, Paul Gerard Guy 8512^, 8531, 8532, 8542, 8584, 8588, 8592, 8602 Richart, John M. e20049, e20661

Richiardi, Lorenzo Richie, Jerome P. Richly, Heike Richman, Laura Richon, Catherine Richter, Emily L. Richter, Michael Richter, Oliver von Richter, Rolf

1582 e16026 4035 e20047 2512 6586 6077 2530, 4041 5549, 5553, 5569, e22102 Richter, Stephan e21518 Richters, Lisa 508 Ricigliano, Mark 4017 Ricke, Jens e22040 Riddell, Angela M. TPS4156 Riddle, Matthew 1578 Rider, Alex e16046 Rider, Jennifer R 5078, 5086 Ridner, Sheila H. 6049, e20531, e20558, e20599 Ridolfi, Laura 3040, 9548, e15589 Ridolfi, Ruggero 3040, 9065, 9070, e20028 Ridwelski, Karsten e14513, e14562 Riebandt, Grazyna e11508 Riechelmann, Rachel Pimenta e15090 Riechelmann, Rachel e14652 Riecken, Kristoffer 7027 Riedel, Elyn 9524 Riedel, Richard F. e20674 Riedemann, Lars 2056 Rieder, Ronald J. 7050 Riely, Gregory J. 7593, 7600, 8009, 8018, 8025, 8032, 8036, 8067, 8083, 8105 Riera-Knorrenschild, Jorge 3643 Riesco Martinez, Maria C. 6552 Riesenberger, Tracy A. e13538 Riess, Hanno 4016 Riess, Jonathan e19147 Riester, Scott M. 10531 Riethdorf, Sabine 11012, 11014 Rietjens, Mario e20634 Rieux, Chantal 9510 Rifkin, Robert M. 5034, 8586, 8596 Rigakos, Georgios 4558 Rigal, Olivier 9510 Rigas, James R. TPS7609 Rigau, Valerie 2067 Riggi, Marcello 8043 Righi, Luisella LBA8005 Rigo, Paul e18007 Rigotti, Nancy 7525 Rihawi, Karim e15615 Riisnaes, Ruth 3062 Rijavec, Erika TPS7606, 8035, 11063 Riley, Christopher 7062 Riley, Tom 1523 Riley, W. Anthony e20638 Rilling, William S. 6586 Rim, Alice 1508 Rimar, Joan 6635 Rimassa, Lorenza TPS4159, e14611 Rimm, David 1085, TPS1609, 6012, 6081, 11075 Rimoldi, Donata 9014 Rimsza, Lisa M. 8562

Rinaldi, Antonio 618, 11058 Rinaldi, Gaetana 9035, 9065, 9070 Rinaldi, Yves 3515 Ring, Brian e18539 Ring, Jennifer E. e18541 Ringash, Jolie 4053, e17007 Ringel, Florian LBA2000 Ringshausen, Ingo TPS4158 Rini, Brian I. 4515, 4520, 4565, 4578, 4586, TPS4593, TPS4595, e13521, e15518, e15534, e15624, e17530 Rinke, Anja 4030 Rinn, Kristine CRA1008 Rinne, Mikael 2015, 2030 Rino, Yasushi 4068 Rio-Frio, Thomas 2615 Rios Ibarra, Clara Patricia e14708, e22016 Rios, Maria 10546, 10548, 10563 Rioufol, Catherine e13594 Ripa, Cristina e20650 Riphagen, Ingrid e22128 Ripple, Michael 2085 Riquet, Marc e22001 Ris, Hans-Beat 7503 Ris, M. Douglas 10009 Rischin, Danny TPS5612 Risio, Mauro TPS3648 Riska, Henrik 7504 Riska, Shaun M. 5082 Rispoli, Anna Iolanda e12021 Rissling, Michelle 9504 Ristic, Mirta TPS8119 Ristow, Kay 8538 Ritch, Paul S. TPS4147, e15082, e15128, e15188^ Ritchie, Alastair W. S. 5012 Ritchie, Diana 1015 Ritgen, Matthias 7004 Ritter, Deborah 8577 Ritter, Timothy 7522, 7579 Rittmeyer, Achim 8014, e19108 Ritzwoller, Debra Pearson 6018 Riva, Giuseppe 6038, 6039 Riva, Nada 11022 Rivadeneira Cabana, José Antonio e14589 Rivard, Colleen Lee e20571 Rivarola, Edgardo G. J. 6596, e17539, e20636, e20656 Rivas Estilla, Ana Maria e22016 Rivas-Ruiz, Francisco e12013 Riveiro, Maria Eugenia e14536 Rivera, Fernando 3511, 3620, 3631, 4098, e14561 Rivera, Lorna 6529, e20606 Rivera, Victor M. 7001, 7063, TPS7129, 8031, 10509 Rivera-Luna, Roberto 3050 Rivera-Rodriguez, Noridza e11610, e19505, e19510 Riviere, Isabelle TPS3115 Rivoire, Michel 3619^ Rivoltini, Licia 9092 Rixe, Olivier 2560, 2609, e13023, e13518 Rixecker, Tanja 8570 Rizack, Tina 619 Rizel, Shulamith e11578

Rizivi, Saiyada N. F. e22128 Rizo, Aleksandra TPS8613^ Rizvi, Azhar e20613 Rizvi, Faraz 9555 Rizvi, Naiyer A. 2530, TPS3106, 7558, 8067, 8072, TPS8121, TPS8122, 9012^ Rizzi, Anna e13514 Rizzi, Daniele 618, 8071 Rizzi, Giada 9512, LBA9514, e20716 Rizzieri, David 7029^, 8535 Rizzo, Alicia e22051 Rizzo, Mimma e14565, e15524, e15528 Rizzo, Monica 562, 3032 Rizzo, Pietro 8071, e14605, e18545 Ro, Jungsil 551, e11584 Roa-Garcia, Diana Marcela e19159 Roach, James e15012 Roach, Mary e15136 Roach, Nancy 6500 Roadcap, Lori 11026 Rob, Lukas e22129 Robar, James 5048 Robb, Claire TPS4156 Robbins, Edward T. 7569 Robbins, Samuel G. 7569 Roberson, Jacquelyn 1557 Robert, Caroline 9004, 9009, 9020, 9028, 9030, 9069, TPS9105^, TPS9106, e20025, e20041 Robert, Francisco 3059, 7591, 8057, e19143 Robert, Nicholas J. TPS11123 Roberto, Vincenza 4136^ Roberts, Andrew Warwick 7018 Roberts, Andrew W. 8520 Roberts, Anne C. 9500 Roberts, John D. 6022 Roberts, Kenneth B. 6511 Roberts, Olumuyiwa Adebola 5606 Roberts, Toni K. e12030 Robertson, Alysia e12573 Robertson, Chris e12507 Robertson, Iain K. e20610 Robertson, John Forsyth Russell e11567 Robertson, Paul Alexander e20569 Robidoux, Andre 574, 1018 Robin, Yves Marie 10525, 10574, 10575 Robinet, Gilles LBA8002, 8059 Robinette, Michael 4568 Robinette, Natasha e17033 Robins, H. Ian 2003, 2004, 2044 Robinson, Anne 5 Robinson, Austin A. e20044 Robinson, Cliff Grant 7523 Robinson, Timothy J. 6554 Robison, Katina 1545, 6590, e20543 Robison, Leslie L. 6544, 9570, 10019, 10022, 10032, 10062 Robles, Carlos Enrique e15550, e19160 Robles, Javier e15111

Robles, Robert Leon Roblin, Douglas Robson, Mark E.

8559 6523 1511, 1552, 1555, e12536 Roby, Katherine 2558 Roca, Lise e14621 Rocafiguera, Albert Oriol 8510, 8527, 8528, 8583 Rocca, Andrea e11521, e16530 Rocchetto, Marco 5548 Rocchi, Palma e16067 Rocco, Gaetano 7602, 8066 Rocconi, Rodney Paul TPS5616 Rocha Lima, Caio Max S. 3007 Rocha, Flavio G. 4043 Rocha, Lucila Soares da Silva 2060, 9561 Rocha, Rafael Malagoli e11503 Roche, Henri Hubert e13519 Rockall, Andrea 2525 Rockhill, Jason K. e13017, e13018, e13041, e20048 Rockich, Kevin 2012 Rockne, Russell e13017, e13018, e13028, e13041 Rocque, Gabrielle Betty e20565 Rodeberg, David A. 10012 Rodeberg, David Anthony 10554 Rodeghier, Mark e17502 Roden, Anja e19013 Rodenhuis, Sjoerd 1010 Roder, David 1581, 6598 Roder, Heinrich 5575, LBA8005 Roder, Joanna 5575, LBA8005, 8044 Rodgers, Valerie e19115 Rodig, Scott J. 8039 Rodin, Gary e20639 Rodler, Eve T. 1090, 10522, TPS10591, e21502 Rodolfo, Monica 9092 Rodon Ahnert, Jordi 2561^, TPS3646 Rodon, Jordi 2016, 2039 Rodrigo, Isabel e12013, e22091, e22131 Rodrigues, Angelica Noguelra 1587 Rodrigues, George e19120 Rodrigues, Gustavo Henrique 7037 Rodrigues, Heloisa Veasey e17554 Rodrigues, Maria Clarissa de Faria Soares 10010 Rodrigues, Pedro Carvalho 6071 Rodriguez Abreu, Delvys e20007 Rodriguez de la Borbolla, Maria e11577 Rodriguez Fahrni, Ana Milena e14570 Rodriguez Lopez, Carmela e16095, e20708 Rodriguez Rubi, David Jose e14617, e19034 Rodriguez Sanchez, Angel e15609 Rodriguez Silva, Claudia e14708 Rodriguez Villalva, Silvia e20705 Rodriguez, Angel Augusto TPS1136 Rodriguez, Blanca e19510 Rodriguez, Cesar Augusto 1027,

e12015, e12558, e22112 Rodriguez, Claire TPS2625 Rodriguez, Cristina P. 4087, 6035, 6061, e15000 Rodriguez, Gladys Isabel e22088 Rodriguez, Ignacio 11078, e22068, e22119 Rodriguez, Jaime 8079 Rodriguez, Jose Reyes e15107 Rodriguez, Juan Jose Jose e22060 Rodriguez, Maria Alma 9538, 9539, e20645 Rodriguez, Maria e19112 Rodriguez, Pedro Camilo 3013 Rodriguez, Pedro e11583 Rodriguez, Rosa D. e15037 Rodriguez-Bigas, Miguel A. 1525, 1546 Rodriguez-Cid, Jeronimo e22151 Rodriguez-Galindo, Carlos TPS9104, 10010, 10011, 10036, 10054, 10061, 10536, e17573 Rodriguez-Garzotto, Analia 9641 Rodriguez-LaRocca, Alicia G. 2612 Rodriguez-Lescure, Alvaro 1027, 1031, e22112 Rodriguez-Martin, Cesar 1031 Rodriguez-Moreno, Juan Francisco 4587, e16028 Rodriguez-Morera, Anna e20704 Rodriguez-Pascual, Jesus 3543 Rodriguez-Peralto, Jose Luis 1041 Rodriguez-Riao, Juan J. e16521 Rodríguez-Villanueva, Julio e12015 Rodrigus, Inez 7534 Roe, Kathrine 3547 Roe, Laura e15508, e15605 Roebert, Justin Kelvin 11015 Roedel, Claus 1121 Roemer-Becuwe, Celia 3601 Roepman, Paul 3530 Roesler, Grant e19141 Roethke, Matthias e16063 Rofe, Charlotte 4508 Rogak, Lauren J. 6575, 6583, e17560 Rogerio, Jaqueline Willemann 2610, 6083 Rogers, Ailin 3549 Rogers, Michelle 6590, e20543 Roggenkamp, Betty 6609 Rogith, Deevakar 6566, 9576 Rogoff, Harry 2542 Rogowski, Wendy e20544 Rogowski, Wojciech e13560, e15045 Roh, Sang Young e15164 Rohan, Thomas E 1524 Rohde, Alejandro e12013 Rohr, Ulrich Peter e11507 Rohrberg, Robert 4009 Rohren, Eric 11079 Rohs, Nicholas e17589 Roila, Fausto 561, 9614 Roitman, Janna e17566 Rojas Llimpe, Fabiola Lorena e14560, e14717, e15154 Rojas Martinez, Augusto e14708 Rojas Puentes, Luis Leonardo e22028 ABSTRACT AUTHOR INDEX

773s

Rojas, Katerin Ingrid

e12038, e12538 Rojas, M. e22207 Rojas-Hernandez, Cristhiam Mauricio e15136 Rojiani, Amyn 2047 Rojo, Federico 11089, e19000, e19109 Rokkones, Erik 5533 Rolfe, Lindsey 4007 Rolfo, Christian Diego 11028 Rolland, Frederic LBA4500, e16009 Rollins, Barrett J 1531, 2030 Roma, Andres e16518 Roma, Anna e15606 Romain, Sylvie 2024 Romaire, Melissa A. 6514 Roman, Laslo 517 Romanini, Antonella e20028 Romano, Alfredo 4059^ Romano, Andrew Michael e11596 Romano, Carmen 11008 Romano, Emanuela 9014, 9025, 9078, e20011 Romano, Giampiero e20681 Romano, Giovanni 11008 Romeder, Franz e15041 Romejko-Jarosinska, Joanna e19535 Romejon, Julien 2615 Romeo, Margarita e16549 Romeo, Maura 1539 Romero Acuna, Luis 1073, 11118 Romero, Alberto Omar 1073, 11118 Romero, Ignacio 1543 Romero, Pedro e20011 Romero, Pierre Charles 1058 Romieu, Gilles e13519 Rommens, Pol Maria e21505 Romond, Edward H. 541 Roncalli, Massimo e14611 Rondan, Mariela e14682 Rondeau, Stephanie 8560 Rondon, Gabriela 7010, 7011, 8561 Rondoni, Cristina e13579 Ronellenfitsch, Ulrich 10566 Rong, Alan 3511 Rong, Xianhui 7111 Ronicke, Erdmuthe 4030 Ronnett, Brigitte M. e16518 Ronzino, Graziana e11517 Ronzoni, Monica 3505, e14560 Roodhart, Jeanine M. L. e16059, e20653 Roodman, David 8589 Roohan, Patrick R. 6565 Rookus, Matti A. 1502 Roos, Daniel 9502 Root, Dana 7601 Root, Elizabeth J. 10071 Roper, Nitin 6613 Ropero, Santiago 2064 Ropert, Stanislas e13589 Roques, Tom LBA4004 Roquet, Florian 9556 Rorive, Andree e11549 Rosa, Marcela Nunes e13557, e13559 Rosales, Monica e20651 774s

Rosales, Veronica A. e20549 Rosanowski, Barbara e16534 Rosario, Roseanne 5536 Rosati, Gerardo e14557 Rosati, Kayla 619, 6574, 8075, e15095 Rosburger, Christian 1114 Roschewski, Mark J. 8597, e19506 Roscoe, Joseph A. e20526 Roscoe, Robyn e22020 Rose, Amy 9043 Rose, April Ann Nicole 1521 Rose, Christian 7002, 8536 Rose, J Bart 4043 Rose, Peter Graham 5530 Rose, Peter 3500 Rose, Shelonitda 5518 Rose, Steven C. e14545 Rosell, Laura e20504, e20657 Rosell, Rafael 2581, 7514, LBA8002, CRA8007, TPS8123, TPS8126, 11010, 11025, 11027, 11028, 11029, 11067, 11078, e15558, e19088, e19089, e22068, e22119 Roselli, Mario e14581 Rosello Keranen, Susana 3551 Rosen, Alyx C. e13571 Rosen, Barry 5561 Rosen, Lee S. 2500, 2540, TPS2619, 3059, 5551, 8093 Rosen, Lisa M. e16546 Rosen, Michael W. e17519 Rosen, Peter J. 8598 Rosen, Steven T. 8576 Rosenbaum, Eli e16023 Rosenbaum, Eric 8610 Rosenbaum, Paula e16087 Rosenberg, Aaron Seth 1580 Rosenberg, Abby R. 9526, 10012 Rosenberg, Elizabeth 6635 Rosenberg, Eric 6605 Rosenberg, Jonathan E. 4525, 4530, TPS4588^ Rosenberg, Per 5544, 5582, e16547 Rosenberg, Robert 3530, 3612 Rosenberg, Shoshana M. 6507 Rosenberg, Steven A. 10008 Rosenblatt, Jacalyn 8558, 8584 Rosenblum, Lauren 11083 Rosenblum, Marc 7120 Rosenfeld, Ludovic 3601 Rosenkranz, Susan J. e20702 Rosenow, Joshua M. 2083 Rosenstock, Julio e12507 Rosenthal, Adam N. 5507^ Rosenthal, Adam 8603 Rosenthal, Andre 3634, e14513, e14562 Rosenthal, David Ira TPS6099 Rosenthal, David S. 6058 Rosenthal, Joseph 9575 Rosenthal, Mark 2017, 5002 Rosenthal, Seth A 9525 Rosenthal, Volkmar e14513, e14562 Rosenwald, Victoria e20607, e20701 Rosetti, Paola e15055 Roshani, Rozita 11071 Rosin, Jennifer 5611


Rosmorduc, Olivier 4127 Rosolen, Angelo 10028 Ross, Ashley E. 5033, 5089 Ross, Brian Dale TPS5094 Ross, Eric A 6500 Ross, Graham 600 Ross, Helen J. 7545, LBA8003 Ross, Jeffrey S. 534, 1009, 8020, 11000, 11020, 11068, 11100, e15035, e22146 Ross, Joseph S. 6511, 6549 Ross, Mark e22177 Ross, Merrick I. 9047 Ross, Patrick 7573 Ross, Paul J. LBA4004 Rossary, Adrien e11552 Rossetti, James M. 7116 Rossetto, Ciro 6003 Rossi, Agnese e20650 Rossi, Benedito Mauro 11038 Rossi, Carlo Riccardo e22036 Rossi, Christopher 10024 Rossi, Elisabetta e22036 Rossi, Gabriela R. 3007, 8094 Rossi, Giorgia 9512, LBA9514, e20716 Rossi, Lorena e13009, e15524, e15529 Rossi, Maura e14657 Rossi, Michael R. e14612 Rossi, Morgana Stelzer e18515 Rossi, Rosalinda e19099 Rossi, Valentina e11581 Rossig, Claudia 2056 Rossignol, Michel 1578 Rosso, Stefano 4129 Rossof, Arthur H. e17519 Rossoni, Gilda 3038, 8035, e13593, e18528 Rossoni, Gloria e18528 Rossouw, Jacques 1505 Rostami, Shahrbano 7069 Rosti, Giovanni e14557, e15514, e15615, e20541 Rostom, Yousry e17013 Rostomily, Robert e13017 Roszkowski, Krzysztof e22197 Roth, Arnaud 3503, 3522, 3526, 3577, 7503, e14544, e15619 Roth, Beat 4538 Roth, Jack A. 1532 Roth, Joshua A. 1505 Roth, Katherine G. 9049 Roth, Leslie e14637 Roth, Patrick 2079, 2092 Rothe, Francoise 3012, 3588 Rothenberg, Stephen M. 6025 Rother, Mark 3620, e17503 Rothkamm, Kai 11116 Rothman, Michael J. 6635 Rothmund, Ralf 5598 Rothschild, Sacha 8060 Rotmann, Andre e22006^ Rotmensz, Nicole 589, 617, 1061, 1595 Rotshteyn, Yakov e16047 Rottenberg, Yakir 1598 Rottenfusser, Andrea 573 Rottey, Sylvie 2521 Rottmann, Heike 3052

Roubakis, Christopher e20642 Roubaud, Guilhem LBA4500 Rougier, Philippe 3525^, 3599 Rouhanifar, Hamed e20694 Roukema, Jan A. e16517 Rouleau, Etienne e20032 Round, Glenys TPS1143 Rounseville, Matthew e22185 Roupret, Morgan e16089 Rouquette, Isabelle 8000, 8100 Roure, Pere 4560 Rousey, Steven e19015 Rousseau, Francis e14600 Rousseau, Frederique e15506 Rousseau, Mathieu e15034 Roussel, Murielle 8513 Rousselot, Philippe H. 7012, 7021, 7023 Roussos, George e22202 Routbort, Mark e20036 Rouvinov, Keren e15597, e15598, e16051 Roux, Audrey 5605 Rouyer, Magali e14514, e14542 Rovatti, Massimo e15086 Roviello, Franco e15148, e22037 Rovithi, Maria 11087 Rovito, Daniela 579 Rowbottom, Jacqui 4013 Rowe, Kerry G. 1582 Rowell, Jessica Lauren 5067 Rowinsky, Eric K. TPS3105^, 7029^, 8582 Rowland, Julia Howe 9594 Rowland, Kendrith M. 1059 Rowley, Braden D. 1582 Roxana, Tudor e19077 Roxburgh, Patricia 2586, 5571 Roy, Amitesh Chandra e14616, e20577 Roy, Angshumoy 10023 Roy, Rajasree e16546 Roy, Rakesh e17024 Roy, Ritu 11048 Roy, Vincent 9510 Royal, Richard E. 4134, 9047 Royce, Melanie 502, 526, 11090 Royer, Nels TPS3109 Royer-Joo, Stephanie 2503 Rozati, Sima 9025 Rozek, Laura S. 9607 Rozencweig, Marcel 517, TPS3117^ Rozenko, Ludmila e20005 Rozumna-Martynyuk, Nataliya e15163, e15566 Rozzanigo, Umberto e13046 Ruan, Dan-Yun 538, 4131, e15021, e16077, e19504 Ruan, Daniel T. 6023 Ruan, Li e22066 Ruano, Santiago 634, e11533 Ruatta, Fiorella e16099 Rubenstein, James L. e19541 Rubenstein, Marvin 2590, e16085 Rubin, Brian 10526 Rubin, Eric H. TPS8118 Rubin, Greg 6621 Rubin, Joshua e13537 Rubin, Mark A. 1554, TPS5096 Rubin, Peter 621

Rubinek, Tami 9630, e11578 Rubini, Michele e14588 Rubini, Vincenza e11502 Rubino, Corrado e20013 Rubinstein, Paul G. e12523 Rubio, Carmen 3543 Rubio, Gustavo e15609, e19000 Rubio, Itziar e13000, e14712 Rubio, Judit e19532 Rubio, M. Jesus TPS5616 Rubnitz, Jeffrey E. 10005 Rucinska, Monika e16097, e20666, e22087 Ruda, Roberta 2084, e13009 Rudas, Margareta 611 Rudas, Margaretha 573, 11093 Ruddy, Kathryn Jean 6507, 9508, e20508 Rudin, Charles M. 7508, 7509, 7598, 8009, 8019, 8085 Rudin, Dan 612 Rudnick, Jeremy David 2019^ Ruebe, Christian 8566 Rueda, Antonio e12013, e22091, e22131 Rueda, Bo R. 5578, e13564 Rueda, Oscar 1015, 1016 Ruel, Christopher 4571 Ruether, Joseph D. 5042 Ruetzel, Jan David e16535 Ruff, Paul 3511, 3574, 3620 Ruffini, Enrico 7602 Ruffion, Alain e16050 Rugge, Massimo TPS3648, 11078 Ruggeri, Benedetta 9614 Ruggeri, Enzo e14557 Ruggeri, Marina 8509 Ruggieri, Eustachio e22104 Ruggiero, Joseph T. e14517, e20549 Rugo, Hope S. LBA509, 523, 527, 558, 561, TPS652, 1006, 1052, 1083, 1087, 1095, 2605, 6562, 6619, 6620, 9581 Rui, Hallgeir TPS1135 Ruijtenbeek, Rob e14629, e14702, e22156 Ruiz Borrego, Manuel 1027, 1031, e11577, e22112 Ruiz de Almodovar, Carmen 2056 Ruiz de Lobera, Abigail e20718 Ruiz Solís, Sebastián e18558 Ruiz, Abraham e17031 Ruiz, Amparo 1027, e22112 Ruiz, Ana L. e11575 Ruiz, Ana Lucrecia e14617, e19034 Ruiz, Jose Alberto e11568 Ruiz, Rachel 9609 Ruiz, Rossana Esther e12538 Ruiz, Yelitza e12544 Ruiz-Borrego, Manuel e11583, e12015 Ruiz-Valdepeñas, Andrea e19532 Ruland, Sandra 2030 Rule, Simon TPS8613^ Rummel, Mathias J. TPS8617, TPS8618 Running, Kelli Lynn 2573 Ruocco, Raffaella e11528 Ruppen, Isabel 9641

Ruscelli, Silvia Rushing, Christel

3517 6506, 6516, 11036 Rushing, Daniel A. 10522 Russell, J. Martin 5012 Russell, John Martin LBA5000 Russell, Ludivine e20645 Russell, Maria 9022 Russell, Roslin 1015, 1016 Russell, Stephen J. 8541, 8600 Russell, Stephen 8516, 8606 Russell, Stuart TPS1144 Russo, Alessandro e19086 Russo, Andrea Lyn e14636 Russo, Antonio 4091, e19084 Russo, Filippo 8564, 10552, 10583 Russo, Giulia 631, e11556 Russo, Lucianna e11569, e13046 Russo, Stefania e11565 Ruste, Sherry Athena Doroja 1550 Rustin, Gordon J. S. 5505, 5514, 9590 Rustogi, Rahul e15554 Rutgers, Emiel J. 587, LBA1001 Rutgers, Joanne K. L. e16518 Rutkowski, Piotr 9013, 9020, 9046, 10500, 10501^, 10503, 10551, 10564, e22046 Rutledge, James e16525 Rutledge, John R. 9583 Rutledge, Robert 5048 Ruzsa, Agnes e12022^ Ruzzo, Annamaria e22206 Ryabaya, Oxana e22097, e22162 Ryan, Aoife M. e15566 Ryan, Charles J. 5004, 5009, 5010, 5013, 5014, 5037, 5076, 5077, 11048 Ryan, Christopher W. 5017, LBA10507, e20627^ Ryan, David P. 3507, TPS3646, 4047, 4090, 4125, TPS4148, e14636, e15012 Ryan, Elizabeth 1558, 11050 Ryan, Gail 2007 Ryan, John A. 4043 Ryan, John 3549 Rybak, Christina 1538 Ryberg, Marianne 7504 Rybicki, Lisa A. 4087, 6035, 6061, 9638, e15000, e20572 Rybka, Witold B. 7039, e19502 Ryckewaert, Thomas 10546 Rye, Ronald 5571 Rye, Tzyvia 5571 Rymkiewicz, Grzegorz e19535 Ryoo, Baek-Yeol LBA4024, LBA10502, 10550, e15026, e15091 Rüssel, Jörn 4035 Ryu, Hee Sug 5568 Ryu, Hyo-Jin e19152 Ryu, Jeong Seon e19152 Ryu, Jin-Sook 10589 Ryu, Keun Won 4105, 4114, e15056 Ryu, Min-Hee LBA4024, LBA10502, 10550, e15026, e15091 Ryu, Samuel 2008, 2065 Ryuge, Nobumitsu e15159 Rzyman, Witold 11069 Røe, Oluf D. e13542

S S, Sudha Murthy e13010 S.Oba, Mari 1047 Sa Cunha, Antonio e14514, e14542 Saab, Raya Hamad 10052 Saad, Everardo D. e19144 Saad, Fred LBA4509, 5010, 5037, 5055, 5059, 5079, 9628, 9640, e16082, e16088 Saad, Sidney Sahran e22074 Saadeh, Charles 8591, e18527, e22003, e22052 Saam, Jennifer 1544 Saba, Nabil F. 2552, 2610, 6022, 6047, 6083, TPS6098, 6611, 7560, e19094 Sabadell, Dolores 537 Sabatini, Silvia 553 Sabatino, Marianna 10008, 10013 Sabatino, Susan A. 6514, 6606 Sabbaga, Jorge e14590, e14652 Sabbatini, Paul 5522^, 5550, 6575, e16510^ Sabbatini, Roberto e15524 Sabel, Michael TPS2103, e13051 Sabelko, Kimberly e20712 Sable-Hunt, Alicia L. TPS1606 Sablin, Marie-Paule e13553 Sablon, Erwin 11086 Sabourin, Jean-Christophe 8099, e14596, e19060 Saburi, Yoshio 8506 Sacchini, Virgilio 1019, TPS3120 Sacco, Cosimo LBA5501, e15514, e15589 Sacco, Joseph J. 4518, 9031 Sacco, Rosario e22104 Sachdev, Jasgit C. 1067, 1068, 2580, 2617, TPS11123, e15128 Sachdev, Pallavi 5591, 9058 Sachdev, Raj 3024 Sacher, Adrian G. 7516 Sachs, Bradley A. 7509 Sacristan, Felipe e15532 Sacristan, Silvia 2064 Sada, Yvonne e17501 Sadahiro, Sotaro 3535 Sadamori, Hiroshi e15161 Sadanaga, Noriaki e15158 Sadaoka, Yuko e15579 Sadeghi, Sarmad 4531, 6545 Sadeh Gonik, Udi e15078 Sadetzki, Siegal 1599, e17536 Sadow, Peter M. e17014 Sadrzadeh, Hossein 3104 Saeed, Anwaar Mohammed e22189 Saeed, Kamran e12033 Saeki, Hiroshi 1056, e15039, e15158, e15173 Saeki, Sho e19016 Saeki, Toshiaki e20576 Saelen, Marie Gron 3547 Saenger, Yvonne M. 3014, 9080, TPS9103 Saenz, Alberto 4560 Saenz, Cheryl C. 6636 Saez, Berta Laquente 4041, e22057 Saez, Ruben A. TPS11122 Safe, Stephen e15618

Safont, Maria Jose 3589, e14509 Safra, Tamar 5505 Safran, Howard 3007, 4000, 6574, 8075, e14637, e15095 Safranek, Peter 10541 Safren, Steven A. e20551 Safwat, Reham e17008 Saga, Yasushi 5552 Sagan, Christine e19151 Sagastibelza, Naira 4560 Sagawa, Tamotsu e15060 Saggia, Chiara e11573 Saghir, Naji e12525 Sagi, Shlomi 5576 Saglam, Sezer e19127 Saglio, Giuseppe 7052^, 7054^ Saha, Sukamal 570, 3582, 3583, e14518, e14566 Saha, Supriya Kumar 570, 3582, 3583 Sahai, Siddharth Kumar 7082, e19526 Sahasrabudhe, Deepak M. 9549 Sahebjam, Solmaz 2517, e18514 Sahin, Aysegul A. 532, 1103, e22081 Sahin, Tayfun e11585 Sahin, Ugur 4080, e11537, e11544, e11545, e11595 Sahmoud, Tarek 505, LBA509, 534, 553, 558, 561, TPS660 Sahnane, Nora e14536 Sahoo, Satya 6538 Sahovic, Entezam A. 7075 Sahrakar, Kamran 2062 Sahu, Arvind e12520 Sai, Yang e19042 Saiag, Philippe 9069 Saiagh, Soraya e20022 Saibene, Gabriella 6020 Said, Jonathan W. 5027, 8559 Said, Rabih 2545, e15556, e22086 Saied, Gamal Moustafa e15571 Saigal, Christopher 4540 Saigusa, Susumu e22205 Sailors, Mary L. 7574, 9646, e17508 Sainato, Aldo 4062 Saint-Aubert, Bernard e14621 Saint-Jean, Melanie e20022 Saint-Martin, Jean-Richard 2505 Saintigny, Pierre TPS8118, e19066 Sais, Elia e19159 Saisho, Hiromitsu e15008 Sait, Sheila N. J. e18018 Saito, Gaku 7548 Saito, Haruhiro 7531, 11055 Saito, Hideo e15570, e15576 Saito, Hiroshi e20609 Saito, Norio e14555 Saito, Shiro e16090 Saito, Toshiaki 5537 Saito, Yuko e20609 Saitoh, Motoaki 5537 Saitoh, Soh e14604 Saiura, Akio 4108 Sajben, Peter e15622 Saji, Shigehira 571 Saji, Shigetoyo 4096 Sajjad, Monique Z. 9072 Saka, Hideo 7518, 8006, e19005 Saka, Wasir 2586 ABSTRACT AUTHOR INDEX

775s

Sakai, Asao Sakai, Daisuke

e19083 4072, 4076, e14551, e14601 Sakai, Shinya 1124 Sakai, Takehiko 6588 Sakaida, Emiko e19054 Sakaizawa, Takao 7548 Sakakibara, Masahiro 1097 Sakakibara, Tomohiro 7530 Sakamori, Yuichi 11041 Sakamoto, Hirohiko 4008 Sakamoto, Junichi 3516, LBA4002, 4096, 4102, e15112 Sakamoto, Kazuhiro 8006 Sakamoto, Masaru e16505 Sakamoto, Naoya 4068 Sakamoto, Shinichi e15521 Sakamoto, Susumu 11052 Sakamoto, Yasuo e14665 Sakashita, Shingo 7517 Sakata, Koichiro 3006 Sakata, Yuh 3519, 3535, 11049, e14604 Sakellari, Ioanna 8567 Sakihama, Hideyasu e14548, e15038 Sakoda, Masahiko e14633 Sakr, Bachir Joseph 619 Saksornchai, Kitwadee e19007 Sakuramoto, Shinichi e15113 Sakuramoto, Sinichi 4019 Sala, Angeles 10529, 10532 Sala, Evis 5545 Sala, María Ángeles LBA8002 Sala, Raul e15610 Saladino, Tiziana e11616, e12021 Salafet, Olga V. e20593 Salama, April K. TPS9103 Salama, Mohamed 11032 Salama, Ossama Eissa 1075 Salangsang, Fernando e13590 Salat, Christoph 516, 1004 Salawu, Abdulazeez 9557 Salazar Piedrahita, Hernan Dario e16102 Salazar, Juliana e14541 Salazar, Paloma e19145 Salazar, Ramon 3525^, 3530, 3612, 3629, 4139, e14554, e14561, e14609 Salazar, Suzanne 8044 Saldivar, Juan-Sebastian 11085 Saleem, Azeem 635, TPS4146 Saleem, Sadia 1560 Saleh, Ahmad e12525 Saleh, Mansoor N. 527, 3616, 4005^, 7591 Salek, Tomas 3575, e14700, e15599 Salem, Mohamed E. e15077, e19009 Salem, Mohamed e13030 Salem, Naji e15506 Salem, Sherine 10044 Sales, V L e17595 Salesi, Nello e12021, e19099 Saletan, Stephen TPS661, 4138, e17520 Saletti, Piercarlo 3503, e14536 Salgado, Roberto 11003 776s

Salgia, Ravi 2570, 6090, TPS7610, 8026, 8031, 8032, e19057 Salhi, Bihiyga 7541 Salhi, Yacine 4524, 4539 Saliba, Rima 8561 Saliba, Wissam e22159 Salih, Helmut Rainer 3054 Salim, Muhammad CRA1008 Salinas, Monica e12516 Salinas-Souza, Carolina 10535 Salisbury, Jeffrey L. e13516 Salkeni, Mohamad Adham e13023, e13518 Sallemi, Claudio e18528 Salles, Gilles A. TPS8614^, TPS8615, TPS8617 Salloum, Ramzi George 5040, 6018 Salman, Asad 5 Salman, Pamela LBA4001, 4021 Salmen, Jessica Christine e22075 Salner, Andrew L. 9620 Salo, Jarmo 7504 Salo-Mullen, Erin E. 1555, 4082, TPS4144, e12536 Salom, Emery Manuel e16525 Salonia, Laura 6039 Saloura, Vassiliki 6065 Saloustros, Emmanouil S. 1045 Salter, Matthew 6063 Saltman, Deborah 9045, e20014 Salto-Tellez, Manuel TPS11120 Saltz, Leonard 1555, 3533, 3605, 3618, 4017, e14508, e15133 Saltzman, W. Mark e15543 Salud Salvia, Antonia 3589 Salud Salvia, Antonieta e14509 Salutari, Vanda LBA5501, e16538 Salvador Bofill, Javier e11583 salvador Garrido, Nuria 5603 Salvador, Daniela e20037 Salvador, Javier e11577 Salvagno, Luigi e15512 Salvarrey, Alexandra 7516 Salvatore, Lisa 3505, 3557, 3563, 3565, 3602, 3603, 3613, 3615, e14531, e14574, e14577 Salvesen, Helga B. 5511 Salvi, Sandra 11063, e22132 Salvini, Jessica 11066 Salvini, Piermario e20650 Salzberg, Marc Oliver 3008 Sam, Xin Xiu e15002 Samanez, Cesar Augusto 7072 Samaniego, Rafael 2064 Samant, Meghna 646 Samanta, Diptirani 6089 Samantas, Epaminontas 582, e19048 Samatar, Ahmed 11059 Samawi, Haider 9596 Samayoa, Kimberly 2071 Sambandam, Sundaresan T. 619 Sami, Amer 3580 Samir, Suzanne e12023 Sammarco, Giuseppe e22104 Sammel, Mary D 6560 Samoila, Aliaksandra 5083, e16005 Samonigg, Hellmut 583, e14537, e15064 Samoylenko, Igor e20042


Samoylova, Olga Sampaio-Filho, Carlos Alberto Sampat, Keeran Ravin Sampayo, Miguel Sampson, John Howard

7004

e12510 e14522 555 2094, e13015^ Samsa, Greg 6506, 6516 Samsa, Gregory e17521 Samson, Benoit 3515 Samuel, Didier e19513 Samuel, Leslie M. 3532, e14561 Samuel, Michael 8524 Samuel, Thomas A. 9094, e17524 San Antonio, Belen 8068 San Lucas, F. Anthony 3623 San-Miguel, Jesùs F. 8510, 8511, 8527, 8528, 8583 San-Miguel, Maria Teresa e20581, e20612 Sanborn, Rachel E. TPS3110 Sanches, Evaristo 3525^ Sanches, Solange e20640 Sanchety, Naveen 1099 Sanchez de Toledo, Jose 10028 Sanchez Gastaldo, Amparo e19105, e19160, e22045 Sánchez Lorenzo, Luisa e14617, e19034 Sanchez Margalet, V. e22073 Sanchez Rovira, Pedro e11583 Sanchez Villegas, Tomas e14692, e14693, e15189, e16102 Sanchez, Fernando Barbosa 5540 Sanchez, Jesus 11033 Sanchez, Jose Javier 11078, e22068 Sanchez, Jose Miguel 11028 Sanchez, Maria Elena e15107 Sanchez, Pedro e15068 Sanchez, Sadie e20570 Sanchez, Teresa Kong TPS4151 Sanchez-Godoy, Pedro 8511 Sanchez-Hernandez, Alfredo 4560 Sanchez-Izquierdo, Dolors 10532 Sánchez-Jiménez, Javier e12015 Sanchez-Lara, Karla e19068 Sanchez-Ronco, Maria 2581, LBA8002, 11028 Sánchez-Rovira, Pedro e12015 Sanchiz, Barbara e16543 Sancho Marquez, Maria Pilar e15533 Sancho Perez, Blanca 1041 Sancho, Aintzane e14628, e14712 Sancho, Gemma e16049 Sanchorawala, Vaishali 8545 Sand, Sharon 1536 Sandbach, John F. 590 Sanden, Mats Olot e22173 Sander, Cindy 9043, 9075 Sanders, Amanda 4547^ Sanders, M. Melinda e22211 Sanderson, Maureen e20523 Sandhu, Shahneen Kaur 2513 Sandhu, Sonia e12523 Sandilya, Vijay Krishna e18012 Sandler, Alan 2518, 8046, 8073, e19141 Sandler, Andrew 5034 Sandler, Howard Mark e17507

Sandmaier, Brenda M. 7034 Sandomenico, Claudia 8066 Sandoval-Sus, Jose D e19140 Sandri, Maria Teresa e22078 Sandrin, Fabio e20634 Sandstrom, Per 3597 Sandström, Per 11097, e15553 Sandusky, George 2529 Sanfilippo, Kristen Marie e17546 Sanfilippo, Roberta 10576 Sanft, Tara Beth 2587, e20546 Sang, Jim e19097 Sang, Yaxiong e14645 Sangai, Takafumi 1097 Sangale, Zaina 5043 Sangalli, Claudia 589, 10519 Sangar, Vineet 4017 Sanger, Warren 3055 Sangha, Randeep S. 2523, 2574, e19147 Sanghera, Sartaj Singh e22143 Sangiolo, Dario e14654 Sangro, Bruno TPS3111 Sanhes, Laurence 7002 Sanidad, Marc A 8115 Sanjuan, Xavier 3629, e14554 Sankar, Sabita 10513 Sankar, Vindira 3016, 4514, 8030 Sankhala, Kamalesh Kumar 2550, 2573 Sanli, Ulus Ali e12018, e13578 Sanmamed, Miguel F. 9074, e18513 Sanmartin, Elena e22147 Sanmugarajah, Jasotha e20706 Sanò, Maria Vita e11526 Sano, Takeshi 4019, 4104, 4108, e15105 Sanoff, Hanna Kelly 6599, e18005 Sansano, Irene 11010, 11025, e22119 Sanson, Marc 2011, 2024, 2028 Santa-Maria, Cesar Augusto TPS1144 Santaballa, Ana 608, e12513 Santacruz, Juan G. 9541 Santagata, Sandro 2030 Santamaria-Pang, Alberto 2097, e14663, e16033, e18502, e22085 Santamarina Cainzos, Isabel 5087, e15542, e22171 Santana, Thaiana ARAGAO e20699 Santana-Davila, Rafael 8090, e17594 Santander, Carmen 4560, e15620 Santarpia, Mariacarmela 8047 Santegoets, Saskia 3029 Santel, Ansgar 2508 Santi, Patricia Xavier e20524 Santiago, Karen J. e19510 Santiago, Lumarie 532 Santiago, María del Mar e11583 Santiago-Walker, Ademi 9020, 11026 Santibañez, Miguel 4555 Santiesteban, Eduardo Rafael 3086 Santillana, Sergio LBA4001 Santinami, Mario 9092 Santinelli, Alfredo e11616 Santini, Daniele 4091, e15528, e19084 Santini, Donatella 4048 Santoni, Giorgio e15513, e15515

Santoni, Matteo

e15513, e15515, e15529 Santoro, Armando 4118, 4121, TPS4159, 5582, 10506, 10517, e14611, e15088, e19020, e19138, e19148, e22145 Santos Ortega, Manuel e20705 Santos, Cristina 3629, e14554, e14609 Santos, Edgardo S e19140 Santos, Eduardo 625, 642, e11603 Santos, Elizabeth Santana e11503 Santos, Fábio Nasser e13050 Santos, Gilda Da Cunha e19032 Santos, Helio B. e22122 Santos, José Sebastião e15190 Santos, Ruth e15059 Santoso, Joseph T. e20673 Santra, Santimukul 3085 Sanxing, Guo 11061 Sanyal, Arun J. 4126 Sanz-Pamplona, Rebeca e14613 Sapari, Nur Sabrina e14507 Saponara, Maristella 10540, e21511, e21523 Sara, Simonetta e13579 Saracchini, Silvana 641 Sarachan, Brian D. e18502 Sarachan, Brion e14663, e16033 Saracino, Valeria e20681 Saragiotto, Daniel F. e14590 Saragoni, Luca e15055 Sarai, Guneet 2034, 6068 Saran, Frank 2002^, 2005^, 2023^ Sarantopoulos, John 2560, 2578, 3541, 4563 Sarashina, Akiko 8056, e19165 Sardi, Armando e15123 Sardnal, Veronique 7002 Sardon, Heidi May 3104 Sareen, Srishti 7569 Sareli, Candice e17540 Sarfaraz, Sami 11034 Sarfraz, Yasmeen 11106 Sargent, Daniel J. 3510, 3514, 3520, 3523, 3533, 3618, 3636, 3637, 3639, 6520 Sargent, Rachel L. 7098 Sarholz, Barbara e14501 Sari, Ebru e19107 Sari, Ismail e18014 Sarici, Saim Furkan e11545, e12563 Sarid, David e11578 Sarimiye, Foluke Oladele e20675 Sarini, Jerome 3035 Sarkar, Chitra e13034 Sarkar, Sandip e12039 Sarkar, Shyamal Kumar e20707 Sarkar, Susanta K. 11006 Sarkaria, Jann Nagina 2014, 2046, 2072 Sarker, Shah-Jalal 4508, 4535 Sarlon, Emmanuelle 9511 Sarmiento, Roberta 3588 Sarnaik, Amod 9011 Sarno, Francesca 2511 Sarno, Maria Anna 589 Sarode, Venetia 8088^ Sarosi, Veronika e19090^ Sarosiek, Tomasz 516

Sarpel, Umut 6640 Sarrel, Kara e12536 Sarris, Evangelos e19111 Sartelet, Herve 10048 Sarti, Samanta 552 Sartor, A. Oliver 5011, 5034, 5038, 5080, e16010, e17570 Sartore Bianchi, Andrea 3581, e14560 Sartore-Bianchi, Andrea TPS3648, 11005 Sartori, Donata e15514 Sartori, Samantha 1594 Sartorius, Ute 3630 Sarwar, Naveed 4508 Sasada, Shinsuke e22053 Sasaki, Clarence 6012 Sasaki, Hidefumi 7529 Sasaki, Jiichiro 7592, e19016 Sasaki, Naoki e16505, e16506, e16519, e21520 Sasaki, Takahide 4075 Sasaki, Takashi e15146 Sasaki, Takeshi 1047 Sasaki, Tohru 4070 Sasaki, Toru e17006 Sasaki, Yasutsuna 3519 Sasako, Mitsuru 4019, 4104 Sasane, Medha 10545, e21514, e21515 Sasano, Hironobu 571, e15071 Sasatomi, Teruo e14684 Sasi, Sharath e22010 Sass, Ellen 7077 Sasse, Andre Deeke e11500, e18534, e20506, e20634 Sasse, Emma C. e18534 Sassolas, Bruno 9069 Sassoon, Ingrid 11006 Sastre, Javier 3604, 4140, 4560 Sastre, Josep Maria e16549 Sastre, Xavier e20032 Sastry, Sangeeta e17500 Sata, Naohiro 4008 Satake, Hironaga 4074 Satchidanand, Yashodhara K. e20573 Satele, Daniel 6533, 6587 Satheesh, C. T. 6624 Sathirachinda, Ataya 11006 Sathyanarayanan, Sriram 5578 Satici, Celal e20502 Satijn, David 3066 Sato, Akihiro 2559, e22082 Sato, Akira 8054 Sato, Hirohiko e14572 Sato, Kazuhiko 3034, e12009 Sato, Mariko 2026 Sato, Naoto 5552 Sato, Nayuko TPS1140 Sato, Nobuaki 571, e12011 Sato, Ryo e15579 Sato, Shinya 5528 Sato, Takami CRA9003, e15563 Sato, Takeo 3556 Sato, Tsutomu e15060 Sato, Tsuyoshi e14651 Sato, Yasuhiro e15060 Sato, Yasushi e15060 Sato, Yasuyoshi e17006

Sato, Yukiko e17006 Sato-DiLorenzo, Aya TPS2627 Satoh, Takefumi e16090 Satoh, Taroh 3519, e14601 Satoh, Toyomi 5537 Satolli, M. Antonietta e19084 Satouchi, Miyako 8105 Satpute, Shailesh R. e15584 Satram-Hoang, Sacha 7016 Sattlberger, Claudia 573 Sattler, Christopher A. 4071 Sattler, Daniel e20623 Saul, Melissa 9075 Saunders, Christobel 1110 Saunders, Ed 5054, e16000 Saunders, Jesse 2515 Saunders, Mark P. 3521, e22035 Saunders, Randall Jesse 7055 Saunthararajah, Yogen e15097 Sausen, Mark 11005 Saussele, Susanne 7051 Sauta, Maria Grazia e20650 Sauter, Guido 5043 Sautiere, Jean-Loup 1122 Sauzedde, Jean-Marc 1114 Sava, Teodoro e15514, e15524, e15615 Savage, Kerry J. 8507, 8552, 9032, e20045 Savani, Bipin N. 3104, 8605, e19539 Savaraj, Niramol e22062 Savarino, Graziana 11063 Savas, Burhan e14683, e14696, e18517 Save, Vicki 10541 Saveliev, Leonid 10055 Savi, Roberta e14574 Savic, Spasenija 7514, 8060 Savignoni, Alexia 1533 Saville, Benjamin R. 1034 Savin, Michael e14545 Savini, Agnese e15529 Savio, Daniele e20562 Savkova, Alexandra 9507 Savoia, Paola 9065 Savona, Michael R. 11102, e22139 Savona, Steven R. 9505 Savulsky, Claudio Isaac e11586 Savvides, Panayiotis 6035, 6045 Sawa, Toshiyuki e20609 Sawada, Kenjiro 5538 Sawafuji, Makoto 7536 Sawaki, Akira 4021, 10543 Sawaki, Masataka e12001 Sawaya, Raymond e13044 Sawka, Carol Anne e17531, e20507 Sawkins, Kate 2017 Sawyer, Doug 2502 Sawyer, Emma e16000 Sawyer, Michael B. 2546, e13503 Sawyers, Charles L. 5030 Sax, Cornelia 2078 Saxena, Renu e19531 Saxman, Scott 8052 Saxton, Jerrold P. 4087, 6035, 6061, e15000 Saynina, Olga e17504 Sbitti, Yassir e20624 Scagliotti, Giorgio TPS8119 Scaife, Lucy e22123

Scalese, Marco Scalia Wilbur, Jennifer Scalone, Simona Scalzo, Anthony Joseph

1086 1545 e22149 9572, TPS9651 Scambia, Giovanni LBA5501, e16538, e16547 Scandurra, Giuseppa e16532 Scanlon, Patrick 9089 Scapulatempo Neto, Cristovam e22154 Scarfone, Giovanna 589 Scarpellini, Paolo 6046 Scarpi, Emanuela 552, 3517, e14512, e15529, e18561 Scarsbrook, Andrew 2525 Scartoni, Simona 5522^, e16510^ Scartozzi, Mario 3591, 4123, e14610, e15081, e15536 Schaaf, Larry J. 1043 Schabath, Matthew B. e22155 Schabel, Matthias e13522 Schacher, Sabina 3503 Schachter, Jacob 9046, e20039 Schackert, Gabriele 2027 Schackmann, Elizabeth A. 1003 Schad, Friedemann e20710 Schade-Brittinger, Carmen 4030 Schadendorf, Dirk 9004, 9020, 9037, 11009, e20028, e20050 Schaefer, Britta LBA3506 Schaefer, Eric Scott TPS8119 Schaefer, Niklas LBA2000 Schaeffer, Edward M. 5033, 5089 Schaeffer, Megan 3507 Schaer, David A. 3003^ Schalij, Martin J. 8568 Schallenkamp, John M. e17533 Schally, Andrew V. 5062, TPS11124, e15596 Schalper, Kurt 11075 Schapira, Lidia 1117, 1133, 6507, e20508 Scharl, Anton J. e17544 Scharpf, Joseph 6035, 6061 Scharpfenecker, Marion M. 7528 Schattner, Mark e15017 Schaub, Diane 3103 Schaub, Richard 3025 Schauer, Silvia e15064 Schechter, Rebecca B. 6066 Scheckermann, Christian e13548 Scheet, Paul A. 3623 Scheffler, Matthias 1589, 8112 Scheffold, Christian e16018 Schein, Jacquie e22020 Scheinberg, David A. 3047 Scheinemann, Katrin 10029 Scheithauer, Werner LBA3506, 3515, 3524, 3643, 4059^ Schell, Michael J. 3644, 6047, 8001 Schellens, Jan HM 2522, 2531, 2536, 2579, 4511 Schellingerhout, Dawid e13044 Schelman, William R. 2513 Schem, Christian 11061 Schembri, Geoff P. 9616 Schenk, Tom L. e20527 Schenone, Aaron e21501 ABSTRACT AUTHOR INDEX

777s

Scher, Howard I. TPS3115, 5004, 5009, 5010, 5013, 5014, 5026, 5030, 5032, 5052, 5065, 5066, 5073, 5083, 5090, 6575, e16001, e16005, e16019 Scherer, Philipp 1560 Scherer, Ralph e22076 Scherpereel, Arnaud 8014, e19056 Scheulen, Max E. 4035, e15088 Scheurlen, Michael e15193 Scheyer, Richard David 2519 Schiavone, Paola 618, e14605 Schiepers, Christiaan e16019 Schiff, David 1, LBA2010, 2013, 2014, TPS2104, TPS2105 Schiff, Edward 4504 Schiff, Peter B. 7523 Schiffman, Joshua David 2026 Schild, Steven E. 7501, 7509, 7510, 7545 Schilder, Russell J. 2504, 3621 Schildhaus, Hans-Ulrich 1589 Schiller, Joan H. 6601, 7508, 8017, 8019, 8046, 8073, 8085, 8088^, 8106, TPS8126 Schilsky, Richard L. 2570 Schimanski, Carl Christoph TPS3124^, 4086 Schimanski, Christoph 3586 Schimmelpfennig, Christoph e15096 Schimmer, Aaron D. 7078 Schimmoller, Frauke 9094, e16018 Schindler, Fernanda e20680 Schindler, Katja 9024, 9025 Schink, Julian C. 626, 5570, 5574, 6609, 6617, e15010, e22093 Schipper, Matthew J. 7522, 7580 Schippinger, Walter e14537 Schirm, Sabine e14545 Schirmacher, Peter e19060 Schirren, Joachim e18503 Schirripa, Marta 3557, 3563, 3565, 3602, 3603, 3613, 3615, e14531, e14574, e14577, e22056 Schirrmacher-Memmel, Silke TPS4591 Schittenhelm, Jens 2059 Schlag, Peter M. e15068 Schlegel, Frank 4009 Schlegel, Robert 7111, e13525 Schlegel, Uwe S. TPS2103 Schlemmer, Heinz-Peter e16063 Schlesinger, Andreas 1589 Schlette, Ellen J. 7098 Schlichting, Christoph 3604 Schlichting, Michael TPS4148 Schlicker, Andreas 3530 Schliemann, Christoph 8548 Schlom, Jeffrey TPS3127, TPS4589, TPS5104, e16036 Schlomm, Thorsten 5043 Schlossman, Robert L. 8531 Schluchter, Mark D. 6500, 6525, e20633 Schluckebier, Luciene Fontes 6071 Schlumberger, Martin 4, 6000, 6092 Schmacher, Jessica e14550 Schmalenberg, Harald 4079 778s

Schmalfeldt, Barbara 508, TPS3119^, 5531 Schmechel, Stephen 10560 Schmeler, Kathleen M. e13534, e16556 Schmid, Andreas e20050 Schmid, Annette Maria e22161 Schmid, Jasmin 1542, 3549 Schmid, Peter 7595 Schmidinger, Manuela e15535 Schmidt, Carl Richard e14535 Schmidt, Eva 8548 Schmidt, Henrik TPS9106 Schmidt, Karsten e13548 Schmidt, Kathy 567 Schmidt, Manuel 3643 Schmidt, Marcus 602, 615, e22112 Schmidt, Marjanka 587 Schmidt, Peter 3531 Schmidt, Thomas 3090, 3588 Schmidt, Wolfgang E. 4009 Schmiedel, Benjamin Joachim 3054 Schmiegel, Wolff H. 4079 Schmitt, David e13566 Schmitt, Karin e22164 Schmitt, Sarah e22048 Schmitt, Thomas 9612 Schmitt-Hoffman, Anne 2566 Schmitz, Jennifer e20050 Schmitz, Jorg e15607 Schmitz, Kathryn 6525 Schmitz, Norbert 8566, 8570 Schmitz, Stephan H. 1589, 3586, 6623 Schmitz-Winnenthal, Friedrich Hubertus 3090 Schmoll, Hans-Joachim 3531, 3533, 3643, 4086, e15096 Schmutzler, Rita K. 11024 Schnabel, Catherine A. 594, 4133, e11504, e15006, e15104, e15130, e19072 Schnabel, Freya Ruth 1500 Schnader, Allison 519 Schnadig, Ian D. e20627^ Schneeweiss, Andreas 591, 640, 1004, TPS1137, TPS1138, 11012, 11023, 11042, 11043, 11061, e11525, e16547, e22075 Schneider, Björn e13053 Schneider, Bryan P. 513, 6527, 9508 Schneider, Charles 1007 Schneider, Claus-Peter 8013, TPS8117 Schneider, Coursen Walker 5090 Schneider, Douglas e22010 Schneider, Jeffrey Gary 599 Schneider, Naye Balzan e12546 Schneider, Neil 6553 Schneider, Robert 1042, 11106 Schneider, Sarah E. e20641 Schneiderer, Timo 3075 Schneiderman, Rosa S. e22125, e22134, e22138 Schnell, David 2523 Schnell, Oliver TPS2103 Schnell, Roland 1589, 8112 Schnittger, Susanne 7051 Schochter, Fabienne e22075


Schoen, Martin W. e17560 Schoen, Michael TPS3124^ Schoenberg, Mark 4523 Schoenfisch, Birgitt 11012 Schoengen, Alfred e20035 Schoettle, Glenn P. 7569 Schoffski, Patrick 6000, 10503, LBA10507, 10551, 10573, e13528 Scholefield, John 3500 Scholl, Suzy 2615, 3053 Schollenberger, Lukas 4086 Scholte, Arthur JHA 8568 Scholtens, Denise M. 1012, 5574 Scholz, Michael LBA3506 Schonberg, Mara A e16006 Schorge, John O. 5604, e13564 Schott, Anne F. 9615 Schott, Anne TPS657 Schott, Sarah 11012 Schouten, Philip C. 11023 Schrader, Iris 11042 Schrader, Kasmintan A. 1552, 4082, e12527, e12555 Schrag, Deborah 3611, 4090, 6506, 6516, 6521, 6522, 6565, 6575, 6583, 7128, 9519 Schramek, Daniel J. 8027, 8028 Schramel, Franz 7534 Schreeder, Marshall T. 7017, 8500, 8501, 8575, e19528 Schregel, Katharina 1023 Schreiber, Andreas 6077 Schreiber, Annette 7051 Schreiber, Fred James 8001 Schreiber, Nicole A e16005 Schroeck, Florian Rudolf 5044 Schroeder, Andreas 3011 Schroeder, Brock 594, e11504, e15104, e15130, e19072 Schroeder, E. Todd TPS9648 Schroeder, Helene e11549 Schroeder, Jan Klaus 602 Schroeder, Mary C. 6542 Schroeder, Michael e17021 Schroeder, Ryan e17507 Schub, Andrea 3051, 7020 Schubert, Julia e13053 Schuchert, Matthew J. 7577 Schuchter, Lynn Mara 9005, 9016, 9017, 9066, 9088 Schuckman, Anne K. 4531 Schuette, Wolfgang 8013, e19060 Schuetze, Scott LBA10507, 10522, 10524, 10584, TPS10591 Schuff, Kathryn e19141 Schuh, Andre C. 7078 Schuh, Anna TPS5615, 7101, 9068 Schuler, Kevin M. 5519 Schuler, Markus Kajo e21518 Schuler, Martin H. 2531, 4080, e14502 Schuler, Ulrich S. e20720 Schulick, Richard D. 4057 Schulmann, Karsten 4080 Schulpher, Mark 636 Schulte, Berit e20652 Schulte, Nathan 3545 Schultes, Birgit Corinna e15012 Schultheis, Anne Maria 3567 Schultheis, Beate 2508, 4009

Schultz, Christopher J. 2033 Schultz, Kris Ann Pinekenstein 10024 Schultz, Nicolai Aagaard 4052 Schultz, Nikolaus 5032 Schultze, Alexander 7027 Schulz, Holger 1589 Schulz, Thomas K. 2558 Schulze, Elisabeth e16547 Schulze, Matthew B 10526 Schulze-Bergkamen, Henning 3008, 3625, 4080 Schumacher, Claudia TPS655^, 1082 Schumacher, Karl Maria 9029, e13525 Schumacher, Ton 3036, 9078, 9085 Schumacker, Pam e17519 Schumann, Andre e22055 Schumann, Christian 8013 Schummer, Michel e22178 Schunselaar, Laurel 7581 Schuster, David M. e15141 Schuster, Stephen J. 8578, TPS8619 Schusterbauer, Claudia 605 Schutzner, Jan 7602 Schuurhuis, Danita 3066 Schuuring, Ed e22042 Schuz, Joachim 6570 Schwaab, Thomas e15604 Schwab, Matthias 2588, e14615 Schwab, Richard e19090^ Schwameis, Richard e16524 Schwandt, Anita 9517 Schwarer, Anthony P. 7053^ Schwartz, Ann G. 1504, 1524, 7561 Schwartz, Brian E. 3508 Schwartz, Cindy L. 10000, 10035 Schwartz, Gary K. CRA9003, 9049, 9060, 10512, 10558, 10580, TPS10592, TPS10594 Schwartz, Jonathan D. 4000 Schwartz, Kenneth A. e13047, e13048 Schwartz, Lawrence H. 3635, 4116, TPS4159 Schwartz, Mark W. e11509 Schwartz, Richard Stephen 2093 Schwartz, Stefan e20521 Schwartzberg, Lee Steven 565, 621, TPS659, 1068, 3631, 8044, 9535, 9619, e15023 Schwartzman, Jacob 5017 Schwarzberg, Abraham B. 4512 Schweber, Sarah J. 2612 Schweizer, Michael Thomas 5023 Schwenkglenks, Matthias 1078, e20542 Schwentner, Lukas 1074, 1096 Schwerdtfeger, Michael e14532 Schwiep, Frances Annelies 10545, e21514, e21515 Schwiertz, Vérane e13594 Schwob, Emilie e17023 Schymura, Maria J. 6565 Schütz, Ekkehard 1537, 5072, 11013, 11060 Schöder, Heiko TPS3115, 4101, 5073, 5090

Schønnemann, Katrine Rahbek e15099 Sciacca, Venerina e19099 Sciamanna, Chris 7553 Scibilia, Giuseppe e16532 Scigliano, Eileen 8579 Scimone, Antonino e19086 Sciot, Raf 10573, e13528 Sciulli, Christin 9043 Sclafani, Francesco e14616 Sclafani, Lisa M. 1019 Scognamiglio, Florinda 5050 Scognamiglio, Giosuè 11037 Scollo, Paolo e16532 Scollon, Sarah 10023 Scolyer, Richard A. 9001 Scopa, Chrisoula D. e18507 Scoppola, Alessandro 9070 Scorilas, Andreas 11117 Scorsone, Kathy 10041 Scosyrev, Emelian 9549 Scott, Andrew Mark 2520, 2583 Scott, Charles B. 9567 Scott, Clare L. 5505 Scott, David 636 Scott, Fiona Elizabeth 2583 Scott, Jeffrey A. 6553, 6629, e15500, e15504, e15538, e17579, e17581, e17582 Scott, Jeffrey W. 2593 Scott, Jennifer 6539 Scott, Pamela 2553 Scott, Sasinya N. 4573 Scotte, Florian 5567, e12504, e19056, e20654 Scotti, Alessandro 2074 Scrable, Heidi e20051 Scribani, Melissa e14709 Scriva, Aurelie 3524 Scriver, Tara 2546 Scully, Peter 2537 Scuro, Manuela 1014 Seah, Davinia Shien e20508 Seal, Brian S. 10590, e14524, e14602, e14658, e16027, e16034 Seano, Giorgio 1065 Searle, Graham 635 Sears, Alan K. 3005, 3097, TPS3126 Seay, Thomas E. 4005^ Sebag-Montefiore, David 3532 Sebastien, Bernard e19049 Sebio, Ana e14541 Sebisanovic, Dragan 11096 Seckl, Michael 7595 Secondino, Simona 4575 Secord, Angeles Alvarez 5509, 5523, e16529 Seddon, Beatrice M. 10518 Sedlacek, Scot M. 590 Sedlackova, Tatiana e22023 Seeger, Robert 10039 Seehofer, Daniel TPS3124^ Seetharam, Mahesh TPS2621, e22110 Seferina, Shanly C. e11558 Sefrioui, David 3536 Segal, Amiel 4037, TPS4144 Segal, Michal TPS4144, e15133 Segal, Neil Howard TPS3107, TPS3110, 3605, 9012^, e14508

Segal, Roanne TPS5099^, 6595 Segal, Stephanie 1566, 1603 Segati, Romana e13514, e15512 Segelov, Eva TPS3649, 9602, e20584 Segev, Yakir 5561 Segota, Zdenka E. TPS3113, 3621 Seguí, Miquel Angel 1031 Seguí-Palmer, Miguel Angel e22112 Segura, Eduardo 4587 Segura, Miguel F. 9091 Sehdev, Amikar 1513 Sehgal, Rajesh 2089, e13040 Sehn, Laurie Helen 8552, TPS8618 Sehner, Susanne e17003 Sehouli, Jalid TPS3119^, 5549, 5553, 5569, 5575, 5582, 5593, e16547, e20688, e20689, e22102 Sehovic, Ivana e12556 Seibert, Karen 11099 Seidel, Christoph e22076 Seidenader, Jonas e16063 Seidensticker, Max e22040 Seidman, Andrew David 514, 6508 Seierstad, Therese 3547 Seifert, Michael e11601 Seipelt, Gernot LBA3506 Seisler, Drew K. 3501, e17538, e20605 Seitz, Jean Francois 9511 Seitz, Stephan TPS11124 Seiwert, Tanguy Y. 6001, 6008, 6010, 6066 Seker, Mesut e15117, e18510 Seker, Metin e14662 Sekeres, Mikkael A. 7008, 7028 Sekhina, Olga e21510 Sekhon, Harmanjatinder S. 8096 Seki, Nobuhiko 9621, e12541 Seki, Shiko e15016 Seki, Tomoko e11598 Sekine, Ikuo 8037, 8064 Sekiya, Masanori e14552 Sekkate, Sakina e16527 Sekulic, Aleksandar 9037 Selby, Mark 3019, 3061, 9055 Selby, Peter 9536, 9551, 9595 Selcukbiricik, Fatih e15117 Selek, Ugur e17588 Selezneva, Inna Anatolievna e12560 Self, Linda e20700 Seliger, Barbara e20040 Seligmann, Bruce e22185 Sella, Avishay e15597, e15598, e16023, e16068 Sella, Tal 1526, e16023 Selle, Frédéric 5504, 5541, 5567, 10505 Sellinger, Christina 1053 Selvadurai, Elizabeth e16000 Selvaggi, Giovanni TPS8119 Semenova, Anna Igorevna 3088 Semenza, Gregg TPS1144 Semiglazov, Vladimir 503, 517, 537, 1014 Semiglazova, Tatyana e13005 Semjonow, Axel 5074 Semple, John 1507 Semple, Sean C. TPS2621

Semrad, Thomas John

e14570, e15073 Sen, Fatma e11534, e11592, e14594, e15569, e20016 Sen, Oishee 4522 Sen, Sounok 6511 Sena, Carla Valéria Santos e18515 Senaldi, Giorgio 2519 Senan, Suresh 7520 Senapati, Surendra nath 6089 Senbabaoglu, Filiz e22004 Sendur, Mehmet Ali Nahit e11553, e11554, e11593, e20614 Senellart, Hélène 8059, e19056 Sener Dede, Didem e15540 Seng, John E. 4038, e15128 Sengar, Manju e18004, e19503 Sengoku, Norihiko 1047 Sengupta, Prattusha e16542 Sengupta, Rajarshi e13537 Sengupta, Saubhik e16542 Sengupta, Shomik e16016 Senin Estor, Clara 7549 Senmaru, Naoto 3638 Sensi, Elisa 3563, 3613 Senterre, Christelle e12515 Senthi, Sashendra 7520 Senyigit, Abdurrahman e18544 Senzer, Neil N. 2504, 3099, 3621, LBA9008, e16043 Seo, Jeong Ju 637, 1088 Seoane, Joan 2016 Seon, Ben K. 3057, 3059 Seoud, Muhieddine A. e12525 Seow, Hsien 5586 Seppo, Antti e19536 Sepporta, Maria Vittoria e13549 Sepucha, Karen 6507, 6527, 9534 Sepulveda, Juan Manuel 2087, e18558 Sepúlveda, Juan Manuel 2016, 2061 Sequeira, Manuel e19097 Sequist, Lecia V. 2524, 8019, 8030, 8085, e22092 Serada, Satoshi 10539 Serdengecti, Suheyla e15117 Serdjebi, Cindy 7117 Sereni, Maria Isabella 5560 Sereno, Maria e15609 Sereti, Irini TPS10595 Sergeev, Urii e15583 Sergenson, Gwen 2523 Sergi, Domenico e15065, e21517 Serie, Daniel 4567, e15539 Serizawa, Masakuni 7572, 7582, 7599, e18556, e19050 Serji, Badr e16527 Serke, Monika 1589, 8013, 8043 Serna, Eva e12019 Serody, Jonathan Stuart 6070 Serpa, Ary e16058 Serpe, Roberto 603, e20556 Serra, Carla 4048 Serra, Luigi 3040 Serra, Olbia e14509, e15111 Serra, Patrizia 5594, e16530 Serra, Sebastian e17543 Serra, Stefano 4049, 11002 Serrano Aybar, Pablo Emilio e14573, e15087

Serrano, Davide Serrano, Gloria

1517 11089, e19000, e19109 Serrano, Mayra e20651 Serrano, Raquel 4098 Serrano, Teresa 4139, e22057 Serrano-Garcia, Cesar 10509, 10510 Serrurier, Katherine M. 1083 Sersch, Martina A. 2603 Serth, Juergen e22076 Seruga, Bostjan 539, e22000, e22015 Servadei, Franco 2048 Servant, Nicolas 2615 Servent, Véronique 1057 Servitja, Sonia e12513 Servois, Vincent 2615, 9057 Sessa, Cristiana 2535, 3008, 5516, e13502 Sessa, Tracey 2031 Sestak, Ivana 506, 575 Setayeshi, Khosro e15195 Sethi, Manish e13546 Sethi, Roshan V 10018 Sethi, Seema 4577 Sethukavalan, Perakaa e16070 Setinek, Ulrike e19093 Seto, Charlie T 7568 Seto, Hiroshi 3034 Seto, Takashi 7529, 8033, 8111, e19016, e19165 Setoguchi, Soko 6504 Seufferlein, Thomas 4034 Severtsev, Aleksey 3508 Sevick, Laura e17557 Sevilla, Isabel 4140, e14648, e15107 Sevin, Emmanuel e16009 Sevinc, Alper e18546, e18560, e20006 Sevinsky, Christopher J. 2097, e14663, e16033 Sexauer, Amy e20638 Sexton, Rachel 8515 Seymour, John Francis 7018, 8520 Seymour, Lesley e19033 Seymour, Matthew T. 3520, 3533 Seynaeve, Caroline 597, 1502, 11045, e22152 Sezgin, Canfeza e12018, e12509, e13578 Sfakianaki, Maria 7594 Sferra, Stella e13579 Sgroi, Dennis 594 Shaaban, Khaled 10044 Shabason, Jacob Ezra 6610 Shabbir-Moosajee, Munira e14680 Shabihkhani, Maryam e17559 Shacham, Sharon 2505 Shacham-Shmueli, Einat e22111 Shack, Lorraine e12505 Shaffer, Michele 9526 Shafi, Ayesha A. e16043 Shafren, Darren TPS3128 Shah, Aadhar TPS3107 Shah, Amishi e15564 Shah, Avani Atul TPS5102 Shah, Binay Kumar e14627, e17598, e20529 Shah, Gunjan L. 1580 Shah, Jatin J. 8585^, 8586, 8596 ABSTRACT AUTHOR INDEX

779s

Shah, Jay Bakul 5069 Shah, Krunal 2566 Shah, Manali 9632 Shah, Manish A. 4082, 4101, TPS4155, e14517, e15022, e15600, e20549 Shah, Manisha H. 4032, 4142, 4143 Shah, Mazhar Ali e12033 Shah, Neil P. 7001, 7012, 7021, 7023, 7063, TPS7129 Shah, Neil 9583 Shah, Nilay 8557 Shah, Nina R. 6636 Shah, Nirali 10008 Shah, Nishit e14637 Shah, Riddhi e22148 Shah, Satish e15014 Shah, Sheetal 8584 Shah, Shetal N. 4515 Shah, Sohela 1552, 7558 Shah, Sunjay 9505 Shah, Umang e13550 Shahabi, Vafa 9052, 9055 Shaham, Dorith e21508 Shaheen, Abdel Aziz 9596 Shaheen, Montaser F. 2578, TPS9103 Shaheen, Shagufta 9558, e18008 Shahid, Rabia K. 3580 Shahid, Tanweer e21519 Shahid, Zainab 8595 Shai, Ayelet 578, 5576 Shaib, Walid Labib e14579 Shaik, Mohammed 570, 3582, 3583, 6567, e14518, e14566 Shain, Kenneth H. 8608, e19516 Shak, Steven 520 Shakil, Shams A. e16101 Shakir, Nazia 4545 Shalgi, Ruth e20548 Shalley, Eve e17560 Shamaa, Sameh 4537 Shamash, Jonathan 4535 Shames, David S. 2507, 6008 Shammo, Jamile M. 7118 Shamon-Taylor, Lisa 2071 Shamseddine, Ali e12525 Shan, Joseph 4054, 8095 Shan, Minghua 5068, 5080 Shan, Ning 9634 Shan, Shigang e15050 Shan, Yan-Shen 4018 Shanafelt, Tait D. 6533, 7015 Shang, Shulian 9021 Shango, Maryann 10584 Shani, Adi 3524 Shani, Ravi M. 9536, 9551, 9595 Shankaran, Veena e14585 Shanmugam, Kandavel 3576 Shannon, Jennifer Anne 4081 Shannon, Jenny LBA4003, TPS4157 Shannon, Kerwin F. 9001 Shanyinde, Milensu 9068 Shao, Qiong 4107, e15047 Shao, Ryan 9090 Shao, Yongzhao 1500, 9021, 9023 Shao, Yu Yun 3554, 4115, e15043, e15182 Shaomei, Li e19085 780s

Shaper, Carl 506 Shapira, Iuliana e16546 Shapira-Frommer, Ronnie 5505, 5518, 11024, e20039 Shapiro, Alice C. e20560 Shapiro, Charles L. 1007, 1023, 1043, 2608 Shapiro, Edan 4552 Shapiro, Geoffrey 2500, 2530, 2585, TPS2627, 8032, 9094 Shapiro, Irina M e13523, e18541 Shapiro, Jeremy David TPS3649, e14583, e14640 Shapiro, Jeremy 3584, TPS5099^ Shapiro, Richard L. 9023, 9054 Shapiro, Richard 9021, 9067 Shaplygin, Leonid e12012 Shaqfeh, Mahmoud 6567 Sharama, Vibhor e17027 Sharan, Kanu 1091 Sharfman, William Howard TPS3110, TPS3114, 9005, CRA9006^, 9016, 9066 Sharid, David e16023 Sharif, Roozbeh e13031 Sharifi, Marina e13532 Sharkey, Robert M. e14508, e15089 Sharma, Atul TPS4162, 7081, 7082, e14501, e15138, e19524, e19526, e19531, e22098 Sharma, Bhuvnesh K. e20052 Sharma, Dayanand 10527, e13014, e13034, e13043, e16511, e20679, e21506, e21522 Sharma, Harbiner 5008 Sharma, Kamal e18012 Sharma, Manish 577, 2571 Sharma, Mehar C. 10527, e19524 Sharma, Navesh K. e14545 Sharma, Neelesh 8114 Sharma, Padmanee 3043, 4527^, 4547^, TPS5093 Sharma, Pratibha 7079 Sharma, Priyanka 1026 Sharma, Rahul e14579 Sharma, Rajni 4523 Sharma, Rohini e15101 Sharma, Sameer 5564, 5579 Sharma, Sunil 2555, 2593, 8010, 10587, e13512 Sharman, Jeff Porter 7017, 7086, TPS7133, 8500, 8501 Sharp, Adam 4549 Sharp, Hadley J. e17588 Sharp, Linda 5084 Sharpe, Kevin 4508 Sharr, Michele TPS7132 Shashidhara, H. P. 6624 Shastri, Surendra Srinivas 2 Shatavi, Seerin Viviane 1541 Shatten, Charlotte 7119 Shau, Wen-Yi e15043 Shaughnessy, John D. 8515 Shaw, Alice Tsang 8010, 8031, 8032, 8083, 8108, TPS8119 Shaw, Andrew Cota 6599 Shaw, Edward G. 2006, 2051, 6564, 9505 Shaw, Fawwaz Ridwan 9042 Shaw, Mary 6583


Shaw, Trudy G. 1573 Shaw, Victoria LBA4004 Shayne, Michelle e20667 Shaywitz, Adam 9628 Shcherba, Marina 6064 She, Desmond 7517 Shea, Thomas C. e13507 Sheaff, Michael 11071 Sheahan, Kieran 3549 Sheblaq, Nagham Ramzi e17528 Shedlock, Kathleen e20540 Sheehan, Andrea 8577 Sheehan, Christine E. 11100 Sheehan, Katherine M. 3549 Sheehan, Natale Tate e20009 Sheehy, Patricia S. TPS8620 Sheflin, Amy 11050 Sheibani, Nadia e22083 Sheidler, Vivian 6564 Sheikh, Nadeem A. 4547^, 5016, 5047^, 5053^ Sheikh, Saifuddin 577 Sheinfeld Gorin, Sherri 6536 Sheinfeld, Joel 4501, 4534 Shelkey, Julia 7554 Shelley, Greg TPS5094 Shelling, Andrew 5536 Shelton, Brent 541 Shelton, Kyla C. 10022 Shelton, Tiffani Dawn e17599, e20714 Shemi, Amotz 4037 Shen Miller, David e20523 Shen, Angela TPS7132 Shen, Chan 6513 Shen, Guoxiang e15126 Shen, Haijiao e19161 Shen, Hong 2022 Shen, Hua e14630 Shen, John P. 11105, e15562 Shen, Keng 5535 Shen, Liji 5011, e16010 Shen, Lin 4097, 4109, TPS4150, 10501^, e14501, e14644, e15174 Shen, Peng e22094 Shen, Robert e19013 Shen, Ronglai 6034, 8025 Shen, Wenyan David e13548, e13551 Shen, Xiaodong 3622, 8008 Shen, Xiaowei 9536, 9551 Shen, Yaoqing e22020 Shen, Yi 1547 Shen, Yu 1569, 4548 Shen, Yun TPS4593, 8072 Shen, Zhi-Xiang 8525 Shen, Zhirong e19067 Sheng, Liming e18531 Sheng, Shijie 5085 Sheng, Weiqi 8547 Sheng, Xi Nan e20027 Shenkier, Tamara Nina 8552 Shenolikar, Rahul e17584 Shenouda, George 6007 Shentu, Yang 7537 Shepardson, Laura 1508 Shepherd, Frances A. 1579, 6543, 7500, 7516, 7517, 7532, TPS7609, 8048, 8072, 11002, 11057, e18514, e19033, e19077 Shepherd, Lois E. 564, 1033

Shepherd, Scott T.C. Sheppard, Elizabeth Sheppard, Sue Sher, David Sher, Naamit Sher, Tamara Sheri, Amna Sherlock, David Sherlock, Jadwiga Sherman, Bonnie Sherman, Eric Jeffrey

2589 e11507 e19015 8069 TPS2102 9520 535 3504 2031 e12509 6024, 6034, 6594 Sherman, Karen L. 10559 Sherman, Laurie Jill 9020 Sherman, Matthew L. TPS4595, TPS6098 Sherman, Steven A. e14576 Sherman, Steven I. 4, 6000, TPS6100 Shermock, Kenneth M. e14658 Sherrill, Gary Bradley 2595 Sherrod, Amanda M. e20555 Shet, Tanuja e19503 Sheth, Vipul e18004 Shetty, Aditya V. e15594 Shetty, Nishitha e18004 Sheveleva, Ludmila P. e20593 Shevrin, Daniel H. 5041 Shi, Chanjuan 3555 Shi, Hong 11026 Shi, Hongliang 5076 Shi, Jack G. 3025 Shi, Jian Hua 8016, 8061 Shi, Liang e19149 Shi, Nianwen e20525 Shi, Qian 3510, 3520, 3533, 3576, 3639, 4026, 4071 Shi, Qiuling 9646 Shi, Runhua e14653, e17585, e19070, e20600 Shi, Weiwei 1013 Shi, Wenjing e20046 Shi, Wenyin 2100 Shi, Yang 8016, 8061 Shi, Yuan-Kai 8525, e19075 Shi, Yuanjun LBA4509 Shi, Zheng Jane 8546 Shia, Jinru 1555, 3609 Shiah, Her-Shyong 4099 Shiau, Carolyn Jane e19032, e19077 Shibata, David e15075 Shibata, Masahiko 3063 Shibata, Taro 4526, 5537 Shibuya, Kazutoshi 11052 Shibuya, Masahiko e18524, e19133 Shichinohe, Toshiaki 3638 Shieh, Felice e19027 Shields, Anthony Frank e15077 Shields, Carol L e15563 Shields, Jerry A. e15563 Shields, Jerry 9021 Shien, Tadahiko 1106, 1116 Shigaki, Hironobu 11065 Shigematsu, Hideo 11111, e22113 Shigematsu, Naoyuki e16090 Shigeoka, Yasushi 1029 Shigeta, Masanobu e15576 Shih, Helen Alice 9064, 10018 Shih, Jin-Yuan 8055

Shih, Joanna H. 4584 Shih, Karin e16546 Shih, Kent C. 2093, 2606, e13045 Shih, Ya-Chen T. 1513, 6513, e20604 Shiina, Takayuki 7548 Shiina, Tsuyoshi e22116 Shikhrakab, Hassan e19064 Shillington, Alicia 6627 Shilo, Konstantin 7542 Shiloni, Eitan 1108 Shim, Byoungyong e14563 Shim, Hyun-Jeong e15121, e17005, e20621 Shim, Seung-Hyuk 5600 Shima, Kanako e19507 Shimada, Hiroyuki 10015 Shimada, Masaaki e15159 Shimada, Mitsuo e14572 Shimada, Muneaki 5526, 5528 Shimada, Naoko e19043 Shimada, Shuichi e15570 Shimada, Tadashi 8033 Shimada, Toshikazu 9621 Shimada, Yasuhiro 3519, 3559, 9621 Shimamatsu, Fumie e19137 Shimanovsky, Alexei 4546 Shimbashi, Wataru e17006 Shimizu, Chikako e20557 Shimizu, Daisuke 1047 Shimizu, David e16501 Shimizu, Hiroaki 4056 Shimizu, Junichi 7529 Shimizu, Ryoichi 3006 Shimizu, Satoshi 2559, e15116 Shimizu, Shigeki e18530 Shimizu, Tadao 1534, e11604, e12026 Shimizu, Tomoharu 4092, e12014 Shimizu, Toshio e20004 Shimizu, Yasuhiro 4008 Shimizu, Yasushi 7550 Shimo, Takahiro e12009 Shimoda, Tadakazu 4104 Shimodaira, Hideki e14597 Shimokawa, Mototugu e15158 Shimokawa, Toshio 4072, e14551 Shimokawa, Tsuneo 8054 Shimokuni, Tatsushi e14548, e15038 Shimoni, Avichai 8556 Shimoyama, Tatsu 3516 Shimoyama, Yoshie 4119 Shimozuma, Kojiro e20609 Shimp, William S. 1080, e11609, e12034, e14646, e19130, e20672, e20697 Shimura, Tadanobu e22205 Shimura, Tatsuo 3063 Shin, Adeline Jae Hyun e12503 Shin, Dong Bok 3595, LBA4024, e19129 Shin, Dong M. 6030, 6083 Shin, Dongbok 3521 Shin, Donghoon 9038 Shin, Eisei e13501 Shin, Hee Young 10051 Shin, Hee-Chul 1039 Shin, Jung-Young 1540

Shin, Kyung Hwan e11584 Shin, Sang Won 6069, 9633 Shin, SeongHoon e20581 Shinagawa, Akiko e16502 Shinde, Bhoopal e18004 Shinde, Vijay 3039 Shindo, Yoshitaro 3006 Shinkai, Tetsu e19040, e19054 Shinohara, Akiyoshi 9637 Shinohara, Nobuo 9623 Shinoto, Makoto e15008 Shinozaki, Eiji 4075, 4108, e15105 Shinozaki, Hirokazu 3006 Shinozaki, Katsunori 3535, LBA4024 Shinya, Morita e16094 Shiomi, Hisanori 4092, e12014 Shioyama, Yoshiyuki e15008 Shiozawa, Manabu e14555 Shirabe, Ken e14633 Shirahata, Mitsuaki 2066 Shirai, Junya e15112 Shirai, Keisuke e20019 Shirai, Toshihiro 8038, e20658 Shiraishi, Kouya 7540 Shiraishi, Taizo e16054 Shirakawa, Yasuhiro e15161 Shiramizu, Bruce 3055 Shirao, Kuniaki e14527, e20585 Shirasaki, Hiroki e19083 Shirouzu, Kazuo e14684 Shiroyama, Takayuki e19021 Shisheboran-Devouassoux, Mojgan 8100 Shitara, Kohei 4075, 4076, e22082 Shiu, Kai-Keen TPS3645 Shkolnik, Michail 4576 Shmueli, Einat 1526 Shogren, Kristen L. 10531 Shoji, Hirokazu 3559 Shoji, Tadahiro TPS3116, 5526 Sholl, Lynette M. 8039, e18512, e22042 Shomron, Noam 578 Shong, Young Kee 4 Shore, Neal D. 5016, 5047^, 9628, 9640 Shore, Neal 5009 Shores, Carol G. 6070, TPS6097 Shorikov, Egor 10055 Short, Pamela 6558 Shostrom, Valerie 7571 Shou, Yaping 2555, 8514 Shoukat, Sana 3032 Shousha, Sami e22194 Showalter, Timothy Norman e17577 Shows, Joseph Ryan e14653 Shpall, Elizabeth J. 7010, 7011 Shparyk, Yaroslav V. 629 Shparyk, Yaroslav 3073, LBA4001, 4506 Shpilberg, Ofer e20595 Shrader, Abigail 1574 Shreenivas, Aditya V. 9530 Shrestha, Prem Raj 8503, 8508, 8573 Shridhar, Vijayalakshmi 11119 Shrivastava, Vikas 622 Shrotriya, Shiva e20572

Shterev, Ivo 4520, 11011, 11053 Shtivelband, Mikhail LBA509, 8095, e22172 Shuangshoti, Shanop e19041^ Shuch, Brian 4584 Shuk, Elyse e20586 Shukla, N. K. TPS4162, 10527, e12539, e21506, e21522 Shukuya, Takehito 7582, 7599, e18556, e19043 Shulkes, Arthur e16016 Shull, Shastin E. 6095 Shulman, Katerina e22111 Shulman, Lawrence N. 1007, 9530 Shum, Merrill Kingman 4054 Shumaker, Grace 621 Shuman, Katie CRA6510, 6518 Shuman, Marc e19541 Shumway, Nathan M. 3096, 3097 Shurell, Elizabeth 10555 Shuster, Lynne T. 9073 Shustik, Chaim 8588 Shustov, Andrei R. 8507 Shute, Justin e20709 Shyu, Wen Chyi 2598 Si, Lu e20027 Si, Xuemei e16015 Sia, Joseph e18559 Siamakpour-Reihani, Sharareh 5509 Sibai, Khaled e17033 Sibson, David R 4518 Sica, Gabriel 2610, 7560, e14612 Sica, Lorenzo e12017 Sicart, Elisabet 2016 Sicchieri, Renata D. e12007 Sickersen, Gaelle 3536 Sickert, Daniel 591 Sicking, Isabel 615 Sicks, JoRean 1563, 7525 Siddartha, Roy e19092 Siddik, Zahid Hussain 2601 Siddiq, Zainab 6505 Siddiqi, Imran 8554 Siddiqui, Mohummad Minhaj 5086 Sideris, Lucas 1018 Sidhom, Iman A. 10044 Sidhu, Gurinder Singh e14690, e19522 Sidhu, Harpreet e20722 Sidhu, Juhee 8594 Sidhu, Kulbir 9527 Sidhu, Roger 3511, 3617, 3620 Sidiropoulos, Nikoletta 11004 Sidransky, David 2511 Sieber, Oliver 3598 Sieberova, Gabriela e22023 Siebler, Juergen 3561 Siedentop, Harald 4 Siedlecki, Janusz A. e22046 Siefert, Mary Lou e20552 Siefker-Radtke, Arlene O. 4528, 4538, 4548 Siegel, Abby B. e15037 Siegel, David Samuel DiCapua 8529, 8532, 8584, 8585^, 8588, e19517 Siegel, Eric R 7597, e15152 Siegel, Erin e15075 Siegel, Petra e20035

Siegfried, Jill 6051, 7577 Sieker, Frank 6077 Sielaff, Timothy D. 4038 Siemens, D. Robert e15616 Siena, Salvatore 4, 3511, 3514, 3581, 3617, 3620, 3636, 3637, TPS3648, 8105, 11005, 11058, e14560, e15188^ Sierocinski, Thomas 4542 Sierra del Rio, Monica 2032 Sieuwerts, Anieta M. 11045, e22106 Siffert, Winfried 584 Sifuentes, Erika 634, e11533 Siggillino, Annamaria e22155 Signoretti, Sabina 4521, 4530, 4570 Signori, Stefano 4062 Signoriello, Simona 11008 Signorovitch, James E. e15500, e15504, e15538 Sigounas, George e14635 Sigurdson, Elin R. e14711 Sikic, Branimir I. 1012, 5565, 5583 Sikov, William M. 619, 1032, 1046, 6574 Sikron, Fabienne 1599, e17536 Silbergeld, Daniel L. e13017 Silberschmidt, Daniel 4135, 8070 Silberstein, Peter T. 5611, 6568, e14641, e14642, e16012, e18501 Silcocks, Paul LBA4004, 9031 Silginer, Manuela 2079 Silini, Enrico Maria 2021 Sill, Michael 3 Silletta, Marianna 10568, e15528 Silman-Steiberg, Yael e20039 silva Oliveira, Saulo e20631 Silva, Ana Gabriela e22122 Silva, Ana Licia Maia e18515 Silva, Elvio e16518 Silva, Fabricio Colacino e13562 Silva, Gualdino e15172 Silva, Matthew D. 11095 Silva, Raquel Ataide Peres 10036 Silva, Samantha Cabral Severino da 5540 Silva, Tereza Giannini Pereira da 6071 Silva, Virgilio Sousa 6017 Silva, Viviane Aline Oliveira e13557, e13559 Silvain, Christine 3513, 3536 Silveira, Willian A. e12007 Silver, Heidi J. e20531 Silver, Joel e19514 Silvera, Deborah 11106 Silverio, Flavio e22176 Silverman, Craig I. e21000 Silverman, Stuart G. e17574 Silvestri, Barbara e20028 Silvestri, Gerard A. 1523 Silvestri, Rosangela e11515 Silvestris, Francesco e16081 Silvestris, Nicola 4091 Silvino, Marina e20691 Sima, Camelia S. 6583, 7558, 7559, 7570, 7593, 8022, 8025 Simantov, Ronit 4572, e13502, e15624 Simeone, Anna e18518 ABSTRACT AUTHOR INDEX

781s

Simeone, Ester

9035, 9070, e20031 Simeonov, Anton 1016 Simes, John 2017 Simiantonakis, Ioannis 1101 Simkens, Lieke H.J. 3502 Simm, Hala D. 8036, e13568 Simmons, Ahkeem James 514 Simmons, Ashley Erickson e13507 Simmons, Christine E. 1551, 6585, e17526 Simmons, Pauline 3016 Simms, Lorinda 8052 Simo-Perdigo, Marc e22119 Simon, George R. 8001 Simon, Iris 3530, 3612 Simon, Jason S. 3003^, 3016 Simon, Jean-Marc 6093 Simon, Laureano 540 Simon, Matthias 2027, 2045 Simon, Melanie 7035 Simon, Michael S. 1524, 3594 Simon, Paul e22163 Simon, Thorsten 10017 Simonassi, Claudio e12518 Simoncini, Maria Claudia e20634 Simone, Charles B. 7578 Simone, Gianni e14565 Simone, Giovanni 8071, e11502 Simonelli, Cecilia 5522^, e16510^ Simonelli, Matteo 4121, e22145 Simons, W. Robert 1050^, 1055^, e17552, e17576 Simos, Demetrios 6597 Simpfendoerfer, Tobias e16063 Simpson, David 8537, 8565 Simpson, Dayna 2586 Simpson, Jennifer 8556 Simpson, Jeremy TPS5612 Simpson, Judy M. e20533 Sims, Robert Brownell 4547^, 5053^ Sinclair, Natalie Faye 619 Sing, Amy Pratt 507, 565 Singer, Christian F. 11032, e11601 Singer, Eric A. 4584 Singer, Samuel 10512, 10520, 10580 Singh, Anurag Kumar e20547 Singh, Arsh e16101 Singh, Baljit 11106 Singh, Beerinder e15600 Singh, Gopal 11060 Singh, Jasmeet Chadha 1042 Singh, J. K. 1071 Singh, Karan P. 6559 Singh, Kathryn E. e12528 Singh, Kirti e13021 Singh, Madhu Sudan 11015 Singh, Manisha 1071 Singh, Margaret e13502 Singh, Nishith K. TPS3127, TPS5104, e16036 Singh, Onkar 2588 Singh, Parminder e16060 Singh, Prashant e22211 Singh, Preet Paul 8587, 8600 Singh, Randeep e20678 Singh, Satwinder Kaugh 3029 Singh, Shalini 3576 782s

Singh, Sharat

3626, 4051, 11113, e14626, e22110 Singh, Shweta e22183 Singh, Simron 6041 Singh, Trevor 3583, e14518 Singhal, Anil K. 8542 Singhal, Nimit e14506 Singla, Abhishek 6568 Sinha, Arvind e14507 Sinha, Rajni 8533, 8534 Sinha, Uma 8574 Sini, Claudio TPS7606, 11063 Sini, Maria Cristina e20013 Sini, Valentina e13009 Sinibaldi, Victoria J. e15597, e15598, e16051, e16068 Sinicrope, Frank A. 3510, 3523, 3576, 4071, e14711 Sinicropi, Dominick 11018 Sinkina, Tatiyana Vladimirovna e12560 Sinn, Bruno Valentin 4016 Sinn, Hans-Peter 11023 Sinn, Marianne 4016 Sint, Kyaw J. 9584 Sintini, Michele e13007 Sippel, Rebecca S. e17025 Siqueira, Sheila Aparecida Coelho e15090 Sirard, Cynthia e22203 Siravegna, Giulia 11005 Sirera, Rafael 11073, e22147 Sirinoglu Demiriz, Itir e18014 Siriwardena, Ajith K. e14547, e15072 Sirohi, Bhawna 8053 Sirskyj, Danylo 4568 Sirulnik, L. Andres 7111 Sisani, Michele e16093 Sissung, Tristan 2514 Sit, Laura 6575 Sittampalam, G. Sitta e22048 Sittampalam, Gurusingham Sitta e18523 Siu, Lillian L. 2505, 2517, 2534, 2561^, TPS2618, 6033, 6045, 11002, 11016, e17515 Siu, Lillian 6041, e18514 Sivakumaran, Praveen e15577 Sivanandan, Ananth e16069 Sivarajan, Kulumani M. 8044 Siveke, Jens T. 4086, e15088 Sivendran, Meera 3014 Sivendran, Shanthi 3014 Sivgin, Serdar e15623 Sivik, Jeffrey Michael 7039 Siziopikou, Kalliopi P. 626, TPS666, 6617, e22093 Sjoquist, Katrin Marie 3520, 4081, TPS4157, TPS5614 Skalicky, Pavel e22109 Skalidaki, Dimitra e14639 Skarbnik, Alan P. 11092 Skartved, Niels Jorgen Ostergaard 3551, 6002 Skates, Steven James 5507^ Skedgel, Chris e17564 Skee, Donna 8502 Skelton, Rachael 8088^ Skene, Anthony 1015


Skerman, Helen Skettino, Sandra L. Skinner, Heath D.

9516 7016 4078, 4083, 4085, e15013 Skirbe, Heidi e20701 Sklar, Charles A. 10004, 10019, 10032 Skoble, Justin 4040^ Skoneczna, Iwona Anna 4529, 5002 Skoog, Lambert e22126 Skor, Maxwell N. 11101 Skoro, Nevena 6638 Skovlund, Eva 3571, 3597 Skowronska, Anna 4029, e15093, e15162 Skrypnikova, Marina e12027 Skrzypski, Jeremy e11529 Skrzypski, Marcin Tomasz 11069 Skubitz, Amy 10560, 10561 Skubitz, Keith M. 10560, 10561 Slack, Rebecca 1546, 3600, e16038 Slaets, Leen 587, LBA1001 Slama, Borhane 7002 Slamon, Dennis J. 610, TPS652, 1054, LBA4001, 5510, 5515 Slater, Shannon TPS1144 Slavin, John 10567 Slavin, Shimon 2073, 3100 Slebos, Robbert 6016 Sleckman, Bethany G. 4012 Sledge, George W. 6527, 9508 Sleijfer, Stefan 2522, 10553, 10573, 11045, e16504, e22106 Slevin, Finbar e16069 Sliesoraitis, Sarunas e18002 Slimane, Khemaies 6036 Slimani, Sonia 2068 Slingluff, Craig L. TPS3114, TPS3118^, TPS3125 Sliwkowski, Mark X. 645 Sloan, Jeff A. 6587, 7545, 9513 Sloan, Jeff 6533 Slone, Stacey A. 7084, e18001 Slotman, Ben J. 7520 Slottke, Rachel 5017 Slovin, Susan F. TPS3115, 5090 Slusarczyk, Magdalena 2576 SM, Karandikar 6084 Smaglo, Brandon George TPS2624 Smail, Marc 1114 Smakal, Martin 3511, 3620 Small, Eric Jay 4520, 5006, 5009, 5010, 5011, 5026, 5047^, 5077, 11053 Small, Isabele Avila 6071 Small, William 9527 Smallwood, Alicia 6642 Smart, Janie e22048 Smart, Melody L. 2611, e12002 Smeland, Sigbjorn LBA10504 Smeltzer, Jacob Paul 8538 Smeltzer, Matthew 7569 Smerage, Jeffrey B. 9615 Smias, Christos 8567 Smid, Marcel 2597, 10573 Smilde, Tineke Jacoba e17549 Smiskol, Paul TPS9647 Smit, Egbert F. 7514, 8029, 8065, e19138

Smit, Johan 8502, 8530 Smit, Johannes W. A. 4 Smit, Vincent T. H. B. M. 1028, e22106 Smith, Amy A. 10030 Smith, B Douglas 3104 Smith, Barbara L. 1100 Smith, Barbara Lynn 647 Smith, Barry H. e14517 Smith, Brian J. 8563, e15052 Smith, Cardinale B. 7543 Smith, Carly J. 10040 Smith, Carrie L. e20518 Smith, Daryn W. 4577, 5085, 6045, e22168 Smith, Daryn 5041 Smith, David C. 2540, 3002^, 4514, 4545, 5026, TPS5094, CRA9006^ Smith, David C 5039 Smith, David 3504 Smith, Deborah A. 2536 Smith, Denis Michel 3599, e14514, e14542 Smith, Donald e19097 Smith, Elizabeth 6642 Smith, Frederick P. 565 Smith, Gary L. 9517, e13509 Smith, Holly 2558 Smith, Ian E. 525, 529, 555 Smith, Irma 8074 Smith, J. Keith 515 Smith, John W. 563 Smith, Jon e20048 Smith, Julia Anne 1042, 1500 Smith, Karen L. 11054 Smith, Katrina H. 2013, TPS2104 Smith, Ken R. 1582 Smith, Kim 9079 Smith, Kyle 1538 Smith, Lon S. e22088 Smith, Lynette 3055 Smith, Malcolm A. 2036 SMITH, Martina 598 Smith, Mary Lou e20712 Smith, Matthew R. 5009, 5010, 5026, 5037, 5059 Smith, Matthew Raymond 5001 Smith, Matthew 11094 Smith, Maureen e14550 Smith, Mitchell R. 8576 Smith, Mitchell Reed 7126 Smith, Myles J.F. 10537 Smith, Quentin R 514 Smith, Scott E. e19511 Smith, Stephen James e14516 Smith, Susan A. 4536 Smith, Thomas J. 9578, 9636, e20638 Smith, Webb A. 10022 Smith-Machnow, Victoria TPS3124^ Smith-Marrone, Stephanie 6034 Smithers, Bernard Mark 9001 Smits, Kim M e14503 Smits, Marion 2001 Smolders, Yvonne H. C. e22174 Smolej, Lukas 7101 Smolkin, Mark E. 6599, e11596 Smoragiewicz, Martin 7551 Smorenburg, Carolien H. 595, 1072 Smothers, James F. 3044

Smotkin, David e22009 Smyrk, Thomas C. 3523, 3576 Smyth, Elizabeth Catherine TPS2626, 4020, TPS4156 Snaebjornsson, Petur 3552 Snavely, Anna C e15507 Snell, Michael Robert 8114 Sneller, Vesna 5542 Snider, Jessica Nicole 1068 Snively-Solomon, Jolie 4501 Snodgrass, Susan M. 2013 Snuderl, Matija 2056 Snyder, Carrie L. 1573 Snyder, Claire Frances 6519 Snyderman, Michael e22038, e22039 So, Charlene TPS7132 So, Kyeong A. 5539 So, Peter e19041^ Soares, Fernando A. e21507 Soares, Fernando A e22154 Soares, Joao Marcos A. e22122 Soares-Pires, Filipa e19069 Sobanko, Joseph 9017 Sobecks, Ronald M. 7008 Sobhani, Iradj 3585, e14525 Sobocki, Patrik e16066 Sobol, Robert W. 11105 Sobrero, Alberto F. 3514, 3637, LBA4001, e14561 Sobrero, Alberto 3636 Socinski, Mark A. 7500, 8004, 8009, 8012, 8039, 8044, 8073, 8086, TPS8126, e19022, e19037, e19038, e19150 Sodhi, Monish 2550 Soe, Aye Min e19508 Soeda, Hiroshi e14597 Soejima, Toshinori 7583 Soejima, Yoshifumi 8006 Soeling, Ulrike 640 Soerensen, Bente Thornfeldt 7504 Soerensen, Morten Mau 2505, 2522 Soergel, Fritz 8112 Soffietti, Riccardo 2084 Soga, Tomoyoshi e15568 Sogabe, Susumu e14604 Soh, I Peng Thomas e14507 Soh, Shigehiro e15579 Sohal, Davendra 4087, e15000 Sohji, Sunao e15527 Sohl, Jessica 513, e17574 Sohl, Stephanie Jean e20532 Sohn, Bo Hwa 4113 Sohn, Byeong Seok 10550 Sohn, Byung Ho 1070, e11512 Sohn, Christof 11012 Sohn, Eun Joo e12005 Sohn, Sang Kyun 3553, e18017 Soiffer, Robert 1531 Sojka, Ludek e22129 Sokol, Lubomir 9072 Sokoll, Lori J. 5573 Sokoloff, Mitchell e16060 Solak, Mustafa e11595, e12521, e12563 Solass, Wiebke e16523 Solbach, Christine 615

Solberg, Arne Solberg, Gretchen Soldatenkova, Victoria Soldic, Zeljko Solheim, Olesya Soliman, Hatem Hussein

4553 TPS3112 e19148 e15603 5533 3026, 3069 Soliman, Pamela T. 5596, 5608, e16556 Soliman, Sonya 10044 Solinger, Alan 3009 Solis Hernandez, Maria Del Pilar e14617 Solit, David B. 9060, e15017 Solodkij, Vladimir Alekseevich e13545 Solomayer, Erich 1121 Solomko, Eliso e22097, e22162 Solomon, Benjamin J. 2520, 8032, 8105, e22092 Solomon, Sarah 10511 Solomon, Stephen Barnett TPS3120 Solow, Henry L. 5058 Som, Peter M. 6019, 6062 Somaiah, Navita 11116 Somani, Naresh 6084 Somashekhar, S. P. e11510 Somasundaram, Raj e18523 Somer, Bradley G. 5019 Somer, Robert A. 1091 Somerville, Lesley 9590 Somlo, George 619, 1024 Sommeijer, Dirkje Willemien 3520, TPS5612, TPS5614 Son, Jeewoong 2565, e13505 Sonabend, Adam e13017 Sone, Takashi e18564, e19083 Soneji, Dharmesh 1099 Soneson, Charlotte 3526 Song, Cheryn e15516, e15519 Song, Chunyan 646 Song, Eun-Kee 4013, LBA4024, 9633 Song, Ga Won e15020 Song, Hong-Suk 8521 Song, Hunho e17026 Song, James 563 Song, Jin e22010 Song, Kevin W. 8510, 8527, 8528, 8583, 8588 Song, Kyo Young e15164 Song, Roman e22066 Song, Wei e18550 Song, Xinni 542, 574, 6595, 9032 Song, Xishuang e15582 Song, Yong Sang e20530 Song, Yong 8042 Sonis, Stephen T. 9530, 9535, 9620 Sonkin, Dmitriy 7111 Sonmez, Ozlem e18510 Sonnenblick, Amir e21508 Sonnenburg, Daniel 4557 Sonneveld, Pieter 8517 Sonobe, Syoko e19021 Sonoda, Hiromichi 4092, e12014 Sonoda, Norikazu e14604 Sonpavde, Guru 4524, 4539, 4551, 4563, e15549, e15555

Soo, Ross A. 7565, e17017 Sood, Anup e22085 Soon, Yu Yang 4066 Soong, Richie Chuan Teck e14507 Soori, Gamini S. 1059, 3640, 4026, e14526 Soper, John T. 5607 Soran, Atilla 1098, 9643 Soraru’, Mariella e20541 Sorbye, Halfdan 3571, 3597, e14710 Sorensen, A. Gregory 513 Sorensen, Jens Benn 7504, e19148 Sorensen, Morten 2092 Sorensen, Poul 10066 Sorgatz, Kristine e17538, e20605 Soria Rivas, Ainara 4140, e15169 Soria, Jean-Charles 2512, 2524, 2535, 2606, 2609, 3000, 3001, 3010, 3035, 4574, 7505, 7604, 8000, 8008, 8059, TPS8124, 9556, e19058, e22092, e22153 Soriano, Gabriela 6528 Soriano, Rosalia e22144 Soriano, Virtudes e20007 Sorio, Roberto LBA5501, 5542 Sorkin, Mia 1565 Sormani, Mariapia 546 Sosa, Aaron R 6072 Sosa, Eduardo V. 5077 Sosman, Jeffrey Alan 2528, 3000, 3001, 3002^, TPS3114, 4505, 4521, CRA9003, 9005, CRA9006^, 9010, 9016, 9019, 9066, TPS9105^ Sosunov, Eugene 6640 Sotelo, Miguel J. e11561 Sothi, Sharmila e15085 Sotiriou, Christos 528, 3012, 11003, 11061, e12008 Soto Parra, Hector J. e11526 Soto Reyes Solis, Ernesto e22151 Soto, Arturo 10517 Soto-Perez-de-Celis, Enrique 634, e11533 Sotomayor, Paula 4582 Sottotetti, Elisa e22056 Soubeyran, Pierre-Louis 2032, 9564, e20513 Soubrier, Florent 1528 Soucek, Pavel 11051 Souchet, Simon e18508 Soucy, Genevieve 4060, e15094 Souglakos, John 3520, 3533, 7594 Souhami, Luis LBA4510, 5588 Souhan, Erin 1596 Soulieres, Denis TPS4594, 6041, e22159 Soulos, Pamela R. 6511, 6549 Souquet, Pierre Jean 7505, 8009, 8081, 8099, e19058, e19060 Soussain, Carole 2032 Soussan-Gutman, Lior e11578, e22111 Souza, Ciro 5059 Souza, Fabiano Hahn e20506 Souza, Flavia e20601 Souza, Kimberly e22188 Soverini, Simona 7025 Sowers, Noelle 2587 Soyer, Philippe 3642 Soyfer, Viacheslav e21521

Sozzi, Fausta 5559, e17548 Spaans, Johanna e17563 Spaczynski, Marek e20518 Spada, Francesca e15124, e15147 Spada, Manoela Tavares Arruda e22176 Spaeth, Dominique 510 Spaggiari, Lorenzo 7602 Spagnolo, Francesco 9070 Spahn, Guenther e20710 Spalding, James e16080 Spanik, Stanislav 4556, e15599 Spano, Jean-Philippe 5567, 6093, e12504 Sparano, Joseph A. 560, 1003, 1024, 1118, 2591, 4011, 5517, 8524, 9508 Sparber, Cornelia 573 Sparreboom, Alex 2592, 2597 Spartalis, Eleftherios e18542 Spathis, Anna 9503 Spatz, Alan 9032 Spazzapan, Simon e22149 Spears, Melissa Ruth 5012 Specchia, Giorgina 7025 Specenier, Pol M. 2061, 6002 Specht, Jennifer M. 1089, 1090 Specht, Katja 581, 10508 Specht, Michelle Connolly 647 Speck, Rebecca M 6560 Spector, Neil e13517 Spector, Nelson 7053^ Spector, Yael e22173 Speers, Caroline 1044, 3569, 6502, 9577, 9593, e14603 Speers, Corey 1025, 2052 Speiser, Daniel E 9014, 9078 Speiser, Paul e16524 Speller, Abigail e14620 Spencer, Andrew 8589 Spencer, Christina 6043 Spencer, Sarah Ellen e22048 Spencer, Stuart 9004 Sperandeo, Marco e18518 Sperandi, Francesca e18509 Sperduti, Isabella e12031, e15057, e16053, e17555, e20619, e22206 Sperger, Jamie e22141 Sperinde, Jeff 604 Sperk, Elena 1120, 1121 Speyer, James L. 1042 Spicer, James F. 3035, CRA8007, TPS8126, 9627 Spicer, Jonathan e15034 Spiegel, David 9504, 9532, 9533 Spiegelman, Vladimir S. e18537 Spiegelmann, Roberto e13002 Spiegle, Gillian 6639 Spiekermann, Karsten 7051 Spielman, Calan e15029 Spielmann, Marc e11607 Spiers, Laura 5562 Spigel, David R. 3002^, TPS7608, LBA8003, 8004, 8008, 8012, 8030, 8044, 8062, 8086, 8091, 8095, TPS8119, TPS8120, 11080, 11102, e15006, e15501, e19062, e19150, e22092 Spigno, Fabio e12518 Spiliotaki, Maria e22101 Spiliotis, John 9557 ABSTRACT AUTHOR INDEX

783s

Spina, Michele 8524 Spindler, Karen-Lise Garm e19163 Spinelli, Tulla e20538 Spinoglio, Giuseppe e14657 Spira, Alexander I. 7500 Spiro, Timothy Peter 1038, 6577 Spisek, Radek 3076, e16002, e22129 Spitale, Alessandra e14536 Spitaleri, Gianluca 2556 Spitler, Lynn E. TPS3128, LBA9008 Spittle, Cynthia 9023 Spitzer, Dirk e16508 Spivak, Jerry L. 7032 Spivey, James R. e15033 Spivey, Vicky e22164 Spoelstra, Femke 7520 Sponghini, Andrea 6027 Sponziello, Francesco e14605, e18545 Spoozak, Lori Ann 5592 Sporn, Nora e20551 Sportelli, Peter 8575, e19528 Sposto, Richard 2049, 10039 Spoto, Chiara e15528 Spraggs, Colin F. 4519 Sprague, Brian 1512 Spratlin, Jennifer L. TPS4593, e14575, e14595, e14715 Sprauten, Mette 4562 Spreafico, Anna 5039, e17515 Spreafico, Carlo e12017 Sprick, Martin 11012 Spriggs, David R. 5545, e13509 Springer, Marco 3090 Springett, Gregory M. 4040^, e15075 Sproat, Lisa Ostrosky 7047 Sprod, Lisa TPS9651 Spunt, Sheri L. TPS10591 Spurgeon, Stephen Edward Forbes 7003, 8519, 8526 Squadroni, Michela e20650 Squarcina, Paola 9092 Squiers, Linda 9608 Squire, Jeremy 2053, 11085 Squires, Matthew TPS651, TPS5616, 7111 Sreedhara, Meera 8097 Sreenivas, Vishnu kumar e12539 Sreenivasappa, Shylandra B. e12523 Sridhar, Epari e19503 Sridhar, Srikala S. 4524, 5039, 5058, e11542, e16082, e16088, e17523 Sridharan, Ashwin 7125 Sridharan, Swetha e15510 Srimuninnimit, Vichien 558, 561, e14501 Srinivas, B. J. e19092 Srinivas, Sandy 4565, 4578, 4586, e15518 Srinivas, Shanthi 1602, 9567, e15561 Srinivasan, Ananth 11006 Srinivasan, Ashok 10021 Srinivasan, Ramaprasad 4584 Srinivasan, Shankar 8596 Sriram, N. 8017 784s

Sriuranpong, Virote TPS661, 8021, e17004, e19041^ Srivas, Rohith 11105 Srivastav, Shanti P. 577 Srivastav, Sudesh e12503 Srivastava, Apurva K. 11103, e22080 Srivastava, Geetika 3640, e14526 Srivastava, Kirti e17020 Srivastava, Kunal e20012 Srivastava, Vikas Kumar e17020 Srkalovic, Gordan CRA1008 Srock, Stefanie 555 Srovnal, Josef e22109 St. Germain, Diane C. e17560 St. John, John 11010, 11067 St. Pierre, Michelle e19502 Staals, Eric L. 10571 Stabilini, Cesare 9557 Stacchiotti, Silvia 10516, 10565, 10568, 10576 Stacey, Mark 1573 Stack, Edward C. 4530 Stacker, Steven 10567 Staddon, Arthur P. 6094, 10506, 10517, 10522, TPS10591, e13512 Stadler, Walter Michael 4012, 4524, TPS4590, 5028, 5081, e17511 Stadler, Zsofia Kinga 1511, 1552, 1555, 3605, TPS4144, e12527, e12536 Stadtmauer, Edward Allen 8578 Staebler, Annette 1020 Staettner, Stefan 3558 Staffurth, John LBA5000 Stafkey-Mailey, Dana 10590 Stager, Victoria 9101 Stagg, Robert J. 2540 Stahel, Rolf A. 7503, 7514, 7587, 8060, 11010, 11028 Stal, Olle 594 Stalder, Lukas 8060 Stallard, Nigel TPS656 Stalmeier, Peep FM e20583 Stamatakis, Lambros 4584 Stamatopoulou, Sofia 11117, e20635 Stamatoullas, Aspasia 7002, TPS8615 Stambler, Nancy 5018, e16047 Stambolic, Vuk 1033 Stamm, Katrin e12517 Stamos, Michael J. e12528 Stamouli, Maria e20642 Stampfer, Meir J. 5086 Stampfli, Claire 3601 Stampleman, Laura 8599 Stan, Rodica 3093^ Stancari, Alessandra e13579 Stancel, Heather 10009 Stanford, Janet L. 6532 Stanford, Marianne 3030 Stanganelli, Ignazio e15529, e20013 Stangler, Thomas 3075 Stanisz, Greg J. 4583 Stanley, Andrew LBA5000 Stanley, Jeffrey 9607 Stanojevic, Goran 9557 Stanton, Louise 3504 Stanton, Paul 7579, 7580


Stany, Michael Stanzione, Brigida Stapelkamp, Ceilidh

e16525 e11528 9040, 9044, e20012 Stark, Azadeh 5581 Starmans, Maud HW e18559 Starnawski, Michal 9036 Starnes, Sandra Lynne 7502, 7524 Starodub, Alexander 3022, 4563, e15557 Starr, Mark 4520 Starr, Shane e14635 Starz, Hans 9098 Stas, Marguerite e13528 Stathopoulos, Efstathios 7594 Stauch, Martina LBA3506 Staudinger, Matthias 8604 Stauffer, Paul e15560 Staveley-O’Carroll, Kevin F 10538 Staverosky, Julia e16057 Stavraka, Chara 2576 Stavridi, Flora 582 Stavris, Karen TPS1145, TPS1609 Steadman, Kenneth 2616, TPS2624 Stearns, Vered 515, TPS1144, 11019 Stebbing, Justin e22194 Stecker, Katrin e14513, e14562 Steding-Jessen, Marianne 6570 Steeg, Patricia Schriver 514 Steeghs, Neeltje 4580 Steegmann, Juan Luis 7053^, 7054^ Steel, Emma 1559, e20660 Steel, Jennifer Lynne 9507 Steele, Jeremy 11071 Steele, Savanna D. 3009, e17586 Steele, Scott e14500 Steen, Preston D. 2562 Stefanczyk, Marta e16097 Stefanick, Marcia L 1504 Stefano, Volinia 7573 Steffen, Bjoern 7012, 7021 Steffen, Ingo e15071 Steffens, Claus-Christoph 3604 Stega, Damian e22095 Stegelmann, Frank 7051 Steger, Guenther G. 573, 611 Steger, Ulrich 3538, e15193 Steggerda, Susanne 7014 Stein, Andrew Marc 11082 Stein, Lincoln D. 11016 Stein, Mark N. 2553, 2582, 5041, 5085 Stein, Rob TPS656 Stein, Stacey 4084 Stein, Stacy 1042 Stein, Wilfred Donald 4585, e22213 Steinbach, Daniel 10017 Steinbach, Joachim Peter LBA2000, LBA2009, 2061, TPS2103 Steinbacher, Julia 3054 Steinberg, Amir S. e20570 Steinberg, Hani e20039 Steinberg, Joyce 548 Steinberg, Kim A. e15136 Steinberg, Seth M. TPS4589, 6524, 8026, 10013, 10522, 10588, TPS10595, e19506 Steinberg, Seth M TPS5095

Steinberger, Allie Steiner, Mariana

10071 578, 1108, 5576, e22111 Steiner, Mitchell S. e16015, e19100 Steingart, Richard 630 Steinger, Brunhilde e20517 Steiniche, Torben 5532 Steinle, Alexander 3054 Steinmann, Angela e15029 Steinmetz, Kristina 4100 Steinmetz, Tilman 4009, e14502 Steinseifer, Jutta 503, 525 Stella, Philip J. 1059, 2014, 3501 Stellhorn, Robert e17510 Stelts, Sundae e20673 Stemmer, Salomon M. 508, 1040, e20548, e20595 Stempel, Michelle 1019, 1021 Stene, Guro Birgitte 9562 Stenehjem, David D. e11541, e20043 Stenina, Marina e12027, e16509 Stenmo, Kajsa e15553 Stenning, Sally P. 4020, TPS4156 Stensland, Kristian D 6540, 6613 Stenson, Kerstin 6008 Stenzel, Karsten G e14532 Stepanek, Vanda M. T. 11086, e13591 Stepankiw, Mika e15544, e15545 Stepanova, Evgenia e22097, e22162 Stepanski, Edward J. e15508, e15605 Stepansky, Asya 11047 Stephan, Carsten 5074 Stephanazzi, Jean e17514 Stephanie, Heller e20700 Stephans, James 11018 Stephans, Kevin L. 4087, e16004 Stephen, Frank e20039 Stephens, Catherine L e17533 Stephens, Craig 3527, 11062 Stephens, Derek 10015 Stephens, Matthew e22084 Stephens, Moira e20615 Stephens, Phil 534, 1009, 1051, 9002, 11000, 11020, 11100, e22146 Stephens, Philip J. 8020, 8023, 10513, 11068, e15035 Stephenson, Andrew J. e16004 Stephenson, Joe 5018 Stephenson, Judith J. 6627 Stephenson, Patricia 8032 Steplewski, Klaudia 4042 Stergiopoulos, Sotirios G. 4138 Sterin, Greg e13017 Stern, Jamie 8555 Stern, Jennifer C. 2524, e22092 Stern, Lee e14576, e15511 Sternas, Lars 8510, 8527, 8528, 8583, 8585^ Sternberg, Cora N. 4513, 4524, 5011, 5023, 5059, 5079 Sternberg, David W. e13502 Sterry, Wolfram e20035 Stetler-Stevenson, Maryalice 10008, e19506 Steurer, Stefan 5043 Stevanato, Paulo Roberto 10586, e21507

Steven, Neil 9031 Stevens, Glen 2065 Stevens, Mark 541 Stevens, Rick J. 6508 Stevens-Brogan, Michelle e15014 Stevenson, Kristen 6088 Stevenson, Laura TPS4156 Stevenson, Robert e16048 Steward, Kristopher K. 3024 Steward, William P. TPS3645 Stewart, A. Keith 8589 Stewart, Andrew 3582, 3583 Stewart, David J. 2601, 8104, e19066 Stewart, Grant 4508 Stewart, James A. CRA1008 Stewart, John e16082 Stewart, Patricia S. TPS4588^, TPS5101, TPS5103 Stewart, Stanford 3004 Stewart, Sunita 10064 Stewart, Suzanne B. 6631 Sticca, Robert P. 4026 Stickel, Juliane 7019 Stieber, Volker W. 2006, 2051 Stieger, Pascale 9071 Stieler, Jens 4016 Stierner, Ulrika K. 4553 Stiff, Patrick J. 4012, e19511 Stigall, Kristi 4548 Stilgenbauer, Stephan 7004, 7014, 7015, 7101 Stinchcombe, Tom 8039 Stinco, Sergio e20650 Stine, Jessica E. e16529 Stineman, Margaret G. 6560 Stintzing, Sebastian LBA3506, 3557, 3565, 3566, 3567, 3568, 4110, 4111, e14538, e14543, e14714, e15009, e15022 Stjepanovic, Neda 1509 Stockdale, Andrew 4508 Stockerl-Goldstein, Keith 8543, 9559 Stockhammer, Florian LBA2000 Stockler, Martin R. 4544, 5542, TPS5612, TPS5614, e22175 Stockman, Beth A. 10047 Stockman, David e20034 Stoebenau, Joseph E. 2536 Stoeckle, Eberhard 10582 Stoeger, Herbert 583 Stoehlmacher, Jan e17021 Stoehlmacher-Williams, Jan 3538 Stoffel, Elena Martinez 1530 Stojadinovic, Alexander e14500 Stokes, Dennis C. 10021 Stokes, Michael Edward 6546 Stokoe, Christopher T. 590 Stolley, Melinda e11572 Stoltz, Adeline 10579 Stoms, George B. e14517 Stone, John F. 7605, 9022 Stone, Patrick 9503 Stone, Richard M. 7050 Stone, Steven 5005, 5043 Stopeck, Alison 567, 1089, 8562, 9628, 9640, e20514 Stopfer, Jill 1510

Stoppa-Lyonnet, Dominique 1528, 1533 Storek, Benjamin e20575 Storer, Barry 7034, e20048 Stork, Lisette 3612, TPS11122, e22117 Stork-Sloots, Lisette 11090 Storm, Hans H 4536 Storniolo, Anna Maria 515, 527, 1052 Storozhakova, Anna E. e19047 Story, Michael D. 6011 Stotz, Michael 4110, 4111, e15009 Stovall, Marilyn 4536, 10062 Stragliotto, Silvia e22036 Strahs, Andrew Louis 4513, 4564 Strait, Christine TPS10072 Straley, Kimberly 4125 Strasser, Florian 9560 Straten, Per thor 8084 Strati, Paolo 7102 Stratton, Kelly Lynn 1552, e12527, e12555 Stratton, Michael R. 9085 Stratton, Steven Paul e16060 Straube, Eberhard e20652 Straube, William 7523 Strauss, Gary M. 1584, 7533, e12535 Strauss, Hans-Georg 5531 Strauss, William 580, 11040 Straver, Marieke Evelien LBA1001 Stravodimos, Kostas 4558, e15619 Stravodimou, Athina e20011 Street, Richard L. 10023 Street, Thomas K. 7086, 8586, 8596 Streich, Guillermo Juan e11600 Streicher, Howard 3026, 3069 Streicher, Katie e20047 Streit, Michael R. W. 8009, 8029 Streitbuerger, Anne 10518 Streja, Leanne e17542 Strelkowa, Natalja 2521 Strenger, Rochelle 619 Stretch, Cynthia e13503 Strevel, Elizabeth Laureen 5517, e17503 Stricker, Carrie Tompkins 9639, e20553 Stricker, Thomas 6010 Strickland, Andrew 4081, TPS4157 Strickland, Stephen Anthony 3104 Strickler, John H. 11036 Striefler, Jana Kaethe 4016 Strieter, Robert M. TPS3118^ Stright, Adam e13547 Strigo, Tara 6530 Strimpakos, Alexios S. e19087, e19111 Stringer, Erica Michelle 11101 Strippoli, Sabino 9065 Strittmatter, Nicole e14620 Stroh, Christopher 3537, 4021 Strom, Charles M. 7601 Stromberger, Carmen 6014 Strommer, Sabine e16042 Stroncek, Dave 10008, 10013 Strong, Vivian E. 4082, 4101, e15079 Strosberg, Jonathan R. 4032,

4142, 4143, e15126 Strother, Robert Matthew 2502, 2529, 2555, 3059 Strotman, Lindsay Nicole e22141 Stroud, Steve e13529 Stroup, Antoinette M. 6532 Stroupe, Angela 6547 Stroupe, Kevin e14578 Stroyakovsky, Daniel 5544 Strumberg, Dirk 2508, 4009, e16523 Stuart, Bruce C. e17584 Stuart, Charlotte e14666 Stuart, Darrin D e13590 Stuart, Gavin 5502 Stuart, Helen 11094 Stuart, Joshua M. 5006 Stuart, Mary 531 Stuart-Harris, Robin 1079 Stubbs, Andrew 5047^ Stuckey, Ashley 1545, 6590, e20543 Studeman, Kimberly e15123 Studeny, Matus TPS4160, 4506 Studer, Gabriela e17019 Stuebs, Patrick e14532, e22040 Stuenzi, Thomas 10064 Stukov, Aleksandr Nikolaevich e13005 Stults, Dawn Michelle 8091 Stummer, Walter LBA2000 Stupp, Roger 2007, LBA2009, 7503 Sturgis, Erich M. 1567, 6087, TPS6100 Sturm, Isrid e20575 Sturm, Julia 3098 Stutvoet, Simone 9029 Styblo, Miroslav 2515, 7055 Styblo, Toncred Marya 562 Stylianou, Spyros 2539 Styrmisdottir, Edda Lind 9089 Stålhammar, Jan e16066 Stöckle, Michael 5019 Störkel, Stephan 4507^ Su, Dan 4094, e18520, e18531, e22050 Su, Jack M. 2036 Su, Jian e18547 Su, Kang-Yi e22067 Su, Lih-Jen e16055 Su, Pei-Fang 8019 Su, Shan-Yu e20604 Su, Wu-Chou e19002 Su, Xinying 7552, 8045 Su, Yu-Chieh e13585 Su, Zheng 4039 Suarez, Ana e11531 Suarez, Cristina 2039, e16045 Suarez, Jaime e17589 Suarez, Javier e14589 Suarez-Almazor, Maria 6634 Suazo, Juan F. e12566, e12570, e22165 Subbiah, Ishwaria Mohan 9544 Subbiah, Vivek 2506^, 2611, 11086, e13575, e13591, e17554 Subramani, Arasakumar e22030 Subramaniam, Deepa Suresh 2616, TPS2624

Subramanian, Harihara 3103 Subramanian, Janakiraman 7563 Subramanian, Sai Shanmugam e15120 Subramanian, Subbaya e22007 Subtil, Fabien 3525^ Subudhi, Sumit Kumar 5083 Suchorska, Bogdana 2045 Suciu, Gabriel P e11575 Sucker, Antje 11009 Sud, Shelly e14598 Suda, Margaret 6023 Suda, Takafumi 8038, e20658 Sudo, Kazuki 4083, 4085, e15013, e15053 Sudo, Tamotsu 5526, 5528 Suedhoff, Thomas 3538 Suenaga, Mitsukuni 4108, e15105 Suetsugu, Atsushi e22011, e22012 Suetsugu, Takayuki e19016 Suetterlin, Marc 1120, 1121 Sufan, Roxana 2523 Sufliarsky, Jozef 5504, e22023 Sugarbaker, David 7588 Sugawara, Gen 4119 Sugawara, Shunichi 7518, 7530, e19142 Sugawara, Yoshifumi 1124, 11111 Sugie, Tomoharu e22116 Sugihara, Kenichi 3518, 3519 Sugihara, Masahiro 3535, 11049 Sugimori, Kazuya e15109 Sugimoto, Mikio e16054 Sugimoto, Naotoshi 4072, e14551 Sugino, Keishi 11052 Sugiura, Fumiaki 3006 Sugiura, Makiko 11055 Sugiura, Masahiro e15521 Sugiyama, Eri 7557 Sugiyama, Naoyuki e15568 Sugiyama, Takayuki e15568 Sugiyama, Tomohide e19164 Sugiyama, Toru TPS3116, 3535, 11049, e20576 Suh, Dong-Hoon e20530 Suh, EunRan 9017 Suh, John H. 2033, 2070, 2096, e15537 Suh, Jungho e15036 Suh, Sung-Suk 7573 Sui, Dawen e20034 Sui, Jane Sze Yin e14515, e20550 Sui, Yunxia 2097, e14663, e16033, e22085 Suina, Kentaro e19043 Suissa, Samy 1518 Sukari, Ammar 6045, TPS6098, 7561, e13030, e17033, e19009 Sukbuntherng, Juthamas 7056, 7057 Sukhai, Mahadeo A. 11002 Sukov, William R. 4071 Sukumar, Rohit e13546 Sukumaran, Shawgi 6541, e20577 Sukumvanich, Paniti 5585 Suleiman, Ahmed Abbas 8112 Sulfaro, Sandro 641 Sulkes, Aaron e15078, e20595 Sullivan, Daniel 3026, 3069, 5517, 8608, e19516 ABSTRACT AUTHOR INDEX

785s

Sullivan, John Sullivan, Kristen A.

e12555 7086, 8586, 8596 Sullivan, Mark 4508 Sullivan, Maryann 9567, e14661 Sullivan, Patrick S. e14618 Sullivan, Richard N. 8034 Sullivan, Richard e12515 Sullivan, Ryan J. 9010, 9015, 9019, 9028, 9029, 9064, 9076 Sullivan, Sean D e17527 Sulman, Erik P. 1, LBA2010, TPS2106 Suman, Vera J. 502, 526 Sumi, Minako 7540 Sumi, Toshiyuki e20676 Sumita, Yoshinori e22191 Summer, Stephen J. 10042 Summerell, Amelia 4543 Sumpter, Katherine Anne TPS4156 Sumrall, Susan V. 521, 522 Sun, Can-Lan 6537, 10004 Sun, Charlotte C. 5580, 5608, e20637 Sun, Gordon H. 6044 Sun, Guo-ping 4025, 4109 Sun, Haibo 7519 Sun, James 534 Sun, Jessica D. e13527 Sun, Jianyu e22169 Sun, Jong-Mu 11113, e15573, e15613, e19051, e19128, e22092 Sun, Jujie e18533 Sun, Lele e22026 Sun, Mai 6051 Sun, Peng 3507, 9005, 9016 Sun, Pengling 10054 Sun, Ping 5561 Sun, Ruirui e16551 Sun, Shi-Yong 2610 Sun, Sophie 1102, e19131 Sun, Weimin 7601 Sun, Xiaer 5573 Sun, Xindong e15030, e15167, e19011 Sun, xu Shan e17019 Sun, Yan 4109, 7507, e19075, e19161 Sun, Yi e22026 Sun, Yihong 4109 Sun, Yu-Nien 3048, e19103 Sun, Yuliang 2613, e13570 Sun, Yun-Fan e22133 Sun, Zhifu 1037 Sun, Zhuoxin 7126 Sunakawa, Yu 4111, e14543, e15022 Sundadaraman, Srinath e17540 Sundar, Sudha 5587 Sundby Hall, Kirsten LBA10504 Sundstrom, Stein 7504 Suner, Ali e11559, e18510, e18546, e19107 Sung, Jae Sook e22025 Sung, Janice S. TPS3120 Sunkavalli, Venkata Ratnam e14694 Sunwoo, John 3015 Sunyach, Marie-Pierre 10582 Supko, Jeffrey G. 2065, TPS2105, 2542, e19502 Supko, Jeffrey G. TPS2627 Suppan, Christoph 583 Surati, Mosmi 9579 786s

Sureda, Manuel 3074, e22120 Suri, Deepali TPS7130 Surikova, Ekaterina Igorevna e16515, e22002 Surmeli, Zeki Gokhan e12018, e13580 Surmelioglu, Ali e22061 Surmont, Veerle F 7541 Susumu, Nobuyuki 5590 Suter, Thomas 525 Suto, Akihiko 1047 Sutradhar, Rinku 1002 Sutton, Gregory Ryan e13574 Sutton, S Scott 5091 Suttorp, Meinolf 10017 Suyama, Takahito e15521 Suzuki, Akihiro 4078, e15053 Suzuki, Akiyuki 11031 Suzuki, Daisuke 4056 Suzuki, Hanae e13569 Suzuki, Haruko e18554 Suzuki, Hidekazu e19021 Suzuki, Hiroyuki e19162 Suzuki, Kenichi 9621 Suzuki, Kenji 7575, e18549 Suzuki, Koyu 1126, e11524 Suzuki, Masato 10543 Suzuki, Mitsuaki 5552 Suzuki, Motohisa 6086 Suzuki, Satoshi 3063 Suzuki, Takao e14597 Suzuki, Tatsuya 8551 Suzuki, Tiberu-Hiroshi 1097 Suzuki, Yasuhiro 1047 Suzuki, Yuichiro e15565 Suzuki, Yutaka e19076 Suzumura, Tomohiro 7564, e19053, e20682 Suzushima, Hitoshi 8506 Svabova, Veronika e22023 Svane, Inge Marie 3028, 8084 Svegliati Baroni, Gianluca 4123 Svetlovska, Daniela 4556, e15599 Svoboda, Marek 1063 Svrcek, Magali 3585 Swahn, Fredrik 4031 Swain, Sandra M. 644, 646, TPS1139, 6561, 11054 Swami, Nadia e20639 Swami, Umang e13550 Swamy, Thirumalai e15120 Swann, R. Suzanne 9013, 9044, e20012, e20038 Swanson, Gregory P. 5005 Swanson, Kenneth D. 2080 Swanson, Kristin e13017, e13018, e13028, e13041 Swarbrick, Alex 1053 Swart, Ann Marie 5500 Swart, Rachel Elizabeth e13574 Swedeh, Amer 7064 Sweeley, Charles e13047 Sweeney, Christopher 4561, 4563, 5021, 5026, 5056, TPS5101 Sweeney, Jennifer 7070, 8518 Sweet, Joan 5070, e15510 Sweet, William e20030, e20038 Swen, Jesse J. 4580 Swenson, Karen K. e20560 Swenson, Wade T. e17512


Swern, Arlene S.

7086, 8586, 8596 Swetha, Iyer 7544 Swetter, Susan M. 9061, e20026 Swiecicki, Paul L. 2596 Swift, Regina A. 8598, 8599, e20044 Swinnen, Lode J. 7009 Swinson, Daniel 4023 Swisher, Stephen 2601, 4083, 4085, 11079, e15013, e15053 Switaj, Tomasz e22046 Switzky, Julie 8009 Sycova-Mila, Zuzana 4556, e15599 Sydes, Matthew Robert 5012, LBA10504 Syed, Aamir Ali e12033 Syed, Binafsha Manzoor e11608 Syed, Fayaz ahmed e16545, e17028 Sykes, Jenna R e19032 Sylvester, Richard 4529 Sym, Sun Jin 3595, e19129 Symanowski, James Thomas 5572, e21504 Symmans, William Fraser 532, 535, 1005, 1013, 1017 Symon, Zvi 1503, 9630 Symons, Heather J. 7009 Syn, Wing Kin 4518 Syngal, Sapna 1530 Synold, Timothy W. 2018 Syrigos, Konstantinos N. TPS7609, e19087, e19111 Syrigos, Kostas N. e22049 Szablowski, Jerzy O. e13588 Szabo, Eva 1516, 7513, 8026 Szado, Tania TPS658 Szajek, Lawrence 11083 Szalay, Aladar A. 3098 Szallasi, Zoltan 3036 Szarek, Michael 7029^ Szasz, Attila Marcell 1549, e15523 Szczesna, Aleksandra 8043 Szczudlo, Tomasz K. 7053^ Sze, Ming 6556 Szekely, Borbala 1549 Szendroi, Attila e15523 Szendroi, Miklos e15523 Szerlip, Nicholas e13030 Szkorupa, Marek e22109 Szmit, Sebastian e18529 Szmulewitz, Russell Zelig 5020, e16006, e16084 Sznol, Mario 3002^, 3003^, 4505, 4514, 9005, CRA9006^, 9012^, 9016, 11075 Szpakowski, Jean-Luc 9645 Szucs, Thomas D. e12529 Szumera-Cieckiewicz, Anna e22046 Szwarc, Marcelo e16030 Szydlo, Richard e22194 Szymonifka, Jackie e14636 Sørebø, Øystein 9569 Sørhaug, Sveinung 9562

T Taal, Walter Taback, Nathan

2001 6535, 6628, 9518

Tabar, Viviane 514 Tabarroki, Ali 7008 Tabata, Masahiro e19040 Tabata, Masarhiro e19124 Tabata, Tsutomu 11049, e14631 Tabatabai, Ghazaleh 2081, TPS2103, e20050 Tabchy, Adel 11013 Taber, Angela Marie 8075 Taberna, Miren e17010 Tabernero, Josep 1011, 2563, 3001, 3511, 3514, 3524, 3525^, 3530, 3551, 3612, 3620, 3622, TPS3649, 4000, 4005^, 4058^, 4059^, 4135, TPS4150, TPS4155, TPS4158, 9029, e14554, e14561, e15188^, e19002 Tabing, Reena e20507 Taboada, MB 7549 Tabori, Uri 10029 Tabouret, Emeline 2024 Tabuse, Hiroyuki e14623 Tacchetti, Paola 8509 Tacey, Mark 3584 Tachikawa, Ryo 8098, e19017, e19045 Tacyildiz, Nurdan 10068 Tada, Hirohito 7518, 8037 Tada, Minoru e15146 Tada, Satoshi e19076 Tada, Takuhito 7564 Tadepalli, Jyothirmayee S. 9023 Tadj, Melanie e15593 Tafreshi, Alireza e18559 Taga, Takashi 10050 Tagawa, Scott T. TPS5096, TPS5100, 11081, e15600 Tageja, Nishant 8597, e19506 Taggart, Melissa W. 1525, 4134 Tagliaferri, Mary Ann e15023 Taglietti, Paula Mendonca e14691 Taguchi, Kenichi 7529 Taguchi, Takahide 6004 Taguchi, Tetsuya 1106, 1116 Taguri, Masataka e15109 Tahara, Ko 3006 Tahara, Makoto 4074, e13586 Tahata, Takashi e13504 Tahir, Mavira e11542 Tahiri, Sanaa 4011, 4014 Tahtaci, Gozde e15540 Tai, Datchen Fritz 5551 Tai, Wai Meng David 6618, 9029, 9509 Tai, Wai Meng 8107 Tai, Yu-Chong 5062 Taibi, Eleonora e11527 Taichman, L. Susan 568 Taïeb, Julien 3525^, 3536, 3585, e22121 Taillandier, Luc 2020, 2032, 2067 Taillibert, Sophie 2080, 3065^ Taimen, Pekka 1554 Taira, Koichi e14551, e15016 Taira, Naoya 8506 Taira, Naruto TPS654, 6588 Taira, Tetsuhiko 7572, 7582, 7599, e18556, e19050, e19074 Tait, Nancy TPS648 Tajiri, Tatsuro 10038

Takada, Akinori Takada, Anna Takada, Kohichi Takada, Masahiro Takada, Minoru

6086 TPS3116 e15060 e22116 3072, 8006, e18530 Takada, Ryoji e15150 Takagi, Keigo 11052 Takagi, Tomofumi e14604 Takagi, Yusuke e18524, e19133 Takahara, Naminatsu e15146 Takahari, Daisuke 3519, 4076, e14527 Takahashi, Akiko 7512 Takahashi, Fumiyuki e19043 Takahashi, Hideaki 2559, e22082 Takahashi, Hiroyo 1107 Takahashi, Kazuhisa e19043 Takahashi, Keiichi 3518, 3519 Takahashi, Maiko e11598 Takahashi, Masato 613, 1534 Takahashi, Masazumi LBA4002 Takahashi, Minoru e15060 Takahashi, Naoto LBA4002 Takahashi, Nobutaka e13500, e16507 Takahashi, Norihiko e14548, e15038 Takahashi, Osamu 9629 Takahashi, Rie e20051 Takahashi, Ryo e19010^ Takahashi, Satoru 614 Takahashi, Shunji e11587, e13504, e15527, e17006, e20510, e22027, e22190 Takahashi, Suzuyo 5552 Takahashi, Takao 3516, e14527 Takahashi, Tiago Kenji e20691 Takahashi, Toshiaki 7556, 7572, 7582, 7599, e18556, e19050, e19074 Takahashi, Tsuyoshi 10539 Takahashi, Yasuo e15060 Takahashi, Yuko TPS1140, e11524 Takai, Yujiro 11052 Takalkar, Amol e17585, e19070 Takamatsu, Hiroyuki 8601 Takamatsu, Naofumi e13569 Takamochi, Kazuya 7575, e18549 Takano, Angela 8107 Takano, Atsushi 3092, 11104 Takano, Masashi 5590, 11049, e16505, e16506, e16519, e21520 Takano, Tadao 5537 Takano, Toshimi 613, 1048^, LBA4024, 9628 Takao, Shintaro 1029 Takaoka, Naohisa e15568 Takashima, Atsuo 3559 Takasu, Atsuko e20004 Takats, Zoltan e14620 Takatsuki, Mitsuhisa e14633 Takayama, Kanako 6086 Takayama, Koichi 8111, e19016, e20609 Takayama, Tadatoshi 4126 Takayama, Tatsuya e15568 Takayama, Tetsuji e15060 Takayashiki, Tsukasa 4056 Takebayashi, Katsushi 4092

Takebe, Naoko

2035, 2553, 4011, 6022, 7508, 10558 Takeda, Koji 7529, 8056, 9621, e14551, e20609 Takeda, Masayuki e19165 Takeda, Naoko 3034 Takeda, Satoru e16505 Takeda, Shugaku 4573 Takeda, Tetsu 7548 Takehara, Kazuhiro 5526, 5528 Takei, Hiroyuki 571, e22019 Takei, Yuji 5552 Takekuma, Munetaka e16507 Takemoto, Shigeki 8506 Takemura, Hideki 6004 Takemura, Masahiko 5538 Takenaka, Yukinori 6082 Takenoshita, Seiichi 3063 Takeoka, Hiroaki e19137 Takeshima, Nobuhiro 5526 Takeshita, Jumpei 8098, e19017, e19045 Takeshita, Masafumi 8111 Taketa, Takashi 4083, 4085, e15013, e15053 Taketani, Kenji 1056 Taketomi, Akinobu e14548, e15038 Takeuchi, Kengo 8033 Takeuchi, Maya e16549 Takeuchi, Satoshi TPS3116, 7550, 11079 Takeuchi, Yoshito e13511 Takeyoshi, Izumi e22019 Takhar, Harminder Singh 6541, e20577 Taki, Junichi e16072 Takigawa, Nagio e19023, e19124 Takiguchi, Nobuhiro LBA4002 Takiguchi, Tomomi 9621 Takiguchi, Yuichi e19054 Takii, Yasumasa 3535 Takimoto, Masafumi e12035 Takimoto, Rishu e15060 Takinishi, Yasutaka 3519 Takkar, Puneet 1099 Takumi, Furuya 3006 Takuwa, Teruhisa e18557 Talamini, Renato e22149 Talamo, Giampaolo 7039, e19502 Talamonti, Mark S. 3007 Talasaz, AmirAli 11096 Talbot, Denis Charles 8051^ Talbot, Toby 3018 Taldone, Tony 11076 Taleh, Jegane e17003 Taliaferro-Smith, LaTonia e14618 Talianski, Alisa e13002 Talley, Anitra W. 4055 Tallman, Martin S. 7100, 7126 Talpaz, Moshe TPS3113, 7001, 7048, 7063, 7109, 7110, TPS7129 Talukdar, Shobhana e16552 Talvas, Jeremie e17022 Talwar, Rajnish 1099 Tam, Brenna 10555 Tam, Constantine TPS7130 Tam, Moses M. e13033 Tam, Orlena e22083 Tam, Vincent Channing 6622, e17569

Tamagawa, Hiroshi 3516 Tamai, Koji 8098, e19045 Tamaki, Yasuhiro 1107 Tamarelli, Carrie M 6616 Tamashiro, Andressa Sayuri e20524 Tamberi, Stefano e15055 Tamboli, Pheroze 4516 Tamborini, Elena 3641 Tamburini, Emiliano 3517 Tamimi, Rulla M. 6507, e20508 Tamiya, Akihiro e19021 Tamiya, Motohiro e19021 Tamkus, Deimante 6567 Tammemagi, Martin 1523 Tamura, Atsuhisa 8006 Tamura, Kazuo e20576 Tamura, Kenji e20557 Tamura, Nobuko e11514 Tamura, Paula e22176 Tamura, Taro e18530 Tamura, Tomohide 7540, 8033, 8064, e13504, e13511 Tan, Angelina D. 7502, 7524, 7545 Tan, Antoinette R. 1091, 2553, 2582 Tan, Bien Soo 8107 Tan, Chee Seng e14507 Tan, Cindy e17541 Tan, Cong 8547, e14685 Tan, Daniel H.Y. e13027 Tan, Daniel Shao-Weng 6618, 8010, 8107, TPS8119, 9029, 9509 Tan, David Shao Peng 2505, 2534, 3062 Tan, Doreen Chek Yee e22107 Tan, Eng Huat 8043, e17017 Tan, Eng-Huat 6618, 8107, 9509, e19002 Tan, Fenlai e19161 Tan, Iain B. 2091, TPS4151, 9552, e14520, e15002 Tan, Iain BeeHuat 4020, e13027 Tan, Karen Mei Ling e22107 Tan, Li Tee 3500 Tan, Min-Han 4565, 4578, 4586, e13582 Tan, Ming e13566 Tan, Patrick 4020, 4113, e14520, e15002 Tan, Pui San e11591 Tan, Qiang 7514 Tan, Tingting e15559 Tan, Tira Jing Ying 9552 Tan, Winston 521, 522, 5082, e16061 Tan, Yee Pin 6589 Tan, Yew-Oo 6063 Tan, Zheng e19006 Tanabe, Kazuaki LBA4002, 4102 Tanabe, Kazunari e15527, e15576 Tanabe, Kenneth 4125 Tanabe, Masahiko 1106, 1116, e11587 Tanabe, Mikiko 1047 Tanabe, Satoshi 4070 Tanabe, Shunsuke e15161 Tanabe, Yuko e20557 Tanaka, Aki e16507

Tanaka, Chie 4088, e14552, e14614 Tanaka, Chihiro 3535 Tanaka, Fumihiro 7583 Tanaka, Hidenori 7564 Tanaka, Hideo 5590 Tanaka, Hiroaki 3006 Tanaka, Junji 4072 Tanaka, Kaoru 7529 Tanaka, Katsuaki e15109 Tanaka, Kimihiro 1056 Tanaka, Koji e14631, e22205 Tanaka, Kosuke e19017, e19045 Tanaka, Kuniya e22011, e22012 Tanaka, Maki 3099 Tanaka, Maria Florencia 7112 Tanaka, Michael S. e15073 Tanaka, Satoru 1106, TPS1140 Tanaka, Shota 2029 Tanaka, Takehiro 1106 Tanaka, Tomohiro 8033 Tanaka, Yoko 1105 Tanaka, Yusaku e15159 Tanas, Munir 10526 Tandon, Nidhi e19095 Tandon, Pragati e16546 Tandon, Vickram 3017 Tandra, Pavankumar 8572 Tandstad, Torgrim 4503, 4553 Taneichi, Akiyo 5552 Tang, Bi Xia e20027 Tang, Cha-Mei 11046 Tang, Chuanning 10544 Tang, Cuiju 4106 Tang, Joseph 4132 Tang, Junfang e19149 Tang, Lanhua 1604 Tang, Laura H. 4082, TPS4144 Tang, Lei 5045 Tang, Patricia 9596 Tang, Ruilei TPS4154, e14645 Tang, Siau-Wei e20588 Tang, Ximing 2601, 7552, 8079, 8102, TPS8118 Tang, Y. F. 4117 Tang, Ying Margie e14625, e14661, e14681 Tang, Yun-hsin e16537 Tang, Yuting e14704 Tang, Zhongwen 9028 Tangka, Florence K. 6514 Tanguy, Marie-Laure 2020, 2032 Tani, Tohru 4092, e11555, e12014 Taniere, Philippe 11094 Taniguchi, Cynthia e20668 Taniguchi, Hirokazu 3559, 4104 Taniguchi, Kazuya e19153 Taniguchi, Naoyuki 7550 Taniki, Toshikatsu e15016 Tanimoto, Mitsune e19023, e19040, e19124, e19167 Taningco, Lilia 10501^ Tanino, Hirokazu 1029 Tanioka, Maki 5528 Taniyama, Tomoko 7540 Tanna, Vaishali 2071 Tannapfel, Andrea 4079 Tannenbaum, Stacey 1586, e11611, e12547 Tannir, Nizar M. 4516, 4517, 9642, e15594, e15611, e15612 ABSTRACT AUTHOR INDEX

787s

Tannock, Ian 5002, 5025, 5058, 9555, 11002, e14582, e15616, e20639, e22000 Tanovic, Adnan 5566 Tanrıkulu, Abdullah e18544 Tanriverdi, Kahraman e19512 Tansini, Aline e13557, e13559 Tantravahi, Srinivas Kiran e15518 Tanvetyanon, Tawee 6022, 6047, 6531, 8001 Tanzi, Silvia e20612 Tao, Hui-Qing 1588 Tao, Kaiyi 4094 Tao, Li e15125 Tao, Min 8015 Tao, Qian e17017 Tao, Shiqiang 6538 Tao, Yuzhen e14615 Tao, Zhengchao e22018 Tap, William D. 9501, 10512, 10555, 10558, 10580, TPS10592, TPS10594 Taphoorn, Martin JB 2007, LBA2009, 2011 Tapia, Gustavo e16549 Taplin, Mary-Ellen 5003 Tarabaric, Dolores 4041 Taran, Florin-Andrei 1030, 5598 Taran, Rakesh 577 Taran, Tanya 505, LBA509, 553, 557, 558, 561, TPS660 Tarantini, Luigi 631, e11556 Tarbell, Nancy 10018, e17553 Tarhan, Cagla e16526, e16528, e16536 Tarhini, Ahmad A. 3041, CRA9007, 9038, 9043, 9075 Tarifa, Antonio e14589 Tarleton, Kenneth 9642 Tarlov, Elizabeth e14578 Tarnawski, Rafal LBA2009 Taron, Miquel 11025, 11028, 11078, e15558 Tarpgaard, Line Schmidt 3572, e14710 Tarrats, Antoni e16549 Tarrazzi, Francisco e17540 Tartas, Sophie e17011, e17012 Tartour, Eric e22121 Tas, Faruk e11592, e20016 Tasdelen, Ismet e17529 Tasdogan, Burcak Evren 9587 Tashima, Rumiko e11557, e13536 Tashiro, Naoki 8111 Taskoylu, Burcu e14662 Tassell, Vanessa Roberts 8105, 8108 Tassi, Valentina e22155 Tassignon, Aurelie 2053, 5042 Tassy, Philippe e19540 Tastekin, Didem e11592, e14533, e20016 Tateishi, Keisuke e15146 Tateoka, Hiroshi e15179 Tateyama, Miki e14604 Tatli, Ali Murat e14683, e14696, e18517 Tato-Costa, Joana e22072 Tatsuguchi, Ayako e13569 Tatsumoto, Naokuni LBA4002 Tattersall, Martin H.N. 10516 788s

Taub, Jeffrey Warren e20646 Taub, Robert N. LBA10507 Taube, Janis M. 3002^, 3016 Taube, Tillmann e13511 Tauchi, Katsunori 9637 Tauchi-Nishi, Pamela e16501 Tauer, Kurt W. TPS659, 8044 Tauler, Jordi e22051 Taus, Alvaro 2522 Tavakkoli, Fatemeh e18543 Tavares, Monique Celeste e20640, e20644 Taveras, Yohana 6640 Tavolari, Simona e15003 Tawbi, Hussein Abdul-Hassan 9043, 9075 Tawfik, Bernard e18002 Taxy, Jerome B. 5028 Tay, Jason 8593 Tay, Kiang Hiong e15102, e15137 Tay, Miah Hiang 4576, 5059 Taylor, Barry S. 11004 Taylor, Carrie T. 612 Taylor, Clive R. 3016 Taylor, Donald 9563 Taylor, Harold e17502 Taylor, Ian 6041 Taylor, John C. e13563 Taylor, Kelly A. TPS1606 Taylor, Kerry TPS7131 Taylor, Matthew Hiram 2518 Taylor, Natalie 5054 Taylor, Nicholas A. 6070 Taylor, Paul 7595 Taylor, Sara Kristina 518 Taylor, Thomas H. 3578, e12528 Taylor-Weiner, Amaro 9015, 11009 Tazawa, Hiroshi e15161 Tazi, Karim e20019 Tchakov, Ilian 2579 Tchorzewska-Korba, Hanna e18529 Tea, Muy-Kheng Maria e11601 Teagno, Joseph 6538 Tebbutt, Niall C. 2583, 3520, 3528, 3531, 3533, 3545, 4006, 4081, TPS4153, TPS4157, e14506 Tee, Goh Yeow 2574 Teegavarapu, Purnima Sravanti e15594 Tefera, Eshetu 9077 Tefferi, Ayalew LBA7000, 7109, 7110 Teh, Bin S. e13032 Tehfe, Mustapha Ali 4000, e15094, e22159 Teich, Nelson 6071 Teich, Vanessa 6071 Teichgraeber, Volker e11507 Teira, Pierre 10048 Teissier, Eric 5544 Teixeira, Luis e15188^ Teixeira, Luiz Carlos e20634 Teixeira, Manoel Jacobsen 2060 Teixeira, Rui e22072 Teixeira, Yolanda e22074 Teixido, Cristina 4135 Teixido, Jordi 11027 Tejani, Mohamedtaki Abdulaziz 9533


Tejedor, Alberto e13535 Tejero, Rut 7547 Tejpar, Sabine 3522, 3526, 3577, 3588, 3626, e14544, e14561 Tejura, Bindu LBA4509 Teker, Fatih e11506 Tekgunduz, Emre e18014 Teletaeva, Gulfiya Midhatovna 3088 Tellew, John e13590 Tellez, Teresa e22091 Telli, Ferhat e14660 Telli, Melinda L. 1003 Tello, Jose Ignacio e16071 Temam, Stéphane 3035 Tembhare, Prashant e19506 Temel, Jennifer S. 6529, TPS9649, e20551 Tempany, Clare M. 9500, e16026 Tempelhoff, G. F. TPS3119^ Tempero, Margaret A. 4014, 4055 Tempfer, Clemens e16523 Temple, Graham 4506 Temple, Larissa K. F. 3605 Templeton, Arnoud J. 539, 4130, 5058, e22000, e22015 Temraz, Sally e12525 Ten Haken, Randall K 7522 Ten Tije, Albert J. 3502, e14586 Tench, Shawnda 7008 Tendulkar, Rahul D. e16004 Teneriello, Michael 5520 Teng, Mabel Joey 4029, e15093, e15162 Tennant, Lucinda 8094 Tennevet, Isabelle 2020 Tenney, Meaghan Elizabeth TPS5612 Tennstedt, Pierre 5043 Tennstedt-Schenk, Cornelia 3634 Tenti, Elena e13579 Teo, Jin Yao e15102 Teo, Marissa e15097 Teo, MinYuen e13020, e15019, e15163, e15566, e20687 Teo, Yi Ling e13582 Teofilovici, Florentina TPS1136, CRA8007, TPS8126 Teoh, Deanna Gek Koon e20571 Teot, Lisa A. LBA10504, 10528 Teplinsky, Eleonora 11106 Tepperberg, James H. 11070 ter Woorst, Joost e18562 Terachi, Toshiro e15576 Terada, Keith Y. e16501 Terada, Tomonori 6004 Teramoto, Norihiro 5526 Teramukai, Satoshi 6004, 6576 Terao, Yasuhisa e16505 Terasaki, Yasushi 8601 Terasawa, Risa TPS1140 Terashima, Masaaki e19165 Terashima, Masanori 4019 Terebelo, Howard R. 8586, 8596 Terekhova, Svetlana Aleksandrovna e12560 Terme, Magali e22121 Ternant, David 2599 Terpos, Evangelos 8589 Terrasa, Josefa 4560

Terricabras, Marta Terrier, Philippe

3629 10574, 10575, 10578 Terry, Charles R 9019 Terry, Raya D. e17009 Terstriep, Shelby A. 9513 Terzi, Eleonora e15149 Tesauro, Manfredi e14581 Tesch, Hans 591, 1004, 11042, e11525, e20563 Tesei, Anna e22056 Tesi, Paolo 9554 Tesniere, Antoine e17514 Tessari, Anna 3008, 3641, e12017, e14716 Tesselaar, Margot Et 6057 Tesser-Gamba, Francine 10533, 10534 Tessier, Jean 2092, e13508 Testa, Joseph R. e18541 Tester, William J. e17578 Testi, Adele 3641 Testori, Alessandro 9027, 9030, 9065, 9548 Testori, Ornella e20694 Tetteh, Leticia 9056^ Tetzlaff, Michael T. e20034 Teule, Alex 4139, 4140, e12516 Tevaarwerk, Amye 2607 Tew, Alice e16048 Tew, Gregory N. e15543 Tew, William P. 5550, 9545 Tewari, Krishnansu Sujata 3, 5527 Tey, Jeremy Chee Seong 4066 Tezcanli, Evrim e11539 Tfayli, Arafat e12525 Thai, Zung TPS4149 Thakkar, Jigisha P. 2069 Thaler, Josef e14537, e15041 Thaler, Joseph 3525^ Thalheimer, Markus 9612 Thall, Peter F. 7006, 7074 Thalmann, George N. 5012 Tham, Chee Kian 2091, e13027 Tham, Ivan Weng Keong 4066 Thanos, Anastasios e16037 Thariat, Juliette e17019 Thatcher, Nick 3053, 7500 Thayanithy, Venugopal e22007 Theaker, Jane e22035 Theaux, Ricardo Alejandro e13036 Theeler, Brett James e13039 Theil, Gerit e22055 Thein, Mya Sanda e22034 Thellenberg-Karlsson, Camilla 5002 Theobald, Matthias e21505 Theocharis, Stamatios e22160 Theodore, Christine LBA4500, e15607 Theodosopoulos, Theodosios e15114 Theodoulou, Maria 606, 9515 Theriault, Richard L. 1006, 1022 Thery, Jean Christophe 5567, e12504 Theuer, Charles P. 3057, 3059 Thézenas, Simon 4028 Thiadens, Saskia R.J. e20558 Thibaudeau, Valerie e17567

Thibodeau, Stephen N. 3523, 3576 Thiébaut, Raphaële 3562, e14600 Thieblemont, Catherine 8502 Thiede, Stephanie Margaret e22141 Thiel, Falk 5531 Thiel, Robert 643 Thiele, Juergen 7030 Thierstein, Sandra 7503 Thiery-Vuillemin, Antoine e15607 Thiessen, Brian 2053 Thillai, Kiruthikah 3018 Thippeswamy, Ravi 7043 Thirlwell, Christina e15085 Thirlwell, Michael P. e15044 Thirot-Bidault, Anne 3585 Thivolet, Francoise 8100 Thoennissen, Nils Heinrich 8548 Tholander, Bengt 5544 Thom, Bridgette 9524 Thomas, Anish 6524, 7513, TPS7607, 8026 Thomas, Anthony George 6574 Thomas, Charles R. 4073 Thomas, Charles e19013 Thomas, Cheryl B e20608 Thomas, Christine R. 1098 Thomas, Christoforos 2545 Thomas, Christopher Y. 6021, 6030 Thomas, Dafydd G. 10045 Thomas, David Morgan 10567 Thomas, Deborah A. 7024, 7074, 7092, 7095 Thomas, Fabienne e13519 Thomas, Gary W. e15014 Thomas, George e13518 Thomas, Gillian 5530 Thomas, Hala e13518 Thomas, Joseph e11588 Thomas, Karen e16000 Thomas, Luc 9093 Thomas, Marlene 2522 Thomas, Melanie B. 4121 Thomas, Michael 8068, e19060 Thomas, Pascal Alexandre 7602 Thomas, Robert J. 5008 Thomas, Sachdev P. 4012, 7506, 8596, e17590 Thomas, Sachdev 8586 Thomas, Shirley e20597 Thomas, Sufi M. 6051 Thomas-Schoemann, Audrey e15592, e17514 Thomason, Adelyn 9068 Thomassin, Jeanne e15506 Thompson, Alastair Mark 1033 Thompson, Carrie A. 8504, 8563 Thompson, Christopher J. e13022 Thompson, Dana Shelton 2544, 3564, 5513 Thompson, Darby J. S. 5033, e16044 Thompson, E Aubrey 520, 1037, 4567 Thompson, James E. e18018 Thompson, John A. TPS3109, TPS3112, e20048 Thompson, John F 9001 Thompson, Jonathan 8505 Thompson, Joyce 4023, 7595

Thompson, Lisa 11094 Thompson, Patrick Andrew 2036 Thompson, Robert Houston 4567 Thompson, Simon e20713 Thompson, Stephen F. e14576 Thompson, Trevor 6606 Thompson, Wesley e15018 Thomsen, Frederik Birkebæk 4532 Thomsen, Inger Birthe Moerk 8084 Thomsen, Maria Ferløv 4532 Thomson, Damien B. 9516 Thomson, Nicola 9590 Thomson, Simon David e12032 Thomssen, Christoph 555, e17544 Thongprasert, Sumitra 8087, 8092 thor Straten, Per 3028 Thorn, Mitchell 3079 Thorn, Molly e17566 Thorne, Tracy e15557 Thornton, Anne M. CRA1501 Thornton, Patrick TPS8619 Thorpe, Jason D. e22178 Thorpe, Roland 6032 Thorsheim, Helen 514 Thosani, Sonali e17016 Threatt, Stevie 2094, e13015^ Thudi, Nanda K. 1012 Thuler, Luiz Claudio Santos 1587, 9589 Thulkar, Sanjay TPS4162, e19526, e19531, e21522 Thunnissen, Erik 8065, 11085 Thurlimann, Beat J. K. 529 Thurner-Herrmanns, Elisabeth 11042 Thuss-Patience, Peter C. 4080, 4086, TPS4158, e20575 Thyparambil, Sheeno e19057 Thyss, Antoine 10506 Tiab, Mourad 8513 Tian, Jiaying 9054, 9067 Tian, Ying 3616, 3617, 3620, 8503, 8508, 8573 Tiangco, Beatrice 8034 Tibaldi, Carmelo 11066 Tibau Martorell, Ariadna 550 Tibau, Ariadna 539 Tiberio, Guido Alberto Massimo e15148 Tidwell, Michael 7049 Tie, Jeanne 3584, 3598, 11015, e14583, e14608 Tielen, Ronald 10549 Tien, Yu-Yu 6542 Tierno, Montserrat 11025 Tiersten, Amy 1042, TPS3122 Tiessen, Kyoko 9536, 9551, 9595 Tiezzi, Daniel Guimaraes e12007 Tijeras-Raballand, Annemilai 6036 Tike, Pramod K. e15120 Tilahun, Yaphet e14546 Tilki, Metin e22061 Timar, Jozsef e15523 Timcheva, Constanta e11586 Timilshina, Narhari 7067, 7071

Timmer, Wolfgang e20538 Timmerman, Dirk 5549, e22102 Timmerman, John 3024, TPS3108, TPS3113 Timmerman, Robert D. 7523, 8074 Timotheadou, Eleni 582 Timothy, Quek 6541 Timpson, Paul e15029 Tinat, Julie TPS1607 Tindle, Hilary 1504, 1524 Ting, Saskia e14502 Tinhofer, Inge 6014 Tinianow, Jeffrey 11083 Tinker, Anna 5042, e22020 Tirado-Gomez, Maribel e19505 Tirapu, Iñigo e13543 Tireli, Mustafa e17529 Tirelli, Umberto 8524 Tirona, Maria R. B. Tria 2089, e13040 Tirouvanziam-Martin, Anne TPS3117^ Tiscione, Brynn 8607 Tiseo, Marcello e18561 Tishler, Roy B. 6058 Titin, Christina e14507 Tiu, Ramon Velasquez 7008 Tjan-Heijnen, Vivianne C. e11558, e17549 Tjokrowidjaja, Angelina 4544 Tjulandin, Sergei 503, 4005^, 4010, 5516, e12027, e14674, e15005, e15194, e15583, e15585, e16509, e22097 Tjulandina, Alexandra e16509 Tkaczuk, Katherine Hanna TPS648, 1091, e20574, e22034 To, Christine e18514 To, Ka Fai e15048 Tobena, Maria e14541 Tobias, Jeffrey S. 1121 Tobin Vealey, Kristen E. e22170 Tobinai, Kensei 8506, 8551 Tobisawa, Yuki e15565 Tobisu, Kenichi 4526 Tocchetti, Carlo G. 631 Tochigi, Naobumi 11052 Tochigi, Tatsuo e15570 Tod, Michel TPS2625, 5547, e13594, e15592 Todaka, Akiko e14623, e15031 Todd, Mary Beth 5059, TPS5097, e17510 Todisco, Gabriele 3038, e13593 Todoroff, Karen e20649 Todorovic, Maja e14654 Todorovic, Marija 8502 Toebes, Mireille 9085 Toepelt, Karin 8112 Tofanetti, Francesca Romana e22155 Tofas, Polydore e20642 Toffolatti, Luisa 11058 Tognelli, Flavio 6596, e20636, e20656 Tognetto, Michele e17551, e20617 Toh, Han Chong 4117, e15097 Toh, Ying e15137 Tohnai, Iwai 6060, 6086, 6096 Tohyama, Hiroaki e11605

Tohyama, Shigeru e15179 Toi, Masakazu 505, 571, 613, TPS652, 1048^, e12011, e22116 Toishi, Masayuki 7548 Toiyama, Yuji e14631, e22205 Tokai, Yukiko e11605 Toker, Alper 7602 Tokes, Annamaria e15523 Tokin, Christopher A. 11098 Tokito, Takaaki 7582 Tokuda, Yutaka 1047 Tokuhira, Atsushi 5538 Tokunaga, Eriko 1056 Tokunaga, Shoji e14633, e19016 Tokunaga, Yoshimasa e22108 Tokunaga, Yukihiko e14551 Tol, Jolien 3552 Tolaney, Sara M. 1065, 1100, 2500, 2585 Tolcher, Anthony W. 2500, 2503, 2517, 2540, 2602, TPS2618, 10506, e22088 Toldos, Oscar 1041 Toledano, Alain e20654 Toledo, Maria Del Val 2064 Toledo, Silvia R. C. 10533, 10534, 10535 Tolentino, Angelica L. 7121 Toll, Benjamin A. 1561 Toloudi, Maria e14699 Tom, Ashlyn K. 9501 Tom, Ashlyn 9524 Tom, Sabrina e14673 Toma, Andrea 7002 Tomao, Silverio e14574 Tomaru, Utano 7550 Tomasek, Jiri 2533, 4000, 4138 Tomasello, Chiara 8047 Tomasello, Gianluca 3505, 4112, e15086, e15502 Tomasevic, Zoran e20659 Tomasevic, Zorica e14676, e20659 Tomassetti, Paola 4031 Tomassi, Ottaviano e13514 Tomaszewski, Joseph E. 11103, e22080 Tomatis, Mariano 4129 Tombal, Bertrand 5001, 5002 Tomczak, Piotr 4513 Tome, Oliver 1082, TPS1141 Tome, Wolfgang A. 4093 Tome, Yasunori e13577 Tomida, Kaori e11555 Tomii, Keisuke 8098, e19017, e19045 Tominaga, Yoshiaki 7548 Tomita, Dianne e20616 Tomita, Kichinobu 6004 Tomita, Naohiro 3518 Tomita, Yoshihiko 4526, TPS4592 Tomizawa, Yoshio 8006 Tomlin, Irene 2061 Tomlinson, Ben Kent 2569, 8049 Tomlinson, Gail Elizabeth 10037 Tomlinson, George A. 6625, 7067, 7071 Tommasi, Luigi e20694 Tomonaga, Masao 8506 Tomono, Yasuko e15161 Tomori, Akihisa e15016 ABSTRACT AUTHOR INDEX

789s

Tomos, Periklis e18542 Tonchev, Anton e14669 Toner, Guy C. 10567 Tonev, Anton e14669 Tong, Fuzhong 1084, e12006 Tong, Guang-Quan 1588 Tong, King Mong e19039 Tong, Li e19149 Tong, Tommy R. e22196 Tong, Yan 4557 Tong, Zhongsheng 1064 Tonini, Giuseppe 3505, 10568, e14565, e15528, e16538, e19084, e20512 Tonkin, Katia Sonia 1033, 9640 Tonn, Joerg Christian 2027, 2045 Tonzi, Peter 10536 Toomey, Kathleen 8586, 8596 Toomey, Sinead 3549 Topalian, Suzanne Louise 3002^, TPS3110, CRA9006^ Topcuoglu, Pervin 7038, e18009, e18010 Topp, Max S. 7020 Topping, Donna L. 1076 Toppmeyer, Deborah 1091, 2582 Toppo, Laura 4112, e15086, e15502 Topuzov, Eldar 4000 Toralles, Betania 1539 Torchio, Martina e20647 Toretsky, Jeffrey 10042 Torii, Masae e22116 Torlakovic, Emina 8096 Tormo, Eduardo e12019 Torregrosa, Maria Dolores e12020, e20643 Torrejon, Davis Yuri e16045 Torrent, Juan Jose e16549 Torres, Ana 9541 Torres, Antoni e20652 Torres, Carlos e19505 Torres, Luis M. 9563 Torres, Mylin Ann 562 Torres, William E. 2610 Torres-Cabala, Carlos A. e20034 Torresi, Umberto e11616 Torri, Valter LBA8005, e14611 Torri, Vamsee 5042 Torsello, Angela e15057, e21517, e22206 Torta, Riccardo 6039 Tortora, Giampaolo e15057, e16053, e17555 Toruner, Murat e18010 Torzilli, Guido 4129 Tosarello, Davide 6020 Tosato, Giovanna TPS10595 Toscano, Giuseppe e19086 Toshiyasu, Takashi e17006 Tosi, Diego e20512 Tosi, Mario e14596 Toso, Silvia e13514 Tosoni, Alicia 2021 Tosteson, Anna NA 559 Toth, Jennifer 7553, e18506, e18552 Toubeau, Michel 11007 Touboul, Chantal 1562 Tougeron, David 3513, 3536, 3576, 3614 790s

Toulmonde, Maud 10574 Toumpanakis, Christos 4031 Touqir, Zahra 9558 Tourani, Jean Marc 3513, 3536 Tournigand, Christophe 569, 3515, 3520, 4069, e14525 Touzeau, Cyrille 8513, 8530 Towbin, Alexander 10047 Town, Ajia 10509 Townsend, Amanda Rose e14506 Toyama, Tatsuya 614, TPS654 Toyoki, Yoshikazu e15179 Toyosaki, Kayo 2559 Toyoshima, MIkio 8038, e20658 Toyozumi, Yasuo e11557 Trabulsi, Edouard John 5061 Trachtenberg, John 5070 Traeger, Lara e20551 Trager, Stephanie 9511 Tragomalos, Nikolaos e20642 Traifi, Sara e17528 Trail, Pamela 2502, 2517, TPS2618 Traina, Tiffany A. 606, 1052 Trainer, Alison 1559, e20660 Tralongo, Paolo e11526, e14557 Tran, An 9075 Tran, Anh L. 7056 Tran, Ben 3584, 3598, 11015 Tran, Binh N. 9527 Tran, Duc Quang 7035 Tran, Hai T. 4042, 6067, 8102, 11044 Tran, Linh M 10555 Tran, Mai Ngoc-Ahn 4538 Tran, Minh-Thu 2553 Tran, Namphuong 5014, TPS5097 Tran, Phuoc T. 4039, e15028 Tran, Simon e22191 Tran, Theresa 6091, e17030 Tran, Tri TPS11121 Tran-Thanh, Danh 8096, e22159 Trappey, Alfred F. 3096, 3097, TPS3126 Trappey, Francois 3005 Trarbach, Tanja 3538, 4080, 4127, e14502 Traut, Alexander 1577 Traverse-Glehen, Alexandra TPS8615 Traverso, L. William 4043 Travis, Lois B. 4536 Travis, William D. 7558 Traynor, Anne M. 2607, 9566, e17025, e18537 Treacy, Daniel 9015 Tredan, Olivier 1031, 1058, 2615 Treese, Christoph e15068 Trefzer, Uwe 9020, e20028 Trehan, Ram Swarup 6629, e17579, e17581, e17582 Trehy, Roisin 11071 Treilleux, Isabelle 510 Tremblay, Lise 7500 Tremmel, Robert e20592 Tremont-Lukats, Ivo 2019^, TPS2106 Trent, Jonathan C. 10521, e17508 Trent, Kerry 9075 Trenta, Patrizia 3505 Trentham-Dietz, Amy 6606


Treon, Steven P. TPS8620 Trepel, Jane B. 2527, 3004, TPS4589, TPS5095, e15177, e19097 Tresch, Emmanuelle 536, 544 Tresserra, Francesc e22119 Tretarre, Brigitte 2067 Trevarthen, David R. 6005 Trevino, Lindsey S. e16043 Trevisan, Diego e13046 Trevisani, Franco e15088 Triana, Jaime e12571 Tribius, Silke e17003 Triche, Timothy J. 4542, 5033, 11040 Trick, William e17593 Triebel, Frederic e20011 Trieu, Vuong N. e15076 Trif, Almos e11575 Trifiro, Mark e14615 Trigo Perez, Jose Manuel 7500 Trigonis, Ioannis TPS4146 Trillet-Lenoir, Veronique N. e13594 Trillo-Tinoco, Jimena 2085 Trillsch, Fabian e16535 Trimarchi, Giuseppe 1062 Trinh, Ryan K. 3024 Trinkaus, Kathryn 633, e19158 Triolo, Renza e11569 Triozzi, Pierre L. e13521 Tripathy, Debu 523, 609, TPS9648, e13515 Tripathy, Sasmita e13013 Trippett, Tanya M. 10007, 10027, 10030 Tripsas, Christina TPS8620 Trister, Andrew Daniel e13017 Trneny, Marek 7101 Trnkova, Zuzana e14507 Trobaugh-Lotrario, Angela D. 10037 Trock, Bruce J. 5027 Troiani, Teresa e14565 Trojan, Jorg 4079, TPS4159 Trojanec, Radek 1063 Trojniak, Marta Paulina e12534 Trolese, Anna Rita e17551, e20617 Troncoso, Patricia 5069 Trone, Denise 7012, 7021, 7023 Trooskens, Geert 3552 Trope, Claes 5533 Trosman, Julia R. 626, 6609, 6617, e15010, e22093 Trotti, Andy 6007 Trouilloud, Isabelle 3536 Troutner, Emily 3015 Trovato, Francesca M. e18518 Trovato, Guglielmo M. e18518 Troyan, Susan 1117, 1133 Truant, Stephanie 3599, e15134 Trudeau, Caroline TPS658 Trudeau, Maureen E. 6625, 6628 Truini, Mauro TPS7606, 11063, e22132 Trujillo-Paolillo, Alini 10535 Trukova, Kristen 5036 Truman, Matt 8021 Trumper, Lorenz H. TPS8611 Trumpp, Andreas 11012 Trung, Pham 11034 Trunk, Marcus 4065

Truong, Bao Truong, Hong Truong, Minh-Tam Truong, Mylene Truong, Quoc Van Truong, Thach-Giao

10011 4584 TPS6099 7098 8557 1095, 2605, TPS2623 Trusilova, Elena e15156 Trusolino, Livio TPS3648, 11005, e14654 Truxova, Iva 3076 Tryakin, Alexey e14674, e15194, e15583, e15585, e16509 Trygstad, Carl TPS8123 Trypaki, Maria 7594 Trypsianis, Grigorios e15063 Tsai, Chang-Sung 4018 Tsai, Chun-Ming e19041^ Tsai, Donald Edward 8578 Tsai, Fuu-Jen 1600 Tsai, Huei-Ting 9077 Tsai, Hui-Jen e13554 Tsai, Julie 8021 Tsai, Michaela L. 565 Tsai, Nicole 8556 Tsai, Susan TPS4147, 11046, e15082 Tsang, Walter 3578, 9082, e14529 Tsangaris, Theodore TPS1145, TPS1609 Tsantoulis, Petros e15619 Tsao, Anne S. 7527, TPS8118, 11044 Tsao, Che-Kai 5015, e16032 Tsao, Ming Sound 2053, 7516, 7517, 8096, 11057, 11109, e18514, e19031, e19032, e19077, e22042 Tsao, Ming-Sound 6543, 7532, 11002 Tsao-Wei, Denice D. 4531, 5062, 8554, 9632, e16020 Tsaur, Grigory 10055 Tschmelitsch, Joerg e14537 Tschöpe, Inga 5504 Tse, Archie N. 2583 Tse, Warner H 8104 Tse, William W. 7040, 7058 Tseng, Jennifer 6030 Tseng, Jill 5589 Tseng, Yolanda Diana 5024 Tsien, Christina 2052 Tsilioni, Irini e22202 Tsimafeyeu, Ilya e22097, e22162 Tsimberidou, Apostolia Maria 1051, 2545, 2604, 2611, 9544, 11086, e13534, e13575, e13591, e22086 Tsionou, Christina e12524 Tsirigotis, Panagiotis e20642 Tsobanis, Eric TPS4157 Tsongalis, Gregory J. 6617, e15010, e22093 Tsoref, Daliah 5517 Tsou, Hsiao-Hui 4018 Tsoukalas, Grecory 11117, e20635 Tsoukalas, Nikolaos 11117, e12537, e20635, e22160 Tsuboi, Kenji e14552 Tsuboi, Masahiro 3072 Tsubosa, Yasuhiro TPS4152, e15016 Tsubota, Yu 1111 Tsubouchi, Kazuya e19167

Tsuburaya, Akira LBA4002, 4096, 4102, 4104, e15112 Tsuchihara, Katsuya 7512, e19076, e22082 Tsuda, Hiroshi 5590 Tsuda, Masahiro 4072 Tsuda, Takashi 4076 Tsugawa, Koichiro 1047 Tsuji, Akihito e14527 Tsuji, Fumito TPS8123 Tsuji, Yasushi 4076 Tsujii, Hirohiko e15008 Tsujimoto, Masahiko 10539 Tsujinaka, Toshimasa 4072, e14551 Tsukahara, Kiyoaki 6004 Tsukamoto, Taiji 4526, e15588 Tsukiyama, Iwao 6086 Tsukuda, Hiroshi e20682 Tsung, Allan 9507 Tsunoda, Hiroko 1126, e11524 Tsuruga, Yousuke e15038 Tsuruta, Nobuko e19016 Tsurutani, Junji e13501, e19165 Tsushima, Takahiro e14623, e15016 Tsuta, Koji 7540, e19076 Tsutani, Yasuhiro e18563, e22053 Tsutsui, Atsuko 3556 Tsutsui, Tateki 5538 Tsuzuki, Tomoyuki e15159 Tu, Dongsheng 3528, TPS3647, 4053, 4061, 5502, 6557, e17525 Tu, Shi-Ming e15575 Tu, Yinggang e14615 Tubbs, Raymond R. 8113, 11091, e15000, e22042 Tubiana-Mathieu, Nicole 3515 Tuccari, Giovanni 1062 Tuccia, Fausto 641, e11556 Tucker, Erin 5017 Tucker, Lue-Yen 9645 Tucker, Noah 9610 Tucker, Steven e22107 Tufman, Amanda e19108 Tuli, Abdullah e19071 Tullos, Amanda 8595 Tulpule, Anil 8554, 8559 Tulsky, James A. 6506, 6516, e20674 Tuma Guariento, Ricardo e20680 Tumedei, Maria Maddalena e16530 Tumino, Rosario 5594 Tummes, Dirk 8112 Tumolo, Salvatore 641, 3599, e14557 Tun, Nay Min e19508 Tunariu, Nina 2535, 3062 Tunceli, Ozgur e18543 Tung, Nadine M. 1117, 1133 Tunon de Lara, Christine 566 Tunon, Peter 4577 Tuppo, Catherine e20558 Tural, Deniz e15117 Turan, Nedim e14533, e14662 Turbiglio, Marco 10572 Turchet, Elisa e22149 Turcich, Michelle 2570 Turcott, Jenny e19068 Turcotte, Simon 4060 Tureci, Oezlem 4080 Turer, Aslan 1560

Turgay, Murat Turgut, Burhan Turgut, Mehmet Turhal, Nazim S.

e18010 e18014 e19500 e14660, e20502, e20503 Turhan, Ali e19513 Turi, George 599 Turin, Ilaria 4575 Turkbey, Ismail B. e15177 Turker, Turker e15623 Turkevich, Vladimir 9500 Turkina, Anna G. 7054^ Turkoz, Fatma P. e12521, e12563 Turna, Hande e20006 Turnbull, Barry TPS8620 Turnbull, James D. e15511 Turnbull, Kathleen Wyant 7099 Turner, Christopher D. 7001, 7063, TPS7129 Turner, Jane e20615 Turner, Nancy A. e13590 Turner, Natalie Heather 11072 Turner, Nicholas C. TPS2626 Turner, P. Kellie 5551 Turner, Patricia Kellie 8093 Turner, Taylor 5509 Turner, Tracy TPS3113 Turnwald, Brian 6580, 9604, 9605 Turpin, Brian TPS10591 Turturro, Francesco 8561 Tuscano, Joseph M. 8533 Tuset, Victoria e16549 Tuttle, Jay 8093 Tuttle, Todd M. e12506 Tuzi, Alessandro e22149 Tuzlali, Sitki e11534 Tveit, Kjell Magne 3571, 3597 Twardowski, Przemyslaw 4571 Twelves, Christopher 1049^, 1050^, 1055^, 1087, 2525, e11586 Twigg, Jeremy 5500 Twist, Clare 10039 Twumasi-Ankrah, Philip e13006 Tyagi, Neha 570 Tye, Lesley 8032 Tykodi, Scott S. 2533, e20048 Tyldesley, Scott 1044, 1551, 5035, e16086 Tyler, Allison Janine e16022 Tyler, Lisa 8610 Tyler, Robert Claude 5016, 5034 Tymrakiewicz, Malgorzata e16000 Tyson, Rose Marie e13001 Tzankov, Alexandar 2566 Tzivelekis, Spiros e15046 Tzonis, Panagiotis 3095, e16037 Tzovaras, Alexandros 11117, e20635

U Ubeda, Belen Ubel, Peter A Ubillos, Luis Ucar, Ozgul Uchida, Junji Uchida, Keiichi Uchida, Shinji Uchida, Toshiki Uchitomi, Yosuke Uchiyama, Kazuhisa

e22119 6506, 6516 e14682 e20614 e19153 e22205 e14633 8551 e19016 TPS1140

Udagawa, Harushi TPS4152 Udar, Nitin e22177 Uddin, Mohammad 11076 Udovitsa, Dmitry e11586 Udud, Katalin TPS7609, 8029 Ueda, Koji e13569 Ueda, Ryuzo 8506 Ueda, Shinya 8056 Ueda, Takashi e15526, e15531 Ueda, Takeshi e15527 Ueda, Yuka 10038 Ueda, Yutaka 5538 Uehara, Fuminari e13576, e13577 Uehara, Hiroyuki e15150 Uehara, Keisuke 3535, e14552 Ueki, Tomoyuki 4092 Uemoto, Shinji e15054 Uemura, Hiroji e16098 Uemura, Hirotsugu e15588, e16092 Ueno, Makoto e15109 Ueno, Naoto T. 532, 1005, e22064 Ueno, Shinichi e14633 Ueno, Takayuki 571 Ueoka, Hiroshi e19008, e19124 Uesaka, Katsuhiko 4008, e15031 Ugalde, Aitziber 10529, 10532 Ugalde, Irene e14628 Ugolin, Nicolas 6055 Ugolini, Giampaolo 9557 Ugurel, Selma 11009 Uhlen, Mathias e14580 Uhm, Joon H. 2025 Uhm, Minyong 6559 Uhrhammer, Nancy 1057, 1058 Uihlein, Arlette H 7532 Uike, Naokuni 8506 Ukaegbu, Chinedu I 1530 Ulahannan, Susanna Varkey e15177 Ulbright, Thomas M. 4554 Ulcickas Yood, Marianne 523, e16035 Uldrick, Thomas S. 10588, TPS10595 Uleer, Christoph TPS1137 Ulivi, Paola e14512, e15055, e16530, e22056 Ullah, Shahid 1581, 3592 Ulmer, Hans Ulrich 640 Ulrich, Alexis 3090 Ulrich, Frey 584 Ulusakarya, Ayhan e19513 Ulys, Albertas LBA4509 Umeda, Tomoko e11555, e12014 Umehara, Yutaka e15179 Umekawa, Kanako 7564, e19053 Umemura, Shigeki 7512, 7557, 8078, e19076, e22082 Unal, Emel 10068 Unal, Olcun Umit e14533, e14705, e18546, e19107 Uncu, Dogan e14705, e19107, e20614 Underhill, Craig 3528, TPS3649, 4081 Underhill, Marc e14698 Undevia, Samir D. 2570 Ung, Mony e19036 Ung, Yee e17531 Unger, Joseph M. 8562 Unger, Nicole 4138

Ungerleider, Richard S. 3099 Ungersma, Sharon E. 11095 Ungtrakul, Teerapat e17004 Unlu, Emine Ozgur e19071 Unlu, Ozan e11544 Uno, Hajime 7128 Untch, Brian R. e15079 Untch, Michael 525, 644, 646, 1004, 1020, 11061, e17544, e20616 Unzeitig, Gary Walter 502, 526 Uozumi, KImiharu 8506 Upadhyay, Shivanck 9558, e18008 Upalawanna, Allison TPS5616 Uphold, Heatherlun e20646 Uppal, Hirdesh 645 Uppalapati, Srihari 7080 Uprety, Dipesh e17598 Ura, Takashi e15016 Urakcı, Zuhat e18544 Urakci, Zuhat e14662, e18546 Uram, Jennifer N. 4040^ Urano, Shinichi e15161 Uras, Cihan e11539 Urba, Susan 4011 Urba, Walter John 2518, TPS3107, TPS3110, TPS3114, 9050 Urbach, David R. 5007 Urbach, Horst LBA2000 Urban, Damien e17535 Urban, Elisabeth TPS3119^ Urban, Laszlo e19090^ Urban, Nicole D. e22178 Urban, Patrick TPS650^ Urbanic, James John 6564 Urbano, Cristina e19159 Urbauer, Diana L. 1569, 2611, 6566 Urbini, Benedetta 2021 Urbini, Milena 10540, e21523 Uren, Aykut 10042 Uri, Shiri e20548 Uriol, Esther e14617 Urken, Mark L. 6091, e17030 Urman, Alexandra 8036 Urman, Bulent e22004 Urnovitz, Howard B. 1537, 5072, 11013, 11060 Ursem, Carling e17516 Ursu, Renata 3065^ Urun, Yuksel 4570, e11511 Usakova, Vanda 4556, e15599 Usharani, Malur R. 6624 Usher, Josh 4128 Ushijima, Kimio 5537 Usichenko, Taras e16534 Usinger, Deborah 6530 Uslu, Ruchan e11501, e12018, e12509, e13578, e13580 Usman, Sadaf e12033 Usmani, Naheed 10035 Usmani, Saad Zafar 8515, 8517, 8539, 8595, 8603 Usó, Marta 11073, e22147 Ustoyev, Yelena 10512 Ustuner, Zeki e15191 Usul Afsar, Cigdem 9587 Utikal, Jochen 9020 Utkan, Gungor e11511, e20655 Utsunomiya, Atae 8506 Utsunomiya, Setsuo 4076 Uttamsingh, Shailaja 8073 ABSTRACT AUTHOR INDEX

791s

Uyeda, Lisa Uyeno, Lori Uygun, Kazim Uygur, Meliha Melin Uysal, Mukremin Uzan, Serge Uzilov, Andrew V. Uzunoglu, Faik G. Uzunoglu, Selim Uzzan, Bernard

8044 e17542 e11585 e11540 e14683, e14696, e18517 566 11010, 11067 11014 e13578, e13580 1583

V Vaananen, Riina-Minna 1554 Vaccaro, Gina M. e20702 Vaccaro, Vanja e15057, e21517 Vachani, Carolyn e20671 Vacirca, Jeffrey L. 565, 5034 Vadodkar, Aditi 1046 Vaezi, Mohammad 7069 Vago, Luca 7007 Vago-Ady, Nora 9057 Vagrhese, Teena e13529 Vahanian, Nicholas N. 3007, 3026, 3069, 8094 Vahdat, Linda T. 1024, 1118, e20641 Vaid, Ashok K. 8053 Vaidya, Jayant S. 1121 Vaidya, Rakhee 4071 Vaillant, Brian D. 2019^ Vaillant, Francois e22144 Vainio, Harri 1514 Vaiou, Maria e16083 Vaishamayan, Ulka N. 4565, 4578 Vaishampayan, Ulka N. 4521, 4577, 4586, TPS4590, 5020, 5041, 5085, e15518 Vaishnavi, Aria 8023 Vaissiere, Nathalie 8043 Vajkoczy, Peter 2077, TPS2103 Vakiani, Efsevia 3609, e15017 Vaklavas, Christos 527, 1052 Valabrega, Giorgio e11581 Valachis, Antonis 624, 1119, 1568 Valagussa, Pinuccia 503, 537, 1014 Valda Toro, Patricia 11019 Valdes, Mario 9550 Valdes-Mas, Rafael e12516 Valdez, Riccardo 7047 Valdiviezo, Priscila I. e12566, e12570, e22165 Valdora, Francesca e22132 Valduga, Francesco e15514 Valencia, Alfonso 2511 Valent, Alexander 592 Valente, Mariana de Freitas e12562 Valente, Monica 4136^ Valentini, Antonella 2048 Valenza, Roberto e11526 Valeri, Michele e11616, e14557 Valero, Maria e11577 Valero, Vicente 532, 601, 1005, 1017, 1022, 1118, 6630, e12550 Valeta, Amanda 11106 Valette, Pierre-Jean TPS2625 Valgiusti, Martina e14512, e15055 Validire, Pierre 3639, 4069 Vallabhajosula, Shankar 11081 792s

Vallacchi, Viviana 9092 Valladares Ayerbes, Manuel 5087, e15532, e15542, e22171 Vallarelli, Simona e16081 Valle Pereda, Miguel e18513 Valle, Jose 3019 Valle, Juan W. 3504, LBA4004, 4006, 4120, TPS4146, e15061, e15085, e22035 Vallee, Audrey e19046, e19151 Vallejo Benítez, Ana e22073 Vallejo, Carlos Teodoro 1073, 11118 Vallejo, Yli Remo e13538 Vallejos, Carlos S. e12566, e12570, e22165 Vallette, Francois e18532 Vallier, A-L TPS667, 1015 Vallini, Ilaria e11573 Valls, Nuria e13543 Valluri, Jagan 2089, e13040 Valmorri, Linda 3040 Valori, Vanna Maria 576 Valsecchi, Matias Emanuel e15563 Valsuani, Chiara 3505, 3615 Valteau-Couanet, Dominique 10016 Valtorta, Emanuele TPS3648 Valverde, Claudia María 4550, 10529, 10532, e16045 Valvo, Manuela e22078 Vamvakas, Lampros 1045 van ‘t Veer, Laura J. 587 Van Akkooi, Alexander Christopher Jonathan e20035 Van Allen, Eliezer Mendel 6023, 9015, 10536, 11009 Van Alphen, Robbert Jeroen e11548 Van Alstine, Lindsay Joy 4501, 4534 van Arkel, Cynthia e18562 Van Arsdale, Anne 5592 van Asperen, Christi J. 1502 van Berge Henegouwen, Mark I. e15103 Van Boven, Wim-Jan 7534 van Buren, Marit 9085 Van Criekinge, Wim 3552, e14503 van Cutsem, Eric TPS2622, TPS3124^, 3514, 3525^, 3531, 3551, 3573, 3574, 3588, 3604, 3617, 3636, 3637, 4005^, 4041, TPS4148, TPS4158, e14561, e14656 van de Poll-Franse, Lonneke V. e16517 van de Sandt, Leonie 615 Van De Velde, Cornelis J. H. 595, 597, LBA1001, 1028, e20545, e22106, e22152 Van De Velde, Helgi 8545, e19509 van de Ven, Saskia 1028, e22106 Van De Water, Willemien e20545 Van de Wouw, Agnes W. e11558, e17549 Van Den Bent, Martin J. 2001, 2007, LBA2009, 2011 van den Berg, Adrienne e14702 Van Den Berg, Hendrik 10031


van den Berkmortel, Franchette W. P. J. 2001, e11558, e17549 van den Borne, Ben e18562 Van Den Bosch, J. 1072 Van Den Bossche, Karel e13528 van den Brom, Rob 3036 van den Brule, Adriaan e14629 van den Eertwegh, Alfons J.M. 3036 Van Den Eynde, Marc 4041 van den Hoff, Joerg e21518 van den Loosdrecht, Arjan A 3029 Van Den Neste, Eric 8536 van den Oord, Rosanne e14629 van der Biessen, Diane 2579 Van Der Graaf, Winette T.A. 6057, 10500, 10549, 10553, e20583 van der Groep, Petra e22174 van der Heide, Agnes e20515 Van der Hoeven, Jacobus J.M. 3502 van der Holt, Bronno 2001, 2597, 8517 van der Horst, G.T.J. e11548, e13513 Van Der Jagt, Richard H. C. 8535, 8537, e19518 van der Jagt, Richard 8565 van der Linden, Yvette 9502 van der Mijle, Huub LBA1001 Van der Mijn, Johannes C. 11087 van der Noll, Ruud 2579, 4511 Van der Peet, Donald L. 11087 van der Ploeg, Hidde TPS3647 Van Der Rijt, Carin C. D. e20515 van der Straaten, Tahar 595, 597, e22152, e22156 van der Torren, Adelheid M.E. 3502 van der Velden, Ankie M.T. 1072, e16059 Van Der Wall, Elsken e22174 van Diest, Paul J. e22174 van Dijk, Laura 9085 van Doorn, H. C. e16504 Van Echo, David C. TPS3126 van Eijsden, Rudy 10573 van Engeland, Manon 3552, e14503 van Erp, Nielka P. 2592, 10547 Van Erps, Joanna e14587^ Van Ewijk, Reyn 1074 van Galen, Anne M. 11045 van Gelder, Teun e11548 van Gorp, Toon 5549, e22102 van Grieken, Nicole C.T. 3552 Van Hazel, Guy A. 3574 Van Hazel, Guy TPS3649 Van Herpen, Carla M.L.- 6057 van Heuvel, Irene 2001 Van Hoof, Achiel 8507 Van Hummelen, Paul 5524 Van Kampen, Roel J.W. e11558, e17549 Van Laarhoven, Hanneke W. M. 1028, e15103, e22106 VAN Laethem, Jean Luc 3560 Van Laethem, Jean-Luc 3524, 3525^, 3562, 3617, LBA4003 Van Leeuwen, Barbara 9557 van Leeuwen, Flora E. 4536

van Leeuwen-Stok, Elise Van Loon, Katherine Van Looy, Thomas Van Maele, Georges Van Meerbeeck, Jan P.

1028 4022 e13528 7541 7541, 7584, 7585 Van Meter, Emily Marie 7084, e18001 van Oort, Inge 5055 van Os, Theo AM 1502 van Pel, Renee 7528 Van Poppel, Hendrik 5001 Van Poznak, Catherine H. 507, 515, 1052, 9628, 9640 Van Poznak, Catherine 568 Van Praagh-Doreau, Isabelle e11615 Van Putte, Bart 7534 Van Raemdonck, Dirk 7602 Van Rhee, Frits 8539, 8595, 8603 Van Riel, Johanna MG e17549 van Rooij, Nienke 9085 van Royen, Martin E. 5064 van Ryn, Michelle 6528 van Schaik, Ron H.N. 597, 2597, 4580 Van Schanke, Arne 10026 Van Schil, Paul 7534 van Soest, Robert J. 5064 van Straten, Bart e18562 van t Veer, Mars B 8568 van Tienhoven, Geertjan LBA1001 Van Tine, Brian Andrew LBA10507, 10526, 10585, TPS10592, e21501 van Tinteren, Harm 1072, 3036, 3502, e22128 van Veldhuisen, Dirk 525 Van Veldhuizen, Peter J. e22048 van Warmerdam, Laurens 1028 van Weerden, Wytske M. 5064 Van Zandwijk, Nico 7586 Van Zee, Kimberly J. 1019, 1020 Van Zuylen, L e20515 Van-Praagh, Isabelle 1057, e16021 Vanazzi, Sara e15067 VanDenBerg, Dustin 11019 Vandenbroucke-Menu, Franck 4060 Vandendries, Erik 2574 Vanderbeeken, Marie-Catherine e12008 Vanderkwaak, Timothy J. e20648 VanderLaan, Paul A 8050 Vandermeer, Lisa 6595 VanDerslice, James 1582 Vanderwalde, Ari M. LBA9008, 9083 VanderWalde, Noam Avraham 6018 VanderWeele, David James 5028 VanderWeele, Robert Alan 3041 Vanderweele, Tyler J. 6529 Vandris, Katherine 4011 Vanella, Vito 9548 Vang, Choua e17583 Vangveravong, Suwanna e16508 Vanhuyse, Marie e15044 Vankamamidi, Venkata Sampath e15143 Vankina, Srilakshmi 9606 Vannier, Michael 4012

Vannucci, Jacopo e22155 Vansant, Gordon 11108 Vansteenkiste, Johan F. 8010 Vansteenkiste, Johan 8063 Vanzulli, Angelo e14560 Vapiwala, Neha 6610 Vaporciyan, Ara A. 1532 Varadan, Vinay 1046 Varadhachary, Gauri R. 4133 Vardy, Janette L. TPS3647, 6556, e14582 Varela Ferreiro, Silvia 7549 Varela Ponte, Rafael e16095 Varella-Garcia, Marileila 3545, 8019, 8023, 8024, 8032, e14612 Varese, Paola e12021 Varetto, Antonella 6039 Varga, Andrea 2512, 2524, 2606, 5049^, 8522, 9556 Vargas, Hebert Alberto 5073, e16001 Vargas-Baez, Carlos A. e22028 Varghese, Anna M. 7593, 7600, 8083 Varghese, Thomas K. 7546 Varilla, Vincent e19514 Varillo, Kristi 7578 Varker, Helen e20525 Varley, Danielle e11602 Varlotto, John M. 7553, 7554, e18506, e18552 Varma, Suresh Chandra 4081 Varricchio, Clara 1517 Vasco, Marina Mendes e18515 Vase, Tabitha 10020 Vasen, Hans FA 1502 Vashi, Pankaj G. 5036 Vashistha, Himanshu e13581 Vasilakopoulou, Maria 6012, 6081 Vasile, Enrico 4062, 11058, e19084, e20711 Vasileiou, Chrysoula e16083 Vasilevsky, Carol-Ann e14615 Vasmatzis, George 7568 Vasquez, David 2511 Vass, Sylvie LBA4510 Vassal, Gilles 2512, 2577, 10048 Vasselli, James Robert 8045 Vasson, Marie-Paule e11552, e17022 Vassos, Demetrios e19087 Vastola, Francesca e20541 Vasuri, Francesco e15003 Vasuveda, S 10558 Vatn, Morten H 3607 Vattemi, Emanuela e13009, e15514 Vaudano, Giacomo Paolo e20562 Vaughan, Michelle Margaret TPS5612, TPS5614 Vaughn, David J. 4524, e15584 Vaury, Alexandra 4504, 4576 Vavougios, George e22202 Vazart, Celine e14600 Vazeille, Clara e20535 Vazquez Pazos, Dario 5087 Vazquez Tunas, Lidia Maria e14706 Vazquez, Ana Maria 3086, TPS3123 Vazquez, Begona 3074 Vazquez, Federico 503 Vazquez, Josep 3012 Vazquez, Silvia e17010

Vazquez-Estevez, Sergio 4560, 4587, 7549, e15609 Vazquez-Martin, Alejandro e19003, e19159 Veal, Gareth J. 10033 Vecchiarelli, Silvia 4048, e15069 Vecchione, Loredana 3626 Veccia, Antonello 5050, e16031, e16078 Veenstra, David L. e19001 Veeraputhiran, Muthu Kumaran 5041 Veering, Dettie 9557 Vega-Saenz de Miera, Eleazar 9054, 9067 Vehling-Kaiser, Ursula LBA3506, 3586 Veillard, Anne-Sophie 4081 Vekhter, Benjamin 1513 Velasco, Susanne e15517 Velasco-Hidalgo, Liliana 3050 Velazco, Rodolfo e22165 Velazquez, Ana I. 7041, e20024 Velazquez, Lorena 585 Velcheti, Vamsidhar 6012, 11075 Velculescu, Victor E. 2511, 11005 Velikova, Galina 1050^, 1055^ Velinova, Silviya e20544 Velis, Evelio e17540 Velloso Medrado Santos, Joao Paulo e14590 Veltkamp, Sanne C. LBA1001 Veltri, Enzo e19099 Venditti, Olga e15528 Venerandi, Laura e15149 Venesio, Tiziana 10552 Venkatakrishnan, Karthik 2555, 2567, 2598 Venkataraman, Kalyanasundaram 10020 Venkatesan, Aradhana e15177 Venkatesh, Sudhakar e14507 Venkatramani, Rajkumar 10020 Venna, Suraj S. 9077 Venner, Peter M. e15503 Venook, Alan Paul 3507, 3611, 4014, 4022, 4126, 11011, e14564, e14569, e17570 Venticinque, Joan e20712 Venturini, Filippo 3581, 11058 Venturino, Paola e19020 Venugopal, Parameswaran 7106, 7108, 8559 Venuta, Federico 7602 Venzon, David J. 10588 Veomett, Nicholas J. 3047 Vera, David R. 11098 Vera, Ruth e14509, e14589 Vera-Badillo, Francisco Emilio 5058, e22000, e22015 Verbist, Berit M. 6057 Vercambre, Sophie e20630 Verdecchia, Giorgio Maria 3040 Verderame, Francesco e16078 Verdun, Juan e14589 Verduzco Garza, Barbara e22016 Veresezan, Liana 1104 Vergamini, Lucas B. 10054 Vergara, Ismael A. 4542, 5089 Vergara, Victoria 6088

Vergara-Lluri, Maria Espera 10555 Vergara-Silva, Andrea 3022 Vergez, Sebastien 6053 Verghis, Jaclyn e14508 Vergidis, Dimitrios 11016 Vergidis, Joanna e20045 Vergnenegre, Alain LBA8002, 11010, 11027, 11029, 11078, e22068 Vergo, Maxwell Thomas 3540 Vergote, Ignace 5502, LBA5503, 5504, 5505, 5516, 5520, 5549, 5569, 5575, 5582, 5591, 5593, TPS5613, e16547, e22102 Verheul, Henk M. W. 3552, 4566, 11087 Verhoef, Cornelis e14584 Verhoeven, Nanda M. e20653 Verillaud, Benjamin 6079 Verlicchi, Alberto e18561 Verma, Amit 7125 Verma, Ramesh e16019 Verma, Shailendra 542, e12522 Verma, Udit N. e15200 Vermaelen, Karim Y. 7541 Vermorken, Jan Baptist 7534 Vernhout, Rene 2001 Veronese, Maria Luisa 9046 Veronesi, Paolo e20634 Verp, Marion S. 1506, 11084 Verploegen, Sandra 3066 Verri, Elena 6003 Verrier, Carmel S. 1068 Verschraegen, Claire F. 2578, e15106 Versele, Matthias 7014 Verselis, Sigitas Jonas TPS2627, 6088 Vershinina, Sofia e13005 Verslype, Chris 4041 Versteegh, Michel I.M. 7534 Verstovsek, Srdan 7011, 7030, 7090, 7112, 7115 Vertakova-Krakovska, Bibiana 4556, e15599 Vertogen, Bernadette 3517 Verusio, Claudio e14611 Verweij, Jaap 2597, 10553 Verzhbitskaya, Tatiana 10055 Verzoni, Elena e15528, e15589 Vescio, Robert A. 8598, 8599 Veselkov, Kirill e14620 Vesole, David H. 8584 Vesole, David H. 8543 Vestal, Robert E. 2575 Vetsika, Kiriaki E. e14639 Vetto, John T. 3099 Vey, Norbert TPS3117^ Veyrat-Follet, Christine e19049 Veyret, Corinne 1104, e11529 Veys, Isabelle e12008 Viada, Carmen 3013 Viale, Agnes 4082 Viale, Giuseppe 529, 617, 1061 Viana, Luciano S. 5002 Viardot, Andreas 8566 Vibert, Eric 3606 Vicente, Hector A. e20715 Vicente, Vicente 585, 3042 Vicente-Conesa, Maria Angeles 585

Vicentini, Roberto e14596 Vici, Patrizia e12031, e15065 Vick, Nicholas 2019^, 2076 Vickers, Michael M. 4053, 6622, 9596 Victoria, Iván e14588, e17580 Victorino, Ana Paula e14568 Victory, Jennifer e14709 Vidal, Christian M. e13523, e18541 Vidal, Laura e17580, e22200 Vidal, Maria TPS665, 1011 Vidal, Michel e15592 Vidart, Jose Antonio e16543 Vidaurre, Tatiana e12538 Videtic, Gregory M. M. 4087, e15000 Vidigal, Paula Vieira Teixeira e15199 Vidigal, Veronica e22074 Vidovic, Adria e16019 Vidya, Veldore H. e19092 Vieillard, Marie-Helene e12552 Vieira, Fernando Meton e14568 Vieira, Thibault e19036 Vieitez de Prado, Jose Maria 3604, e14617, e14648, e18513 Vieito Villar, Maria 7549 Vieito, Maria 5603, e16095, e20708 Vielh, Philippe 2512, 7604 Viens, Patrice TPS663 Vietor, Nicole e17575 Viganò, Maria Grazia 3038, 8066, e13593 Viganò, Maria G e18528 Vigil, Carlos Enrique 7072, e12570 Vignaud, Jean-Michel 8100 Vigoda, Ivette Sara 1118 Viguier, Jérôme 1562, 6563 Vij, Ravi 8532, 8542, 8543, 8588, 9559, e17546 Vijai, Joseph 1552, 1554, e12527, e12555 Vijayvergia, Namrata 9546 Vikhrova, Anastasia S. e20042 Vikström, Anders 8014 Vilajosana, Ester e17010 Vilar Sanchez, Eduardo 1525, 1546, 3512, 3623, 3632 Vilaro, Marta 1509 Vilchez, Rocio e15609 Vilella, Ramon e22200 Villa, Diego 1102, 1585, 8552 Villa, Eugenio e14611 Villa, Federica 1086 Villablanca, Judith 10039 Villabona, Carles 4139 Villagra, Victor 6503 Villalobos, Maria L. e15609 Villalobos, Victor Manuel 5565, 5583 Villalona-Calero, Miguel Angel 1023, 8039 Villaluna, Doojduen 10528 Villalva, Claire 3513 Villano, John L. 2062, 2069, 2080, 2099 Villanueva Palicio, Noemi e19034 Villanueva, Alberto 3629 Villanueva, Cristian 1122, e11579 Villanueva, Luis Marcelo 3573 ABSTRACT AUTHOR INDEX

793s

Villanueva, M. J. 7549 Villareal, Vicente e11583 Villarreal-Garza, Cynthia Mayte 634, e11533 Villaruz, Liza Cosca e19022 Villatoro, Rosa e22091, e22131 Villegas Mejia, Carlos Raul e14692, e14693, e15189, e16102 Villegas, Juan Fernando e15550 Villella, Jeannine A 3030 Villena, Marco 7072 Villeneuve, Jodie 9536, 9551, 9595 Villet, Richard 566 Villosio, Nicolo e22132 Vinayak, Shaveta 1003 Vinayan, Anup e15608 Vinayanuwattikun, Chanida e17004 Vince, Bradley e16075 Vincendeau, Sebastien 5074 Vincent, Andrew D. 7528, e22128 Vincent, Francois LBA4510 Vincent, Loïc 2530, e14539 Vincent, Marc e14600 Vincent, Patrick e13529 Vincent-Salomon, Anne 2615, e11607 Vincenzi, Bruno 10568, e15528, e16538 Vines, Douglass 4049 Vingiani, Andrea 1517 Vinnicombe, Sarah 4535 Vinnyk, Yurii Oleksiiovych 629 Vinolas, Nuria 7547 Vinuales, Ana e11538 Vinyals, Francesc e22057 Viora, Tiziana e20562 Viqueira, Andrea e16028 Virani, Sean e16086 Viret, Frederic 3515 Virgili, Núria e15111 Virgo, Katherine S. 6526, e16029, e16039, e17506 Virion, Jean Marc 2067 Virizuela, Juan Antonio e12015, e15586 Virnig, Beth A. e12506 Visa, Joana e19003 Visca, Paolo e19052 Visconte, Valeria 7008 Vishnevskaja, Yana e12027 Vishnubhatla, Sreenivas TPS4162, 10527, e21522 Vishnubhotla, Priya 3085 Viskochil, David 10522 Vismara, Chiara 6046 Vismarra, Marco 4112 Visscher, Daniel W. 2562, 5546 Visser, Jan Marinus 3075 Visser, Otto 8556 Visseren-Grul, Carla 8068, e19148 Vissotto, Eduardo de Figueiredo e20640 Visvader, Jane E. e22144 Visvanathan, Kala 1514, 1572, 1601 Viswanathan, Akila N. 5588 Viswanathan, Shankar 6064 Vitale, Antonella 7025 Viteri Ramirez, Santiago 11025, 11027, 11029, e22119 794s

Viteri, Santiago 11067 Vithala, Madhuri V. e20509 Vitolins, Mara 6564 Vitoria, Webster de Oliveira e16030 Viudez, Antonio e14589, e14648 Vivancos, Ana 4135, 8070 Vives, Marta e22057 Vizzard, Margaret e20509 Vladimirov, Vladimir Ivanovich 548, 3508 Vladimirov, Vladimir e11586 Vladimirova, Liubov Yu e14701, e19047 Vladislav, Ioan Tudor 7605 Vlahovic, Gordana 2094, e13015^, e22166 Vletter-Bogaartz, Judith M. 597 Vo, Lien 11108 Voccia, Isabelle 8034 Voci, Amy 507 Vocila, Linda TPS2621, TPS11123 Vodala, Sadanand 10509 Voebel-De Jong, Margreet 11087 Voegeli, Michele 8560 Voehringer, Matthias TPS3124^ Voeller, Donna 11034 Voest, Emile E. 1010, 2522, 2536, e20653 Vogel, Charles L. 610, 1031, TPS11124 Vogel, Rachel Isaksson 9606, e20571, e22007 Vogelbaum, Michael A. 1, LBA2010 Vogelstein, Bert 11015 Vogelzang, Nicholas J. 2533, 4524, 4579, 5013, 5016, 5018, 5026, 5060, 5068, 7527, e15500, e15504, e15538, e16020 Vogl, Sonja e11601 Vogl, Thomas J. e15061 Vogl, Ursula Maria e15535 Vogl, Wolf-Dieter 11088 Vogt, Tobias 2023^ Vogt, Ulf e18511 Voit, Christiane A. e20035 Vokes, Everett E. 6008, 6010, 6022, 7506, 7510, 8026, 8039 Volandes, Angelo E. e20586 Volchenboum, Samuel Louis 10015 Volet, Julien 3614 Volk, Robert J. 1564 Volkheimer, Alicia D. 7103 Volm, Matthew 1042 Volovat, Constantin D. 4021, e17572 Volz, Nico Benjamin 3557, 3565, 3566, 3567, 3568, 4110, 4111, e14538, e14543, e14714, e15009, e15022 Volzone, Francesco 8564 Vomvas, Dimitrios e19110 von Abel, Ekkehard TPS1137, 11043 von Bodman, Christian 9580 von Borstel, Reid e20592 von Bubnoff, Nikolas 10508 Von Deimling, Andreas 2007, 2027 von der Maase, Hans 4502 von Dincklage, Jutta e17587 von Heydebreck, Anja 3537 von Hofe, Eric e16037


Von Hoff, Daniel D. 4005^, 4038, 4058^, 4059^, 4063, 11001, e15128, e15188^, e22110 von Knebel Doeberitz, Magnus 4065 von Mehren, Margaret 10503, 10511, 10514, 10551 Von Minckwitz, Gunter 610, 1004, 1020, 1082, TPS1137, TPS1138, TPS1141, 11061 Von Moos, Roger 3503, 3604, 5079, e20514 Von Pawel, Joachim TPS7608, LBA8011, e19108 Von Roemeling, Reinhard 3508 von Schweinitz, Dietrich 10037 von Stackelberg, Arend 10007 Von Verschuer, Ulla 3586, TPS4591 Von Weikersthal, Ludwig Fischer 4086 von Wichert, Goetz 3586, 4034, 4080 Vontela, Namratha 1067 Voogd, Adri C e11558, e17549 Voong, Cynthia 4007 Voong, K Ranh e15028 Vorobeychikov, Eugene Vladimirovich 3088 Voron, Thibault e22121 Vos, M. Caroline e16517 Vose, Julie 8505, 8533, 8572 Voss, Jesse S. 2025, 11119 Voss, Martin Henner 4573, TPS4593, TPS4595, e15517 Voss, Stephan D. 10071 Vourli, Sophia e20642 Vredenburgh, James J. TPS2102, e13015^ Vree, Robert 595 Vreeland, Timothy J. 3005, 3096, 3097, TPS3126 Vriens, Birgit 1028 Vucetic, Zivjena 5555, 5563 Vugrin, Davor e14643 Vujaskovic, Zeljko e15560 Vukelja, Svetislava J. 590 Vukovic, Vojislav M. TPS1136, CRA8007, TPS8126, e19097 Vuletich, Christine e17587 Vulih, Diana 9517 Vulsteke, Christof 1078 Vuylsteke, Peter 8063 Vyberg, Mogens e11507 Vyzula, Rostislav e14622

W Waage, Anders 8517 Waal, Andrei Ivanovich 3088 Wabinga, Henry 10070 Wacheck, Volker 8093, e16042 Wachsberger, Phyllis R. 2100 Wachsmann, Grischa TPS1137 Wachula, Ewa e13560, e15045 Wack, Claudine 2560 Wacker, Michael e16055 Wactawski-Wende, Jean 1504, 1524, 3594 Wada, Noriaki 1113 Wada, Russell 644

Waddell, Nicola e15029 Waddell, Thomas K. 7516, e18503 Wade, James Lloyd 2560, 4011 Wade, Raymond 8591, e18527, e22003, e22052 Wadehra, Madhuri 3080 Wadhwa, Roopma 4083, 4085, e15013 Wadhwa, Vivek K. 5057 Wadlow, Raymond Couric 4090 Wadsley, Jonathan LBA4004, 4023, e15085 Wadsworth, Christina 7595 Wadsworth, Trad 6083 Wagle, Nikhil 1531, 6023, 9015, 11009 Wagner, Andrea 3514, 3636, 3637 Wagner, Andrew J. 10511 Wagner, Andrew 10514 Wagner, Eric R. 10531 Wagner, Harald 1082, TPS1141 Wagner, Isaac 6508 Wagner, Joseph e22083 Wagner, Lars M. 10522 Wagner, Ludwig 2040 Wagner, Lynne I. 6005, 9527, e20527 Wagner, Stephanie Ann 4010, e15005 Wagner, Thomas 3586 Wagner, Wolfgang e18511 Wagner-Gund, Barbara 8590 Wagner-Johnston, Nina D. 7003, 7017, 8500, 8501, 8519, 8526 Wagner-Johnston, Nina 8505 Wagstaff, John 3053 Waguespack, Steven e17016 Waheed, Mian Adnan 8603 Waheed, Sarah 8515, 8539, 8595, 8603 Waheed, Shahid e12569 Wahl, Richard L. TPS2105 Wahner Hendrickson, Andrea Elisabeth 5546 Wai, Elaine 1551 Wainberg, Zev A. 2580 Wakabayashi, Go e20576 Wakabayashi, Hiroshi e16072 Wakabayashi, Mark Tsuneo 5599 Wakabayashi, Toshihiko e13012 Wakamiya, Karen 2071 Wakatsuki, Takeru 3527, 3557, 3565, 3566, 3567, 3568, 4110, 4111, e14538, e14543, e14714, e15009, e15022 Wakayama, Kenji e15038 Wakelee, Heather A. 1504, 1524, 2524, 6581 Wakiya, Taiichi e15179 Wakuda, Kazushige 7599 Wakui, Hiroshi e13504, e13511 Walbert, Tobias e20703 Waldman, Adam 635 Waldman, Frederic 7601 Waldschmidt, Dirk 4118 Walenkamp, Annemiek M. E. 2001, 2050 Walewski, Jan Andrzej TPS7133, e19535 Walk, Eric E. e11507

Walker, Chelsey P. e13581 Walker, Heather 5048 Walker, Ian 11094 Walker, Joan L. 3077 Walker, John W. T. e15503 Walker, Kimberly 8577 Walker, Mark S. 8044, 9619, e13574, e15508, e15605 Walker, Paul R. 1069, 6584, e19154 Walker, Russell M 2528, 2547 Walkiewicz, Marzena 11072 Walkley, Janelle 8571 Walko, Christine Marie 2595, e13507 Wall, Louise e20608 Wall, Najme 4553 Wallace, Anne M. 11098 Wallace, James Alfred 4012 Wallace, Michelle 1123, e16008 Wallace, Robert B. 6602, e19065 Waller, Cornelius F. 7051 Waller, Edmund K. 7035, 8540 Walls, Robert e12500 Wallwiener, Diethelm 1030, 5598 Wallwiener, Markus 1030, 5598, 11012 Walpole, Euan Thomas 9516 Wals, Jacob J. 3502 Walsh, Declan 9638, e20572, e20597 Walsh, Elaine 10530, e12533 Walsh, Gerald M. 2575 Walsh, Naomi 632, 1066 Walsh, Robert e14637 Walsh, Tom CRA1501 Walsh, William Vincent 8097 Walshe, Margaret B. 1542 Walter, Christina 5598 Walter, Kim 6008 Walter, Paige 5523 Walter, Thomas 4031, 4130 Walters, Kelly Kaiser e19113, e19117 Walton, Robert 1080, e11609, e12034, e14646, e19130, e20672, e20697 Waltzman, Roger J. 11082 Walz, Jochen e15506 Wampfler, Jason A. 7545 Wan, Dante 1585 Wan, Huiping 7507 Wan, Jiang e19161 Wan, XiangBo 538, 4131, e15021, e16077 Wan, Xiaolin 10025 Wandel, Simon 9029 Wander, Lionel 4046 Wanders, Jantien 1049^, 1050^, 1055^, e11586 Wanebo, Harold J. 6081, e14599 Wang, Aijuan e22094 Wang, Andrew e13546 Wang, Ange 1504 Wang, Antai 560 Wang, Bei 644, 646 Wang, Biyun 1064 Wang, Bruce 6626 Wang, Chang-Li 7537, e19161 Wang, Changyu 3061 Wang, Chen 5510 Wang, Chenguang 6559

Wang, Chieh-Mei e13588 Wang, Christopher 7569 Wang, Chunting e13592 Wang, Dakun 7532 Wang, Dian 6007 Wang, Edina e13546 Wang, Ena TPS3122 Wang, Eric e14545 Wang, Erjian 4121 Wang, Eunice S. e18018 Wang, Evelyn 2580 Wang, Fang 4107, e15047 Wang, Feng 6050 Wang, Feng-Hua 4107, e15047 Wang, Fenghao e14602 Wang, Fengmei e15040, e15050 Wang, Frank Y 10509 Wang, Geng e15135 Wang, Guanjun 3031, e18550 Wang, Haibin 5558 Wang, Hao 6013 Wang, Hong Gang e13533 Wang, Hongkun 2616, TPS2624 Wang, Hongmei 7521 Wang, Hsiu-Po 4099 Wang, Huamin 4133 Wang, Huei 5079, 9628, 9640, e20512 Wang, Huiyun e15135 Wang, Jen C. e16101 Wang, Jian-Jun 1547 Wang, Jianhua e15030 Wang, Jianming 8584 Wang, Jiayu 2614 Wang, Jie Jun 4025 Wang, Jie 7507, 8101, e19061^, e19067, e19091, e19101, e19136, e22096 Wang, Jin-Wan 4109, e15622 Wang, Jing 6011 Wang, Jingbo 7579 Wang, Jingyuan TPS8612, 10028 Wang, Jisheng 2022 Wang, Jiwen e18531 Wang, Jiying e19082 Wang, Jue 1512 Wang, Jun 1103, 1547 Wang, Junye e19161 Wang, Kai 8020, 11000, 11020, e22146 Wang, Karen 2092 Wang, Kung-Liahng 5512 Wang, Li 6608, e12010, e14689, e16080, e16516, e19122 Wang, Liang e15547 Wang, Lin 6006, 6051, e19075 Wang, Lisa 2534, 5039 Wang, Lu 7559, 7600, 8022, 8067 Wang, Lulu e20574 Wang, Lvhua e15030 Wang, Meilin 4106 Wang, Mengzhao e19135 Wang, Michael 8529, TPS8613^ Wang, Nanya 3031, e15198 Wang, Pei e16520 Wang, Qi-Long e14634 Wang, Qiao e15622 WANG, Qifeng e14667, e14685 Wang, Qing 511, 636 Wang, Qiong 5512

WANG, Quing 510 Wang, Qun 1547 Wang, Renzhi 2022 Wang, Rong 6549 Wang, Ruixue 10026, 10027 Wang, Samuel J. 4073 Wang, Shu 1084, e12006 Wang, Shuhang 8101, e19061^, e19067, e19091, e19101, e19136 Wang, Si-Yu 1547, 7519 Wang, Siyuan 1084, e12006 Wang, Song 3009 Wang, Stephani Chang e14653 Wang, Tao TPS8123 Wang, Tao-Yeuan e22118 Wang, Teh-Chun 8554 Wang, Tian Tian 538, 4131, e16077 Wang, Ting Ting e14507 Wang, Trent P e14625, e14661, e14681, e15561 Wang, Vivian TPS1134 Wang, Wei e20001, e22043 Wang, Weidong e16520 Wang, Weili 7522, 7580 Wang, Weixin 8597 Wang, Wenshi 9011 Wang, Wenting 3529 Wang, Xiang 2022 Wang, Xiaodong e19067 Wang, Xiaofang 5597 Wang, Xiaofei F. 7510, 8039 Wang, Xiaojia 1064 Wang, Xiaojing 8546 Wang, Xiaopei e15185 Wang, Xicheng 4097 Wang, Xin Shelley 7574, 9646, e17588 Wang, Xin e14707 Wang, Xiuqiang 7601 Wang, Xiuyan TPS3115 Wang, Xuan e20027 Wang, Xuemei 4517, 5069, 7098, e15611 Wang, Xuexia 10004 Wang, Xufang e15500, e15504 Wang, Yan V. TPS1142^ Wang, Yan 5565, e13527, e18504 Wang, Yandong e15040 Wang, Yang 5016, 5053^ Wang, Ye e14615 Wang, Yi e22168 Wang, Yi-Zarn 4141, e15139 Wang, Yijun e15040, e15050 Wang, Ying 1005, 9588 Wang, Yinxiang e19161 Wang, Yisong 7513, 11034 Wang, Yixin 5045 Wang, Yongbao 8115, 9100 Wang, Yongsheng e20692 Wang, Yuehong e22054 Wang, Yuhui e16516 Wang, Yuling e22169 Wang, Yunfei 590, e19015 Wang, Yuyan 8101, e19061^, e19067, e19091, e19101, e19136 Wang, Zhaohui e14668, e16043, e20649 Wang, Zhaoxi e19080, e19081 Wang, Zheng 7537 Wang, Zhengrong e16516

Wang, Zhijie 8101, e19061^, e19067, e19091, e19101, e19136 Wang, Zhiqiang e15047 Wang, Zhiwei 10006 Wang, Zhong Hua 1064 Wang-Gillam, Andrea 4040^, 4051 Wang-Lopez, Qian e11615 Wangefjord, Sakarias 3579, e14580 Wangpaichitr, Medhi e22062 Wani, Sachin 4051 Wank, Stephen 2532 Wannesson, Luciano 8560, 11029 Wapnir, Irene 1003 Ward, Brent 9607 Ward, Elizabeth M. 6569 Ward, Jean 6074 Ward, John Francis 5069 Ward, Kevin C. 1130, 6523, 9579, e16029, e16039 Ward, Kristy K. 6636 Ward, Leigh C. 9616, e20533 Ward, Stacey Anne e13537 Ward, Suzanne e20521 Warde, Padraig Richard 4503, e15510 Warden, Charles 5599 Wardley, Andrew M. 529, TPS667 Warfe, James 6538 Wargo, Jennifer Ann 9015 Waring, Paul Michael TPS3649 Warlaumont, Mary e14641, e18501 Warneke, Carla L. 9047 Warneke, James 9102 Warner, Andrew 7520, e19120 Warner, Ellen 1002, 1507, e17523 Warner, Lindsay Louise Morgenstern 5577 Warner, Steven 6011 Warnick, Ronald e13023 Warren, Diane TPS8620 Warren, Graham Walter 1561, 1566, 1603, 4067 Warren, Joan L 6521, 6522, 6604 Warren, Katherine E. 2036, 2101, 2554 Warrick, Andrea 7513, e19141 Warrier, Sanjay 1053 Warsi, Ghulam 6023 Warzocha, Krzysztof 7066 Wasan, Ellen e15084 Wasan, Harpreet 2576, 3500, 3509, TPS3645, TPS3649, 4007, 4120 Washington, Kimberly E. e17574 Washington, Mary Kay 3555 Wasif, Nabil 9034 Wasilewski-Masker, Karen 10062 Wasser, Martin N. 1028 Wasserman, David Warren e14553 Wasserman, Yoram e22125 Wassermann, Johanna 6093 Wassman, Robert e22173 Wassmann, Karl 9080 Watanabe, Atsushi e22082 Watanabe, Junichiro e11563 Watanabe, Kageaki e18524 Watanabe, Kazuyoshi e19083 Watanabe, Kenichiro 10038 Watanabe, Koichiro e20585 Watanabe, Koshiro e19054 ABSTRACT AUTHOR INDEX

795s

Watanabe, Masahiko 3518, 3519, 3556, 4110, 4111, e15009, e15022, e15113, e15122 Watanabe, Masayuki 11065, e14665 Watanabe, Mika e14597 Watanabe, Morihiro e13510 Watanabe, Rira 2583 Watanabe, Shinichiro e15161 Watanabe, Shun-ichi 8037 Watanabe, Tomoo e14651 Watanabe, Toshiaki 3518 Waterhouse, David Michael LBA8003, 8062, 8091 Waterkamp, Daniel 3521, 3604, 3619^ Waterman, Gabriel N. e20044 Waters, Justin S. e15085 Waterston, Ashita Marie LBA9000 Watson, Clare e15029 Watson, Dorothy 6501, 11053 Watson, Holly e17509 Watson, Joelle e17514 Watson, Mark 633 Watson, Melanie 8540 Watson, Sarah 4069 Watson, Sydeaka 6066 Watt, Stuart 11016 Wattson, Daniel A. 9064 Waxman, Ian TPS4592, TPS9106 Waymer, Sharon 7077 Wayne, Alan S. 10008 Wayne, Jeffrey D. 10559 Wayne, Peter M. 6058 Wuerstlein, Rachel TPS649 WB, Ma 2022 Wdowik, Melissa 1558 Weaver, Amy 5577, 9073 Weaver, Andrew 3500 Weaver, David T. 11064, e18541 Weaver, Donald L. 559, 1000 Weaver, Kathryn E. e20532 Weaver, Kathryn E. 6564 Weaver, Robert LBA8003 Webb, Charles D. 8062 Webb, Tonya e22034 Webber, Kate 9602 Webber, Lee C. 5514 Webber, Nicolas P. 10521 Weber, Beatrice E. 1058, LBA5501, 5504, 10505 Weber, Ben e14591 Weber, Donna M. 8531 Weber, Jeffrey S. 9005, 9009, 9011, 9016, 9041, 9053, 9056^, 9059, 9072, TPS9105^, TPS9107^ Weber, Jeffrey 9079 Weber, Johann 9014 Weber, Karsten E. e22112 Weber, Matthias 4031 Weber, Michael e22090 Webster, Kimberly e20527 Webster, Scott 2071 Weck, Karen E. e14522 Weckstein, Douglas 500 Wedding, Ulrich 9553 Wedel, Steffen 5019 Weder, Walter 7503, 7514, 7587, 7602 Wee, Bee 9503 Wee, Hwee Lin e13582 796s

Weekes, Colin D. Weeks, Jane C.

4059^ 1006, 1553, 6528, 6529 Wefel, Jeffrey Scott 1, 2003, 2004 Wege, Henning e15088 Wegener, William A. e14508, e15089 Wehbe, Ahmad Mouhamad 9090 Wehler, Thomas e21505 Wei, Alice Chia-chi e14573, e15087 Wei, Bing 1588 Wei, Caimiao 5584, 8079 Wei, Cuihong e19032 Wei, Guojian e14619 Wei, Jian-Jun 5574 Wei, Lai e14535 Wei, Li 538, 4131, e16077 Wei, Lihui 5512 Wei, Min 9632 Wei, Shi 623 Wei, Wei 7006 Wei, Wenbin 1063 Wei, Xinyu 4005^, 4059^, e15188^ Wei, Ye 3610 Wei, Yuquan e13592 Weichenthal, Michael e20028 Weichle, Thomas e14578 Weichselbaum, Ralph R. 6010 Weickhardt, Andrew James 3545 Weide, Benjamin e20050 Weidhaas, Joanne B. 6016 Weidler, Jodi 604 Weidmann, Jens 3008 Weidner, Susan M 9535 Weigang-Koehler, Karin 4035 Weigel, Brenda 2538, 10554 Weigel, Michael TPS1141 Weigel, Nancy 579, e16043 Weigel, Tracey L. e17595, e18537 Weijenberg, Matty P. e14503 Weil, Robert J. 514 Weile, Jan e20652 Weimann, Arved e15096 Wein, Axel 3561 Weinberg, J. Brice 7103 Weinberg, Uri e22125, e22134, e22138 Weinberg, Vivian K. 5077, 11048 Weinberger, Morris 6555 Weindel, Michael D. e15077 Weiner, Jennifer 11103 Weiner, Louis M. 2616, TPS2624 Weiner, Russell 11059 Weinigel, Martin e20688 Weinstein, Douglas 2532 Weinstein, John N. 6011 Weir, Alexander TPS8119 Weir, Genevieve 3030 Weir, Scott 2558 Weir, Tiffany 1558, 11050 Weisberg, Jeffrey Ira TPS3128 Weisberger, Emily 3605 Weise, Steffen 3634 Weisel, Katja C. 8510, 8527, 8528, 8544, 8583 Weisenthal, Larry e22188 Weiser, Martin R. 3605 Weiskopf, Kipp 3015 Weiss, Brian D. 10039 Weiss, Geoffrey R. TPS3118^, TPS3125


Weiss, Glen J. Weiss, Glen Weiss, Jan Weiss, Jared

8031 2617 e20558 6094, TPS6097, TPS6098 Weiss, Jennifer e14550 Weiss, Jocelyn 7586 Weiss, Lawrence 2097, e19536, e22085 Weiss, Mark Adam 7086 Weiss, Matthew e15028 Weiss, Matthias 8592, 9533, e19517 Weiss, Michael e20046 Weiss, Robert M. e15543 Weiss, Rudolf 8524 Weiss, Stephanie E. 8069 Weisser, Martin 2522 Weissinger, Florian 4086 Weissler, Mark C TPS6097 Weissman, Benjamin 1536 Weissman, Joel S. 6544 Weissman, Jonathan S. 11010, 11067 Weitman, Steven 2578, 3541 Weitner, Bing Bing 8036, 9087 Weitz, Juergen 3090, 3538, 3588 Weitzel, Jeffrey N. 1024, 1536, e20651 Weitzen, Rony e15597, e15598 Weitzenkamp, David e18032 Weitzman, Aaron 5026, 9094 Welaya, Karim Youssry 1075 Welch, Roberto e20641 Welch, Stephen 518, 5517, 5518, 11016 Welcher, Rosanne 2071 Weldon, Christine B. 626, 6609, 6617, e15010, e22093 Wellbrock, Jasmin 7027 Wellde, Anne S. 11010, 11067 Wellde, George W. 11010, 11067 Wellens, Jasmien e13528 Weller, Michael LBA2009, 2027, 2045, 2059, 2079, 2081, 2092, TPS2103 Welling, Theodore Hobart TPS3111 Wells, George A 4050 Wells, Jeremy Clady e17524 Wells, Karen e16035 Wells, Nancy L. e20555 Wells, Samuel A. 6074 Welsh, Allison 5030 Welslau, Manfred TPS3119^ Welzel, Grit 1120, 4065 Welzel, Julia 9098 Welzel, Thomas e15574 Wen, Chua Hui e22107 Wen, Feng TPS4154, e14645 Wen, Jie 2543 Wen, Jing 2552, e15135 Wen, Jing-Yun 538, 4131, e16077, e19504 Wen, Kai Sheng 5057 Wen, Limin e19042 Wen, Patrick Y. 2012, 2013, 2015, 2030, 2044, 2046, 2047, 2054, 2075, TPS2102, TPS2104, 2500 Wen, Qiuting 2044 Wen, Shao e22024 Wen, Sijin 4548 Wen, Wei 8021, e22092

Wen, Wenhsiang Wen, Yong Hannah Wen, Yujia Wendland, Merideth M.

11001 1552 2571 2003, 2004, 2047 Wendt, Michael e16534 Wendtner, Clemens M. 7004, 7015 Wendum, Dominique 4127 Wenes, Mathias 3588 Weng, David Edward 2504, 3621 Weng, Li 8511 Weng, Wen-Kai 3015 Weng, Xiaoduan 6041, e22159 Wenger, Michael 7004 Wengert, Georg 11088 Wengrod, Jordan 9067 Wenham, Robert M. 5517 Wenham, Robert Michael 2513, 10556 Wentzensen, Nicolas 4065 Wenz, Frederik K. 1120, 1121, 4065 Wenzel, Lari B. 5542, 6632, 6633 Wenzlaff, Angie 7561 Werbrouck, Patrick 5001 Werner, Dominique 4095, 4100 Werner, Douglas TPS4149 Werner, Lillian 5056 Werner, Michael Edward e13546 Werner, Theresa Louise e13522 Werner-Wasik, Maria 1, 2008, LBA2010, 2100 Wersäll, Peter e15553 Werutsky, Gustavo e12510 Wery, Jean-Pierre 3544 Weschenfelder, Rui e14679 Wesolowski, Robert 1023, 1043, TPS11122 Wesseling, Jelle 1010 Wesseling, Pieter 2011 Wessels, Judith A. M. 597, e22152 Wessels, Lodewyk F. A. 1010, 3530 Wessling, Gabriele e16533 Wessling, Johannes 8548 West, Derek e22204 West, Douglas 7544 West, Michael e22083 Westeel, Virginie 7515, e19058 Westenberg, Helen LBA1001 Westermann, A.M. e16504, e16547 Westin, Eric H. 2567 Westin, Shannon Neville 2611, 5521, 5524, 5580, 5584, 5596, 5608, e13591, e16556, e20637 Weston, Brian 4078, 4083, 4085, e15013, e15053 Westphal, Manfred 2027 Westra, William H. 6005, 6013 Wetering, Sandra van 3029 Wetzler, Meir 7066, 7073, 7088, e18018 Weyer, Geerd 607 Weyerbrock, Astrid LBA2000, LBA2009 Whaley, Sesilya 7039 Whang, Hwee Yong 6063 Wharton, Rose TPS5615, 9503 Wheater, Matthew 4549 Wheatley, Keith 10031 Wheatley-Price, Paul 4053, e14598, e19024

Wheeler, Cosette 1576 Wheeler, David A. 8577, 10023 Wheeler, Heather E. e13541 Wheeler, Helen 2017, 2061 Wheeler, Marcia e15543 Wheeler, Stephanie B. 6503, 6572 Whelan, Jeremy 10031, LBA10504, 10518 Whelan, Timothy Joseph 564, 1033 Wheler, Jennifer J. 1051, 2506^, 2545, 2604, 2611, TPS2619, 9544, 11086, e13534, e13575, e13591, e22086 Whiley, Matt 2092 Whitaker, Earlene 6561 Whitby, Denise TPS10595 White, Eileen 2553 White, Evan Carl e15001 White, Jeff D. 2589, 4535, 9590 White, Jeff 10517 White, Kathryn e20615 White, Kevin P. 5028, 6008, 6010 White, Sandra 9590 White, Shane 11072, e18559 White, Tricia e13001 White, Yvonne Alexandra e11509 Whitehead, Robert P. e14711 Whiting, Scott e20033 Whitlock, James 10003, 10007 Whitman, Eric D. 3022, TPS3128 Whitmore, James Boyd 5034 Whitney, Charles W. 5530 Whitney, John 6508 Whittaker, Naomi e14641 Whittemore, Alice S. 1548 Whittle, Jeffrey C. 8090, e17594 Whittle, Marty 512 Whitworth, Pat W. e22117 Whorf, Robert C. 5513 Whyler, Elaine 6515 Whyte, David B. e22066 Whyte, Jill Suzanne e16546 Wiater, Katarzyna e22046 Wicht, Johannes e15070 Wick, Jo 2558, e22048 Wick, Wolfgang 2002^, 2005^, 2007, LBA2009, 2023^, 2039, 2061, TPS2103 Wickenhauser, Claudia 10508 Wickham, Robert 10009 Widemann, Brigitte C. 2554, 10522 Widhalm, Georg 2078 Wiebe, Meagan 6639 Wiebringhaus, Frank TPS1141 Wiechmann, Volker e15096 Wiechno, Pawel J. 5019 Wieczorek, Jodi e19015 Wiedemann, Bea 10566 Wiedemann, Florian e20623 Wiedenmann, Bertram e15071 Wieder, Robert 1091 Wieland, Scott 2550, e13572, e13581, e15128 Wiemer, Erik A. C. 2597, 5064, 10573, e11548, e13513, e16504 Wiener, Erik e22017 Wierda, William G. 7018, 7024, 7098, 7102, 8520 Wiering, Bastiaan e14584 Wiernik, Peter H. e12527

Wiese, David

570, 3582, 3583, e14518, e14566 Wiese, Kristin 7118 Wieshmann, Hulya 4132 Wiesner, Georgia L. TPS1606 Wiezorek, Jeffrey S. 3511 Wigginton, Jon M. 3002^, 3003^, TPS3106, TPS3107, TPS3108, TPS3109, TPS3110, TPS3111, TPS3112, TPS3113, TPS3114, 4514, 8030, CRA9006^, 9012^ Wigle, Dennis A. 4026, 7568, e18538, e19013 Wigler, Michael 5030 Wiktor, Anne E. 4071 Wilbaux, Melanie 5547, e16050 Wilcken, Nicholas 543, e20584 Wilcox, Rebecca e15106 Wild, Aaron Tyler 4039, 4057, e15028 Wilder-Romans, Kari 1025 Wildes, Tanya Marya 8586, 9559, e21501 Wildey, Gary e18526 Wildiers, Hans 1078 Wilding, George 2513, 2607 Wilding, Jenny e14544 Wilfong, Lalan S. 6607 Wilhelm, Francois 7031 Wilhelm, Olaf 4507^ Wilhelm, Scott 5080, e14507 Wilisch-Neumann, Anette e22140 Wilke, Celine e12008 Wilke, Derek 5048 Wilke, Hansjochen 4086 Wilkerson, Julia 4585, e14592, e22213 Wilkerson, Matthew 7576 Wilking, Ulla e22126 Wilkinson, Jeffrey 7605, 9022 Wilkinson, John Ben 1123 Wilkinson, Rosemary e16000 Wilkinson-Ryan, Ivy e16508 Wilks, Sharon 505 Willenbacher, Wolfgang 8589 Willey, Joanne 7046, 8607 Willey, Richard 6030 William, William Nassib 6011, 6030, 6087, 8079 Williams, Amy 6023 Williams, Ann L. 3104 Williams, Anthony 7509 Williams, Charles C. 3091, 8001 Williams, Christina D. 7538, 7539, 8090 Williams, Corinne E. TPS5612 Williams, David A. 9615 Williams, Erica H. 6561 Williams, Grant Richard 9543, e20582 Williams, Gretchen M. 10024 Williams, Hilary e15085 Williams, Jacqueline P. e20526 Williams, James Andrew 4121 Williams, Janet L. 9642, e20528, e20612, e20626 Williams, Jessica e13575 Williams, John C. 3081 Williams, Joshua C. M. e20009 Williams, Loretta A. 9646, e17508

Williams, Madeleine M. A. 5008 Williams, Marissa 7586 Williams, Mark 11083 Williams, Michael E. TPS3108, 7046, 8533, 8534, 8607, e19517 Williams, Michelle D. 6011, 6067 Williams, Nicole 1046 Williams, Norman R. 1110 Williams, Paul 11017 Williams, Richard Thomas 3511 Williams, Ross 4583 Williams, Sarah 5587 Williams, Scott G. e16016 Williams, Terence Marques e14535 Williamson, Stephen K. 2558, e22048 Willingham, Field F. e14618 Willis, Benjamin 1520 Willis, Daniel Levi 4538 Willis, Scooter 5565, 5583 Willman, Cheryl L. 7028 Wilmink, Johanna e15103 Wilner, Keith D. 8032 Wilson, Beverley 10029 Wilson, Carmen L. 10062 Wilson, Carolyn F. 9502 Wilson, Claire 7532 Wilson, David O. 7577 Wilson, Dawn TPS4595, TPS6098 Wilson, Don 7551 Wilson, John e14535 Wilson, Karen M. e12000 Wilson, Karla 10020 Wilson, Kate TPS3649 Wilson, Kathryn M. 5078, 5086 Wilson, Melissa 9017, 9088 Wilson, Michelle 1081, 5536 Wilson, Peter M. D. 3557, 4110, 4111, e14538, e14543, e15022 Wilson, Peter 4535 Wilson, Richard H. 2586, TPS3645 Wilson, Timothy G. e15522 Wilson, Timothy 11003 Wilson, William R. 7074 Wilson, Wyndham Hopkins 8524 Wiltshire, Robin 10547 Wimberger, Pauline 3078, LBA5503, 5531, 5556, 5575, e16547 Winder, Lewis 6078 Windham, Justin P. 8115, 9100 Winell, Jeremy e20701 Winer, Eric P. 500, 501, 513, 515, 529, 616, 630, TPS664, 1007, 1032, 1065, 1100, TPS1134, 6507, 9581, e17574, e20508 Winer, Joel e17597 Winer-Jones, Jessamine 580, 11040 Winfree, Katherine B. e20629 Wing, Claudia e13541 Winger, Dan 4103 Winick, Naomi Joan 10001, 10002 Winkler, Frank 2059 Winn, Daniel 6553, 6629, e17579, e17581, e17582 Winquist, Eric 1605, 5042, 6041, 11016, e12549, e16082, e16088 Winslow, John William 604 Winter, Des C. 3549

Winter, Jane N. 8576 Winter, Kathryn A. 5588 Winterbotham, Melanie 9590 Winterbottom, Linda e20588 Winterhalder, Ralph C. 3503 Winterhoff, Boris 5510 Winters, Paul 9586 Wirsching, Hans-Georg 2081 Wirth, Gregory J. e15619 Wirth, Lori J. 6000, 6023, 6025, 6029, 6051, TPS6098, e18512 Wirths, Stefan 7019, 10562 Wirtz, Ralph M 582, 615 Wischnewsky, Manfred 1096 Wise, Paul e17504 Wisinski, Kari Braun 2607, e17025 Wislez, Marie 7505, e19036, e19056, e19058 Wisniewski, Michal 604 Wisniewski, William 1546 Wisnivesky, Juan P. 7533, 7543, e16551 Wison III, David M. 1016 Wissel, Paul Stephen 2031, 2536 Wistuba, Ignacio Ivan 2601, 6011, 7527, 7552, 8019, 8079, 8085, 8102, 8104, TPS8118, e19057 Withers, Laura 9611 Witkamp, Frederika E. e20515 Witt, Donald James e22142 Wittenberg, Michael 4030 Witteveen, Petronella 2536 Wittig, Burghardt 3643 Witzens-Harig, Mathias 8566 Witzig, Thomas E. 8504, 8522, 8533, 8534 Wizemann, Monika 2534 Wiznia, Lauren e20017 Wizorek, Joseph J. 7577 Wo, Jennifer Yon-Li 4047 Woehrmann, Bernhard 4035 Woelber, Linn Lena 5531, e16535 Woell, Ewald e15041 Woerns, Marcus A. e15088 Woerth, Florence 9511 Wogu, Adane Fekadu 6503, 6534 Wohl, Hope e20712 Wolanski, Andrew TPS2627 Wolanskyj, Alexandra P. 7064 Wolchok, Jedd D. 3003^, TPS3107, TPS3110, TPS3114, TPS3120, CRA9003, 9009, 9012^, 9024, 9049, 9052, 9053, 9059, 9060 Wolden, Suzanne L. 6034, 10012 Wolf, Andreas 3048, 3051, 7020 Wolf, Bradley Aaron 7569 Wolf, Brigitte e14537 Wolf, Gregory T. 9607 Wolf, Ido 9630, e11578, e17536 Wolf, Juergen 1589, 8010, 8112, e12517 Wolf, Martin TPS7609 Wolf, Robert C. 2058 Wolfe, Joanne 9526 Wolff, Antonio C. 515, 1052, 9515, 11019 Wolff, Kerstin 3561 Wolff, Robert A. 1051, 2545, 4133, 4134, 9544, 11086, e13534, e13575, e13591, e22086 ABSTRACT AUTHOR INDEX

797s

Wolff, Steven N. e20523 Wolfgang, Christopher Lee 4039, 4057, e15028 Wolfson, Julie Anna 6537, 9575 Wolfson, Michael 6550 Wolin, Edward M. 4031, e13572, e15004, e15126 Wolmark, Norman TPS666, 1000, TPS1139 Woloschak, Gayle 3083, e22204 Wolpin, Brian M. 4090 Woltering, Eugene 4141, e15139 Wolters, Regine 1096 Womack, Chris 8045 Won, Helen H. 7593, 7600, 8022 Won, Jong-Ho 11030, e22199 Won, Minhee 1, 2003, 2004, LBA2010, 2033, 2047 Wondergem, Marielle 8556 Wong, Andrea Li Ann e14507 Wong, Audrey 6585, e17526 Wong, Chihunt e22183 Wong, Eric 2080, 2082 Wong, Florence Lennie 9575 Wong, Han Hsi e21503 Wong, Harvey 2503 Wong, Hilda 4117 Wong, Hui-li 3584, 3598, 11015, e14583, e14608, e14640 Wong, Jason 3578 Wong, Joyce 4117 Wong, Julia S. 1133 Wong, Karmen 6063 Wong, Kenneth 2049 Wong, Kit Man 1579 Wong, Lilly 2606, 8522, e15004 Wong, Linda 9542 Wong, Lucas 3600, 4054 Wong, Mabel 3062 Wong, Michael K.K. e15500, e15504 Wong, Nan Soon 2588 Wong, Nicole 4081 Wong, Ralph 3528 Wong, Rebecca TPS3647, 4077, 9502 Wong, Sandra L. 6637, 10524 Wong, Serena Tsan-Lai 1091, 2582 Wong, Shu Fen 3584 Wong, Steven e16052 Wong, Stuart J. 6022 Wong, Susan 2071 Wong, Terence e22166 Wong, Tracy S. 5039 Wong, Vivien e16047 Wong, Winnifred M. e12030 Wong, Winston 6553, 6629, e17579, e17581, e17582 Wong, Yu-Ning 4524, 4525, 6500, e15559 Woo, Hyun Young 4122^ Woo, Jung Hee TPS3105^ Woo, Mi-Young e15051 Woo, Sang Myung 4045 Woo, Sook Young 1088 Wood, Benjamin J. 6035, 6061 Wood, Bradford J. 10013 Wood, Brent L. 10001 Wood, Christopher G. 4516 Wood, Douglas E. 7546 Wood, John 2018 798s

Wood, Katie 2507, 5020 Wood, Laura D. 4057 Wood, Laura S. 4515, e15534 Wood, Lori 4565, 4578, 4586, 5048, e15518 Wood, Lynne e20700 Wood, Marie E. TPS1608, e12000 Wood, Marie 1512 Wood, Patricia Ann TPS7132, 11082 Wood, Penelope J. e16044 Wood, Peter 8537, 8565 Wood, Sarah TPS4146 Wood, Steve e17502 Wood, Tina Evans 4058^ Wood, Wendy 3504 Wood, William Allen 7119 Woodcroft, Kimberley J. e16035 Woode-Amissah, Ruth e16000 Woodley, Laura 635 Woodman, Richard John 9585 Woodman, Scott e20036 Woods, Corinne e14524 Woods, Kevin E. e14618 Woods, Ryan 1585, 3569, 3590, 9577 Woodworth, Davis C. 2055 Wooldridge, James E 8093 Wooten, Michael e14576 Worden, Francis P. 6022 Worden, Francis 9607 Worden, Rebekah 8036, e13568 Wormanns, Dag e18508 Worsfold, Andrew e16046 Wotherspoon, Andrew 4020, e14616, e19543 Woulfe, Bernie 1591 Woyach, Jennifer Ann 7014, 7077 Wozniak, Agnieszka 10573, e13528 Wozniak, Antoinette J. 2524, 7561, 11109, e13030, e19009 Wray, Lynette 11054 Wrba, Friedrich 2040 Wrba, Fritz e14537 Wright, Alexi A. 9523 Wright, Cara Elizabeth 11083 Wright, Casey 7586 Wright, Frances Catriona 1002, 1018, 9571 Wright, Jason Dennis 6505, 6509 Wright, John Joseph 1118, TPS4589, TPS5095, TPS5102, 11103, e16017 Wright, Paul e22126 Wright, Quentin G. e13523 Wroblewski, Kristen 1506, 9528, 11084 Wroblewski, Mark 7027 Wroclawski, Marcelo L. e16030, e16058 Wrona, Ania 7514 Wu, Abraham Jing-Ching 3605 Wu, Albert W. 6519 Wu, Benjamin 3048, 3051 Wu, Bin 2012 Wu, Bing 2538 Wu, Bingcao e18543 Wu, Charlotte e17519 Wu, Chengyu e22014, e22209, e22210 Wu, Christina Sing-Ying 1556, 4014, e14535


Wu, Chunjing Wu, Eric Q.

e22062 642, 7093, 10545, e11603, e21514, e21515 Wu, Eric 9570 Wu, Fei 8547 Wu, Frank S. 8029, 9020 Wu, Grant 11044 Wu, Hanmo e18520, e18531 Wu, Helen Y. e22092 Wu, Hong 10555 Wu, Hong-Gyun 1590, e18555 Wu, Jackson S. Y. 9502 Wu, Jasmanda e14656 Wu, Jennifer J. 2606 Wu, Jenny 3001 Wu, Ji-xiang e15181 Wu, Jiamin e15029 Wu, Jie 4094 Wu, Justin TPS6097 Wu, Kehua 2570 Wu, Lin 8021, e22092 Wu, Lingying 5512 Wu, Meina 8101, e19061^, e19067, e19091, e19101, e19136, e19161 Wu, Qiang 5512 Wu, Shaoyuan 4094 Wu, Shengjie 10034 Wu, Shenhong 9622, e13571, e13573, e14713, e15578, e20602, e20611 Wu, Tsung-Teh 4026, 4071 Wu, Wenting 2046 Wu, William 1525 Wu, Xiang-Yuan 538, 4131, e15021, e16077, e19504 Wu, Xiao-Cheng 6606, e12501, e17522 Wu, Xiaobin e22026 Wu, Xiaoling 2606, 8522, e15004 Wu, Xiaoxia 8097 Wu, Xifeng 1532, 4078 Wu, Yi Long 1547, 7537, 8016, 8021, 8042, 8061, TPS8123, e18547, e19042 Wu, Yin Ying e22096 Wu, Yongjie e14634 Wu, Yuehui 8027, 8028 Wu, Yun 1103, e12002 Wubbenhorst, Bradley 1510 Wudhikarn, Kitsada 8563 Wujcik, Debra e20523 Wun, Theodore 8049 Wyant, Tim TPS3646 Wyatt, Jeremy e20517 Wyczechowska, Dorota e13581 Wyen, Christoph 8524 Wykes, Richard e22175 Wylie, James LBA5000 Wyngaard, Peter 11017 Wynn, Nigel e22162 Wynne, Melissa 7559 Wynne, Rochelle e20536 Wysocki, Piotr Jan 604, e13560 Wysocki, Piotr e15045 Wyvill, Kathleen 10588, TPS10595 Wöckel, Achim 1074, 1096

X Xanthopoulos, Eric

5609

Xavier, Marcelo Antonio Pascoal e15199 Xenidis, Nikolaos e15063 Xi, Liqiang 7513, 8026 Xia, Bing 6635, 8041, 8076 Xia, Dengsheng e22191 Xia, Jin e22085 Xia, Wenle e13517 Xia, Zhongjun 7507 Xian, Shuang e13592 Xiang, Cunli 2073 Xiang, Jialing e14707 Xiangtao, Yan e19085 Xiao, Jian e14704 Xiao, Jie 5525 Xiao, Jing e16516 Xiao, Lianchun 4083, e15013, e15053, e15594, e15612 Xiao, Shaowen 10557, e15166 Xiao, Xuren e15547 Xiao, Ying 5588 Xiao, Yuanyuan 3001 Xie, Conghua e15125 Xie, Fei 1084, e12006 Xie, Li-Qun 1588 Xie, Ling e22026 Xie, Mian e15567 Xie, Shang-Nao e12557, e22050 Xie, Sharon 9639 Xie, Xiaodong e15582 Xie, Xiaoqi 2553 Xie, Xing 5512, 5535 Xie, Yang 8088^ Ximenez de Embun, M. Pilar 9641 Xing, Jinliang 1532 Xing, Yan 6087 Xiong, Hao 2584^ Xiong, Jian ping 6026 Xiong, Shigang 5062, e16020 Xiong, Youxin e15545 Xiros, Nikolaos e12524 Xiu, Bing 8538 Xiu, Joanne 2041 Xiu, Qingyu 7507 Xiying, Shao e11589, e12557 Xu, Binghe 505, 628, 1064, 1087, 2614 Xu, Chong-Rui 8042 Xu, Chun-fang 4519, 4569 Xu, Enping 4078 Xu, Fangping e18547 Xu, Haiyan e18520 Xu, Jian 2507 Xu, Jian-Ming LBA4001, 4025, 4109, 10503, 10551 Xu, Jianhua 2543 Xu, Jianmin 3610, e14523 Xu, Jianming e14644 Xu, Lei 2056 Xu, Li 1567 Xu, Lian TPS8620 Xu, Liang Guo 8024 Xu, Lin 1547 Xu, Lu 2540 Xu, Peng 4012 Xu, Qinghua 8547 Xu, Qunli e13523, e18541 Xu, Ren 1588 Xu, Rui-Hua 4025, 4107, 4109, e15047

Xu, Shanlin e18533 Xu, Shen-Hua e22050 Xu, Shuichan 2606, 8522 Xu, Shun 1547 Xu, Ting 7521 Xu, Tong 11040 Xu, Wayne 10561 Xu, Wei 1579, 4077, 6543, 9017, 9088, 9536, 9551, 9595, 11057 Xu, Xiao wei 9017 Xu, Xiaolei 2071 Xu, Xing 1554 Xu, Yang e22103, e22133 Xu, Yi 2012 Xu, Yong e15125 Xu, Yucheng 11040 Xu, Zhaolin 8096 Xu, Zhi 4106, 10544 Xue, Xiaonan 8524 Xue, Yuwen 7552 Xue, Zhengyu 4519, 4569 Xyrafas, Alexandros 7503 Yılmaz, Ufuk e18540

Y Y, Rangal 1125 Yabar, Alejandro e20023 Yablon, Corrie TPS5094 Yabroff, K. Robin 6521, 6522, 6604 Yabusaki, Hiroshi 4104 Yabuuchi, Shinichi 4063 Yadala, Nalini e15120 Yadav, Manisha 1508 Yadav, Prashant e11546 Yadav, Rajesh R. e20626 Yadav, Ruchi e19012 Yadav, Sunil 3580 Yadav, Swetha Siddappa e15548, e15552 Yaegashi, Nobuo 5593 Yaffe, Martin 1507 Yagata, Hiroshi 1126, e11524, e20683 Yagerman, Sarah 9018 Yagi, Hiroshi e15579 Yagi, Nobutaka 8056, e19165 Yaginuma, Hiroshi e19162 Yagishita, Shigehiro 7540 Yaguchi, Toyohisa e14552 Yajima, Yoko e13586 Yakirevich, Evgeny e14637 Yalcin, Bulent e15540 Yalcin, Ilker TPS1136 Yalcin, Selim e11532, e16526, e16528, e16536 Yalcin, Suayib 4009, 4576, e15168 Yalçintas Arslan, Ülkü e11559, e18510 Yamada, Hirohide e20717 Yamada, Junichi 3034 Yamada, Kazuhiko e19137 Yamada, Kouzo 7531, 11049, 11055 Yamada, Reiko E 3024 Yamada, Seiko Diane 9528 Yamada, Shigeru e15008 Yamada, Takanobu e15112 Yamada, Takashi 8038, e20658 Yamada, Tesshi e15080

Yamada, Yasuhide 3519, 3559, 4096, e13504, e13511 Yamada, Yoshiya 9501 Yamada, Yuko e22082 Yamadori, Tadahiro e19021 Yamaga, Iku e22116 Yamagami, Kazuhiko 613, 1029 Yamagami, Wataru 5590 Yamaguchi, Hironori e15027 Yamaguchi, Nise Hitomi e13562, e22176 Yamaguchi, Norihiro 8050 Yamaguchi, Satoshi 5528 Yamaguchi, Takashi e14555 Yamaguchi, Takuhiro TPS654, 1111, 6588, e12541, e14597, e15570 Yamaguchi, Tsuyoshi 4092, e12014 Yamaguchi, Yuri e22019 Yamai, Takuo e15150 Yamamoto, Chizuko 1111 Yamamoto, Daigo 1111 Yamamoto, Harukaze e20557 Yamamoto, Hayato e15565 Yamamoto, Hideyuki e19521 Yamamoto, Hiroshi 4092, e12014 Yamamoto, Kaichiro 11049 Yamamoto, Kazuhide 3071 Yamamoto, Kazuhito 8506 Yamamoto, Naohito 613 Yamamoto, Natsuyo e15146 Yamamoto, Noboru 7540, 8064, e13504, e13511 Yamamoto, Nobuyuki 7518, 7556, 7572, 7582, 7599, 8033, 8105, 9621, e13500, e18556, e19050, e19074, e20576 Yamamoto, Noriko 4108 Yamamoto, Satomi e18530 Yamamoto, Suguru e19010^ Yamamoto, Yoshifumi 6082 Yamamoto, Yutaka 571, TPS654 Yamamura, Roseli e20640 Yamamura, Yoshitaka 4088 Yaman, Melek e12036 Yaman, Sebnem e20614 Yamanaka, Hidetoshi e16090 Yamanaka, Takeharu 4075, 7518, 7529, 7583, 9621, e15031, e22082 Yamaoka, Toshimitsu e19164 Yamashiro, Hiroyasu 613 Yamashita, Hiroko 571, 614 Yamashita, Keishi 3556, e15113, e15122 Yamashita, Mason 8523 Yamashita, Nami 1056 Yamauchi, Hideko 1106, 1126, 1534, 9629, e11524, e20510, e20590, e20683, e22064 Yamauchi, Teruo 9629 Yamazaki, Kentaro e14623 Yamazaki, Kosuke 613 Yamazaki, Naoya 9623 Yamazaki, Tomoko 4074, e13586 Yan, Andrew 6625 Yan, Fengxia e12573 Yan, Hong hong 7537, 8042 Yan, Houling 9567 Yan, Hui 6605 Yan, Pu 3526, 3577 Yan, Qiao Xie e20027

Yan, Su 3047 Yan, Zhen 4094 Yanagihara, Ronald H. e20518 Yanagisawa, Junn e22019 Yanagita, Yasuhiro 6588 Yanagitani, Noriko e13504 Yanase, Kumiko 7048 Yang, Annie e22183 Yang, Arvin TPS9105^ Yang, Chih-Hsin 8055 Yang, Daniel X. 1522 Yang, Daniel 2029 Yang, Deqi 1084, e12006 Yang, Donghua 6006, 6028 Yang, Dongyun 2501, 3527, 3565, 3566, 3567, 3568, 4110, 4111, 4128, 11062, e14538, e14543, e14714, e15009, e15022, e16073, e17559 Yang, Eddy Shih-Hsin 623 Yang, Fei e13588 Yang, Guang TPS8620 Yang, Guohua e22186 Yang, Haiyan e15062, e19073 Yang, Hong e15135 Yang, Hongjian e12557, e22050 Yang, Houpu 1084, e12006 Yang, Hwai-I 1600 Yang, Hye-Ryung 4045 Yang, James Chih-Hsin e19132 Yang, Jia e18533 Yang, Jiandong 10024 Yang, Jianning 7018, 8520 Yang, Jie 7537 Yang, Jinji 8015, 8042, e18547, e19042 Yang, Jun 2510 Yang, Kang 1547 Yang, Katherine e16019 Yang, Maolin 6080 Yang, Michael e18526 Yang, Muh-Hwa e13584 Yang, Nancy e22066 Yang, Pan-Chyr 8055 Yang, Ping 7545, 7568, 11119, e19013 Yang, Qifeng 5535 Yang, Qun-ying 2022, e13037 Yang, Shuyuan 2022 Yang, Sung Hyun LBA4024, 8521 Yang, Tsai-Shen e14501 Yang, Xiaoping e16055 Yang, Xin-Rong e22133 Yang, Xue-Ning 7537, e18547 Yang, Xuejun 2022 Yang, Xun 4094 Yang, Yaewon e18553 Yang, Yaping 10023 Yang, Ying 7077 Yang, Yiping 11074 Yang, Zhi Zhang 8538 YangKolodji, Gloria Wangrong 609, e13515 Yannaki, Evangelia 8567 Yano, Masahiko TPS4152 Yano, Michihiro 10038 Yano, Shuya e13576, e13577, e22014 Yao, Bin e12530 Yao, James C. 4036, 4142, 4143 Yao, Min 6035

Yao, Nengliang 6558, 7553 Yao, Song TPS9647 Yao, Xiaopan TPS1609, 4084 Yao, Yihong e20047 Yao, Yinan e22054 Yao, Yu 2022 Yao, Yuanquing 5512 Yap, Bonnie 6612, 9520 Yap, Timothy Anthony 2608, 3062 Yap, Yoon Sim 505, 524, 2588, 6589, 9506, e20566 Yapicioglu, Sena e18540 Yapur, Lorena e20007 Yaqubie, Amin 9060 Yarchoan, Robert 10588, TPS10595 Yardley, Denise Aysel 505, 523, 553, 557 Yared, Jean TPS648 Yarlagadda, Naveen e15604 Yarnold, John 5, 11116 Yaron, Yifah 6090 Yasar, Nurgul e11540, e15100, e19107 Yasdik, Hatice e12509 Yassin, Dina 10044 Yasuda, Kazumasa 8038, e20658 Yasuda, Shigeo e15008 Yasuda, Yuri e12532 Yasue, Tomomi e19021 Yasufuku, Kazuhiro 7516 Yasui, Hirofumi e13500, e14623 Yasui, Tomoyo e20676 Yasui, Toshimichi 6082 Yasui, Wataru 4068 Yasui, Yutaka 10004, 10032 Yasumizu, Yota e16094 Yasuno, Shinji 613 Yaszemski, Michael J. 10531 Yatabe, Yasushi 8096, e12001, e22042 Yatawara, Mahendra e17507 Yates, Patsy 9516, e20615 Yau, Cindy Y. F. 2505 Yau, T. K. 4117 Yau, Thomas Cheung 4117, e14501 Yau, Thomas 4125 Yavuz, Basak e19512 Yavuz, Ekrem e11534 Yavuz, Gulsan 10068 Yazar, Aziz e11539 Yazawa, Takashi 3063 Yazbeck, Victor Y. e13587 Yazici, Omer Kamil e18546 Yazici, Ozan e11559, e15191, e20614 Yazilitas, Dogan e11559, e14662 Ychou, Marc 3514, 3542, 3636, 3637, 4028 Ye, Allison Y. e20589 Ye, Ding-Wei e15622 Ye, Gang e15547 Ye, Hong 6577, e16008 Ye, Hua 4106, 10544 Ye, Le-chi 3610 Ye, Linyang e15547 Ye, Ming e15030 Ye, Sheng-Long 4126 Ye, Wei 2564 Ye, Wei-Wu 7590, e11589, e12557 Ye, Weilan e14505 Ye, Xiangyang e16091 ABSTRACT AUTHOR INDEX

799s

Ye, Xiangyun Ye, Xiaobu

e19014 2034, 2044, 2054, 2065, TPS2105, 6068 Ye, Xun 8547 Ye, Yang 2545, e22086 Ye, Yining LBA9008 Ye, Yuanqing 1532 Ye, Zhenqing 7573 Yeap, Beow Y. 4047, 8069, 8083, 10018 Yeap, Shang Heng 543 Yeatman, Timothy Joseph 3644 Yedwab, Erik 6515, e17565 Yee, Grace Pei Chien e22005 Yee, Jasmine e20584 Yee, Karen W. L. 7078 Yegen, Gulcin e11534 Yeh, Eren 1065, 1105 Yeh, Kun-Huei 3554, 4099, e13554, e14501, e15127, e19523 Yeh, Su-Peng 6052 Yeh, Yi-Chun 3554, e15043 Yehia, Lamis 1527 Yelensky, Roman 534, 1009, 1051, 8020, 9002, 11000, 11020, 11100, e15035, e22146 Yellapa, Aparna 5579 Yelle, Louise 1049^, 1050^, 1055^ Yemma, Michael e22143 Yen, Aihua Edward e16043 Yen, Chueh-Chuan 4099 Yen, Katharine 4125 Yen, Ming-Shyen 5512 Yen, Thomas Y 9635 Yen, Yun 3089 Yendamuri, Saikrishna S. 4067 Yengkhom, Indibor singh e17029 Yennurajalingam, Sriram 9642, TPS9650, e20528, e20581 Yeo, Charles e15183 Yeo, Hyun Yang e14606 Yeo, Winnie e15048 Yepes, Andres e12571 Yerby, Brittany 11095 Yerganian, Scott B. 2530 Yerushalmi, Rinat 639, 1585 Yesil, Atakan e22061 Yesilipek, Akif 10067 Yeung, Choh L 10025, 10040 Yeung, Isis Ching e11574 Yeung, Ivan 4049 Yi, Eunhee S. 11119 Yi, Feng e14505 Yi, Min 1103 Yi, Nengjun 1548, e15049 Yildirim, Selman e18521 Yildiz, Ferah e15168, e16526, e16528, e16536 Yildiz, Ibrahim e11592, e14594, e15569, e20016 Yildiz, Levent e19500 Yildiz, Ramazan e14705 Yilmaz, Bahiddin e11506, e14697 Yilmaz, Gulden e18009 Yilmaz, Merve e20503 Yilmaz, Mette K. N. 4052, e15099 Yilmaz, Ugur e11559 Yim, Barbara e17593 Yim, Ga Won 5557 Yim, John H. e17542

Yin, Donghua Yin, Gang Yin, Hui Yin, Jing Yin, Lihong Yin, Ray Yin, Rutie Ying, Anita Ying, Kejing Yip, Desmond

612 e16520 1518 4017 11091, e22032 e13538 5512 e17016 e19161 3528, e14583, e14640 Yip, Po Yee e18500 Yip, Sonia TPS4157 Yip, Stephen e22020 Yip, Vincent S. 4132 Ylstra, Bauke 3552 Yock, Torunn I. 10018, e17553 Yoh, Kiyotaka 7512, 7557, 8056, 8058, 8078, 11031, e19076 Yokoi, Kohei 7583 Yokom, Daniel William e15591 Yokomise, Hiroyasu e18503, e22108 Yokomizo, Yumiko e16098 Yokomura, Koshi 8038, e20658 Yokoo, Hideki e15038 Yokota, Isao e20609 Yokota, Souichirou e20609 Yokota, Tomoya 4074, e14623 Yokoyama, Hiroyuki e14552 Yokoyama, Takuma 11049 Yokoyama, Taro e20609 Yokoyama, Yukihiro 4119 Yom, Cha Kyong e22063 Yomoda, Makiko e18524 Yomoda, Satoshi 2559 Yomota, Makiko e19133 Yonan, Yousif e18552 Yoneda, Kazue e18557 Yoneda, Taro e19083 Yonekawa, Hiroyuki e17006 Yonemori, Kan e20557 Yonesaka, Kimio e20682 Yoneyama, Kimiyasu 1113 Yoneyama, Takahiro e15565 Yoneyama, Tohru e15565 Yong, Candice e16027 Yong, Ma Zhi 1588, e19085 Yong, Wei Sean 6589, 9506, e20566 Yong, Yvonne Fong Ling 1535 Yoo, Bongin 523 Yoo, Changhoon LBA10502, e15026 Yoo, George H. e17033 Yoo, Sun Mi 5056 Yoo, Young Hoon e12005 Yook, Jeong Hwan 10550, e15091 Yoon, Dok Hyun e15051 Yoon, Hannah 2083 Yoon, Harry H. 2562, 4026, 4071 Yoon, Hong Man 4105, e15056 Yoon, Hyungeun e18530 Yoon, Ki Tae 4122^ Yoon, Ki Young 4105 Yoon, Sam S. 10520 Yoon, Seung Kew 4126 Yoon, Shinkyo e15091 Yoon, Sung Jin e19019 Yoon, Yong Sik 3628 Yordanova, Roumyana 9055


Yorio, Jeffrey Thomas 9096 York, Sergernne 7092 Yorozu, Atsunori e16090 Yoshida, Atsushi 1106, 1116, 1126, e11524, e20683 Yoshida, Chikako 5552 Yoshida, Hiroyuki e20676 Yoshida, Kazuhiro 3519, LBA4002, 4096, e14527, e20576 Yoshida, Kazuo 7548 Yoshida, Koji 3006 Yoshida, Masahiro e19054 Yoshida, Motoki 3518, 3519, e14527, e14551, e14601 Yoshida, Sei e13529 Yoshida, Shinichiro 8506 Yoshida, Takashi 8601 Yoshida, Tatsuya 8078 Yoshida, Tsukasa e19134 Yoshida, Yoshio e16502 Yoshidaya, Fumi 1126 Yoshidome, Hiroyuki 4056 Yoshihama, Tomoko 5590 Yoshikawa, Kozo e14572 Yoshikawa, Takaki 4068, 4102, 4104, e15112 Yoshikawa, Yukinobu 4008 Yoshimatsu, Kazuhiko 3006 Yoshimi, Michihiro 8006 Yoshimoto, Naoki e19053 Yoshimoto, Nobuyasu 614 Yoshimura, Masahiro 7518 Yoshimura, Naruo 7564, e19053 Yoshinami, Tetsuhiro e14551 Yoshino, Ichiro 7518 Yoshino, Kiyoshi 5538 Yoshino, Kunitoshi 6004 Yoshino, Shigefumi 3006, LBA4002 Yoshino, Takayuki 3514, 3636, 3637, 4075, e13500, e13510, e14527, e22082 Yoshioka, Hiroshige 7518, 8033, 11041, e19017, e19023, e19040, e19167 Yoshitomi, Hideyuki 4056 Yoshiya, Tomoharu e18563 Yoshizawa, Akitaka e20591 Yosuke, Fujii 11031 Yothers, Greg 3618 You, Benoit TPS2625, 5547, e13594, e16050, e19515 You, Changxuan e19161 You, Chao 2022 You, Y. Nancy 1525, 1546 Youn, Trisha 1105 Younan, Rami 1018 Younes, Anas 7070, 8502, 8518, 8523, 8535, TPS8612, e12554 Young, Alicia 3594 Young, Anna-Mary 2608, 3062 Young, Brandon Michael 5583 Young, Geneva 11100 Young, George David e22187 Young, Ken H 8561 Young, Robert H e16518 Young, Robyn R. 553, 1068 Young, Rosemary 4081, e15188^ Young, Sabrina 10039 Young, Teresa 9590 Younger, Anne 2502, 2529

Younger, W. Jerry Youngren, Jack Younis, Tallal Younos, Ibrahim Yount, Susan Yousaf, Nadia Yousif, Nasser Ghaly Youssef, Ramy F. Youssoufian, Hagop Yovine, Alejandro Javier

513 5006 e17564 9056^ e20527 10569 e15092 4581 3022 TPS651, TPS5616 Ysebeart, Loic TPS7131 Yu, Ami 4045 Yu, Bennett Winston e20512 Yu, Bin 9011, 9056^ Yu, Bo e22026 Yu, Celeste 11002 Yu, Chang Sik 3628, 10550 Yu, Changhong e16004 Yu, Chi-Chia e13585 Yu, Chong-Jen 8021, 8055, e19041^ Yu, Elaine e14585 Yu, Evan Y. 4525, 5003 Yu, Haifeng e15062, e19073 Yu, Hao 6026 Yu, Helena Alexandra 7593, 8018, 8025 Yu, Hua 3631 Yu, Huixin 4580 Yu, Irene S. 9624 Yu, James B. 1522, 6511, 6549 Yu, Jason 3590 Yu, Jei-Hwa e13011 Yu, Jiang 2555, 8514 Yu, Jing 4097 Yu, Jinming e13052, e15030, e15167, e15180, e15197, e18533, e18551, e19011 Yu, Joanne Linda e17523 Yu, Jong Han 1070, e11512 Yu, Kenneth H. 4017, TPS4144 Yu, Lanfang e22094 Yu, Lei e15181, e18519 Yu, Li 8525 Yu, Margaret K. TPS5097 Yu, Ming-Chih e19029, e19030 Yu, Ming-Sun 4018 Yu, Minshu 2514 Yu, Ping e19004 Yu, Ren 7086 Yu, Ron 2503, TPS4150, e14505 Yu, Shi Ying e20580, e20695 Yu, Shi-ying 4025 Yu, Shiying 4109 Yu, Shufei e18504 Yu, Simon e15048 Yu, Steven e17559 Yu, Sung-Liang e22067 Yu, Tiffany 3640 Yu, Tony 3098 Yu, Wansik 4105 Yu, Xin 8510, 8527, 8528 Yu, Xiyong e19042 Yu, Yiting 7125 Yu, Yongfeng e19014 Yu, Yuefei 7060, 8591, e18527, e22003, e22052 Yu, Zhinuan 8544, 8583 Yuan, Constance e19506 Yuan, Jianda 3003^, TPS3120, 9052

Yuan, Jianlin Yuan, Lin Yuan, Ma Dai Yuan, Peng Yuan, Ying Yuankai, Shi Yuasa, Takeshi

e15547 8547 e15125 2614 2063 8087, 8092 4565, 4578, 4586, e15518 Yuce, Deniz e15168 Yucel, Idris e11506, e14697 Yue, Huibin 9037 Yue, Jinbo e18533, e19011 Yue, Lili e13038 Yuen, Geoffrey 2602 Yuh, Bertram E. e15522 Yuh, Young Jin 8521 Yuki, Satoshi 3638, 4075, 4076, e14604 Yukinori, Ozaki e14670 Yuksel, Sinemis e11540, e14662, e15100 Yumuk, Perran Fulden e14660, e20503 Yun Peng, Liu 4025 Yun, Fan e15062, e19073 Yun, Hwan Jung 9633 Yun, Jina 11030, e22199 Yun, Lingsong 6535, 6628 Yunes, Jose A 10536 Yung, W. K. Alfred 2015, 2019^, 2042, TPS2106, e13039 Yunokawa, Mayu e20557 Yunus, Furhan 1068 Yust-Katz, Shlomit 2063 Yusuf, Rafeek Adeyemi 6566, 9576

Z Zaanan, Aziz 3536, 3585 Zaatar, Adel e14501 Zabicki Calvillo, Katherina 1117, 1133 Zabor, Emily C. 9049 Zabotina, Tatiana e20042 Zacchia, Alessandra e11526, e11527 Zach, Leor e13002 Zacharchuk, Charles M. 612 Zafar, Yousuf 6506, 6516, 6551, 6578, 9560, e17562 Zafarana, Elena 11058 Zafeiriou, Zafeiris e14639 Zafferri, Valeria 6593 Zafman, Kelly 519 Zafra, Marta 3042 Zagaja, Gregory e16084 Zagar, Timothy 1069 Zage, Peter 10041 Zagonel, Vittorina 2028, 2043, 3505, 3563, TPS3648, 5548, 6593, e11573, e14574, e15606 Zagzag, David e13033 Zahid, Khawaja Farhan e22099 Zahir, Muhammad Nauman e14680 Zahm, Dirk Michael 1004 Zai, Silvia e14657 Zaid, Tarrik M. 5580, 5584 Zaino, Richard J. e16518 Zaiss, Matthias R. TPS4591 Zaizen, Yoshiaki e19137 Zajac-Kaye, Maria e13547, e13556

Zakalik, Dana 1541, 1557 Zakharia, Yousef 7105 Zakharova, Tatiana e15583, e15585 Zaki, Mohamed H. 8510, 8527, 8528, 8532, 8583, 8584, 8585^, 8588 Zakikhani, Mahvash e14615 Zakin, Lorraine B. e20654 Zakowski, Maureen Frances 7593, 7600 Zalcberg, John Raymond 3520, 3528, 3531, 4000, 10500, e14624 Zalcman, Gerard 7505, 7515, 8000, 8027, 8081, e19056 Zalewski, Christopher 2554 Zalewski, Pawel TPS4594 Zalles, Carola Maria 1515 Zalupski, Mark M. 10524 Zamani, Ayse Gul e18521 Zamarchi, Rita e22036 Zambetti, Milvia 503, 537, 1014 Zamora, Ivonne 9541 Zamora, Pilar 608 Zampino, M. Giulia e14560, e22078 Zanardi, Alessandra e13579 Zanation, Adam M. 6070, TPS6097 Zanatta Sarian, Luis Otavio e20634 Zanconati, Fabrizio 546 Zander, Dani e18552 Zander, Thomas 1589, e12517 Zandstra, Frances Ann e20645 Zanellato, Rebecca Melo e20631 Zanelotti, Arnaldo 1061 Zanesco, Tatiana e15155 Zanetta, Sylvie e11529 Zang, Dae Young 4013, LBA4024, e17026 Zang, Richard e13590 Zang, Rongyu LBA5503, 5512 Zanghì, Mariangela 1062 Zaniboni, Alberto 3505 Zaninelli, Marta e13514 Zanirato, Sonia e20647 Zannella, Vanessa E. 5070 Zanon, Carlo 11005 Zanoni, Michele 11022 Zanotti, Laura 5560 Zanovello, Paola e22036 Zanzonico, Pat 3033, TPS3115 Zaorsky, Nicholas George e17577 Zapata, Adriana e13581 Zapata-Tarres, Marta 10056, 10058, 10059 Zapatka, Marc 7014 Zarba, Juan Jose e11538 Zardavas, Dimitrios 528, 575 Zarei, Khosrow e20544 Zaric, Bojan CRA8007, TPS8126 Zaric, Gregory S. 1605, e12549 Zarkar, Anjali M. e16048 Zarkua, Varlam e15194 Zarour, Hassane M. 9009 Zastrow, Leonhard e20688, e20689 Zatarain, Lauren Azure 6049, e20531 Zattoni, Filiberto e15606 Zauderer, Marjorie Glass 6508, 7570

Zaun, Silke Zaveleva, Elina Zawadi, Ayman Zawistowki, Jon Zazo, Sandra

e19060 e22162 3542 512 11089, e19000, e19109 Zazulina, Victoria 8016, 8061 Zbuk, Kevin M. e20522 Zdzienicki, Marcin 10564 Zee, Benny C. Y. 6015 Zee, Ying Kiat e14507 Zegarac, Milan e14676, e20002 Zeger, Gary 3527, 11062 Zeghibe, Catherine A. e17574 Zeh, Herbert 4038, 4040^ Zehir, Ahmet 3101 Zeichner, Simon B. 6548, e11575 Zeidan, Amer 7126, e17584 Zeillemaker, Anneke 595 Zeillinger, Robert 5575, e16524 Zeimet, Alain G. 5569, e16524 Zeissig, Gisela e15096 Zeitzer, Jamie M. 9504, 9532 Zekri, Abdel-Rahman 4537 Zekri, Jamal M. 9568, e20613 Zekri, Jamal e19035 Zelcer, Shayna M. 10029 Zeldenrust, Steven R. 8516, 8541, 8600, 8606 Zelek, Laurent H. 1583 Zelenetz, Andrew David 7005, e17570 Zeliadt, Steven B. 7546 Zelig, A. e22069 Zelinsky, Kathy 5004 Zell, Jason A. 3578, e12528, e14529 Zelnak, Amelia Bruce 562, e11582 Zemanova, Milada e15581 Zembutsu, Hitoshi 11053 Zenali, Maryam e22177 Zenda, Sadamoto 4074, e13586 Zender, Chad 6035 Zeng, Hui 10003 Zengel, Baha e12018 Zenger Hain, Julie 1557 Zengin, Nurullah e15175, e15191, e18510, e20614 Zepeda, Kristopher 7060, 8591, e18527, e22003, e22052 Zer, Cindy 3081 Zerbib, Robert Albert TPS3117^ Zerutoc, Chris 6604 Zeuli, Massimo e22206 Zevon, Michael 1566, 1603 Zeyher, Claus 8084 Zeynalova, Samira 8566, 8570, e15096 Zgurova, Nedyalka e14669 Zhai, Yongliang 7551, e19039 Zhan, Min-Ning 1588 Zhang, Baohui 9519, e20606 Zhang, Bifeng 11035 Zhang, Bin 605 Zhang, Bing 3555 Zhang, Chaohua e19097 Zhang, Danjie 5051 Zhang, Dongqing e22169 Zhang, Guantao 9091 Zhang, Guo-Qiang 6538 Zhang, Guojing e14612

Zhang, He-long 4025 Zhang, Helong 7507 Zhang, Honghong e14707 Zhang, Hui 10034 Zhang, J e14689, e19122 Zhang, Jian 1064 Zhang, Jianan 2057 Zhang, Jianjun 6087 Zhang, Jianmin 2022 Zhang, Jiaqing 1084 Zhang, Jie 553, e11602, e17520, e22137 Zhang, Jing CRA1501 Zhang, Jingdong e15160 Zhang, Jingsong 4541 Zhang, Jingyu 2097, e22085 Zhang, Jiping e22163 Zhang, Joshua 8031 Zhang, Julie e13529 Zhang, Jun 1023 Zhang, Kathy e12530 Zhang, Keqin e15547 Zhang, Lan e22081 Zhang, Lei 8533, 8534, e19098, e22014, e22209, e22210 Zhang, Li 6026, 7507, 8015, 8042, 8089, e19161 Zhang, Liang 7519 Zhang, Ling 11059, e13564 Zhang, Linna 10041 Zhang, Liwei 2022 Zhang, Liying 6639, e16070 Zhang, Mengping 8503, 8508, 8573 Zhang, Nan 5029 Zhang, Ning 6630 Zhang, Paul J. 519 Zhang, Pengfei TPS4154, e14645 Zhang, Pin 2614 Zhang, Pingkuan 5512 Zhang, Qiang 6007, TPS6099 Zhang, Qifang 4571 Zhang, Qifu e15582 Zhang, Qin e15050 Zhang, Qing 5535 Zhang, Qingxiu e22177 Zhang, Qingyuan 1064 Zhang, Qiuying e14578 Zhang, Shanwen e15166, e22024 Zhang, Sheng Dong e15047 Zhang, Shenwen 10557 Zhang, Shizhen 4538 Zhang, Shucai e19161 Zhang, Song 1560 Zhang, Tian e22166 Zhang, Tinghua e14598 Zhang, Tong 11002, 11016 Zhang, Vivian 11026 Zhang, Wei 8088^, 11091, e22032 Zhang, Wei-Jing 8525 Zhang, Weijia 9091 Zhang, Weimin 8015 Zhang, Wen e14644 Zhang, Wenjun 5045 Zhang, Wenping (Wendy) TPS5099^ Zhang, William 5072 Zhang, Wu 3557, 3565, 3566, 3567, 3568, 4110, 4111, e14538, e14543, e14714, e15009, e15022 Zhang, Xia e22108 ABSTRACT AUTHOR INDEX

801s

Zhang, Xiang 2022 Zhang, Xianglan 4089 Zhang, Xiaodong 4097, e15174 Zhang, Xiaoli e15180, e15197 Zhang, Xiaoling 3016 Zhang, Xiaotian 4097, e15174 Zhang, Xu e15135, e15547 Zhang, Xuchao 1547, e18547 Zhang, Ya 1005 Zhang, Yan e14704 Zhang, Yi 594, e15006 Zhang, Yinghong 6631 Zhang, Yiping e19161 Zhang, Yong TPS651, e13576, e22011, e22012, e22013, e22209 Zhang, Yubei e13538 Zhang, Yue 7033 Zhang, Yuewei e15024 Zhang, Yufeng 6630, e15544, e15545, e15556 Zhang, Yumin 2520 Zhang, Zhen 5573 Zhang, Zhengdong 4106 Zhao, Binsheng 3635 Zhao, Fen e13052 Zhao, Fengmin e20520 Zhao, Hengjun 3031, e15198 Zhao, Hong 2510, 8015 Zhao, Hui 5558, e19044 Zhao, Huijun 8048 Zhao, Huiwu e22163 Zhao, Jun 8101, e19061^, e19091, e19101, e19136 Zhao, Lili 10524, 10584 Zhao, Ming e13576, e22011, e22012, e22013 Zhao, Mingfang 8042, e19004 Zhao, Peng e22192 Zhao, Qiang 11048, e15062 Zhao, Shan e13524 Zhao, Shanshan 5092 Zhao, Shushan 1604 Zhao, Song e22212 Zhao, Sumin e13517 Zhao, Wei 1586, e11611 Zhao, Weiqiang 6005, 7542 Zhao, Xie-Lan 8525 Zhao, Xiuhua 6047, 8001, 9011 Zhao, Yongjun e22020 Zhao, Yu e19080, e19081 Zhao, Yujie 2557 Zhao, Zhiguo 9019 Zhao, Zhihui 7050 Zhao, Zhongyun 9045, e20014 Zheng, Deyou e22009 Zheng, Di e19082, e22137 Zheng, Hao W. 10003 Zheng, Jianbiao 8601 Zheng, Lei 4057, 4063, e14647, e15028 Zheng, Li 8045 Zheng, Li-Mou e22066 Zheng, Ping TPS666 Zheng, Shusen e14530, e22192

Zheng, Weihui 4094 Zheng, Yi e22192 Zheng, Yonglan CRA1501 Zheng, Yulong e22192 Zheng, Zhendong e15582 Zheng, Zhiyuan e14524 Zheng, Zhong 8001 Zhengxue, Han e17000 Zhi, Jianguo 10514 Zhi, Xiaofei e13542 Zhi, Xin 4031 Zhong, Fengming 9567, e14625, e14661, e14681, e15561 Zhong, Haijun 4109 Zhong, Hua e19018 Zhong, Liz 8107 Zhong, Mei-zuo 4025 Zhong, Meizuo 1604 Zhong, Runbo e19018 Zhong, Wenzhao 7537, e18547 Zhong, Yunshi 3610, e14523 Zhou, Anwu e22192 Zhou, Bingsen e13538 Zhou, Bo 1084, e12006 Zhou, Caicun 8015, 8016, 8061, e19166, e22044, e22066, e22186 Zhou, Cathy e15014 Zhou, Eric 9529 Zhou, Fang-Jian e15622 Zhou, Fei e19166 Zhou, Jian 5525 Zhou, Jianying e22054 Zhou, Jun 4097, e15174 Zhou, Jun-tian 4025 Zhou, Karl TPS3128 Zhou, LF 2022 Zhou, Lin e19055 Zhou, Lingsha 7112 Zhou, Lixin 1084 Zhou, Ming-Ming 9091 Zhou, Nai-Kang 1547 Zhou, Qin 5545, 5550, 5595 Zhou, Qing 8042, e18547, e19042 Zhou, Xi Kathy 6048 Zhou, Xiao Hua 7546 Zhou, Xiaofei 2528, 2598 Zhou, Xinming 1547, 4094, e15062 Zhou, Yi TPS4154, e14645 Zhou, Ying e20514 Zhou, Youwen e20045 Zhu, Andrew X. 4047, 4125, e14636 Zhu, ChangQi 7517 Zhu, Dexiang 3610, e14523 Zhu, Fang 6006, 6028 Zhu, Guangying e15030 Zhu, Guili e15137 Zhu, Hui 4515, 4565, 8113 Zhu, Jianqing 5512 Zhu, Joy 4010, e15005 Zhu, Jun 8525 Zhu, Junjia 7039 Zhu, Meijun 10509, 10510 Zhu, Min 3048, 3051 Zhu, Pei e19135


Zhu, Peixuan Zhu, Shu chai Zhu, Wei Zhu, Xiang Zhu, Xiaofu Zhu, Xiaolei Zhu, Xinhua Zhu, Yanyan Zhu, Yuan Zhu, Yunzhong Zhu, Zhenggang Zhuang, Sen Hong

11046 e15030 e20047 e11590 e11574 e20602 e16057 5076 8553 7507 e22169 TPS8613^, TPS8614^ Zhuang, Yan 7521 Zhukovsky, Eugene 3068 Zhuo, Minglei 8101, e19061^, e19067, e19091, e19101, e19136 Zick, Aviad 1598, e21508 Zickafoose, Barbara 6561 Zidouh, Ahmed e20516 Ziebermayr, Reinhard 3643 Ziel, Kathryn e14564, e17570 Zielinski, Christoph 573, 611, 1040, 2040, 2059, 3053, TPS7608, e15535, e20693 Ziemendorff, Gabriele 11043 Ziemiecki, Ryan 553 Ziepert, Marita 8566, 8569 Zieren, Jurgen e16523 Ziesmer, Steven 8538 Zifchak, Larisa e17009 Zijlstra, Jose M 8556 Zilembo, Nicoletta 8035, e15589 Zilli, Thomas e15619 Zimet, Allan Solomon e18559 Zimmer, Lisa 11009 Zimmerman, Jacquelyn W. e15049 Zimmerman, Todd M. 8514 Zimmerman, Zachary Franklin e20048 Zimmermann, Andreas 6623 Zimmermann, Annamaria 8068 Zimmermann, Benedikt 4542 Zimmermann, Camilla 9518, e20639 Zimmermann, Martina 3098 Zingone, Adriana 8597, e19506 Zinner, Ralph 1051, 2604, 2611, LBA8003, 11086, e13534, e13575, e13591, e22086 Zins, Karin 11032 Zinzani, Pier Luigi 8507, 8533, TPS8614^, TPS8616, TPS8617, TPS8618 Ziogas, Argyrios e14529 Ziomek, Marzenna e13560 Zippel, Douglas e20039 Zippelius, Alfred 7503, 8060 Ziv-Av, Amotz 2073, 3100 Zivi, Andrea 2608, 4511, 5052 Ziyeh, Sharvina 4014 Zlatarov, Aleksandar e14669 Zlotta, Alexandre 4568 Zoccali, Carmine e21517

Zoernig, Martin e15070 Zoghbi, Marwan 2501 Zografos, Georgios e12537 Zohar, Sarah 2577, 6576 Zok, Jolanta 604, e13560, e15045 Zola, Fabio Eduardo e15190 Zoli, Wainer 11022, e14512, e16530, e22056 Zollinger, Raphael 11071 Zonder, Jeffrey A. 8542 Zonno, Kristilyn Dillman 1544 Zoratto, Federica 3602, 3603, 3613, e14531, e14574 Zorkani, Nabila 4069 Zornosa, Carrie C. 4142, 4143 Zorrero, Cristina 1543 Zorsky, Paul e20512 Zorzino, Laura e22078 Zou, Bingwen e15125 Zouaoui, Sonia 2067 Zoulamoglou, Menelaos e12537 Zourikian, Taline e15034 Zrounba, Philippe 6056, e17011, e17012 Zubiri Oteiza, Leyre e19114 Zucali, Paolo A. 4121, e22145 Zuccalã , Valeria e22104 Zuchlinski, Diamond 8597, e19506 Zugmaier, Gerhard 7020, 10007 Zujewski, JoAnne 2514 Zukiwski, Alexander A. 592, 593, 596, 2608, 5602, e11535, e11543, e16548 Zulfikar, Bulent 10043 Zulfikar, O. Bulent e18006 Zullig, Leah L. 6555 Zuluaga-Toro, Tania e15108, e15145 Zulueta, Javier e19027 Zumdahl, Therese e13568 Zunarelli, Elena 2021 Zuo, Zhixiang 6008, 6010 Zuo, Zhuang e20036 Zuppani, Henrique Bortot e13003 Zuradelli, Monica e12021 Zurita, Amado J. e16038, e22047 Zustovich, Fable 2043, 5050, 5548, e15512, e15524, e15606, e16031, e16078 Zuziak, Dorota 604 Zvereva, Nela TPS2627 Zvirbule, Zanete 4080, 5541, 8034 Zvosec, Cecilia CRA1501 Zwaan, Christian M. 10007 Zweegman, Sonja 8517 Zwemer, Eric 9529 Zwenger, Ariel Osvaldo 1073, 11118 Zwick, Carsten 8566, 8569, 8570 Zwicker, Jeffrey 8558 Zwicky, Karen E. e20560 Zwiefel, Karin 1101 Zyczynski, Teresa Maria e16035 Zygmunt, Marek e16534 Zykova, Tatyana A. e16514

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